Background and aims: Acute on chronic liver failure (ACLF) yields the highest risk of short-term mortality, along the spectrum of cirrhosis. We evaluated whether the rising prevalence of nonalcoholic steatohepatitis (NASH) in the United States is reflected among waitlist registrants with ACLF. Methods: We analyzed the United Network for Organ Sharing (UNOS) registry, years 2005-2017. Patients with ACLF were identified using the EASL-CLIF criteria and categorized into those with NASH, alcoholic liver disease (ALD), and hepatitis C virus (HCV) infection. Statistical analysis included linear regression and Chow's test to determine significance and divergence in trends, and Fine and Grey's competing risks and Cox proportional hazards regression to assess waitlist outcomes. Results: Between 2005 and 2017, waitlist registrants for NASH-ACLF rose 331.6% (p<0.001). ALD-ACLF increased 206.3% (p<0.001), while HCV-ACLF declined 45.2% (p=0.018). This increase in NASH-ACLF occurred across all UNOS regions, rising by 666.7% in region 11. The NASH-ACLF population is aging, and currently 31.5% of the group is age 65 or older. Although NASH-ACLF candidates did not have greater 90-day waitlist mortality (SHR=0.84, 95% CI 0.77-0.92) relative to other etiologies, since 2014, 90-day waitlist mortality has improved for ALD-ACLF (HR=0.78, 95% CI 0.70-0.88) and HCV-ACLF (HR=0.76, 95% CI 0.67-0.85) but not for NASH (HR=0.93, 95% CI 0.81-1.08). Conclusions: NASH is the fastest rising etiology of cirrhosis among transplant registrants with ACLF in the United States. Since 2014, waitlist outcomes have 4 improved for ALD-ACLF and HCV-ACLF, but not for NASH-ACLF. With the aging NASH population, patients with NASH-ACLF may eventually have the highest risk of death on the waiting list.

Background and aims No effective pharmacotherapy for methamphetamine (MA) use disorder has yet been found. This study evaluated sustained-release methylphenidate (MPH-SR) compared with placebo (PLA) for treatment of MA use disorder in people also undergoing behavioural support and motivational incentives. Design This was a randomized, double-blind, placebo-controlled design with MPH-SR or PLA provided for 10 weeks (active phase) followed by 4 weeks of single-blind PLA. Twice-weekly clinic visits, weekly group counseling (CBT), and motivational incentives (MI) for MA-negative urine drug screens (UDS) were included. Setting Treatment sites were in Los Angeles, California (LA) and Honolulu, Hawaii (HH), USA. Participants 110 MA-dependent (via DSM-IV) participants (LA = 90; HH = 20). Measurements The primary outcome measure is self-reported days of MA use during the last 30 days of the active phase. Included in the current analyses are drug use (UDS and self-report), retention, craving, compliance (dosing, CBT, MI), adverse events, and treatment satisfaction. Findings No difference was found between treatment groups in self-reported days of MA use during the last 30 days of the active phase (p=0.22). In planned secondary outcomes analyses, however, the MPH group had fewer self-reported MA use days from baseline through the active phase compared with the PLA group (p=0.05). The MPH group also had lower craving scores and fewer marijuana-positive UDS than the PLA group in the last 30 days of the active phase. The two groups had similar retention, other drug use, adverse events, and treatment satisfaction. Conclusions Methylphenidate may lead to a reduction in concurrent methamphetamine use when provided as treatment for patients undergoing behavioural support for moderate to severe methamphetamine use disorder but this requires confirmation.

Methamphetamine (METH) is an addictive stimulant, and METH users have abnormal brain structures and function. The aims of this study were to investigate the relationships between impulsivity, brain structures, and possible sex-specific differences between METH users and non-drug using Controls. Structural MRI and the Barratt Impulsiveness Scale (BIS) questionnaire were completed in 124 subjects: 62 METH (ages 41.2 ± 1.4 years, 34 males) and 62 Controls (ages 43.3 ± 2.3 years, 36 males). Independent and interactive effects of METH use status and sex were evaluated. Relationships between METH usage characteristics, brain morphometry, and impulsivity scores were examined. METH users had higher impulsivity scores, on both the Cognitive and Behavioral Factors from the BIS (p < 0.0001–0.0001). Compared with same-sex Controls, male METH users had larger, while female METH users had smaller, right superior frontal cortex (interaction-p = 0.0005). The male METH users with larger frontal volumes and female METH users with smaller or thinner frontal cortices had greater Cognitive impulsivity (interaction-p ≤ 0.05). Only female METH users showed relatively larger nucleus accumbens (interaction-p = 0.03). Greater impulsivity and thinner frontal cortices in METH users are validated. Larger superior frontal cortex in male METH users with greater cognitive impulsivity suggest decreased dendritic pruning during adolescence might have contributed to their impulsive and drug use behaviors. In the female METH users, smaller frontal cortices and the associated greater impulsivity suggest greater neurotoxicity to these brain regions, while their relatively larger nucleus accumbens suggest an estrogen-mediated neuroprotective glial response. Men and women may be affected differently by METH use.

Purpose: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and has the potential risk for progressing to nonalcoholic steatohepatitis (NASH), which is associated with a greater risk for complications of chronic liver disease. Noninvasive testing has been evaluated for diagnosis, risk stratification, disease progression, and assessing response to therapy. The purpose of this narrative review was to outline the current noninvasive testing modalities for the diagnostic evaluation of NAFLD and NASH, while discussing possible markers that could be used for monitoring response to therapies.Methods: The PubMed and Cochrane databases were searched for relevant articles that evaluated the diagnosis of NAFLD/NASH with serum biomarkers and/or imaging.Findings: Serum biomarkers, imaging modalities, and combinations/serial algorithms involved in the diagnosis of NAFLD and NASH are outlined. In addition, noninvasive modalities that have been used for assessing response to therapies in clinical trials are discussed.Implications: Liver biopsy currently remains the gold standard for diagnosis and is often used in clinical trials to assess treatment response. However, developing safe and accessible noninvasive modalities for diagnosis and monitoring will have greater impact and relevance, as biopsy may not always be feasible in all clinical settings. (Clin Ther.

Context:The optimal lower extremity venous ultrasound (US) protocol to diagnose deep venous thrombosis of the popliteal and more proximal veins is unclear.Objective: To determine the three-month rate of symptomatic venous thromboembolism (VTE) and clinical outcomes of inpatients and ambulatory patients with normal findings on single venous ultrasound of the popliteal and more proximal veins (single proximal US).Design: Single proximal US results and clinical data of all inpatient and ambulatory patients with suspected acute deep venous thrombosis were retrospectively reviewed during a 12-month period between January and December 2014. Three-month followup data were reviewed for all these patients, who received all their care from a single geographically isolated health maintenance organization.Main Outcome Measures: Three-month rate of symptomatic VTE and clinical outcomes after an initially normal single proximal US result.Results: Of 1295 patients, 111 (8.6%) were found to have acute deep venous thrombosis on the initial proximal US. Of the remaining 1184 patients with initially normal results on proximal US who were sampled at 3-month follow-up, 1075 patients (90.8%) had no venous thromboembolic event. Among the others, 11 (0.9%) had a subsequent imaging-confirmed venous thromboembolic event, 53 (4.5%) died (none owing to venous thromboembolism), and 45 (3.8%) did not complete follow-up.Conclusion: Symptomatic VTE after an initially normal single proximal US result occurred in less than 1% of this cohort. Therefore, serial proximal US is unnecessary for most of our patients, and its elimination will save time and out-of-pocket expenses.

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Methamphetamine (METH) is an addictive stimulant adversely affecting brain structure and function. The aim of this study was to investigate impulsivity and brain structures, and sex differences on these variables, between METH users and non-drug user controls (CON). Structural MRI was performed in 124 subjects: 62 METH (ages 41.2±1.4 years, 34 males, 28 females) and 62 CON (ages 43.3±2.3 years, 36 males, 26 females). FreeSurfer 5.1 automated morphometry was used to measure brain morphometry. Subjects completed the Barratt Impulsiveness Scale (BIS) questionnaire, which measures six factors. 2-way and repeated measures ANCOVA, co-varying for age, education, depressive symptoms, and intracranial volume, evaluated for independent and interactive effects of group status and sex. Relationships between METH usage characteristics, brain volumes, and impulsivity scores with significant group differences were examined with Pearson correlations. METH users had higher impulsivity scores in a majority of the factors (p<0.001-0.05). Male METH users had larger right superior frontal volumes compared to CON, while female METH users had smaller volumes compared to CON (p=0.02). Groupby-volume interactions were found in the right superior frontal (p=0.02) and right insula (p=0.02). In the male METH users, greater volumes in these regions were associated with less self-control. Female METH users had larger accumbens compared to female CON (p=0.03). METH users had consistently thinner left frontal cortical regions compared to CON (p=0.003). Consistent with prior reports, METH users were more impulsive and had thinner left frontal cortices than CON. Male METH users had larger superior frontal and insula volumes than CON, which was associated with less self-control (p=0.009-0.05). This was not seen in the female METH users, possibly due to a protective effect of estrogen from neuroinflammation in these regions. This suggests that men and women may be affected differently, and sex should be accounted for in brain morphometry studies.3