Patients with Nonalcoholic Steatohepatitis and Advanced Liver Disease Have the Lowest Cardiorespiratory Fitness.

BACKGROUND & AIMS: Cardiorespiratory fitness and liver fibrosis are independently associated with poor outcomes in patients with nonalcoholic steatohepatitis (NASH), however, conflicting reports exist about their relationship. We aimed to better characterize the relationship between cardiorespiratory fitness and liver histology in a cross-sectional study of patients with biopsy-proven NASH. METHODS: Participants aged 18-75 years completed VO2peak fitness assessment using symptom-limited graded exercise testing. Participants were compared by liver fibrosis stage and NAFLD Activity Score (NAS). Multivariable models were constructed to assess factors related to relative VO2peak, including liver fibrosis and NAS. RESULTS: Thirty-five participants with mean age 48 ± 12 years and body mass index 33.5 ± 7.6 kg/m2 were enrolled. Seventy-four percent of participants were female and 49% had diabetes. A dose-dependent relationship was found between relative VO2peak and liver fibrosis. Relative VO2peak was significantly lower in participants with advanced fibrosis (F3 disease- 15.7 ± 5.3 vs. ≤ F2 disease- 20.7 ± 5.9 mL/kg/min, p = 0.027). NAS > 5 was also associated with lower relative VO2peak (22.6 ± 5.7 vs. 16.5 ± 5.1 mL/kg/min, p = 0.012) compared to NAS ≤ 5. With multivariable modeling, advanced fibrosis remained independently predictive of relative VO2peak while NAS trended towards significance. DISCUSSION AND CONCLUSIONS: Advanced liver fibrosis is independently associated with cardiorespiratory fitness in patients with NASH. This may explain the incremental increase in mortality as liver fibrosis stage increases. Further research is needed to determine if exercise training can improve cardiorespiratory fitness across multiple stages of liver fibrosis and directly reduce morbidity and mortality in patients with NASH.

INvestigation of the impact of a Pharmacist in a Hospital At Home Care Team (IN PHACT).

Background: In November 2020, Island Health, with the support of the British Columbia Ministry of Health, introduced the Hospital at Home (HaH) care model at Victoria General Hospital in Victoria, British Columbia. Given the acuity of the patients anticipated to receive care through this model, questions arose regarding how the delivery of clinical pharmacy services on which inpatients rely on could be included. With limited supporting evidence for the inclusion of a clinical pharmacist, Island Health launched the HaH program with 2 clinical pharmacists who provide services 7 days a week during daytime hours. The aim of this study is to assess the impact of the HaH pharmacist on patient care, from the perspective of the pharmacists serving in this role, patients, caregivers and program stakeholders. Methods: This prospective, observational mixed-methods study was conducted from December 2021 to March 2022. Data collection involved the HaH pharmacist documenting daily clinical activities and resolving drug therapy problems, patients and caregivers completing a 4-question postdischarge phone survey and program stakeholders completing a 9-question online survey and an optional 7-question interview. Results and Interpretation: It was found that one of the most significant roles the pharmacist plays is in identifying indications for medication therapy and making recommendations to initiate therapy where there is an absence. There was high congruence between patient, caregiver and stakeholder perceptions that the HaH pharmacist positively affects patient care within the Island Health model. Conclusion: This study provides support for the integration of a dedicated clinical pharmacist in the HaH care model.

Change in MRI-PDFF and Histologic Response in Patients With Nonalcoholic Steatohepatitis: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Magnetic resonance imaging proton density fat fraction (MRI-PDFF) offers promise as a non-invasive biomarker of treatment response in early-phase nonalcoholic steatohepatitis (NASH) trials. We performed a systematic review to quantify the association between a ≥ 30% reduction in MRI-PDFF and histologic response in NASH. METHODS: We searched the Cochrane Library, Embase, Medline and trial registries through May 2020 for early-phase clinical trials that incorporated MRI-PDFF and examined histologic response following intervention in adults with NASH. Subjects were classified as MRI-PDFF responders (relative decline in liver fat ≥30%) or non-responders (relative decline in liver fat <30%). MRI-PDFF responders versus non-responders were compared. Primary outcome was histologic response defined as a 2-point improvement in NAFLD Activity Score with at least 1-point improvement in lobular inflammation or ballooning. Secondary outcome was NASH resolution. Proportions and random effects odds ratios (OR) with corresponding 95% confidence intervals (CI) were calculated. RESULTS: Seven studies met inclusion criteria, comprising 346 subjects (median age 51 years; 59% female; 46% with diabetes). MRI-PDFF responders were significantly more likely to have a histologic response (51% vs 14%, P < .001; OR 6.98, 95% CI 2.38-20.43, P < .001) and NASH resolution (41% vs 7%, P < .001; OR 5.45, 95% CI 1.53-19.46, P = .009) compared to non-responders. CONCLUSIONS: This meta-analysis demonstrates that a ≥30% relative decline in MRI-PDFF is associated with higher odds of histologic response and NASH resolution. These results support the use of MRI-PDFF in non-invasive monitoring of treatment response in early-phase NASH clinical trials and provide helpful data for sample-size estimation for histology-based assessment.

Evaluation of a Hyperbaric Oxygen Therapy Intervention in Individuals with Fibromyalgia.

OBJECTIVE: To evaluate the feasibility and safety of hyperbaric oxygen therapy (HBOT) in patients with fibromyalgia (FM). DESIGN: A cohort study with a delayed treatment arm used as a comparator. SETTING: Hyperbaric Medicine Unit, Toronto General Hospital, Ontario, Canada. SUBJECTS: Eighteen patients diagnosed with FM according to the American College of Rheumatology and a score ≥60 on the Revised Fibromyalgia Impact Questionnaire. METHODS: Participants were randomized to receive immediate HBOT intervention (n = 9) or HBOT after a 12-week waiting period (n = 9). HBOT was delivered at 100% oxygen at 2.0 atmospheres per session, 5 days per week, for 8 weeks. Safety was evaluated by the frequency and severity of adverse effects reported by patients. Feasibility was assessed by recruitment, retention, and HBOT compliance rates. Both groups were assessed at baseline, after HBOT intervention, and at 3 months' follow-up. Validated assessment tools were used to evaluate pain, psychological variables, fatigue, and sleep quality. RESULTS: A total of 17 patients completed the study. One patient withdrew after randomization. HBOT-related adverse events included mild middle-ear barotrauma in three patients and new-onset myopia in four patients. The efficacy of HBOT was evident in most of the outcomes in both groups. This improvement was sustained at 3-month follow-up assessment. CONCLUSION: HBOT appears to be feasible and safe for individuals with FM. It is also associated with improved global functioning, reduced symptoms of anxiety and depression, and improved quality of sleep that was sustained at 3-month follow-up assessment.

Low-dose empagliflozin as adjunct-to-insulin therapy in type 1 diabetes: A valid modelling and simulation analysis to confirm efficacy.

AIM: To confirm the observed reduction in HbA1c for the 2.5 mg dose in EASE-3 by modelling and simulation analyses. MATERIALS AND METHODS: Independent of data from EASE-3 that tested 2.5 mg, we simulated the effect of a 2.5 mg dose through patient-level, exposure-response modelling in the EASE-2 clinical study. A primary semi-mechanistic model evaluated efficacy considering clinical insulin dose adjustments made after treatment initiation that potentially limited HbA1c reductions. The model was informed by pharmacokinetic, insulin dose, mean daily glucose and HbA1c data, and was verified by comparing the simulations with the observed HbA1c change in EASE-3. One of two empagliflozin phase 3 trials in type 1 diabetes (EASE-3 but not EASE-2) included a lower 2.5 mg dose. A placebo-corrected HbA1c reduction of 0.28% was demonstrated without the increased risk of diabetic ketoacidosis observed at higher doses (10 mg and 25 mg). Since only one trial included the lower dose, we aimed to confirm the observed reduction in HbA1c for the 2.5 mg dose by modelling and simulation analyses. RESULTS: The simulated 26-week mean HbA1c change was -0.41% without insulin dose adjustment and -0.29% at 26 weeks with insulin dose adjustment. A simplified (descriptive) model excluding insulin dose and mean daily glucose confirmed the -0.29% HbA1c change that would have been observed had the EASE-2 population received a 2.5 mg dose for 26/52 weeks. CONCLUSIONS: The HbA1c benefit of low-dose empagliflozin directly observed in the EASE-3 trial was confirmed by two modelling and simulation approaches.

Clinical Cirrhosis Dilemmas: Survey of Practice from the 7th International Coagulation in Liver Disease Conference.

INTRODUCTION AND AIM: Hemostatic disorders in chronic liver disease and cirrhosis show continued expansion of research efforts. However, clinical decision making is often practiced on an individual patient level as consensus guidelines are lacking. We aimed to better assess individual day-to-day clinical practice through gauging clinicians' responses to common clinical scenarios. MATERIALS AND METHODS: A series of ten clinical scenarios (seven procedural coagulation and three thrombosis management) were posed to conference attendees utilizing real-time polling software (Poll Everywhere). Responses were binomial and were submitted as "Agree" or "Disagree." Results were displayed real time following a standardized response period and an open-forum discussion ensued between conference faculty and attendees following response submission. RESULTS: Twenty conference attendees participated in the clinical scenario plenary session. In general, agreement rates were high. All but one of the ten clinical scenarios had ≥ 70% agreement. Agreement was based both on procedural risk, with greatest agreement seen for low-risk procedures (80-93%), and on peri-procedural coagulation parameters of platelet count and fibrinogen level where > 50,000µ/L and 120 mg/dL were the most agreed upon thresholds, respectively. 75-95% agreement was reached when surveying the need for anticoagulation for mesenteric vein thrombosis in liver transplant candidates; slightly less (71%) agreement was found when deciding to proceed with anticoagulation in non-liver transplant candidates with mesenteric vein thrombosis. CONCLUSIONS: While large-scale, methodologically rigorous randomized controlled trials are lacking to guide clinical decision making in patients with coagulation disorders and chronic liver disease, consensus expert opinion regarding mitigating peri-procedural bleeding risk and treatment of thrombosis appears consistent and strong.

Caring for patients with pain during the COVID-19 pandemic: consensus recommendations from an international expert panel.

Chronic pain causes significant suffering, limitation of daily activities and reduced quality of life. Infection from COVID-19 is responsible for an ongoing pandemic that causes severe acute respiratory syndrome, leading to systemic complications and death. Led by the World Health Organization, healthcare systems across the world are engaged in limiting the spread of infection. As a result, all elective surgical procedures, outpatient procedures and patient visits, including pain management services, have been postponed or cancelled. This has affected the care of chronic pain patients. Most are elderly with multiple comorbidities, which puts them at risk of COVID-19 infection. Important considerations that need to be recognised during this pandemic for chronic pain patients include: ensuring continuity of care and pain medications, especially opioids; use of telemedicine; maintaining biopsychosocial management; use of anti-inflammatory drugs; use of steroids; and prioritising necessary procedural visits. There are no guidelines to inform physicians and healthcare providers engaged in caring for patients with pain during this period of crisis. We assembled an expert panel of pain physicians, psychologists and researchers from North America and Europe to formulate recommendations to guide practice. As the COVID-19 situation continues to evolve rapidly, these recommendations are based on the best available evidence and expert opinion at this present time and may need adapting to local workplace policies.

Liver transplant candidates have impaired quality of life across health domains as assessed by computerized testing.

INTRODUCTION AND OBJECTIVES: Liver transplantation candidates are among the most comorbid patients awaiting lifesaving intervention. Health related quality of life (HRQOL) measured by instruments that incorporate dynamic computerized adaptive testing, could improve their assessment. We aimed to determine the feasibility of administration of the Patient-Reported Outcomes Measurement Information System (PROMIS-CAT) in liver transplant candidates. MATERIALS AND METHODS: Liver transplantation candidates were prospectively enrolled following a review of their available medical history. Subjects were given a tablet computer (iPad) to access the pre-loaded PROMIS CAT. RESULTS: 109 candidates with mean age 55.6±8.6 years were enrolled in this pilot study. Mean MELD-Na score was 16.3±6.3; 92.6% had decompensated liver disease. Leading etiologies of cirrhosis included hepatitis C (34.8%), nonalcoholic steatohepatitis (25.7%) and alcohol (21.1%). Subjects with MELD-Na score>20 had the most significant impairment in HRQOL (anxiety/fear+5.9±2.7, p=0.0289, depression+5.1±2.5, p=0.0428, fatigue+4.3±2.6, p=0.0973) and physical impairment (-7.8±2.5, p=0.0022). Stage of cirrhosis and decompensated liver disease were predictive of impaired HRQOL but Child-Pugh Turcotte score was not. Hepatic encephalopathy was the strongest independent predictor of impaired HRQOL, with significant impairment across all domains of health. CONCLUSIONS: Liver transplant candidates have significantly impaired HRQOL across multiple domains of health as measured by PROMIS-CAT. HRQOL impairment parallels disease severity. Future study is needed to determine how best HRQOL could be systematically included in liver transplantation listing policy, especially in those candidates with hepatic encephalopathy.

Decreased portal vein velocity is predictive of the development of portal vein thrombosis: A matched case-control study.

BACKGROUND & AIMS: Portal vein thrombosis (PVT) in cirrhosis may lead to hepatic decompensation and increased mortality. We aimed to investigate if decreased portal vein (PV) velocity is associated with future PVT. METHODS: Data on adult patients with cirrhosis and PVT between January 1, 2005 and July 30, 2015 were obtained. Cases with PVT were matched by age, gender and Model for End-stage Liver Disease (MELD) score to corresponding controls without PVT. Cox proportional hazards models, receiver operator curves and Kaplan Meier curves were constructed. RESULTS: One hundred subjects (50 matched pairs) with mean age 53.8±13.1 y and MELD score 14.9±5.5 were included in our analysis. Sixty-four percent were male and 76% were Child-Turcotte-Pugh Class A or B. Baseline characteristics (prior to development of PVT) were similar, except for baseline PV velocity (16.9 cm/s, 95% CI 13.9-20.0 PVT vs 25.0, 95% CI 21.8-28.8 no PVT, P<.001). 30 PVT subjects had PV velocity <15 cm/s compared to five without PVT (P<.001). On adjusted multivariable analysis, PV velocity was the strongest independent risk factor predicting PVT development (HR 0.86, 95% CI 0.80-0.93). The predictive value for PVT development was greatest for flow <15 cm/s (c-statistic 0.77). PV velocity <15 cm/s had a highly significant association with future PVT (HR 6.00, 95% CI 2.20-16.40, P=<.001). CONCLUSIONS: Decreased PV velocity is associated with increased risk of future PVT. Patients with cirrhosis and decreased PV velocity are a high-risk subgroup that warrants further investigation with prospective study.

Predictors of Mortality in Cirrhosis Inpatients With Clostridium difficile Infection.

BACKGROUND: Clostridium difficile is a bacterial pathogen associated with significant morbidity and mortality in patients with cirrhosis. GOALS: Our primary aim is to identify variables that are predictive of poor outcomes in cirrhosis patients with C. difficile infection (CDI). We also aim to further characterize the risk factors for developing CDI and risk of mortality in this patient population. STUDY: A total of 200 subjects with a diagnosis of cirrhosis and CDI were matched to 200 cirrhosis inpatients without CDI. The groups were compared to evaluate variables associated with decreased survival for cirrhosis inpatients with CDI as well as risk factors for developing CDI. RESULTS: Cirrhosis patients with CDI were more frequently prescribed antibiotics during their hospitalization (P=0.002) and cared for in an intensive care unit (ICU) (P<0.001). Preadmission proton pump inhibitor and spontaneous bacterial peritonitis (SBP) prophylactic antibiotic use were not significantly different between the 2 cohorts. CDI subjects had an increased 30-day mortality (44% vs. 28.5%, P=0.034), however overall mortality was not significantly different (P=0.2). The multivariable logistic regression model demonstrated an increased 30-day and overall mortality in the CDI population was independently associated with albumin <3 g/dL and ICU admission. CONCLUSIONS: C. difficile infections are associated with a significant increase in 30-day mortality, but not overall mortality. Risk factors of ICU admission and antibiotic exposure were associated with the diagnosis of CDI in cirrhosis patients. Hypoalbuminemia and ICU admission were found to be strong predictors of increased mortality in cirrhosis patients with CDI.

Drug interactions between rifamycin antibiotics and hormonal contraception: a systematic review.

BACKGROUND: Rifamycin antibiotics are commonly used for treatment of tuberculosis, but may reduce the effectiveness of hormonal contraception (HC). OBJECTIVES: To determine whether interactions between rifamycins and HC result in decreased effectiveness or increased toxicity of either therapy. SEARCH STRATEGY: We searched MEDLINE, Embase, Cochrane and clinicaltrials.gov through May 2017. SELECTION CRITERIA: We included trials, cohort, and case-control studies addressing pregnancy rates, pharmacodynamics or pharmacokinetic (PK) outcomes when HC and rifamycins were administered together versus apart. Of 7291 original records identified, 11 met inclusion criteria after independent review by two authors. DATA COLLECTION AND ANALYSIS: Two authors independently abstracted study details and assessed study quality using the United States Preventive Services Task Force grading system. Findings are reported descriptively. MAIN RESULTS: Studies only addressed combined oral contraceptives (COCs) and none reported pregnancy rates. Quality ranged from good to poor. Rifampin increased the frequency of ovulation in two of four studies, and reduced estrogen and/or progestin exposure in five studies. Rifabutin led to smaller PK changes than rifampin in two studies. In one study each, rifaximin and rifalazil did not alter hormone PK. CONCLUSIONS: No studies evaluated pregnancy risk or non-oral HCs. PK and ovulation outcomes support a clinically concerning drug interaction between COCs and rifampin, and to a lesser extent rifabutin. Data are limited for other rifamycins. TWEETABLE ABSTRACT: Rifampin and rifabutin reduce systemic exposure of oral contraceptives, but no studies have evaluated pregnancy risk.

Geographic variation in liver transplantation persists despite implementation of Share35.

AIM: Geographic disparities persist in the USA despite locoregional organ sharing policies. The impact of national organ sharing policies on waiting-list mortality on a regional basis remains unknown. METHODS: Data on all adult liver transplants between 1 February 2002 and 31 March 2015 were obtained from the United Network for Organ Sharing/Organ and Transplantation Network. Multivariable Cox proportional hazards models were constructed in a time-to-event analysis to estimate waiting-list mortality for the pre- and post-Share35 eras. RESULTS: In the analyzed time period, 134 247 patients were listed for transplantation and 54 510 received organs (42.8%). Listing volume increased following the introduction of the Share35 organ sharing policy (15 976 candidates pre- vs. 18 375 post) without significant regional changes as did the number of transplants (7210 pre- vs. 8224 post). Waiting-list mortality improved from 12.2% to 8.1% (P < 0.001). Adjusted waiting-list mortality ratios remained geographically disparate. Region 10 and region 11 had lower hazard ratios (HR) but still had increased mortality (1.46, 95% confidence interval [CI] 1.34-1.60, P < 0.001; and HR 1.49, 95% CI 1.37-1.62, P < 0.001, respectively). Regions 3 and 6 had increased HR with persistently elevated waiting-list mortality (1.79, 95% CI 1.66-1.93, P < 0.001; and HR 1.29, 95% CI 1.16-1.45, P < 0.001, respectively). Model for End-state Liver Disease (MELD) exception continued to propagate a survival benefit (HR 0.65, 95% CI 0.63-0.68, P < 0.001). CONCLUSIONS: Although overall waiting-list mortality has decreased, geographic disparities persist, but appear reduced despite broader sharing policies enacted by Share35. The advantage afforded by MELD exception, while still present, was diminished by Share35 as organs are being shifted to MELD >35 candidates. The disparities highlighted by our findings imply a need to review current allocation policies to best balance local, regional, and national transplant environments.

Editorial: Severe Acute Liver Injury: Cause Connects to Outcome.

Severe acute liver injury (ALI) is a common condition with little objective study of its natural history and outcomes. In this paper by Koch et al. and the Acute Liver Failure (ALF) Study Group, the authors utilize a consensus definition of ALI requiring newly elevated bilirubin, alanine aminotransferase (ALT), and international normalized ration (INR) without evidence of hepatic encephalopathy (HE), with HE as the key differentiator of ALI from ALF. They show significantly higher rates of progression to ALF, liver transplantation, or death in non-acetaminophen etiologies of ALI. This study's findings provide guidance in supporting careful allocation of scarce critical care and liver transplant resources for ALI patients.

Editorial: "Lean" NAFLD: Metabolic Obesity with Normal BMI Is It in the Genes?

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. "Lean" NAFLD represents a patient subpopulation with hepatic steatosis evident on imaging with normal BMI. This paper by Feldman and Eder et al. illustrates the mild but clear metabolic differences and genetic connections in Caucasian lean NAFLD patients compared with obese NAFLD and healthy controls. Their findings highlight key similarities of lean and obese NAFLD compared with lean healthy subjects. This paper characterizes "lean" NAFLD as a unique phenotype with specific genetic associations deserving of further investigation in the greater scheme of elucidating the pathophysiology of fatty liver.

Insula and amygdala resting-state functional connectivity differentiate bipolar from unipolar depression.

OBJECTIVE: Distinguishing depressive episodes due to bipolar disorder (BD) or major depressive disorder (MDD) solely on clinical grounds is challenging. We aimed at comparing resting-state functional connectivity (rsFC) of regions subserving emotional regulation in similarly depressed BD and MDD. METHOD: We enrolled 76 in-patients (BD, n = 36; MDD, n = 40) and 40 healthy controls (HC). A seed-based approach was used to identify regions showing different rsFC with the insula and the amygdala. Insular and amygdalar parcellations were then performed along with diagnostic accuracy of the main findings. RESULTS: Lower rsFC between the left insula and the left mid-dorsolateral prefrontal cortex and between bilateral insula and right frontopolar prefrontal cortex (FPPFC) was observed in BD compared to MDD and HC. These results were driven by the dorsal anterior and posterior insula (PI). Lower rsFC between the right amygdala and the left anterior hippocampus was observed in MDD compared to BD and HC. These results were driven by the centromedial and laterobasal amygdala. Left PI/right FPPC rsFC showed 78% accuracy differentiating BD and MDD. CONCLUSION: rsFC of amygdala and insula distinguished between depressed BD and MDD. The observed differences suggest the possibility of differential pathophysiological mechanisms of emotional dysfunction in bipolar and unipolar depression.

Three-Dimensional Analysis of Nasal Symmetry Following Primary Correction of Unilateral Cleft Lip Nasal Deformity.

OBJECTIVE: To evaluate nasal symmetry using three-dimensional photogrammetry following primary tip rhinoplasty with or without an internal splint in patients with unilateral complete cleft lip/palate. DESIGN: We captured three-dimensional images of patients with unilateral complete cleft lip/palate who underwent nasolabial repair by rotation-advancement of the lip and primary tip rhinoplasty, either with or without an internal resorbable splint, and normal control subjects. We assessed nasal symmetry by identifying the plane of maximum symmetry and the root-mean-square deviation between native and reflected surfaces. PATIENTS/PARTICIPANTS: We imaged 38 controls and 38 subjects with repaired unilateral complete cleft lip/palate (20 with, 18 without an internal splint). RESULTS: Nasal asymmetry root-mean-square deviation clustered between 0.19 and 0.50 mm (median = 0.24 ± 0.08 mm) for controls; whereas, those with repaired unilateral complete cleft lip/palate ranged from 0.4 to 1.5 mm (median = 0.75 ± 0.40 mm). Although root-mean-square deviation ranges overlapped, patients with repaired unilateral complete cleft lip/palate had significantly greater asymmetry than controls (P < .001). We found no difference in asymmetry between patients with or without an internal splint (P = .5). CONCLUSIONS: Three-dimensional photogrammetry was used to successfully compare symmetry among different patient and control groups. Although "normal" nasal symmetry was attained in some patients following cleft lip/nasal repair, most had persistent asymmetry compared with normal controls. Placement of a resorbable internal splint did not improve symmetry in patients with unilateral complete cleft lip/palate.