The majority of patients with nonalcoholic fatty liver disease (NAFLD) have “simple steatosis,” which is defined by hepatic steatosis in the absence of substantial inflammation or fibrosis and is considered to be benign. However, 10%–30% of patients with NAFLD progress to fibrosing nonalcoholic steatohepatitis (NASH), which is characterized by varying degrees of hepatic inflammation and fibrosis, in addition to hepatic steatosis, and can lead to cirrhosis. The cause(s) of progression to fibrosing steatohepatitis are unclear. We aimed to test the relative contributions of dietary fat and dietary cholesterol and their interaction on the development of NASH. We assigned C57BL/6J mice to four diets for 30 weeks: control (4% fat and 0% cholesterol); high cholesterol (HC; 4% fat and 1% cholesterol); high fat (HF; 15% fat and 0% cholesterol); and high fat, high cholesterol (HFHC; 15% fat and 1% cholesterol). The HF and HC diets led to increased hepatic fat deposition with little inflammation and no fibrosis (i.e., simple hepatic steatosis). However, the HFHC diet led to significantly more profound hepatic steatosis, substantial inflammation, and perisinusoidal fibrosis (i.e., steatohepatitis), associated with adipose tissue inflammation and a reduction in plasma adiponectin levels. In addition, the HFHC diet led to other features of human NASH, including hypercholesterolemia and obesity. Hepatic and metabolic effects induced by dietary fat and cholesterol together were more than twice as great as the sum of the separate effects of each dietary component alone, demonstrating significant positive interaction. Conclusion Dietary fat and dietary cholesterol interact synergistically to induce the metabolic and hepatic features of NASH, whereas neither factor alone is sufficient to cause NASH in mice.

Food provided on a periodic basis can act as a potent synchronizer, being a stronger zeitgeber than light for peripheral oscillators in mammals. In fish, however, little is known about the influence of feeding time on the circadian pacemaker and the relationship between central and peripheral oscillators. The aim of this research was to investigate the influence of mealtime on the activity rhythms, and on central (brain) and peripheral (liver) oscillators in zebrafish. The authors tested different feeding times under a light-dark (LD) cycle and the endogenous origin of food-anticipatory activity (FAA) by feeding zebrafish at a fixed time under constant bright-light conditions (LL). The authors then measured locomotor activity and the expression of the clock gene per1 in animals under a LD cycle and fed at random times during the light phase, with restricted feeding at the mid-light phase (ML) or with restricted feeding during the mid-dark phase (MD). Finally, the authors measured locomotor activity and per1 expression in fish maintained under LL under either random feeding or scheduled feeding. Zebrafish displayed FAA in all the groups fed at a fixed time but not when feeding was randomly scheduled. Under LL, fish entrainment persisted, and when released under fasting conditions FAA free-ran with a circa-24-h period. The expression of per1 in the brain of fish under LD showed a daily rhythm with the acrophase (peak time) at the end of the dark phase regardless of feeding schedule. This brain rhythm disappeared in LL fish under both random feeding and scheduled feeding. Feeding at MD advanced the phase of per1 in the liver by 7 h compared with the ML-fed group phase (23:54 versus 07:23 h, respectively). In addition, under LL scheduled feeding entrained the rhythms of per1 expression in the liver. This study reveals for the first time that scheduled feeding entrains peripheral oscillators in a fish species, zebrafish, which is a powerful model widely used for molecular genetics and for the study of basic clock mechanisms of the vertebrate circadian system.

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Macromolecular proton fraction (MPF) is a quantitative MRI parameter determining the magnetization transfer (MT) effect in tissues and defined as a relative amount of immobile macromolecular protons involved into magnetization exchange with mobile water protons. MPF has a potential for quantitative assessment of fibrous tissue due to intrinsically high MPF specific for collagen. The goal of this study was to investigate a relationship between histologically determined fibrosis stage and MPF in the liver parenchyma measured using a recently developed fast single-point clinically-targeted MPF mapping method. Optimal saturation parameters for single-point liver MPF measurements were determined from the analysis of liver Z-spectra in vivo based on the error propagation model. Sixteen patients with chronic hepatitis C viral infection underwent 3T MRI using an optimized liver MPF mapping protocol. Fourteen patients had prior liver biopsy with histologically staged fibrosis (METAVIR scores F0-F3), and two patients had clinically diagnosed cirrhosis (score F4 was assigned). The protocol included four breath-hold three-dimensional scans with 2×3×6 mm3 resolution and 10 transverse sections: 1) dynamic acquisition of MT-weighted and reference images; 2) dynamic acquisition of three images for variable flip angle T1 mapping; 3) dual-echo B0 map; and 4) actual flip-angle imaging B1 map. Average liver MPF was determined as the mode of MPF histograms. MPF was significantly increased in patients with clinically significant fibrosis (scores F2-F4, n=6) compared to patients with no or mild fibrosis (scores F0-F1, n=10): 6.49±0.36% vs. 5.94±0.26%, P<0.01 (Mann-Whitney test). MPF and fibrosis score were strongly positively correlated with the Spearman's rank correlation coefficient 0.80 (P<0.001). This study demonstrates the feasibility of fast MPF mapping of the human liver in vivo and confirms the hypothesis that MPF is increased in hepatic fibrosis and associated with fibrosis stage. MPF may be useful as a non-invasive imaging biomarker of hepatic fibrosis.

Objective The purpose of this study was to assess if an end-of-life communication intervention with patients with COPD led to higher long-term documentation of advance care planning discussions at the end-of-life. Background We previously demonstrated that providing clinicians a brief patient-specific feedback form about patients’ preferences for end-of-life communication improved the occurrence and quality of clinician communication about end-of-life care. Methods The study was conducted at the Puget Sound VA Healthcare System. Among those individuals enrolled in the intervention study (2004–2007) who had died during the follow-up period (up to 2013), we assessed if patients in the intervention arm had more goals of care discussions and formal advance directives completed as compared to patients in the control arm. We conducted logistic models accounting for provider level clustering, adjusting for age, FEV1, and race. Results Among the 376 patients in the parent study, 157 died, of which 76 were in the intervention arm and 81 in the control arm. The mean age was 72.5 (SD 9.1), 99% were male, with a mean FEV1% predicted of 45 (SD 17.8). Over an average duration of 3.6 years (from the time of the first study appointment to death), 115 (73%) patients engaged in 451 unique end-of-life care discussions. The intervention was not associated with a higher percentage of patients with documented end-of-life conversations (I:C 75% vs 72%, p=0.63) or completion of advance care directives (26% vs 29%, p=0.55). Conclusions Despite initially improving the occurrence of end-of-life conversations, the intervention did not increase the documentation of subsequent conversations about end-of-life care, nor did it improve documentation of advance directives. Seventy-five percent of the patients in our cohort had documented follow-up conversations showing most have these conversations, but there is room for improvement and an unclear impact on goal-concordant care. Future research should focus on testing multi-faceted, longitudinal, system-level interventions to enhance conversations about goals of care that promote goal-concurrent care.

Integration between oncology and palliative care among the 6 VA medical centers varies considerably. Nurses delivering palliative care embedded in oncology teams may facilitate the integration of these subspecialties.

Context. Palliative care research has focused on patients with disease-specific conditions. However, older patients with multimorbidity may have unmet palliative care needs.Objectives. We assessed symptom burden and quality of life among veterans with multimorbidity and sought to determine if their bothersome symptoms were addressed and treated in the primary care setting. We sought to identify specific diagnoses that may account for greater symptom burden. We hypothesized that patients with a higher number of diagnoses would experience greater symptom burden and poorer quality of life.Methods. We identified veterans at high risk of hospitalization or death using a validated prognostic model. We administered cross-sectional surveys via telephone, The Memorial Symptom Assessment ScaledShort Form and Veterans RAND 12, to randomly selected patients in primary care in the VA Health Care System from May to December 2015. We assessed if their most bothersome symptom was addressed and treated during their most recent visit. Regression models identified specific diagnoses accounting for greater symptom burden and patient predictors of high symptom burden and poor quality of life.Results. Patients (n ¼ 503) reported (10.6 AE 5.5) active symptoms and poor physical quality of life. Patients reported pain and dyspnea as their most bothersome symptoms (n ¼ 145 [29%] and n ¼ 57 [11%], respectively). Most patients acknowledged their clinicians assessed (n ¼ 348 [74%]) and treated (n ¼ 330 [70%]) their most bothersome symptom. Physical symptoms (78%, P < 0.0001) were more likely to be addressed than psychological symptoms (55%, P < 0.001). Patients diagnosed with obesity or depression experienced greater physical symptom burden. Younger patients reported greater symptom severity than older patients (P < 0.01). Younger patients and those with greater multimorbidities reported lower self-perceived quality of health than older patients and those with fewer multimorbidities (P ¼ 0.01 and P < 0.01, respectively). Conclusion.Outpatients with multimorbidity have high symptom burden, unaddressed symptoms, poor quality of life, and unmet palliative care needs. Our findings support standardization of comprehensive symptom assessment and management in primary care for veterans with multimorbidities, which may ameliorate symptoms and improve quality of life. J Pain Symptom Manage 2019;57:880e889.

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