Acute Stress Enhances Memory and Preference for Smoking-Related Associations in Smokers.

INTRODUCTION: Nicotine dependence follows a chronic course that is characterized by repeated relapse, often driven by acute stress and rewarding memories of smoking retrieved from related contexts. These two triggers can also interact, with stress influencing retrieval of contextual memories. However, the roles of these processes in nicotine dependence remain unknown. AIMS AND METHODS: We investigated how acute stress biases memory for smoking-associated contexts among smokers (N = 65) using a novel laboratory paradigm. On day 1, participants formed associations between visual stimuli of items (either neutral or related to smoking) and places (background scenes). On day 2 (24 hours later), participants were exposed to an acute laboratory-based stressor (socially evaluated cold pressor test; N = 32) or a matched control condition (N = 33) prior to being tested on their memory recognition and preferences for each item and place. We distinguished the accuracy of memory into specific (ie, precisely correct) or gist (ie, lure items with similar content) categories. RESULTS: Results demonstrated that the stressor significantly induced physiological and subjective perceived stress responses, and that stressed smokers exhibited a memory bias in favor of smoking-related items. In addition, the stressed group displayed greater preference for both smoking-related items and places that had been paired with the smoking-related items. We also found suggestive evidence that stronger smoking-related memory biases were associated with more severe nicotine dependence (ie, years of smoking). CONCLUSIONS: These results highlight the role of stress in biasing smokers toward remembering contexts associated with smoking, and amplifying their preference for these contexts. IMPLICATIONS: The current study elucidates the role of acute stress in promoting memory biases favoring smoking-related associations among smokers. The results suggest that the retrieval of smoking-biased associative memory could be a crucial factor in stress-related nicotine seeking. This may lead to a potential intervention targeting the extinction of smoking-related context memories as a preventive strategy for stress-induced relapse.

Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification. METHODS: We examined at-risk individuals (NAFLD cohort, n = 2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank [UKBB] cohort, n = 364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5). RESULTS: In the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver (p = 0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants (p <10-13). The association between PRS and HCC was mainly mediated through severe fibrosis, but was independent of fibrosis in clinically relevant subgroups, and was also observed in those without severe fibrosis (p <0.05). In the UKBB cohort, PRS predicted HCC independently of classical risk factors and cirrhosis (p <10-7). In the NAFLD cohort, we identified high PRS cut-offs (≥0.532/0.495 for PRS-HFC/PRS-5) that in the UKBB cohort detected HCC with ~90% specificity but limited sensitivity; PRS predicted HCC both in individuals with (p <10-5) and without cirrhosis (p <0.05). CONCLUSIONS: Our results are consistent with a causal relationship between hepatic fat and HCC. PRS improved the accuracy of HCC detection and may help stratify HCC risk in individuals with dysmetabolism, including those without severe liver fibrosis. Further studies are needed to validate our findings. LAY SUMMARY: By analyzing variations in genes that contribute to fatty liver disease, we developed two risk scores to help predict liver cancer in individuals with obesity-related metabolic complications. These risk scores can be easily tested in the clinic. We showed that the risk scores helped to identify the risk of liver cancer both in high-risk individuals and in the general population.

Higher Heart-Rate Variability Is Associated with Ventromedial Prefrontal Cortex Activity and Increased Resistance to Temptation in Dietary Self-Control Challenges.

Higher levels of self-control in decision making have been linked to better psychosocial and physical health. A similar link to health outcomes has been reported for heart-rate variability (HRV), a marker of physiological flexibility. Here, we sought to link these two, largely separate, research domains by testing the hypothesis that greater HRV would be associated with better dietary self-control in humans. Specifically, we examined whether total HRV at sedentary rest (measured as the SD of normal-to-normal intervals) can serve as a biomarker for the neurophysiological adaptability that putatively underlies self-controlled behavior. We found that HRV explained a significant portion of the individual variability in dietary self-control, with individuals having higher HRV being better able to downregulate their cravings in the face of taste temptations. Furthermore, HRV was associated with activity patterns in the ventromedial prefrontal cortex (vmPFC), a key node in the brain's valuation and decision circuitry. Specifically, individuals with higher HRV showed both higher overall vmPFC blood-oxygen-level-dependent activity and attenuated taste representations when presented with a dietary self-control challenge. Last, the behavioral and neural associations with HRV were consistent across both our stress induction and control experimental conditions. The stability of this association across experimental conditions suggests that HRV may serve as both a readily obtainable and robust biomarker for self-control ability across environmental contexts. SIGNIFICANCE STATEMENT: Self-control is associated with better health, but behavioral and psychometric self-control measures allow only indirect associations with health outcomes and may be distorted by reporting bias. We tested whether resting heart-rate variability (HRV), a physiological indicator of psychological and physical health, can predict individual differences in dietary self-control in humans. We found that higher HRV was associated with better self-control and improved predictions of choice behavior. Specifically, higher HRV was associated with more effective downregulation of taste temptations, and with a diminished neural representation of taste temptations during self-control challenges. Our results suggest that HRV may serve as an easily acquired, noninvasive, and low-cost biomarker for self-control ability.

Autonomy, decisions, and free will.

Can humans make decisions? Can machines? What ethical questions arise from using robotics in the education of children? Or in elderly care? These were some of the topics of the interdisciplinary college (IK), which took place from the 25th of March to the 1st of April in Günne, next to Lake Möhne. During this one-week spring school, more than 40 well-known lecturers from around the globe gave 170 participants an insight into a cornucopia of topics surrounding "autonomy, decisions, and free will".

Pupil dilation predicts individual self-regulation success across domains.

Multiple theories have proposed that increasing central arousal through the brain's locus coeruleus-norepinephrine system may facilitate cognitive control and memory. However, the role of the arousal system in emotion regulation is less well understood. Pupil diameter is a proxy to infer upon the central arousal state. We employed an emotion regulation paradigm with a combination of design features that allowed us to dissociate regulation from emotional arousal in the pupil diameter time course of 34 healthy adults. Pupil diameter increase during regulation predicted individual differences in emotion regulation success beyond task difficulty. Moreover, the extent of this individual regulatory arousal boost predicted performance in another self-control task, dietary health challenges. Participants who harnessed more regulation-associated arousal during emotion regulation were also more successful in choosing healthier foods. These results suggest that a common arousal-based facilitation mechanism may support an individual's self-control across domains.

BOLD activity during emotion reappraisal positively correlates with dietary self-control success.

We combined established emotion regulation and dietary choice tasks with fMRI to investigate behavioral and neural associations in self-regulation across the two domains in human participants. We found that increased BOLD activity during the successful reappraisal of positive and negative emotional stimuli was associated with dietary self-control success. This cross-task correlation was present in medial and lateral prefrontal cortex as well as the striatum. In contrast, BOLD activity during the food choice task was not associated with self-reported emotion regulation efficacy. These results suggest that neural processes utilized during the reappraisal of emotional stimuli may also facilitate dietary choices that override palatability in favor of healthfulness. In summary, our findings indicate that the neural systems supporting emotion reappraisal can generalize to other behavioral contexts that require reevaluation of rewarding stimuli and outcomes to promote choices that conform with the current goal.

Dissociable mechanisms govern when and how strongly reward attributes affect decisions.

Theories and computational models of decision-making usually focus on how strongly different attributes are weighted in choice, for example, as a function of their importance or salience to the decision-maker. However, when different attributes affect the decision process is a question that has received far less attention. Here, we investigated whether the timing of attribute consideration has a unique influence on decision-making by using a time-varying drift diffusion model and data from four separate experiments. Experimental manipulations of attention and neural activity demonstrated that we can dissociate the processes that determine the relative weighting strength and timing of attribute consideration. Thus, the processes determining either the weighting strengths or the timing of attributes in decision-making can independently adapt to changes in the environment or goals. Quantifying these separate influences of timing and weighting on choice improves our understanding and predictions of individual differences in decision behaviour.

Hepatocellular metastasis recurrence in liver transplant after treatment with direct antiviral agents.

Chronic HCV liver infection is considered one of the main causes of liver cirrhosis and hepatocellular carcinoma (HCC). For a selected group of patients, orthotopic liver transplantation (OLTx) is the most effective option to cure both liver diseases. After liver transplantation, patients may be at risk of viral infection reactivation and HCC recurrence. HCV recurrence on the transplanted organ can lead to graft cirrhosis and therefore the clearance of virus with antiviral therapies has a pivotal role on the prevention of graft damage. Nowadays, direct antiviral agents (DAAs) represent the choice treatment for HCV recurrence in liver transplanted patients, ensuring high eradication rates. We present the case of a liver transplant recipient who developed, 7 years after OLTx and immediately after a DAAs treatment, a subcutaneous abdominal mass with histological characteristics of HCC.

Sustained virologic response to direct-acting antiviral agents predicts better outcomes in hepatitis C virus-infected patients: A retrospective study.

BACKGROUND: Direct-acting antiviral agents (DAAs) are extremely effective in eradicating hepatitis C virus (HCV) in chronically infected patients. However, the protective role of the sustained virologic response (SVR) achieved by second- and third-generation DAAs against the onset of hepatocellular carcinoma (HCC) and mortality is less well established. AIM: To examine the occurrence of HCC or death from any cause in a retrospective-prospective study of patients treated with DAAs. METHODS: Patients were enrolled from a tertiary academic hospital center for liver disease management that collects subject data mainly from northeastern Italy. The study was conducted in 380 patients (age: 60 ± 13 years, 224 males, 32% with cirrhosis) treated with DAAs with or without SVR (95/5%), with a median follow up of 58 wk (interquartile range: 38-117). The baseline anthropometric features, HCV viral load, severity of liver disease, presence of extra-hepatic complications, coinfection with HIV and/or HBV, alcohol consumption, previous interferon use, alpha-fetoprotein levels, and renal function were considered to be confounders. RESULTS: The incidence rate of HCC in patients with and without SVR was 1.3 and 59 per 100 person-years, respectively (incidence rate ratio: 44, 95%CI: 15-136, P < 0.001). Considering the combined endpoint of HCC or death from any cause, the hazard ratio (HR) for the SVR patients was 0.070 (95%CI: 0.025-0.194, P < 0.001). Other independent predictors of HCC or death were low HCV viremia (HR: 0.808, P = 0.030), low platelet count (HR: 0.910, P = 0.041), and presence of mixed cryoglobulinemia (HR: 3.460, P = 0.044). Considering SVR in a multi-state model, the independent predictors of SVR achievement were absence of cirrhosis (HR: 0.521, P < 0.001) and high platelet count (HR: 1.019, P = 0.026). Mixed cryoglobulinemia predicted the combined endpoint in patients with and without SVR (HR: 5.982, P = 0.028 and HR: 5.633, P = 0.047, respectively). CONCLUSION: DAA treatment is effective in inducing SVR and protecting against HCC or death. A residual risk of HCC persists in patients with advanced liver disease or with complications, such as mixed cryoglobulinemia or renal failure.

The determinants of food choice.

Health nudge interventions to steer people into healthier lifestyles are increasingly applied by governments worldwide, and it is natural to look to such approaches to improve health by altering what people choose to eat. However, to produce policy recommendations that are likely to be effective, we need to be able to make valid predictions about the consequences of proposed interventions, and for this, we need a better understanding of the determinants of food choice. These determinants include dietary components (e.g. highly palatable foods and alcohol), but also diverse cultural and social pressures, cognitive-affective factors (perceived stress, health attitude, anxiety and depression), and familial, genetic and epigenetic influences on personality characteristics. In addition, our choices are influenced by an array of physiological mechanisms, including signals to the brain from the gastrointestinal tract and adipose tissue, which affect not only our hunger and satiety but also our motivation to eat particular nutrients, and the reward we experience from eating. Thus, to develop the evidence base necessary for effective policies, we need to build bridges across different levels of knowledge and understanding. This requires experimental models that can fill in the gaps in our understanding that are needed to inform policy, translational models that connect mechanistic understanding from laboratory studies to the real life human condition, and formal models that encapsulate scientific knowledge from diverse disciplines, and which embed understanding in a way that enables policy-relevant predictions to be made. Here we review recent developments in these areas.

Telomerase reverse transcriptase germline mutations and hepatocellular carcinoma in patients with nonalcoholic fatty liver disease.

In an increasing proportion of cases, hepatocellular carcinoma (HCC) develops in patients with nonalcoholic fatty liver disease (NAFLD). Mutations in telomerase reverse transcriptase (hTERT) are associated with familial liver diseases. The aim of this study was to examine telomere length and germline hTERT mutations as associated with NAFLD-HCC. In 40 patients with NAFLD-HCC, 45 with NAFLD-cirrhosis and 64 healthy controls, peripheral blood telomere length was evaluated by qRT-PCR and hTERT coding regions and intron-exon boundaries sequenced. We further analyzed 78 patients affected by primary liver cancer (NAFLD-PLC, 76 with HCC). Enrichment of rare coding mutations (allelic frequency <0.001) was evaluated by Burden test. Functional consequences were estimated in silico and by over-expressing protein variants in HEK-293 cells. We found that telomere length was reduced in individuals with NAFLD-HCC versus those with cirrhosis (P = 0.048) and healthy controls (P = 0.0006), independently of age and sex. We detected an enrichment of hTERT mutations in NAFLD-HCC, that was confirmed when we further considered a larger cohort of NAFLD-PLC, and was more marked in female patients (P = 0.03). No mutations were found in cirrhosis and local controls, and only one in 503 healthy Europeans from the 1000 Genomes Project (allelic frequency = 0.025 vs. <0.001; P = 0.0005). Mutations with predicted functional impact, including the frameshift Glu113Argfs*79 and missense Glu668Asp, cosegregated with liver disease in two families. Three patients carried missense mutations (Ala67Val in homozygosity, Pro193Leu and His296Pro in heterozygosity) in the N-terminal template-binding domain (P = 0.037 for specific enrichment). Besides Glu668Asp, the Ala67Val variant resulted in reduced intracellular protein levels. In conclusion, we detected an association between shorter telomeres in peripheral blood and rare germline hTERT mutations and NAFLD-HCC.

MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals.

Nonalcoholic fatty liver disease (NAFLD) represents an emerging cause of hepatocellular carcinoma (HCC), especially in non-cirrhotic individuals. The rs641738 C > T MBOAT7/TMC4 variant predisposes to progressive NAFLD, but the impact on hepatic carcinogenesis is unknown. In Italian NAFLD patients, the rs641738 T allele was associated with NAFLD-HCC (OR 1.65, 1.08-2.55; n = 765), particularly in those without advanced fibrosis (p < 0.001). The risk T allele was linked to 3'-UTR variation in MBOAT7 and to reduced MBOAT7 expression in patients without severe fibrosis. The number of PNPLA3, TM6SF2, and MBOAT7 risk variants was associated with NAFLD-HCC independently of clinical factors (p < 0.001), but did not significantly improve their predictive accuracy. When combining data from an independent UK NAFLD cohort, in the overall cohort of non-cirrhotic patients (n = 913, 41 with HCC) the T allele remained associated with HCC (OR 2.10, 1.33-3.31). Finally, in a combined cohort of non-cirrhotic patients with chronic hepatitis C or alcoholic liver disease (n = 1121), the T allele was independently associated with HCC risk (OR 1.93, 1.07-3.58). In conclusion, the MBOAT7 rs641738 T allele is associated with reduced MBOAT7 expression and may predispose to HCC in patients without cirrhosis, suggesting it should be evaluated in future prospective studies aimed at stratifying NAFLD-HCC risk.

Acute Stress Impairs Self-Control in Goal-Directed Choice by Altering Multiple Functional Connections within the Brain's Decision Circuits.

Important decisions are often made under stressful circumstances that might compromise self-regulatory behavior. Yet the neural mechanisms by which stress influences self-control choices are unclear. We investigated these mechanisms in human participants who faced self-control dilemmas over food reward while undergoing fMRI following stress. We found that stress increased the influence of immediately rewarding taste attributes on choice and reduced self-control. This choice pattern was accompanied by increased functional connectivity between ventromedial prefrontal cortex (vmPFC) and amygdala and striatal regions encoding tastiness. Furthermore, stress was associated with reduced connectivity between the vmPFC and dorsolateral prefrontal cortex regions linked to self-control success. Notably, alterations in connectivity pathways could be dissociated by their differential relationships with cortisol and perceived stress. Our results indicate that stress may compromise self-control decisions by both enhancing the impact of immediately rewarding attributes and reducing the efficacy of regions promoting behaviors that are consistent with long-term goals.