The effects of age on functional connectivity (FC) of intrinsic connectivity networks (ICNs) have largely been derived from cross-sectional studies. Far less is known about longitudinal changes in FC ...and how they relate to ageing-related cognitive decline. We evaluated intra- and inter-network FC in 78 healthy older adults two or three times over a period of 4years. Using linear mixed modeling we found progressive loss of functional specialization with ageing, evidenced by a decline in intra-network FC within the executive control (ECN) and default mode networks (DMN). In contrast, longitudinal inter-network FC between ECN and DMN showed a u-shaped trajectory whereby functional segregation between these two networks initially increased over time and later decreased as participants aged. The rate of loss in functional segregation between ECN and DMN was associated with ageing-related decline in processing speed. The observed longitudinal FC changes and their associations with processing speed remained after correcting for longitudinal reduction in gray matter volume. These findings help connect ageing-related changes in FC with ageing-related decline in cognitive performance and underscore the value of collecting concurrent longitudinal imaging and behavioral data.
•Longitudinal ageing decline in functional specialization of the default mode (DMN) and executive control networks (ECN).•Functional connectivity between ECN and DMN showed a u-shaped trajectory.•ECN–DMN functional segregation initially increased and later decreased with ageing.•Decline in ECN–DMN functional segregation associated with rate of decline in processing speed.•These results remained after correcting for ageing-related loss of gray matter volume.
Multiple gastrointestinal (GI) symptoms, including diarrhea, nausea/vomiting, and abdominal pain, as well as liver enzyme abnormalities, have been variably reported in patients with coronavirus ...disease 2019 (COVID-19). This document provides best practice statements and recommendations for consultative management based on a systematic review and meta-analysis of international data on GI and liver manifestations of COVID-19.
We performed a systematic literature search to identify published and unpublished studies using OVID Medline and preprint servers (medRxiv, LitCovid, and SSRN) up until April 5, 2020; major journal sites were monitored for US publications until April 19, 2020. We pooled the prevalence of diarrhea, nausea, vomiting, and abdominal pain, as well as liver function tests abnormalities, using a fixed-effect model and assessed the certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework.
We identified 118 studies and used a hierarchal study selection process to identify unique cohorts. We performed a meta-analysis of 47 studies including 10,890 unique patients. Pooled prevalence estimates of GI symptoms were as follows: diarrhea 7.7% (95% confidence interval CI, 7.2%–8.2%), nausea/vomiting 7.8% (95% CI, 7.1%–8.5%), and abdominal pain 2.7% (95% CI, 2.0%–3.4%). Most studies reported on hospitalized patients. The pooled prevalence estimates of elevated liver abnormalities were as follows: aspartate transaminase 15.0% (95% CI, 13.6%–16.5%) and alanine transaminase 15.0% (95% CI, 13.6%–16.4%). When we compared studies from China to studies from other countries in subgroup analyses, diarrhea, nausea/vomiting, and liver abnormalities were more prevalent outside of China, with diarrhea reported in 18.3% (95% CI, 16.6%–20.1%). Isolated GI symptoms were reported rarely. We also summarized the Gl and liver adverse effects of the most commonly utilized medications for COVID-19.
GI symptoms are associated with COVID-19 in <10% of patients. In studies outside of China, estimates are higher. Further studies are needed with standardized GI symptoms questionnaires and liver function test checks on admission to better quantify and qualify the association of these symptoms with COVID-19. Based on findings from our meta-analysis, we provide several Best Practice Statements for the consultative management of COVID-19.
Background and Aims
The coronavirus‐19 disease (COVID‐19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 virus, is associated with significant morbidity and mortality ...attributable to pneumonia, acute respiratory distress syndrome, and multiorgan failure. Liver injury has been reported as a nonpulmonary manifestation of COVID‐19, but characterization of liver test abnormalities and their association with clinical outcomes is incomplete.
Approach and Results
We conducted a retrospective cohort study of 1,827 patients with confirmed COVID‐19 who were hospitalized within the Yale‐New Haven Health System between March 14, 2020 and April 23, 2020. Clinical characteristics, liver tests (aspartate aminotransferase AST, alanine aminotransferase ALT, alkaline phosphatase ALP, total bilirubin TBIL, and albumin) at three time points (preinfection baseline, admission, and peak hospitalization), and hospitalization outcomes (severe COVID‐19, intensive care unit ICU admission, mechanical ventilation, and death) were analyzed. Abnormal liver tests were commonly observed in hospitalized patients with COVID‐19, both at admission (AST 66.9%, ALT 41.6%, ALP 13.5%, and TBIL 4.3%) and peak hospitalization (AST 83.4%, ALT 61.6%, ALP 22.7%, and TBIL 16.1%). Most patients with abnormal liver tests at admission had minimal elevations 1‐2× the upper limit of normal (ULN; AST 63.7%, ALT 63.5%, ALP 80.0%, and TBIL 75.7%). A significant proportion of these patients had abnormal liver tests prehospitalization (AST 25.9%, ALT 38.0%, ALP 56.8%, and TBIL 44.4%). Multivariate analysis revealed an association between abnormal liver tests and severe COVID‐19, including ICU admission, mechanical ventilation, and death; associations with age, male sex, body mass index, and diabetes mellitus were also observed. Medications used in COVID‐19 treatment (lopinavir/ritonavir, hydroxychloroquine, remdesivir, and tocilizumab) were associated with peak hospitalization liver transaminase elevations >5× ULN.
Conclusions
Abnormal liver tests occur in most hospitalized patients with COVID‐19 and may be associated with poorer clinical outcomes.
Chronic hepatitis B virus (HBV) infection represents a major global health problem, affecting an estimated 257–291 million persons worldwide and is associated with substantial morbidity and mortality ...because of clinical complications, such as liver cirrhosis and hepatocellular carcinoma. Despite existing resources for vaccination, screening, and treatment, the burden of chronic HBV remains significant within the United States (US). Both the World Health Organization (WHO) and US Department of Health and Human Services (DHHS) have articulated formal hepatitis elimination plans, although an updated assessment of the epidemiology and prevalence of chronic HBV is needed to inform these initiatives. The Chronic Liver Disease Foundation (CLDF), a nonprofit 501(c)(3) educational organization dedicated to raising awareness of liver disease, partnered with a panel of leading US hepatologists to conduct an updated literature review to develop a contemporary HBV prevalence range estimate. Panel members researched and evaluated the peer-reviewed literature on HBV prevalence and, in May 2019, discussed their findings during a live HBV epidemiology workshop. The panel proposed an overall estimated prevalence for chronic HBV infection in the US of 1.59 million persons (range 1.25–2.49 million). This review provides a summary of the workshop findings and conclusions, which may serve to inform future initiatives focused on HBV screening and prevention in the US.
Direct-acting antiviral (DAA) therapy is used in patients with HCV-related decompensated cirrhosis with the expectation of improving hepatic function. However, little is known about the long-term ...hepatic benefit of successful antiviral treatment.
Patients with advanced/decompensated cirrhosis (model for end-stage liver disease MELD ≥10), in whom NS5A-containing DAA therapy was initiated prior to September 2018, were included (from the HCV-TARGET cohort). Treatment outcomes and the impact of treatment on short-term and long-term hepatic function were examined.
A total of 642 patients were analyzed. The mean age was 60 years, 68% were male. The median baseline MELD was 12 (range 10–39) and 64% had prior decompensation. Among patients with available virologic outcomes, 90.5% achieved a sustained virologic response at 12 weeks (SVR12). Eighty (24%) patients achieved a clinically significant decrease in MELD by ≥3 points during short-term follow-up (9–26 weeks after the end of treatment). However, in long-term follow-up (median of 4 years after treatment), mean changes in MELD (−0.30 points), total bilirubin (+0.23 mg/dl) and albumin (+0.36 g/dl) were marginal. Fifty-one patients died and 22 underwent liver transplant. In long-term follow-up, a clinically meaningful decrease in MELD of ≥3 occurred in 29% and a final MELD score of <10 was achieved in 25%.
In a large real-world experience of patients with advanced/decompensated HCV-related cirrhosis treated with DAAs, there were only marginal improvements in MELD, total bilirubin, or albumin at long-term follow-up (after achieving SVR12). These patients may remain at high risk of decompensation and must continue to be closely monitored.
NCT01474811.
Hepatitis C virus infection can now be cured with medications, even in patients who have advanced scarring of the liver (cirrhosis). In this study, we evaluated whether liver function improves or deteriorates in the long-term, following successful treatment of hepatitis C in patients with cirrhosis. We found that overall liver function was relatively stable with only 29% of patients achieving a clinically meaningful improvement in liver function, and we therefore believe that these patients require ongoing monitoring.
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•SVR was achieved in 90.5% of patients with advanced/decompensated cirrhosis treated with direct-acting antivirals.•In long-term (>4 years) follow-up, overall mean changes in MELD, total bilirubin and albumin were marginal.•A clinically meaningful decrease in MELD of ≥3 occurred in 29% and a final MELD score of <10 was achieved in 25%.•Patients with advanced/decompensated liver disease should continue to be monitored following SVR.
Chronic hepatitis C virus infection is well-recognized as a common blood-borne infection with global public health impact affecting 3 to 5 million persons in the United States and more than 170 ...million persons worldwide. Chronic hepatitis C virus infection is associated with significant morbidity and mortality due to complications of liver cirrhosis and hepatocellular carcinoma. Current therapies with all-oral direct-acting antiviral agents are associated with high rates of sustained virologic response (SVR), generally exceeding 90%. SVR is associated with a reduced risk of liver cirrhosis, hepatic decompensation, need for liver transplantation, and both liver-related and all-cause mortality. However, a subset of patients who achieve SVR will remain at long-term risk for progression to cirrhosis, liver failure, hepatocellular carcinoma, and liver-related mortality. Limited evidence is available to guide clinicians on which post-SVR patients should be monitored vs discharged, how to monitor and with which tests, how frequently should monitoring occur, and for how long. In this clinical practice update, available evidence and expert opinion are used to generate best practice recommendations on the care of patients with chronic hepatitis C virus who have achieved SVR.
Although previous research suggests that there are hedonic and interpersonal benefits to gifting experiences, consumers often give material gifts rather than experiential gifts. Exploring this ...mismatch, the current research examines when and why consumers prefer to give material versus experiential gifts. The authors propose that gift givers are more likely to give experiential gifts to socially close recipients than socially distant recipients. Since experiences are perceived as more unique than material goods, givers perceive that choosing an experiential gift requires more specific knowledge of a recipient’s preferences to avoid the greater social risk of giving a poorly matched gift. Eight studies provide converging evidence for the proposed effect of social distance on gift preference and demonstrate that this effect is driven by a giver’s knowledge of a recipient’s preferences. Further supporting the mechanism of preference knowledge, the effect of social distance is moderated by the social risk associated with experiential gifts. When experiences contain little social risk—and thus require less knowledge of a recipient—the effect of social distance is significantly mitigated. Together, these results provide answers for why consumers often prefer to give material gifts over experiences, despite the advantage of giving experiences.
Non-alcoholic steatohepatitis (NASH) is defined as hepatic steatosis, inflammation, and hepatocyte injury with or without fibrosis. It has emerged as the second leading indication for liver ...transplantation with a rising death rate in the non-transplantable population. While there are many drugs in evaluation, currently no approved therapies are on the market for this condition. Given this importance, the Food and Drug Administration has provided formal guidance regarding drug development for stopping or reversing NASH or NASH associated fibrosis. The complex pathogenesis of NASH and its bidirectional relationship with metabolic syndrome has highlighted multiple drugs of interest that address metabolic, inflammatory, and fibrotic factors. A few promising liver specific targets include farnesoid X receptor agonists and peroxisome proliferator-activated receptor agonists. Previously studied drug classes such as glucagon-like peptide-1 analogs or sodium/glucose transport protein 2 inhibitors have also demonstrated ability to improve hepatic steatosis. Here we discuss current rationale, scientific work, and preliminary data in combining multiple drugs for the purposes of a multimodal attack on the pathogenesis of NASH. We highlight multiple Phase 2 and Phase 3 studies that demonstrate the potential to achieve a response rate higher than previously assessed monotherapies for this condition. Ultimately, one of these combination strategies may rise above in its safety and efficacy to become a part of a standardized approach to NASH.
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