Inflammation contributes to the pathogenesis of most acute and chronic liver diseases. Inflammasomes are multiprotein complexes that can sense danger signals from damaged cells and pathogens and assemble to mediate caspase-1 activation, which proteolytically activates the cytokines IL-1beta and IL-18. In contrast to other inflammatory responses, inflammasome activation uniquely requires two signals to induce inflammation, therefore setting an increased threshold. IL-1beta, generated upon caspase-1 activation, provides positive feed-forward stimulation for inflammatory cytokines, thereby amplifying inflammation. Inflammasome activation has been studied in different human and experimental liver diseases and has been identified as a major contributor to hepatocyte damage, immune cell activation and amplification of liver inflammation. In this Review, we discuss the different types of inflammasomes, their activation and biological functions in the context of liver injury and disease progression. Specifically, we focus on the triggers of inflammasome activation in alcoholic steatohepatitis and NASH, chronic HCV infection, ischaemia-reperfusion injury and paracetamol-induced liver injury. The application and translation of these discoveries into therapies promises novel approaches in the treatment of inflammation in liver disease.
IMPORTANCE: Massachusetts introduced health care reform (HCR) in 2006, expecting to expand health insurance coverage and improve outcomes. Because traumatic injury is a common acute condition with important health, disability, and economic consequences, examination of the effect of HCR on patients hospitalized following injury may help inform the national HCR debate.
OBJECTIVE: To examine the effect of Massachusetts HCR on survival rates of injured patients.
DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 1,520,599 patients hospitalized following traumatic injury in Massachusetts or New York during the 10 years (2002-2011) surrounding Massachusetts HCR using data from the State Inpatient Databases. We assessed the effect of HCR on mortality rates using a difference-in-differences approach to control for temporal trends in mortality.
INTERVENTION: Health care reform in Massachusetts in 2006.
MAIN OUTCOME AND MEASURE: Survival until hospital discharge.
RESULTS: During the 10-year study period, the rates of uninsured trauma patients in Massachusetts decreased steadily from 14.9% in 2002 to 5.0.% in 2011. In New York, the rates of uninsured trauma patients fell from 14.9% in 2002 to 10.5% in 2011. The risk-adjusted difference-in-difference assessment revealed a transient increase of 604 excess deaths (95% CI, 419-790) in Massachusetts in the 3 years following implementation of HCR.
CONCLUSIONS AND RELEVANCE: Health care reform did not affect health insurance coverage for patients hospitalized following injury but was associated with a transient increase in adjusted mortality rates. Reducing mortality rates for acutely injured patients may require more comprehensive interventions than simply promoting health insurance coverage through legislation.
Dissemination of Evidence-Based Antipsychotic Prescribing Guidelines to Nursing Homes: A Cluster Randomized Trial
OBJECTIVES: To evaluate the effectiveness of efforts to translate and disseminate evidence-based guidelines about atypical antipsychotic use to nursing homes (NHs).
DESIGN: Three-arm, cluster randomized trial.
PARTICIPANTS: NHs in the state of Connecticut.
MEASUREMENTS: Evidence-based guidelines for atypical antipsychotic prescribing were translated into a toolkit targeting NH stakeholders, and 42 NHs were recruited and randomized to one of three toolkit dissemination strategies: mailed toolkit delivery (minimal intensity); mailed toolkit delivery with quarterly audit and feedback reports about facility-level antipsychotic prescribing (moderate intensity); and in-person toolkit delivery with academic detailing, on-site behavioral management training, and quarterly audit and feedback reports (high intensity). Outcomes were evaluated using the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework.
RESULTS: Toolkit awareness of 30% (7/23) of leadership of low-intensity NHs, 54% (19/35) of moderate-intensity NHs, and 82% (18/22) of high-intensity NHs reflected adoption and implementation of the intervention. Highest levels of use and knowledge among direct care staff were reported in high-intensity NHs. Antipsychotic prescribing levels declined during the study period, but there were no statistically significant differences between study arms or from secular trends.
CONCLUSION: RE-AIM indicators suggest some success in disseminating the toolkit and differences in reach, adoption, and implementation according to dissemination strategy but no measurable effect on antipsychotic prescribing trends. Further dissemination to external stakeholders such as psychiatry consultants and hospitals may be needed to influence antipsychotic prescribing for NH residents.
Adherence to evidence-based secondary prevention pharmacotherapy in patients after an acute coronary syndrome: A systematic review
OBJECTIVE: To synthesize current evidence on medication adherence rates and associated risk factors in patients after an acute coronary syndrome (ACS).
METHODS: A systematic review was conducted. Five electronic databases and article bibliographies were searched for publications from 1990 to 2013 which assessed adherence to secondary prevention pharmacotherapy in adults after hospital discharge for an ACS. Identified studies were screened using pre-defined criteria for eligibility. A standardized form was used for data abstraction. Methodological quality was assessed using modified criteria for quantitative studies.
RESULTS: Sixteen studies met our inclusion criteria. Post-discharge medication adherence rates at 1-year ranged between 54% and 86%. There were no consistent predictors of non-adherence across all cardiac medication classes examined.
CONCLUSIONS: Adherence to secondary prevention pharmacotherapy was suboptimal in patients after hospital discharge for an ACS. Risk factors associated with non-adherence were examined in a limited number of studies, and the associations varied between these investigations.
Marriage and parenthood are associated with weight gain and residential mobility. Little is known about how obesity-relevant environmental contexts differ according to family structure. We estimated trajectories of neighborhood poverty, population density, and density of fast food restaurants, supermarkets, and commercial and public physical activity facilities for adults from a biracial cohort (CARDIA, n=4,174, aged 25-50) over 13 years (1992-93 through 2005-06) using latent growth curve analysis. We estimated associations of marriage, parenthood, and race with the observed neighborhood trajectories. Married participants tended to live in neighborhoods with lower poverty, population density, and availability of all types of food and physical activity amenities. Parenthood was similarly but less consistently related to neighborhood characteristics. Marriage and parenthood were more strongly related to neighborhood trajectories in whites (versus blacks), who, in prior studies, exhibit weaker associations between neighborhood characteristics and health. Greater understanding of how interactive family and neighborhood environments contribute to healthy living is needed.
Autism spectrum disorder (ASD) affects 1 in 50 children between the ages of 6 and 17 years. The etiology of ASD is not precisely known. ASD is an umbrella term, which includes both low- (IQ < 70) and high-functioning (IQ > 70) individuals. A better understanding of the disorder and how it manifests in individual subjects can lead to more effective intervention plans to fulfill the individual's treatment needs.Magnetic resonance imaging (MRI) is a non-invasive investigational tool that can be used to study the ways in which the brain develops or deviates from the typical developmental trajectory. MRI offers insights into the structure, function, and metabolism of the brain. In this article, we review published studies on brain connectivity changes in ASD using either resting state functional MRI or diffusion tensor imaging.The general findings of decreases in white matter integrity and in long-range neural coherence are well known in the ASD literature. Nevertheless, the detailed localization of these findings remains uncertain, and few studies link these changes in connectivity with the behavioral phenotype of the disorder. With the help of data sharing and large-scale analytic efforts, however, the field is advancing toward several convergent themes, including the reduced functional coherence of long-range intra-hemispheric cortico-cortical default mode circuitry, impaired inter-hemispheric regulation, and an associated, perhaps compensatory, increase in local and short-range cortico-subcortical coherence.
Alcoholic hepatitis (AH) is a clinical syndrome that was classically characterized by increasing jaundice, hepatomegaly, fever, neutrophilia, and an aspartate aminotransferase (AST):alanine aminotransferase (ALT) ratio of >2. It is a major cause of liver-related hospitalizations in those with a history of heavy alcohol consumption and is also a leading etiology associated with recurrent hospitalizations. Unfortunately, despite its clinical relevance, there are many gaps in knowledge related to this syndrome that represent barriers to the development of effective preventive surveillance, early detection, and therapeutic strategies. This article summarizes the gaps in knowledge and identifies research priorities to fill these gaps.
Recent national trends in acute myocardial infarction hospitalizations in Medicare: shrinking declines and growing disparities
We looked at trends in AMI (acute myocardial infarction) hospitalization rates among elderly Medicare beneficiaries over the 10-year period 2002 to 2011, focusing specifically on whether the post-2007 declines are also more modest for blacks than for whites, potentially reflecting a growing gap in care.
OBJECTIVES: The goal of this study was to determine whether endosomal Toll-like receptors (TLRs) contribute to the clinical manifestation of systemic autoimmunity exhibited by mice that lack the lysosomal nuclease DNaseII.
METHODS: DNaseII/IFNaR double deficient mice were intercrossed with Unc93b13d/3d mice to generate DNaseII-/-mice with non-functional endosomal TLRs. The resulting triple deficient mice were evaluated for arthritis, autoantibody production, splenomegaly, and extramedullary haematopoiesis. B cells from both strains were evaluated for their capacity to respond to endogenous DNA by using small oligonucleotide based TLR9D ligands and a novel class of bifunctional anti-DNA antibodies.
RESULTS: Mice that fail to express DNaseII, IFNaR, and Unc93b1 still develop arthritis but do not make autoantibodies, develop splenomegaly, or exhibit extramedullary haematopoiesis. DNaseII-/- IFNaR-/- B cells can respond to synthetic ODNs, but not to endogenous dsDNA.
CONCLUSIONS: RNA-reactive TLRs, presumably TLR7, are required for autoantibody production, splenomegaly, and extramedullary haematopoiesis in the DNaseII-/- model of systemic autoimmunity.
Historically, providers have lacked reimbursement for obesity management in the primary care setting. In 2011, the Centers for Medicare and Medicaid Services released the decision to reimburse qualified primary care providers for obesity counseling. We are concerned particularly about how the policy might adversely impact high-risk groups, namely racial/ethnic minority and socioeconomically disadvantaged populations.
A 35-Year Perspective (1975 to 2009) into the Long-Term Prognosis and Hospital Management of Patients Discharged from the Hospital After a First Acute Myocardial Infarction
There are limited population-based data available describing trends in the long-term prognosis of patients discharged from the hospital after an initial acute myocardial infarction (AMI). Our objectives were to describe multidecade trends in post-discharge mortality and their association with hospital management practices in patients discharged from all medical centers in Central Massachusetts after a first AMI. Residents of the Worcester, Massachusetts, metropolitan area discharged from all hospitals in Central Massachusetts after a first AMI from 1975 to 2009 comprised the study population (n = 8,728). Multivariable-adjusted logistic regression analyses were used to examine the association between year of hospitalization and 1-year post-discharge mortality. The average age of this population was 66 years, and 40% were women. Patients hospitalized in 1999 to 2009, compared with those discharged in 1975 to 1984, were older, more likely to be women, and have multiple previously diagnosed co-morbidities. Hospital use of invasive cardiac interventions and medications increased markedly over time. Unadjusted 1-year mortality rates were 12.9%, 12.5%, and 15.8% for patients discharged during 1975 to 1984, 1986 to 1997, and 1999 to 2009, respectively. After adjusting for several demographic characteristics, clinical factors, and inhospital complications, there were no significant differences in the odds of dying at 1-year post-discharge during the years under study. After further adjustment for hospital treatment practices, the odds of dying at 1 year post-discharge was 2.43 (95% confidence interval = 1.83 to 3.23) times higher in patients hospitalized in 1999 to 2009 than in 1975 to 1984. In conclusion, the increased use of invasive cardiac interventions and pharmacotherapies was associated with enhanced long-term survival in patients hospitalized for a first AMI.
This auto-ethnographic study describes the changes in the author's thinking and clinical work connected to her first-hand experience of Open Dialogue, which is an innovative, psychosocial approach to severe psychiatric crises developed in Tornio, Finland. In charting this trajectory, there is an emphasis on three interrelated themes: the micropolitics of U.S. managed mental health care; the practice of "dialogicality" in Open Dialogue; and the historical, cultural, and scientific shifts that are encouraging the adaptation of Open Dialogue in the United States. The work of Gregory Bateson provides a conceptual framework that makes sense of the author's experience and the larger trends. The study portrays and underscores how family and network practices are essential to responding to psychiatric crises and should not be abandoned in favor of a reductionist, biomedical model.
Anxiety is related to indices of cortical maturation in typically developing children and adolescents
Anxiety is a risk factor for many adverse neuropsychiatric and socioeconomic outcomes, and has been linked to functional and structural changes in the ventromedial prefrontal cortex (VMPFC). However, the nature of these differences, as well as how they develop in children and adolescents, remains poorly understood. More effective interventions to minimize the negative consequences of anxiety require better understanding of its neurobiology in children. Recent research suggests that structural imaging studies may benefit from clearly delineating between cortical surface area and thickness when examining these associations, as these distinct cortical phenotypes are influenced by different cellular mechanisms and genetic factors. The present study examined relationships between cortical surface area and thickness of the VMPFC and a self-report measure of anxiety (SCARED-R) in 287 youths aged 7-20 years from the Pediatric Imaging, Neurocognition, and Genetics (PING) study. Age and gender interactions were examined for significant associations in order to test for developmental differences. Cortical surface area and thickness were also examined simultaneously to determine whether they contribute independently to the prediction of anxiety. Anxiety was negatively associated with relative cortical surface area of the VMPFC as well as with global cortical thickness, but these associations diminished with age. The two cortical phenotypes contributed additively to the prediction of anxiety. These findings suggest that higher anxiety in children may be characterized by both delayed expansion of the VMPFC and an altered trajectory of global cortical thinning. Further longitudinal studies will be needed to confirm these findings.
BACKGROUND: Few epidemiologic cohort studies have evaluated atrial flutter (flutter) as an arrhythmia distinct from atrial fibrillation (AF).
OBJECTIVE: The purpose of this study was to examine the clinical correlates of flutter and its associated outcomes to distinguish them from those associated with AF in the Framingham Heart Study.
METHODS: We reviewed and adjudicated electrocardiograms (ECGs) previously classified as flutter or AF/flutter and another 100 ECGs randomly selected from AF cases. We examined the clinical correlates of flutter by matching up to 5 AF and 5 referents to each flutter case using a nested case referent design. We determined the 10-year outcomes associated with flutter with Cox models.
RESULTS: During mean follow-up of 33.0 +/- 12.2 years, 112 participants (mean age 72 +/- 10 years, 30% women) developed flutter. In multivariable analyses, smoking (odds ratio [OR] 2.84, 95% confidence interval [CI] 1.54-5.23), increased PR interval (OR 1.28 per SD, 95% CI 1.03-1.60), myocardial infarction (OR 2.25, 95% CI 1.05-4.80) and heart failure (OR 5.22, 95% CI 1.26-21.64) were associated with incident flutter. In age- and sex-adjusted models, flutter (vs referents) was associated with 10-year increased risk of AF (hazard ratio [HR] 5.01, 95% CI 3.14-7.99), myocardial infarction (HR 3.05, 95% CI 1.42-6.59), heart failure (HR 4.14, 95% CI 1.90-8.99), stroke (HR 2.17, 95% CI 1.13-4.17), and mortality (HR 2.00, 95% CI 1.44-2.79).
CONCLUSION: We identified the clinical correlates associated with flutter and observed that flutter was associated with multiple adverse outcomes.
On behalf of the Society of Behavioral Medicine, we present a model of obesity management in primary care based on the 5As counseling framework (Assess, Advise, Agree, Assist, and Arrange). Primary care physicians can use the 5As framework to build and coordinate a multidisciplinary team that: 1) addresses patients' psychosocial issues and medical and psychiatric comorbidities associated with obesity treatment failure; 2) delivers intensive counseling that consists of goal setting, self-monitoring, and problem solving; and 3) connects patients with community resources to assist them in making healthy lifestyle changes. This paper outlines reimbursement guidelines and weight-management counseling strategies, and provides a framework for building a multidisciplinary team to maximize the patient's success at weight management.
An Internet-based Controlled Trial Aimed to Improve Osteoporosis Prevention among Chronic Glucocorticoid Users
OBJECTIVE: To address the low prevention and treatment rates for those at risk of glucocorticoid-induced osteoporosis (GIOP), we evaluated the influence of a direct-to-patient, Internet-based educational video intervention using "storytelling" on rates of antiosteoporosis medication use among chronic glucocorticoid users who were members of an online pharmacy refill service.
METHODS: We identified members who refilled > /= 5 mg/day of prednisone (or equivalent) for 90 contiguous days and had no GIOP therapy for > /= 12 months. Using patient stories, we developed an online video addressing risk factors and treatment options, and delivered it to members refilling a glucocorticoid prescription. The intervention consisted of two 45-day "Video ON" periods, during which the video automatically appeared at the time of refill, and two 45-day "Video OFF" periods, during which there was no video. Members could also "self-initiate" watching the video by going to the video link. We used an interrupted time series design to evaluate the effectiveness of this intervention on GIOP prescription therapies over 6 months.
RESULTS: Among 3017 members (64.8%) exposed to the intervention, 59% had measurable video viewing time, of which 3% "self-initiated" the video. The GIOP prescription rate in the "Video ON" group was 2.9% versus 2.7% for the "Video OFF" group. There was a nonsignificant trend toward greater GIOP prescription in members who self-initiated the video versus automated viewing (5.7% vs 2.9%, p = 0.1).
CONCLUSION: Among adults at high risk of GIOP, prescription rates were not significantly affected by an online educational video presented at the time of glucocorticoid refill.
ClinicalTrials.gov Identifier: NCT01378689.
Metabolic danger signals, uric acid and ATP, mediate inflammatory cross-talk between hepatocytes and immune cells in alcoholic liver disease
Inflammation defines the progression of ALD from reversible to advanced stages. Translocation of bacterial LPS to the liver from the gut is necessary for alcohol-induced liver inflammation. However, it is not known whether endogenous, metabolic danger signals are required for inflammation in ALD. Uric acid and ATP, 2 major proinflammatory danger signals, were evaluated in the serum of human volunteers exposed to a single dose of ethanol or in supernatants of primary human hepatocytes exposed to ethanol. In vitro studies were used to evaluate the role of uric acid and ATP in inflammatory cross-talk between hepatocytes and immune cells. The significance of signaling downstream of uric acid and ATP in the liver was evaluated in NLRP3-deficient mice fed a Lieber-DeCarli ethanol diet. Exposure of healthy human volunteers to a single dose of ethanol resulted in increased serum levels of uric acid and ATP. In vitro, we identified hepatocytes as a significant source of these endogenous inflammatory signals. Uric acid and ATP mediated a paracrine inflammatory cross-talk between damaged hepatocytes and immune cells and significantly increased the expression of LPS-inducible cytokines, IL-1beta and TNF-alpha, by immune cells. Deficiency of NLRP3, a ligand-sensing component of the inflammasome recognizing uric acid and ATP, prevented the development of alcohol-induced liver inflammation in mice and significantly ameliorated liver damage and steatosis. Endogenous metabolic danger signals, uric acid, and ATP are involved in inflammatory cross-talk between hepatocytes and immune cells and play a crucial role in alcohol-induced liver inflammation.
Electronic medical records (EMRs) offer the opportunity to streamline the search for patients with possible delirium. The purpose of the current study was to identify words and phrases commonly noted in charts of patients with delirium. The current study included 67 patients (nested within a cohort study of 300 patients) ages 70 and older undergoing major elective surgery with evidence of confusion in their medical charts. Eight keywords or phrases had positive predictive values of 60% to 100% for delirium. Keywords were charted more often in nursing notes than physician notes. A brief list of keywords may serve as a building block for a methodology to screen for possible delirium from charts, with particular attention to nursing notes, for research and real-time clinical decision making.
Are Members of Long-Lived Families Healthier Than Their Equally Long-Lived Peers? Evidence From the Long Life Family Study
BACKGROUND: The Long Life Family Study (LLFS) is a multicenter longitudinal study of exceptional survival among members of long-lived sibships (probands), their offspring, and spouses of either group. For these four "roles", we asked: Does membership in a long-lived family protect against disease?
METHODS: We used 2008-2010 Beneficiary Annual Summary Files from the Centers for Medicare and Medicaid Services (CMS) to compare prevalences of 17 conditions among 781 LLFS participants in Medicare with those of 3,227 non-LLFS matches from the general Medicare population. Analyses accounted for nesting within LLFS families.
RESULTS: Seven conditions were significantly less common among LLFS probands than their matches: Alzheimer's, hip fracture, diabetes, depression, prostate cancer, heart failure, and chronic kidney disease. Four diseases not strongly linked to mortality (arthritis, cataract, osteoporosis, glaucoma) were significantly more common for LLFS probands. Despite fewer people and less disease in those roles, LLFS offspring and LLFS spouses of either generation also had significantly lower risk for Alzheimer's, diabetes, and heart failure.
CONCLUSIONS: Common, severe mortality-associated diseases are less prevalent among LLFS probands and their offspring than in the general population of aging Americans. Quality-of-life-limiting diseases such as arthritis and cataract are more prevalent, potentially through more diagnosing of milder forms in otherwise healthy and active individuals. LLFS spouses are also relatively healthy. As the younger cohorts age into Medicare and develop more conditions, it will be important to see whether these tentative findings strengthen.