Abstract Objectives We compared the mortality of persons with and without anxiety and depression in a nationally representative survey and examined the role of socioeconomic factors, chronic diseases ...and health behaviors in explaining excess mortality. Methods The 1999 National Health Interview Survey was linked with mortality data through 2011. We calculated the hazard ratio (HR) for mortality by presence or absence of anxiety/depression and evaluated potential mediators. We calculated the population attributable risk of mortality for anxiety/depression. Results Persons with anxiety/depression died 7.9 years earlier than other persons. At a population level, 3.5% of deaths were attributable to anxiety/depression. Adjusting for demographic factors, anxiety/depression was associated with an elevated risk of mortality HR = 1.61, 95% confidence interval (CI)= 1.40, 1.84. Chronic diseases and health behaviors explained much of the elevated risk. Adjusting for demographic factors, people with past-year contact with a mental health professional did not demonstrate excess mortality associated with anxiety/depression while those without contact did. Conclusions Anxiety/depression presents a mortality burden at both individual and population levels. Our findings are consistent with targeting health behaviors and physical illnesses as strategies for reducing this excess mortality among people with anxiety/depression.
To realize potential public health benefits from genetic and genomic innovations, understanding how best to implement the innovations into clinical care is important. The objective of this study was ...to synthesize data on challenges identified by six diverse projects that are part of a National Human Genome Research Institute (NHGRI)-funded network focused on implementing genomics into practice and strategies to overcome these challenges.
We used a multiple-case study approach with each project considered as a case and qualitative methods to elicit and describe themes related to implementation challenges and strategies. We describe challenges and strategies in an implementation framework and typology to enable consistent definitions and cross-case comparisons. Strategies were linked to challenges based on expert review and shared themes.
Three challenges were identified by all six projects, and strategies to address these challenges varied across the projects. One common challenge was to increase the relative priority of integrating genomics within the health system electronic health record (EHR). Four projects used data warehousing techniques to accomplish the integration. The second common challenge was to strengthen clinicians' knowledge and beliefs about genomic medicine. To overcome this challenge, all projects developed educational materials and conducted meetings and outreach focused on genomic education for clinicians. The third challenge was engaging patients in the genomic medicine projects. Strategies to overcome this challenge included use of mass media to spread the word, actively involving patients in implementation (e.g., a patient advisory board), and preparing patients to be active participants in their healthcare decisions.
This is the first collaborative evaluation focusing on the description of genomic medicine innovations implemented in multiple real-world clinical settings. Findings suggest that strategies to facilitate integration of genomic data within existing EHRs and educate stakeholders about the value of genomic services are considered important for effective implementation. Future work could build on these findings to evaluate which strategies are optimal under what conditions. This information will be useful for guiding translation of discoveries to clinical care, which, in turn, can provide data to inform continual improvement of genomic innovations and their applications.
Adverse experiences in childhood and adolescence, defined as subjectively perceived threats to the safety or security of the child’s bodily integrity, family, or social structures, are known to be ...associated with cardiometabolic outcomes over the life course into adulthood. This American Heart Association scientific statement reviews the scientific literature on the influence of childhood adversity on cardiometabolic outcomes that constitute the greatest public health burden in the United States, including obesity, hypertension, type 2 diabetes mellitus, and cardiovascular disease. This statement also conceptually outlines pathways linking adversity to cardiometabolic health, identifies evidence gaps, and provides suggestions for future research to inform practice and policy. We note that, despite a lack of objective agreement on what subjectively qualifies as exposure to childhood adversity and a dearth of prospective studies, substantial evidence documents an association between childhood adversity and cardiometabolic outcomes across the life course. Future studies that focus on mechanisms, resiliency, and vulnerability factors would further strengthen the evidence and provide much-needed information on targets for effective interventions. Given that childhood adversities affect cardiometabolic health and multiple health domains across the life course, interventions that ameliorate these initial upstream exposures may be more appropriate than interventions remediating downstream cardiovascular disease risk factor effects later in life.
Patients with rheumatoid arthritis (RA) receive highly targeted biologic therapies without previous knowledge of target expression levels in the diseased tissue. Approximately 40% of patients do not ...respond to individual biologic therapies and 5-20% are refractory to all. In a biopsy-based, precision-medicine, randomized clinical trial in RA (R4RA; n = 164), patients with low/absent synovial B cell molecular signature had a lower response to rituximab (anti-CD20 monoclonal antibody) compared with that to tocilizumab (anti-IL6R monoclonal antibody) although the exact mechanisms of response/nonresponse remain to be established. Here, in-depth histological/molecular analyses of R4RA synovial biopsies identify humoral immune response gene signatures associated with response to rituximab and tocilizumab, and a stromal/fibroblast signature in patients refractory to all medications. Post-treatment changes in synovial gene expression and cell infiltration highlighted divergent effects of rituximab and tocilizumab relating to differing response/nonresponse mechanisms. Using ten-by-tenfold nested cross-validation, we developed machine learning algorithms predictive of response to rituximab (area under the curve (AUC) = 0.74), tocilizumab (AUC = 0.68) and, notably, multidrug resistance (AUC = 0.69). This study supports the notion that disease endotypes, driven by diverse molecular pathology pathways in the diseased tissue, determine diverse clinical and treatment-response phenotypes. It also highlights the importance of integration of molecular pathology signatures into clinical algorithms to optimize the future use of existing medications and inform the development of new drugs for refractory patients.
It is widely claimed that racial and ethnic minorities, especially in the US, are less willing than non-minority individuals to participate in health research. Yet, there is a paucity of empirical ...data to substantiate this claim.
We performed a comprehensive literature search to identify all published health research studies that report consent rates by race or ethnicity. We found 20 health research studies that reported consent rates by race or ethnicity. These 20 studies reported the enrollment decisions of over 70,000 individuals for a broad range of research, from interviews to drug treatment to surgical trials. Eighteen of the twenty studies were single-site studies conducted exclusively in the US or multi-site studies where the majority of sites (i.e., at least 2/3) were in the US. Of the remaining two studies, the Concorde study was conducted at 74 sites in the United Kingdom, Ireland, and France, while the Delta study was conducted at 152 sites in Europe and 23 sites in Australia and New Zealand. For the three interview or non-intervention studies, African-Americans had a nonsignificantly lower overall consent rate than non-Hispanic whites (82.2% versus 83.5%; odds ratio OR = 0.92; 95% confidence interval CI 0.84-1.02). For these same three studies, Hispanics had a nonsignificantly higher overall consent rate than non-Hispanic whites (86.1% versus 83.5%; OR = 1.37; 95% CI 0.94-1.98). For the ten clinical intervention studies, African-Americans' overall consent rate was nonsignificantly higher than that of non-Hispanic whites (45.3% versus 41.8%; OR = 1.06; 95% CI 0.78-1.45). For these same ten studies, Hispanics had a statistically significant higher overall consent rate than non-Hispanic whites (55.9% versus 41.8%; OR = 1.33; 95% CI 1.08-1.65). For the seven surgery trials, which report all minority groups together, minorities as a group had a nonsignificantly higher overall consent rate than non-Hispanic whites (65.8% versus 47.8%; OR = 1.26; 95% CI 0.89-1.77). Given the preponderance of US sites, the vast majority of these individuals from minority groups were African-Americans or Hispanics from the US.
We found very small differences in the willingness of minorities, most of whom were African-Americans and Hispanics in the US, to participate in health research compared to non-Hispanic whites. These findings, based on the research enrollment decisions of over 70,000 individuals, the vast majority from the US, suggest that racial and ethnic minorities in the US are as willing as non-Hispanic whites to participate in health research. Hence, efforts to increase minority participation in health research should focus on ensuring access to health research for all groups, rather than changing minority attitudes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The anti-inflammatory effects of globular adiponectin (gAcrp) are mediated by IL-10/heme oxygenase 1 (HO-1)-dependent pathways. Although full-length (flAcrp) adiponectin also suppresses LPS-induced ...pro-inflammatory signaling, its signaling mechanisms are not yet understood. The aim of this study was to examine the differential mechanisms by which gAcrp and flAcrp suppress pro-inflammatory signaling in macrophages. Chronic ethanol feeding increased LPS-stimulated TNF-α expression by Kupffer cells, associated with a shift to an M1 macrophage polarization. Both gAcrp and flAcrp suppressed TNF-α expression in Kupffer cells; however, only the effect of gAcrp was dependent on IL-10. Similarly, inhibition of HO-1 activity or siRNA knockdown of HO-1 in RAW264.7 macrophages only partially attenuated the suppressive effects of flAcrp on MyD88-dependent and -independent cytokine signatures. Instead, flAcrp, acting via the adiponectin R2 receptor, potently shifted the polarization of Kupffer cells and RAW264.7 macrophages to an M2 phenotype. gAcrp, acting via the adiponectin R1 receptor, was much less effective at eliciting an M2 pattern of gene expression. M2 polarization was also partially dependent on AMP-activated kinase. flAcrp polarized RAW264.7 macrophages to an M2 phenotype in an IL-4/STAT6-dependent mechanism. flAcrp also increased the expression of genes involved in oxidative phosphorylation in RAW264.7 macrophages, similar to the effect of flAcrp on hepatocytes. In summary, these data demonstrate that gAcrp and flAcrp utilize differential signaling strategies to decrease the sensitivity of macrophages to activation by TLR4 ligands, with flAcrp utilizing an IL-4/STAT6-dependent mechanism to shift macrophage polarization to the M2/anti-inflammatory phenotype.
Altered expression and activity of immunomodulatory cytokines plays a major role in the pathogenesis of alcoholic liver disease. Chronic ethanol feeding increases the sensitivity of Kupffer cells, ...the resident hepatic macrophage, to lipopolysaccharide (LPS), leading to increased tumor necrosis factor alpha (TNF‐α) expression. This sensitization is normalized by treatment of primary cultures of Kupffer cells with adiponectin, an anti‐inflammatory adipokine. Here we tested the hypothesis that adiponectin‐mediated suppression of LPS signaling in Kupffer cells is mediated via an interleukin‐10 (IL‐10)/heme oxygenase‐1 (HO‐1) pathway after chronic ethanol feeding. Knockdown of IL‐10 expression in primary cultures of Kupffer cells with small interfering RNA (siRNA) prevented the inhibitory effect of globular adiponectin (gAcrp) on LPS‐stimulated TNF‐α expression. gAcrp increased IL‐10 mRNA and protein expression, as well as expression of the IL‐10 inducible gene, HO‐1; expression was higher in Kupffer cells from ethanol‐fed rats compared with pair‐fed controls. Although IL‐10 receptor surface expression on Kupffer cells was not affected by ethanol feeding, IL‐10–mediated phosphorylation of STAT3 and expression of HO‐1 was higher in Kupffer cells after ethanol feeding. Inhibition of HO‐1 activity, either by treatment with the HO‐1 inhibitor zinc protoporphyrin or by siRNA knockdown of HO‐1, prevented the inhibitory effect of gAcrp on LPS‐stimulated TNF‐α expression in Kupffer cells. LPS‐stimulated TNF‐α expression in liver was increased in mice after chronic ethanol exposure. When mice were treated with cobalt protoporphyrin to induce HO‐1 expression, ethanol‐induced sensitivity to LPS was ameliorated. Conclusion: gAcrp prevents LPS‐stimulated TNF‐α expression in Kupffer cells through the activation of the IL‐10/STAT3/HO‐1 pathway. Kupffer cells from ethanol‐fed rats are highly sensitive to the anti‐inflammatory effects of gAcrp; this sensitivity is associated with both increased expression and sensitivity to IL‐10. (HEPATOLOGY 2010.)
Forest vulnerability to drought is expected to increase under anthropogenic climate change, and drought-induced mortality and community dynamics following drought have major ecological and societal ...impacts. Here,we showthat tree mortality concomitant with drought has led to short-term (mean 5 y, range 1 to 23 y after mortality) vegetation-type conversion in multiple biomes across the world (131 sites). Self-replacement of the dominant tree species was only prevalent in 21% of the examined cases and forests and woodlands shifted to nonwoody vegetation in 10% of them. The ultimate temporal persistence of such changes remains unknown but, given the key role of biological legacies in long-term ecological succession, this emerging picture of postdrought ecological trajectories highlights the potential for major ecosystem reorganization in the coming decades. Community changes were less pronounced under wetter postmortality conditions. Replacement was also influenced by management intensity, and postdrought shrub dominance was higher when pathogens acted as codrivers of tree mortality. Early change in community composition indicates that forests dominated by mesic species generally shifted toward more xeric communities, with replacing tree and shrub species exhibiting drier bioclimatic optima and distribution ranges. However, shifts toward more mesic communities also occurred and multiple pathways of forest replacement were observed for some species. Drought characteristics, species-specific environmental preferences, plant traits, and ecosystem legacies govern postdrought species turnover and subsequent ecological trajectories, with potential far-reaching implications for forest biodiversity and ecosystem services.
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