National Trends in Cessation Counseling, Prescription Medication Use, and Associated Costs Among US Adult Cigarette Smokers

Importance: Cigarette smoking is the leading cause of preventable disease and death in the United States. When used separately or in combination, smoking cessation counseling and cessation medications have been associated with increased cessation rates. Objectives: To present trends in self-reported receipt of physician advice to quit smoking and in use of prescription smoking cessation medication along with their associated expenditures among a nationally representative sample of active adult smokers in the United States. Design, Setting, and Participants: This repeated cross-sectional study of US adults aged 18 years or older was conducted from July 5, 2018, through August 15, 2018. Data were collected between January 1, 2006, and December 31, 2015, from the Medical Expenditure Panel Survey, an annual US survey of individuals and families, health care personnel, and employers. Participants (n = 29 106) were noninstitutionalized civilians who were randomly drawn from the respondents of the previous year’s National Health Interview Survey. Multivariable logistic regression models were used to examine the associations between sociodemographic factors and receipt of physician cessation advice and use of cessation prescription medication. A 2-part econometric model was used to assess health care expenditures. Main Outcomes and Measures: Trends in self-reported receipt of physician advice to quit and uptake of prescription smoking cessation medications with associated total and out-of-pocket expenditures. Results: The study sample consisted of 29 106 participants, with a mean (SD) age of 57 (10) years and a composition of 13 670 women (47.0%). The results were weighted to provide estimates for 31.2 million active adult cigarette smokers. The proportion of smokers who reported receiving physician advice to quit increased from 60.2% (95% CI, 58.5%-62.0%) in 2006 to 2007 to 64.9% (95% CI, 62.8%-66.9%) in 2014 to 2015, with a P for trend = .001. The odds of receiving physician cessation advice was statistically significantly higher in women (odds ratio [OR], 1.50; 95% CI, 1.39-1.59) and lower among uninsured participants (OR, 0.58; 95% CI, 0.52-0.65). Overall, prescription smoking cessation medication use decreased with a corresponding reduction in total expenditures from $146 million (out-of-pocket cost,$46 million) in 2006 to 2007 to $73 million (out-of-pocket cost,$9 million) in 2014 to 2015. Male (odds ratio [OR], 0.78; 95% CI, 0.66-0.91), uninsured (OR, 0.58; 95% CI, 0.41-0.83), and racial/ethnic minority (African American: OR, 0.51 [95% CI, 0.38-0.69]; Asian: OR, 0.31 [95% CI, 0.10-0.93]; Hispanic: OR, 0.53 [95% CI, 0.36-0.78]) participants were less likely to use prescription smoking cessation medications. Conclusions and Relevance: The lower rates of delivery of physician advice to quit smoking and the lower uptake of known prescription smoking cessation medications among men, younger adults, uninsured individuals, racial/ethnic minority groups, and those without smoking-associated comorbidities may be associated with the higher smoking rates among these subgroups despite an all-time low prevalence of smoking in the United States; this finding calls for a more targeted implementation of smoking cessation guidelines

Growing old in England: economic and social issues

This paper examines the economic and social impact of changes in the duration of working life for the 80 per cent of older adults living in urban England. While some people are experiencing extended retirement because of moving out of paid work in their fifties, a growing minority of those beyond the state retirement age continue in paid employment. This paper highlights the considerable challenges for urban policy makers in addressing the economic and social inclusion of all older adults

Friedewald-Estimated Versus Directly Measured Low-Density Lipoprotein Cholesterol and Treatment Implications

ObjectivesThe aim of this study was to compare Friedewald-estimated and directly measured low-density lipoprotein cholesterol (LDL-C) values.BackgroundLDL-C is routinely estimated by the Friedewald equation to guide treatment; however, compatibility with direct measurement has received relatively little scrutiny, especially at levels <70 mg/dl now targeted in high-risk patients.MethodsWe examined 1,340,614 U.S. adults who underwent lipid profiling by vertical spin density gradient ultracentrifugation (Atherotech, Birmingham, Alabama) from 2009 to 2011. Following standard practice, Friedewald LDL-C was not estimated if triglyceride levels were ≥400 mg/dl (n = 30,174), yielding 1,310,440 total patients and 191,333 patients with Friedewald LDL-C <70 mg/dl.ResultsPatients were 59 ± 15 years of age and 52% were women. Lipid distributions closely matched those in the National Health and Nutrition Examination Survey. A greater difference in the Friedewald-estimated versus directly measured LDL-C occurred at lower LDL-C and higher triglyceride levels. If the Friedewald-estimated LDL-C was <70 mg/dl, the median directly measured LDL-C was 9.0 mg/dl higher (5th to 95th percentiles, 1.8 to 15.4 mg/dl) when triglyceride levels were 150 to 199 mg/dl and 18.4 mg/dl higher (5th to 95th percentiles, 6.6 to 36.0 mg/dl) when triglyceride levels were 200 to 399 mg/dl. Of patients with a Friedewald-estimated LDL-C <70 mg/dl, 23% had a directly measured LDL-C ≥70 mg/dl (39% if triglyceride levels were concurrently 150 to 199 mg/dl; 59% if triglyceride levels were concurrently 200 to 399 mg/dl).ConclusionsThe Friedewald equation tends to underestimate LDL-C most when accuracy is most crucial. Especially if triglyceride levels are ≥150 mg/dl, Friedewald estimation commonly classifies LDL-C as <70 mg/dl despite directly measured levels ≥70 mg/dl, and therefore additional evaluation is warranted in high-risk patients

Differential Ligand Binding to a Human Cytomegalovirus Chemokine Receptor Determines Cell Type–Specific Motility

While most chemokine receptors fail to cross the chemokine class boundary with respect to the ligands that they bind, the human cytomegalovirus (HCMV)-encoded chemokine receptor US28 binds multiple CC-chemokines and the CX3C-chemokine Fractalkine. US28 binding to CC-chemokines is both necessary and sufficient to induce vascular smooth muscle cell (SMC) migration in response to HCMV infection. However, the function of Fractalkine binding to US28 is unknown. In this report, we demonstrate that Fractalkine binding to US28 not only induces migration of macrophages but also acts to inhibit RANTES-mediated SMC migration. Similarly, RANTES inhibits Fractalkine-mediated US28 migration in macrophages. While US28 binding of both RANTES and Fractalkine activate FAK and ERK-1/2, RANTES signals through Gα12 and Fractalkine through Gαq. These findings represent the first example of differential chemotactic signaling via a multiple chemokine family binding receptor that results in migration of two different cell types. Additionally, the demonstration that US28-mediated chemotaxis is both ligand-specific and cell type–specific has important implications in the role of US28 in HCMV pathogenesis

Effect of Host Species on the Distribution of Mutational Fitness Effects for an RNA Virus

Knowledge about the distribution of mutational fitness effects (DMFE) is essential for many evolutionary models. In recent years, the properties of the DMFE have been carefully described for some microorganisms. In most cases, however, this information has been obtained only for a single environment, and very few studies have explored the effect that environmental variation may have on the DMFE. Environmental effects are particularly relevant for the evolution of multi-host parasites and thus for the emergence of new pathogens. Here we characterize the DMFE for a collection of twenty single-nucleotide substitution mutants of Tobacco etch potyvirus (TEV) across a set of eight host environments. Five of these host species were naturally infected by TEV, all belonging to family Solanaceae, whereas the other three were partially susceptible hosts belonging to three other plant families. First, we found a significant virus genotype-by-host species interaction, which was sustained by differences in genetic variance for fitness and the pleiotropic effect of mutations among hosts. Second, we found that the DMFEs were markedly different between Solanaceae and non-Solanaceae hosts. Exposure of TEV genotypes to non-Solanaceae hosts led to a large reduction of mean viral fitness, while the variance remained constant and skewness increased towards the right tail. Within the Solanaceae hosts, the distribution contained an excess of deleterious mutations, whereas for the non-Solanaceae the fraction of beneficial mutations was significantly larger. All together, this result suggests that TEV may easily broaden its host range and improve fitness in new hosts, and that knowledge about the DMFE in the natural host does not allow for making predictions about its properties in an alternative host

Signal Peptide-Dependent Inhibition of MHC Class I Heavy Chain Translation by Rhesus Cytomegalovirus

The US2-11 region of human and rhesus cytomegalovirus encodes a conserved family of glycoproteins that inhibit MHC-I assembly with viral peptides, thus preventing cytotoxic T cell recognition. Since HCMV lacking US2-11 is no longer able to block assembly and transport of MHC-I, we examined whether this is also observed for RhCMV lacking the corresponding region. Unexpectedly, recombinant RhCMV lacking US2-11 was still able to inhibit MHC-I expression in infected fibroblasts, suggesting the presence of an additional MHC-I evasion mechanism. Progressive deletion analysis of RhCMV-specific genomic regions revealed that MHC-I expression is fully restored upon additional deletion of rh178. The protein encoded by this RhCMV-specific open reading frame is anchored in the endoplasmic reticulum membrane. In the presence of rh178, RhCMV prevented MHC-I heavy chain (HC) expression, but did not inhibit mRNA transcription or association of HC mRNA with translating ribosomes. Proteasome inhibitors stabilized a HC degradation intermediate in the absence of rh178, but not in its presence, suggesting that rh178 prevents completion of HC translation. This interference was signal sequence-dependent since replacing the signal peptide with that of CD4 or murine HC rendered human HCs resistant to rh178. We have identified an inhibitor of antigen presentation encoded by rhesus cytomegalovirus unique in both its lack of homology to any other known protein and in its mechanism of action. By preventing signal sequence-dependent HC translocation, rh178 acts prior to US2, US3 and US11 which attack MHC-I proteins after protein synthesis is completed. Rh178 is the first viral protein known to interfere at this step of the MHC-I pathway, thus taking advantage of the conserved nature of HC leader peptides, and represents a new mechanism of translational interference

Fowlpox virus recombinants expressing HPV-16 E6 and E7 oncogenes for the therapy of cervical carcinoma elicit humoral and cell-mediated responses in rabbits

Background: Around half million new cases of cervical cancer arise each year, making the development of an effective therapeutic vaccine against HPV a high priority. As the E6 and E7 oncoproteins are expressed in all HPV-16 tumour cells, vaccines expressing these proteins might clear an already established tumour and support the treatment of HPV-related precancerous lesions. Methods: Three different immunisation regimens were tested in a pre-clinical trial in rabbits to evaluate the humoral and cell-mediated responses of a putative HPV-16 vaccine. Fowlpoxvirus (FP) recombinants separately expressing the HPV-16 E6 (FPE6) and E7 (FPE7) transgenes were used for priming, followed by E7 protein boosting. Results: All of the protocols were effective in eliciting a high antibody response. This was also confirmed by interleukin-4 production, which increased after simultaneous priming with both FPE6 and FPE7 and after E7 protein boost. A cell-mediated immune response was also detected in most of the animals. Conclusion: These results establish a preliminary profile for the therapy with the combined use of avipox recombinants, which may represent safer immunogens than vaccinia-based vectors in immuno-compromised individuals, as they express the transgenes in most mammalian cells in the absence of a productive replication

The Varicella-Zoster Virus ORF47 Kinase Interferes with Host Innate Immune Response by Inhibiting the Activation of IRF3

The innate immune response constitutes the first line of host defence that limits viral spread and plays an important role in the activation of adaptive immune response. Viral components are recognized by specific host pathogen recognition receptors triggering the activation of IRF3. IRF3, along with NF-κB, is a key regulator of IFN-β expression. Until now, the role of IRF3 in the activation of the innate immune response during Varicella-Zoster Virus (VZV) infection has been poorly studied. In this work, we demonstrated for the first time that VZV rapidly induces an atypical phosphorylation of IRF3 that is inhibitory since it prevents subsequent IRF3 homodimerization and induction of target genes. Using a mutant virus unable to express the viral kinase ORF47p, we demonstrated that (i) IRF3 slower-migrating form disappears; (ii) IRF3 is phosphorylated on serine 396 again and recovers the ability to form homodimers; (iii) amounts of IRF3 target genes such as IFN-β and ISG15 mRNA are greater than in cells infected with the wild-type virus; and (iv) IRF3 physically interacts with ORF47p. These data led us to hypothesize that the viral kinase ORF47p is involved in the atypical phosphorylation of IRF3 during VZV infection, which prevents its homodimerization and subsequent induction of target genes such as IFN-β and ISG15