In this study we examined the relationship between indicators of socioeconomic status (SES) and mortality for a representative sample of individuals.
The sample included 3734 individuals aged 45 and ...older interviewed in 1984 in the Panel Study of Income Dynamics. In the current study, mortality was tracked between 1984 and 1994 and is related to SES indicators of education, occupation, income, and wealth.
Wealth and recent family income were the indicators that were most strongly associated with subsequent mortality. These associations persisted after we controlled for the other SES indicators and were stronger for women than for men and for non-elderly than for elderly individuals.
We found that the economic indicators of SES were usually as strongly associated with mortality as, if not more strongly associated with mortality than, the more conventional indicators of completed schooling and occupation.
Background and purpose: Pharmacological analysis of synergism or functional antagonism between different receptors commonly assumes that interacting receptors are located in the same cells. We have ...now investigated the distribution of α‐adrenoceptors, β‐adrenoceptors and cannabinoid‐like (GPR55) receptors in the mouse arteries.
Experimental approach: Fluorescence intensity from vascular tissue incubated with fluorescent ligands (α1‐adrenoceptor ligand, BODIPY‐FL‐prazosin, QAPB; β‐adrenoceptor ligand, TMR‐CGP12177; fluorescent angiotensin II; a novel diarylpyrazole cannabinoid ligand (Tocrifluor 1117, T1117) was measured with confocal microscopy. Small mesenteric and tail arteries of wild‐type and α1B/D‐adrenoceptor‐KO mice were used.
Key results: T1117, a fluorescent form of the cannabinoid CB1 receptor antagonist AM251, was a ligand for GPR55, with low affinity for CB1 receptors. In mesenteric arterial smooth muscle cells, α1A‐adrenoceptors were predominantly located in different cells from those with β‐adrenoceptors, angiotensin receptors or cannabinoid‐like (GPR55) receptors. Cells with β‐adrenoceptors predominated at arterial branches. Endothelial cells expressed β‐adrenoceptors, α‐adrenoceptors and cannabinoid‐like receptors. Only endothelial α‐adrenoceptors appeared in clusters. Adventitia was a rich source of G protein‐coupled receptors (GPCRs), particularly fibroblasts and nerve tracts, where Schwann cells bound α‐adrenoceptor, β‐adrenoceptor and CB‐receptor ligands, with a mix of separate receptor locations and co‐localization.
Conclusions and implications: Within each cell type, each GPCR had a distinctive heterogeneous distribution with limited co‐localization, providing a guide to the possibilities for functional synergism, and suggesting a new paradigm for synergism in which interactions may be either between cells or involve converging intracellular signalling processes.
This article is part of a themed section on Imaging in Pharmacology. To view the editorial for this themed section visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00685.x
The electronics of a general biomedical device consist of energy delivery, analog-to-digital conversion, signal processing, and communication subsystems. Each of these blocks must be designed for ...minimum energy consumption. Specific design techniques, such as aggressive voltage scaling, dynamic power-performance management, and energy-efficient signaling, must be employed to adhere to the stringent energy constraint. The constraint itself is set by the energy source, so energy harvesting holds tremendous promise toward enabling sophisticated systems without straining user lifestyle. Further, once harvested, efficient delivery of the low-energy levels, as well as robust operation in the aggressive low-power modes, requires careful understanding and treatment of the specific design limitations that dominate this realm. We outline the performance and power constraints of biomedical devices, and present circuit techniques to achieve complete systems operating down to power levels of microwatts. In all cases, approaches that leverage advanced technology trends are emphasized.
The discovery of β-adrenoceptors in previously unsuspected cell types is contributing to the rethinking of new drug targets. Recent developments in β-adrenoceptor pharmacology might have excited and ...surprised James Black, given his interest in developing drugs based on the selective manipulation of receptors to alter physiological responses. β-adrenoceptors continue to generate surprises at molecular and pharmacological levels that often require knowledge of receptor location to interpret. In this review, we emphasize the use of fluorescent ligands as the most selective means of demonstrating receptor localization. Fluorescent ligand binding in live tissues can provide quantitative pharmacological data, under carefully controlled conditions, relevant to other signalling parameters. Consideration of the role of β-adrenoceptors in many cell types (previously ignored) is needed to understand the actions of drugs at β-adrenoceptors throughout the body, particularly in the lung epithelium, vascular endothelium, immune cells and other ‘structural’ and ‘restorative’ cell types.
Hidradenitis suppurativa (HS) is a chronic inflammatory disease with a considerable disease burden. Existing treatment options are limited and often suboptimal; a high unmet need exists for effective ...targeted therapies.
To explore the effects of spesolimab treatment in patients with HS.
This randomized, double-blind, placebo-controlled, proof-of-clinical-concept study was conducted at 25 centers across 12 countries from May 3, 2021, to April 21, 2022. Patients had moderate-to-severe HS for ≥1 year before enrollment. Patients were randomized (2:1) to receive a loading dose of 3600 mg intravenous spesolimab (1200 mg at Weeks 0, 1, and 2) or matching placebo, followed by maintenance with either 1200 mg subcutaneous spesolimab every 2 weeks from Week 4-10 or matching placebo. The primary endpoint was the percentage change from baseline in total abscess and inflammatory nodule (AN) count at Week 12. Secondary endpoints were the absolute change from baseline in International Hidradenitis Suppurativa Severity Score System (IHS4), percentage change from baseline in draining tunnel (dT) count, the proportion of patients achieving a dT count of zero, absolute change from baseline in revised Hidradenitis Suppurativa Area and Severity Index (HASI-R), the proportion of patients achieving Hidradenitis Suppurativa Clinical Response (HiSCR50), the proportion of patients with ≥1 flare (all at Week 12), and patient-reported outcomes (PROs).
In this completed trial, randomized patients (N=52) received spesolimab (n=35) or placebo (n=17). The difference (95% confidence interval) versus placebo in least squares mean are reported. At Week 12, the percentage change in total AN count was similar between treatment arms: -4.1% (-31.7, 23.4). There was greater numerical improvement in the spesolimab arm, as measured by IHS4: -13.9 (-25.6, -2.3); percentage change from baseline in dT count: -96.6% (-154.5, -38.8); and the proportion of patients achieving a dT count of zero: 18.3% (-7.9, 37.5). Spesolimab treatment also improved HASI-R and HiSCR50 versus placebo. Spesolimab demonstrated a favorable safety profile, similar to that observed in trials in other diseases.
This exploratory proof-of-clinical-concept study supports the development of spesolimab as a new therapeutic option in HS. ClinicalTrials.gov identifier: NCT04762277.
A systematic literature review was conducted to summarize efficacy and safety data from studies that evaluated tumor necrosis factor inhibitors in patients with juvenile idiopathic arthritis (JIA).
...Relevant publications were identified via online searches (cutoff: March 16, 2021). After screening search results, outcome data were extracted if the treatment arm included ≥ 30 patients. Outcomes were described narratively, with efficacy assessed by JIA-American College of Rheumatology (ACR) response criteria and safety assessed by the incidence of serious adverse events (SAEs) per 100 patient-years (100PY).
Among 87 relevant publications included in the qualitative synthesis, 19 publications described 13 clinical trials. Across the 13 trials, the percentages of patients who achieved JIA-ACR30/50/70/90 responses at Week 12 with adalimumab ranged 71-94%, 68-90%, 55-61%, and 39-42%, respectively; with etanercept (Week 12), 73-94%, 53-78%, 36-59%, and 28%; with golimumab (Week 16), 89%, 79%, 66%, and 36%; and with infliximab (Week 14), 64%, 50%, and 22% (JIA-ACR90 not reported). SAE incidence across all time points ranged 0-13.7 SAE/100PY for adalimumab, 0-20.0 SAE/100PY for etanercept, and 10.4-24.3 SAE/100PY for golimumab (1 study). SAE incidence could not be estimated from the 2 infliximab publications.
Tumor necrosis factor inhibitors are effective and well tolerated in the treatment of JIA, but additional evidence from head-to-head studies and over longer periods of time, especially in the context of the transition from pediatric to adult care, would be useful.
Objective Clinicians may give greater consideration to medical management versus coronary artery bypass grafting (CABG) for coronary artery disease (CAD) at the time of aortic valve intervention. We ...evaluated the prognostic impact of revascularization strategy during aortic valve replacement (AVR). Methods We studied 1308 consecutive patients with significant CAD (≥50% stenosis) undergoing AVR with or with out CABG between 2001 and 2010. Late mortality and its determinants were analyzed using multivariable Cox models. Results Patients undergoing CABG (n = 1043; 18%) had more frequent angina (50% vs 26%; P < .001), left ventricular dysfunction (22% vs 14%; P = .003), advanced (>70% stenosis) CAD (85% vs 48%; P < .001), and incidence of triple-vessel/left-main CAD (44% vs 8%; P < .001). Whereas operative mortality was comparable between patients undergoing AVR plus CABG versus isolated AVR (2.9% vs 3.0%; P = .90), 5-year (72% vs 64%) and 8-year (50% vs 39%) survival was higher following CABG ( P = .007). Adjusting for older age (hazard ratio HR, 1.28 per 5 years), female sex (HR, 1.23), peripheral vascular disease (HR, 1.71), New York Heart Association functional class III to IV (HR, 1.48), and diabetes (HR, 1.50) concomitant CABG at AVR reduced late mortality risk by more than one-third (HR, 0.62, 95% confidence interval, 0.49-0.79; P < .001). CABG continued to confer a survival advantage in patients with moderate (50%-70%) (HR, 0.62; P = .02) and severe (>70%) CAD (HR, 0.62; P = .002). Conclusions In patients undergoing AVR with coexistent CAD, concomitant CABG reduces risk of late death by more than one-third, without augmenting operative mortality. This survival advantage persists in moderate (50% to 70%) and severe (>70%) CAD. These findings underline the prognostic importance of revascularization in this population and should influence decisions regarding revascularization strategy in patients undergoing transcatheter valve therapy.
There is a paucity of data regarding results of surgical management of myocardial bridging. Our objective was to evaluate the clinical outcomes of unroofing procedures in patients with myocardial ...bridging of the left anterior descending (LAD) coronary artery who had chest pain refractory to medical therapy.
Among 274 adult patients diagnosed with myocardial bridging at our institution (1996-2017), 71 underwent surgical intervention. To understand the potential benefit of unroofing, we excluded patients with concomitant operations for other diagnoses or known obstructive coronary disease. The study included 35 patients with preoperative chest pain and isolated LAD coronary artery bridging who underwent surgical unroofing. We analyzed recurrent symptoms, postoperative medication use, and mortality.
Mean age was 48.2 ± 11.2 years (18 men 51%). All patients underwent preoperative coronary angiography. Endothelial dysfunction in the LAD coronary artery bridged segment was confirmed in 20 of 24 patients (83%). Mean cardiopulmonary bypass and cross-clamp times were 47.6 ± 29.8 minutes and 33.7 ± 22.2 minutes, respectively. Median lengths of hospital and intensive care unit stay were 5 days and 1 day, respectively. During follow-up (median, 31 months; 95% confidence interval, 18-49) there were no cardiac-related deaths, and 22 patients (63%) reported no chest pain. Among 13 symptomatic patients, 10 underwent postoperative noninvasive testing, which was negative for ischemia in all cases.
Myocardial unroofing can be performed safely in patients with chest pain and isolated LAD coronary artery myocardial bridging. However, patients should be aware of the potential for recurrent nonischemic chest pain and continued medical therapy despite relief of coronary compression.
The timing of valve repair or replacement in patients with severe aortic valve regurgitation (AR) is controversial. We investigated the effect of left ventricular (LV) function on survival and ...recovery of LV performance and dimensions after correction of chronic severe AR.
We reviewed 530 consecutive patients who underwent aortic valve repair or replacement for severe AR between January 1, 2004, and June 30, 2014.
The 30-day mortality was 0.75%. In multivariate analysis, older age (hazard ratio HR = 1.02, p = 0.03), preoperative LV ejection fraction (EF) <60% (HR = 1.78, p = 0.04), previous myocardial infarction (HR = 2.53, p = 0.01), and previous cardiac operation (HR = 1.82, p = 0.03) were associated with all-cause mortality. Ejection fraction was reduced before hospital discharge but then improved and was greater than preoperative levels at all subsequent intervals. The LV dimensions decreased early postoperatively and continued to decrease thereafter. In multivariate analysis, factors associated with LV dysfunction (EF <60%) 1 year after aortic valve replacement were preoperative LV end-systolic dimension ≥40 mm (odds ratio OR = 5.39, p < 0.01) and previous myocardial infarction (OR = 3.62, p = 0.04).
Preoperative LV dysfunction (EF <60%) had an adverse effect on overall survival after correction of chronic severe AR. Because survival is improved in patients with greater preoperative LVEF and because reverse LV remodeling is more complete with smaller LV dimensions, surgical intervention should be considered promptly in patients with chronic severe AR and deterioration of these indicators during echocardiographic surveillance.
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