Systolic heart failure in the elderly: optimizing medical management.

The aging population with hypertension and coronary artery disease is rapidly increasing worldwide and develops heart failure (HF). A wide range of pharmacotherapeutic drugs are recommended in the HF management guidelines. For the most part, these recommendations are based on the results of studies in the younger population, and most drugs were not adequately tested in the elderly. However, many changes that occur during the aging process affect the response to several of the recommended therapeutic drugs. Physicians will be increasingly involved in managing the expanding elderly population with HF. It is therefore imperative that they recognize ways to use current pharmacotherapeutic agents and the increasing need for novel agents for optimizing the management of the elderly patient with HF.

Atrial fibrillation ablation and heart failure.

Atrial fibrillation (AF) worsens outcome in patients with systolic heart failure and the presence of heart failure (HF) predicts a 5- to 6-fold increase in risk of AF. In addition to loss of atrial systole, AF may contribute to left ventricular (LV) systolic dysfunction due a rapid ventricular rate, irregularity of rhythm and exacerbation of mitral regurgitation due to atrial dilatation. Elimination of atrial fibrillation with catheter ablation can improve ejection fraction and reduce heart failure symptoms and appears superior to AV node ablation and bi-ventricular pacing. AF ablation can restore sinus rhythm in most patients with heart failure. Additional study is warranted to identify which patients will receive maximum benefit from aggressive rhythm control and to determine efficacy in patients with diastolic heart failure.

Acute conversion of persistent atrial fibrillation during dofetilide loading does not predict long-term atrial fibrillation-free survival.

PURPOSE: Pharmacologic conversion of atrial fibrillation and flutter (AF/AFl) is common with dofetilide. We determined whether pharmacologic conversion with dofetilide predicts long-term arrhythmia-free survival. METHODS: We retrospectively studied a cohort of 264 consecutive patients who initiated dofetilide during persistent AF/AFl between 2008 and 2013. Patients were excluded if dofetilide was discontinued prior to five doses or electrical cardioversion was performed prior to four doses. Incidence of and characteristics associated with pharmacologic conversion were determined. Patients were followed for long-term AF/AFl recurrence. Predictors of recurrence were identified using multivariate Cox modeling. RESULTS: Of 205 patients meeting study criteria, 92 (44.9%) converted to sinus rhythm during dofetilide loading. Female gender, history of AFl, greater number of prior catheter ablations, shorter duration of current AF/AFl, and presentation in AFl were all associated with acute pharmacologic conversion (p = 0.001, 0.05, 0.001, 0.003, and 0.003, respectively). In multivariate modeling, longer time since first AF/AFl diagnosis (hazard ratio (HR) = 1.07 per 1-year increase, 95% confidence interval (CI) 1.03-1.10, p < 0.001), longer duration of current AF/AFl episode (HR = 1.01 per 1-month increase, 95% CI 1.00-1.01, p = 0.003) and greater number of failed antiarrhythmic drugs (HR = 1.43 per one drug increase, 95% CI 1.20-1.70, p < 0.001) were independently associated with shorter time to AF/AFl recurrence. Pharmacologic conversion was not significantly associated with time to AF/AFl recurrence (HR = 0.79, 95% CI 0.57-1.10, p = 0.2). CONCLUSIONS: Acute pharmacologic conversion of persistent AF/AFl to sinus rhythm frequently occurs during dofetilide loading. Nevertheless, acute pharmacologic conversion does not predict long-term arrhythmia control, which was moderate at best.

The risk of osteoporosis in Caucasian men and women with obstructive airways disease.

PURPOSE: Because patients with obstructive airways disease may be susceptible to osteoporosis, we sought to determine the association between airflow obstruction and osteoporosis. SUBJECTS AND METHODS: We analyzed data from Caucasian participants (n = 9502) in the Third National Health and Nutrition Examination Survey, conducted in the United States between 1988 and 1994. We used data from dual-energy x-ray absorptiometry measurements of the total femur to determine whether a study participant had osteoporosis (defined as total bone mineral density values < or =2.5 SD below the corresponding mean values from young, healthy participants). We calculated the odds ratio (OR) for osteoporosis in four lung function categories: none, mild, moderate, and severe airflow obstruction. RESULTS: Overall, airflow obstruction was associated with increased odds of osteoporosis compared with without airflow obstruction (OR = 1.9; 95% confidence interval [CI]: 1.4 to 2.5). Participants with severe airflow obstruction were at especially increased risk (OR = 2.4; 95% CI: 1.3 to 4.4). Moderate but not mild airflow obstruction was also associated with osteoporosis. CONCLUSION: Airflow obstruction was an important risk factor for osteoporosis in the study population. These data highlight the importance of measuring bone mineral density in those with moderate-to-severe airflow obstruction for the detection and prevention of osteoporosis-related morbidity.

Pharmacological management to reduce exacerbations in adults with asthma: a systematic review and meta-analysis.

CONTEXT: Over the last 2 decades, many new pharmacological agents have been introduced to reduce the growing morbidity associated with asthma, but the long-term effects of these agents on exacerbations are unclear. OBJECTIVE: To systematically review and quantitatively synthesize the long-term effects of inhaled corticosteroids, long-acting beta2 agonists, leukotriene pathway modifiers/receptor antagonists, and anti-IgE therapies on clinical outcomes and particular clinically relevant exacerbations in adult patients with chronic asthma. DATA SOURCES: MEDLINE, EMBASE, and Cochrane databases were searched to identify relevant randomized controlled trials and systematic reviews published from January 1, 1980, to April 30, 2004. We identified additional studies by searching bibliographies of retrieved articles and contacting experts in the field. STUDY SELECTION AND DATA EXTRACTION: Included trials were double-blind, had follow-up periods of at least 3 months, and contained data on exacerbations and/or forced expiratory volume in 1 second. The effects of interventions were compared with placebo, short-acting beta2 agonists, or each other. DATA SYNTHESIS: Inhaled corticosteroids were most effective, reducing exacerbations by nearly 55% compared with placebo or short-acting beta2 agonists (relative risk [RR], 0.46; 95% confidence interval [CI], 0.34-0.62; P<.001 for heterogeneity). Compared with placebo, the use of long-acting beta2 agonists was associated with 25% fewer exacerbations (RR, 0.75; 95% CI, 0.64-0.88; P =.43 for heterogeneity); when added to inhaled corticosteroids, there was a 26% reduction above that achieved by steroid monotherapy (RR, 0.74; 95% CI, 0.61-0.91; P =.07 for heterogeneity). Combination therapy was associated with fewer exacerbations than was increasing the dose of inhaled corticosteroids (RR, 0.86; 95% CI, 0.76-0.96; P =.65 for heterogeneity). Compared with placebo, leukotriene modifiers/receptor antagonists reduced exacerbations by 41% (RR, 0.59; 95% CI, 0.49-0.71; P =.44 for heterogeneity) but were less effective than inhaled corticosteroids (RR, 1.72; 95% CI, 1.28-2.31; P =.91 for heterogeneity). Use of monoclonal anti-IgE antibodies with concomitant inhaled corticosteroid therapy was associated with 45% fewer exacerbations (RR, 0.55; 95% CI, 0.45-0.66; P =.15 for heterogeneity). CONCLUSIONS: Inhaled corticosteroids are the single most effective therapy for adult patients with asthma. However, for those unable or unwilling to take corticosteroids, the use of leukotriene modifiers/receptor agonists appears reasonable. Long-acting beta2 agonists may be added to corticosteroids for those who remain symptomatic despite low-dose steroid therapy. Anti-IgE therapy may be considered as adjunctive therapy for young adults with asthma who have clear evidence of allergies and elevated serum IgE levels.

Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer.

Gastric cancer is a heterogeneous disease with diverse molecular and histological subtypes. We performed whole-genome sequencing in 100 tumor-normal pairs, along with DNA copy number, gene expression and methylation profiling, for integrative genomic analysis. We found subtype-specific genetic and epigenetic perturbations and unique mutational signatures. We identified previously known (TP53, ARID1A and CDH1) and new (MUC6, CTNNA2, GLI3, RNF43 and others) significantly mutated driver genes. Specifically, we found RHOA mutations in 14.3% of diffuse-type tumors but not in intestinal-type tumors (P < 0.001). The mutations clustered in recurrent hotspots affecting functional domains and caused defective RHOA signaling, promoting escape from anoikis in organoid cultures. The top perturbed pathways in gastric cancer included adherens junction and focal adhesion, in which RHOA and other mutated genes we identified participate as key players. These findings illustrate a multidimensional and comprehensive genomic landscape that highlights the molecular complexity of gastric cancer and provides a road map to facilitate genome-guided personalized therapy.

Ventricular arrhythmias: device therapy and ablation.

There are few randomized, well-controlled studies to guide decision making with respect to the treatment of ventricular arrhythmias in the elderly treated with either device implantation or catheter ablation. Although some data are conflicting, the elderly appear to have a greater degree of risk related to treatment compared with younger ones; however, this increased risk is in part a consequence of age itself and comorbid conditions. Conversely, in terms of benefit, although the data may again be mixed, there is ample information indicating that age should not contraindicate aggressive treatment when accepted indications for intervention exist.

Why do some countries publish more than others? An international comparison of research funding, English proficiency and publication output in highly ranked general medical journals.

National factor(s) influencing publication output in the highest ranked medical journals are largely unknown. We sought to examine the relationship between national research funding and English proficiency on publication output. We identified all original research articles appearing in the five highest ranked general medical journals between 1997 and 2001. Using the country of the corresponding author as the source nation for each article, we determined a standardized publication rate across developed nations. We used multiple regression techniques to determine the influence of national expenditures on research and scores from the Test of English as a Foreign Language (TOEFL), a surrogate for English proficiency, on publication output. There was a significant relationship of national spending on research and TOEFL scores to publication output of developed countries (p = 0.04; p < 0.01, respectively). These two variables explained approximately 71.5% of the variation in publication rate across developed nations around the world (R = 0.85; p < 0.01). Normalized for population size, English-speaking nations and certain northern European countries such as Denmark, The Netherlands, Switzerland, and Sweden had the highest rate of publication in the five highest ranked general medical journals, while Asian countries had generally low rates of publication. Research spending and English proficiency were strongly associated with publication output in the highest ranked general medical journals. While these data cannot be considered definitive due to their observational nature, they do suggest that for English-language medical journals, research funding and English proficiency may be important determinants of publication.

Inhaling to mitigate exhaled bioaerosols.

Humans commonly exhale aerosols comprised of small droplets of airway-lining fluid during normal breathing. These "exhaled bioaerosols" may carry airborne pathogens and thereby magnify the spread of certain infectious diseases, such as influenza, tuberculosis, and severe acute respiratory syndrome. We hypothesize that, by altering lung airway surface properties through an inhaled nontoxic aerosol, we might substantially diminish the number of exhaled bioaerosol droplets and thereby provide a simple means to potentially mitigate the spread of airborne infectious disease independently of the identity of the airborne pathogen or the nature of any specific therapy. We find that some normal human subjects expire many more bioaerosol particles than other individuals during quiet breathing and therefore bear the burden of production of exhaled bioaerosols. Administering nebulized isotonic saline to these "high-producer" individuals diminishes the number of exhaled bioaerosol particles expired by 72.10 +/- 8.19% for up to 6 h. In vitro and in vivo experiments with saline and surfactants suggest that the mechanism of action of the nebulized saline relates to modification of the physical properties of the airway-lining fluid, notably surface tension.