Citations

Abstract Rationale Staphylococcus aureus is commonly cultured from the sputum of patients with bronchiectasis; however, little is known about the prevalence of the organism in these patients, the characteristics of patients who have grown the organism, or its implications. Objectives Determine the relationship between S. aureus and pulmonary function, frequency of exacerbations, and frequency of hospitalization in patients with bronchiectasis Methods The Bronchiectasis Research Registry is a database of adults with non–cystic fibrosis bronchiectasis identified from 13 sites within the United States. Baseline and follow-up demographic, spirometric, microbiologic, and therapeutic data were entered into a central web-based database. Patients were grouped into three cohorts based on their previous respiratory cultures at the time of entry into the Registry: 1) no prior S. aureus or glucose-nonfermenting gram-negative bacilli (NF-GNB) (Pseudomonas, Stenotrophomonas, or Burkholderia spp.); 2) prior S. aureus at least once; or 3) no prior S. aureus but prior NF-GNB at least once. The association between S. aureus isolation and pulmonary function and frequency of exacerbations and hospital admissions was assessed, both at baseline and after 1 year of follow-up. Results S. aureus was cultured from 94 of 830 patients (11.3%) included in the analysis. Patients who had grown S. aureus before entry into the Registry had a frequency of prior exacerbations and baseline pulmonary function that was between that of patients who had grown NF-GNB and those who had grown neither NF-GNB or S. aureus. Similarly, at the first follow-up visit after study entry, patients who had grown S. aureus had a frequency of exacerbations and hospitalizations that was between those of patients who had grown NF-GNB and those who had grown neither NF-GNB nor S. aureus. However, in multivariate analysis, S. aureus was not associated with pulmonary function, frequency of exacerbation, or hospital admissions. There were no significant differences in patient characteristics or outcomes between patients who had methicillin-sensitive and methicillin-resistant S. aureus. Conclusions Staphylococcus aureus does not appear to be an independent risk factor for severe disease in patients with bronchiectasis enrolled in the Bronchiectasis Research Registry.

OBJECTIVE Intensive treatment (INT) of type 1 diabetes reduces the incidence of cardiovascular disease (CVD) events compared with conventional treatment (CONV), but it also results in more weight gain. Our objective was to examine whether excessive weight gain from INT of type 1 diabetes is independently associated with subsequent CVD events. RESEARCH DESIGN AND METHODS Quartiles (Q) of weight gain in 1,213 participants aged 18 years and older at enrollment in the Diabetes Control and Complications Trial (DCCT) were determined within randomized treatment groups (INT vs. CONV) using change in BMI from baseline to the closeout DCCT visits. Effects of this weight gain on CVD risk factors and outcomes during an additional 20 years of observational follow-up were then determined. RESULTS The Q4 INT group experienced greater proportional weight gain (median change in BMI, 6.08 kg/m2), increases in CVD risk factors, and need for medications for hypertension and lipids compared with the Q1–3 INT and comparable CONV groups. Over a mean of 26 years of follow-up, the numbers of major and total CVD events were not statistically different in Q4 compared with Q1–3 of either the INT or CONV group. By year 14, however, the incident CVD event curve became significantly higher in the Q4 INT group than in the Q1–3 INT groups (P = 0.024) and was similar to that for the CONV group. CONCLUSIONS For the first 13 years after DCCT, INT for type 1 diabetes reduced macrovascular events compared with CONV, even when excessive weight gain occurred. After this, total CVD events significantly increased in the Q4 INT group, becoming equivalent to those in the CONV group. Longer follow-up is needed to determine whether this trend continues and results in more major CVD events.

Blood coagulation is essential for physiological hemostasis but simultaneously contributes to thrombotic disease. However, molecular and cellular events controlling initiation and propagation of coagulation are still incompletely understood. In this study, we demonstrate an unexpected role of eosinophils during plasmatic coagulation, hemostasis, and thrombosis. Using a large-scale epidemiological approach, we identified eosinophil cationic protein as an independent and predictive risk factor for thrombotic events in humans. Concurrent experiments showed that eosinophils contributed to intravascular thrombosis by exhibiting a strong endogenous thrombin-generation capacity that relied on the enzymatic generation and active provision of a procoagulant phospholipid surface enriched in 12/15-lipoxygenase–derived hydroxyeicosatetraenoic acid–phosphatidylethanolamines. Our findings reveal a previously unrecognized role of eosinophils and enzymatic lipid oxidation as regulatory elements that facilitate both hemostasis and thrombosis in response to vascular injury, thus identifying promising new targets for the treatment of thrombotic disease.

Objective: The study aimed to evaluate symptoms described by patients with chronic rhinosinusitis with polypoid changes/nasal polyps and their correlation with computed tomography (CT), nasal endoscopy, and intranasal biomarkers. Study Design: Prospective multicenter study symptom data from postsurgical adult chronic rhinosinusitis study participants with recurrent disease refractory to medical therapy were analyzed in comparison with objective data. Methods: Using logistic regression analysis, participant-rated 16-question surveys from 258 participants were assessed for correlation with nasal endoscopy scores, CT percentage of sinus occlusion, and intranasal biomarkers of fungal antigens (Alternaria and Aspergillus), eosinophilic inflammation (eosinophil-derived neurotoxin [EDN] and major basic protein [MBP]), and inflammatory cytokines (interleukins 5 and 13). Results: Study participant assessments revealed increased CT occlusion in participants presenting with greater inability to smell ( P < .019). Mucosal inflammation identified on nasal endoscopy was positively correlated with congestion ( P < .028), runny nose ( P < .002), and ear pain ( P < .007). Elevated EDN was positively correlated in patients with bothersome congestion ( P < .031) and runny nose ( P < .011). Sneezing was positively correlated with multiple markers: Alternaria ( P < .024), interleukin-13 ( P < .027), MBP ( P < .034), and interleukin-5 ( P < .019). Conclusion: Nasal endoscopy, not CT imaging, has the strongest correlation with the 2 cardinal symptoms of congestion and runny nose in CRS patients; these correlate with biomarkers of eosinophilic inflammation.

AbstractThe neurotransmitter dopamine (DA) is known to be involved in a multitude of physiological processes. We investigated sexually dimorphic effects of disruptions in DA homeostasis and its relationship to senescence using three different Drosophila melanogaster mutants namely Catsup (Catsup26) with elevated DA levels, and pale (ple2), Punch (PuZ22) with depleted DA levels. In all genotypes including controls, DA levels were significantly lower in old (45–50‐day‐old) flies compared with young (3–5‐day‐old) in both sexes. Interestingly, females had lower DA content than males at young age whereas this difference was not observed in old age, suggesting that males had a larger decline in DA levels with age. Females, in general, were longer lived compared with males in all genotypes except ple2 mutants with depleted DA levels. This phenotype was abolished in the ple2 rescue flies. Interestingly, females also demonstrated marked age‐related decline in circadian locomotor activity compared with males. Old Catsup26 males with elevated DA levels accumulated significantly lower levels of lipid peroxidation product 4‐hydroxy 2‐nonenal (4‐HNE) compared with age‐matched wild type, ple2 and PuZ22 mutant males. In Catsup26 revertant lines this phenomenon was absent. We also observed a sexually dimorphic response in the expression levels of key stress and aging associated and/or related transcription factor genes across genotypes with elevated or depleted DA levels which was reverted to wild type levels in specific rescue lines. Taken together, our results reveal a novel sexually dimorphic involvement of DA in senescence characteristics of D. melanogaster.

Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real‐world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene–drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs.

This paper describes the goals of the American Society of Health‐System Pharmacists' Pharmacy Practice Model Initiative (PPMI) and its recommendations for health‐system pharmacy practice transformation to meet future patient care needs and elevate the role of pharmacists as patient care providers. PPMI envisions a future in which pharmacists have greater responsibility for medication‐related outcomes and technicians assume greater responsibility for product‐related activities. Although the PPMI recommendations have elevated the level of practice in many settings, they also potentially affect existing clinical pharmacists, in general, and clinical pharmacy specialists, in particular. Moreover, although more consistent patient care can be achieved with an expanded team of pharmacist providers, the role of clinical pharmacy specialists must not be diminished, especially in the care of complex patients and populations. Specialist practitioners with advanced training and credentials must be available to model and train pharmacists in generalist positions, residents, and students. Indeed, specialist practitioners are often the innovators and practice leaders. Negotiation between hospitals and pharmacy schools is needed to ensure a continuing role for academic clinical pharmacists and their contributions as educators and researchers. Lessons can be applied from disciplines such as nursing and medicine, which have developed new models of care involving effective collaboration between generalists and specialists. Several different pharmacy practice models have been described to meet the PPMI goals, based on available personnel and local goals. Studies measuring the impact of these new practice models are needed.

In a test of auditory perception of phonemes, 10 patients with apraxia of speech were compared with 10 matched normal control subjects on a task of pointing to pictures designated by sequences of auditory word stimuli. The test items were 190 sequences of two and three words with minimal variation of initial consonant, final consonant, medial vowel, or multiple phonemes. The apraxic patients made significantly more perceptual errors as a group, but varied considerably in their level of performance. The achievement of some patients was within the range established by the control subjects; that of others was unequivocally inferior. The major deficit in the apraxic group appeared to be impairment of ability to retain the second- and third-syllable consonant elements in three-word sequences. Apraxia of speech can occur in relatively pure form in the absence of auditory perceptual impairment. It can also occur in conjunction with reduced auditory retention span, which impairs the perception of sequences of words which are minimally varied phonemically.