Complications of implantable cardioverter defibrillator therapy in 440 consecutive patients

BACKGROUND: Although more than 150,000 implantable cardioverter defibrillators (ICDs) are implanted yearly worldwide, only few studies systematically examined complications of ICD therapy in large patient cohorts. METHODS: We prospectively analyzed ICD-related complications in 440 consecutive patients who underwent first implantation of an ICD system for primary or secondary prevention of sudden cardiac death within the last 10 years at our institution. All study patients received pectoral nonthoracotomy ICD lead systems with the exception of one patient who had an artificial tricuspid valve. RESULTS: During 46 +/- 37 months follow-up, 136 of 440 patients (31%) experienced at least one complication including implant procedure-related complications in 43 patients (10%), ICD generator-related complications in 28 patients (6%), lead-related complications in 52 patients (12%), and inappropriate shocks in 54 patients (12%). The most serious complications included one perioperative death due to heart failure (0.2%), two ICD system infections necessitating device removal (0.5%) and two perioperative cerebrovascular strokes (0.5%). CONCLUSIONS: We conclude that more than one quarter of ICD patients experience complications during a mean follow-up of almost 4 years, although serious complications such as intraoperative death or ICD system infections are rare in patients with nonthoracotomy ICD systems. Recognition of these complications is the prerequisite for advances in ICD technology and management strategies to avoid their recurrence.     

Amino-terminal pro-brain natriuretic peptide, brain natriuretic peptide, and troponin T for prediction of mortality in acute heart failure

BACKGROUND: Combining testing for natriuretic peptides [amino-terminal pro-brain natriuretic peptide (NT-proBNP) and brain natriuretic peptide (BNP)] and cardiac troponin T (cTnT) may help predict mortality in patients with acute heart failure (HF). METHODS: We studied 209 patients with acute HF at an urban academic center and used ROC curves and multivariate analyses to examine the relationship of outcome to natriuretic peptide and cTnT concentrations at presentation. RESULTS: Higher concentrations of natriuretic peptides and cTnT at presentation were predictors of death at 60 days and 1 year (P <0.001 and P <0.01, respectively, at both time points). Optimal cutoff points for NT-proBNP, BNP, and cTnT for predicting death by 60 days or 1 year were 5562 and 3174 ng/L, 428 and 352 ng/L, and 0.01 and 0.01 microg/L, respectively. Most decedents demonstrated increased concentrations of both natriuretic peptides and cTnT and had a 25% mortality rate at the 60-day time point (P <0.001). Mortality rates were low (<4%) among patients with either no increase or an increase in only 1 marker. Decedents with increases in both a natriuretic peptide and cTnT at presentation had the highest death rate at 1 year (45%, P <0.001). This combination was strongly predictive of death [NT-proBNP plus cTnT: hazard ratio (HR), 7.66; 95% confidence interval (CI), 3.06-17.8; BNP plus cTnT: HR, 6.82; 95% CI, 2.99-16.5]. CONCLUSIONS: A dual-marker strategy incorporating a natriuretic peptide and cTnT is superior to either marker alone for estimating short- and longer-term risk in patients with acute HF.     

Factor VIII inhibitor in a patient with mild haemophilia A and an Asn618-->Ser mutation responsive to immune tolerance induction and cyclophosphamide

We describe a patient with mild haemophilia A (original value of factor VIII activity 0.30 U/ml) who developed an inhibitor (36.1 Bethesda U/ml) which cross-reacted with his endogenous factor VIII. This caused a decline in basal factor VIII level (< 0.01 U/ml) and severe haemorrhagic events. Treatment to induce immune tolerance was started with factor VIII/von Willebrand factor (VWF) concentrates, but inhibitor levels increased progressively and the patient suffered serious bleeding. Cyclophosphamide was administered and, after 8 months treatment, factor VIII levels increased to 0.20 U/ml and the inhibitor could no longer be detected. Screening of his factor VIII gene revealed a missense mutation in exon 13 that predicts substitution of Asn618-->Ser in the A2 domain of factor VIII. Immunoprecipitation analysis showed that the antibodies present in the patient's plasma reacted with metabolically labelled A2 domain and, to a lesser extent, with factor VIII light chain. Inhibitory antibodies were completely neutralized by recombinant A2 domain, whereas no neutralization was observed after the addition of factor VIII light chain (A3-C1-C2) and C2 domain. More detailed analysis showed that the majority of inhibitory antibodies were directed against residues Arg484-Ile508, a previously identified binding site for factor VIII inhibitors. Our findings suggest that immune tolerance therapy and cyclophosphamide were successful in eradicating inhibitory antibodies against a common epitope on factor VIII.     

Human neonatal thymectomy induces altered B‐cell responses and autoreactivity

An association between T‐cell lymphopenia and autoimmunity has long been proposed, but it remains to be elucidated whether T‐cell lymphopenia affects B‐cell responses to autoantigens. Human neonatal thymectomy (Tx) results in a decrease in T‐cell numbers and we used this model to study the development of autoreactivity. Two cohorts of neonatally thymectomized individuals were examined, a cohort of young (1–5 years post‐Tx, n = 10–27) and older children (>10 years, n = 26), and compared to healthy age‐matched controls. T‐cell and B‐cell subsets were assessed and autoantibody profiling performed. Early post‐Tx, a decrease in T‐cell numbers (2.75 × 10⁹/L vs. 0.71 × 10⁹/L) and an increased proportion of memory T cells (19.72 vs. 57.43%) were observed. The presence of autoantibodies was correlated with an increased proportion of memory T cells in thymectomized children. No differences were seen in percentages of different B‐cell subsets between the groups. The autoantigen microarray showed a skewed autoantibody response after Tx. In the cohort of older individuals, autoantibodies were present in 62% of the thymectomized children, while they were found in only 33% of the healthy controls. Overall, our data suggest that neonatal Tx skews the autoantibody profile. Preferential expansion and preservation of Treg (regulatory T) cell stability and function, may contribute to preventing autoimmune disease development after Tx.     

Preventing Loss of Independence through Exercise (PLIÉ): qualitative analysis of a clinical trial in older adults with dementia

Objectives: Preventing Loss of Independence through Exercise (PLIÉ) is a novel, integrative exercise program for individuals with dementia that combines elements of different conventional and complementary exercise modalities (e.g. tai-chi, yoga, Feldenkrais, and dance movement therapy) and focuses on training procedural memory for basic functional movements (e.g., sit-to-stand) while increasing mindful body awareness and facilitating social connection. This study presents analyses of qualitative data collected during a 36-week cross-over pilot clinical trial in 11 individuals.

Methods: Qualitative data included exercise instructors’ written notes, which were prepared after each class and also following biweekly telephone calls with caregivers and monthly home visits; three video-recorded classes; and written summaries prepared by research assistants following pre- and post-intervention quantitative assessments. Data were extracted for each study participant and placed onto a timeline for month of observation. Data were coded and analyzed to identify themes that were confirmed and refined through an iterative, collaborative process by the entire team including a qualitative researcher (SA) and the exercise instructors.

Results: Three overarching themes emerged: (1) Functional changes included increasing body awareness, movement memory and functional skill. (2) Emotional changes included greater acceptance of resting, sharing of personal stories and feelings, and positive attitude toward exercise. (3) Social changes included more coherent social interactions and making friends.

Conclusions: These qualitative results suggest that the PLIÉ program may be associated with beneficial functional, emotional, and social changes for individuals with mild to moderate dementia. Further study of the PLIÉ program in individuals with dementia is warranted.     

High-Level Pan-Azole-Resistant Aspergillosis

High-level pan-azole-resistant Aspergillus fumigatus was recovered from four patients with chronic lung disease. In one patient, the development of progressive resistance followed long-term azole therapy and switching between antifungal azoles. The high-level pan-azole-resistant phenotypes were not associated with a specific cyp51A gene mutation. New strategies that avoid the development of progressive azole resistance are needed.     

Enzymatically catalyzed disulfide exchange is required for platelet adhesion to collagen via integrin alpha2beta1

Integrin alpha2beta1 is the principal adhesive receptor for collagen but platelets also adhere through glycoprotein VI (GPVI). Integrin alphaIIbbeta3 may augment platelet adhesion. We have shown that disulfide exchange is necessary for platelet adhesion to fibrinogen, fibronectin, and collagen. However 2 questions remained: (1) Can activated alphaIIbbeta3 explain the observed role of disulfide exchange in adhesion to collagen, or is this role common to other integrins? (2) Is disulfide dependence specific to the integrin receptors or shared with GPVI? To discriminate adhesive functions of alpha2beta1 from those of alphaIIbbeta3 we used Glanzmann platelets and alphaIIbbeta3-specific antibodies applied to normal platelets. To resolve adhesive events mediated by alpha2beta1 from those of GPVI we used synthetic peptides specific to each receptor. We addressed direct integrin ligation using purified alpha2beta1 and recombinant I domain. We observed the following: adhesion to the alpha2beta1-specific peptide was disulfide-exchange dependent and protein disulfide isomerase (PDI) mediated; membrane-impermeant thiol blockers inhibited alpha2beta1, but not GPVI mediated, adhesion; direct blockade of PDI revealed that it is involved in adhesion through alpha2beta1 but not GPVI; and purified alpha2beta1, but not recombinant I domain, depended on free thiols for ligation. These data suggest that the enzymatically catalyzed adhesion-associated reorganization of disulfide bonds is common to members of the integrin family and specific to this family.     

Compromised peroxisomes in idiopathic pulmonary fibrosis,a vicious cycle inducing a higher fibrotic response via TGF-β signaling

Idiopathic pulmonary fibrosis (IPF) is a devastating disease, and its pathogenic mechanisms remain incompletely understood. Peroxisomes are known to be important in ROS and proinflammatory lipid degradation, and their deficiency induces liver fibrosis. However, altered peroxisome functions in IPF pathogenesis have never been investigated. By comparing peroxisome-related protein and gene expression in lung tissue and isolated lung fibroblasts between human control and IPF patients, we found that IPF lungs exhibited a significant down-regulation of peroxisomal biogenesis and metabolism (e.g., PEX13p and acyl-CoA oxidase 1). Moreover, in vivo the bleomycin-induced down-regulation of peroxisomes was abrogated in transforming growth factor beta (TGF-β) receptor II knockout mice indicating a role for TGF-β signaling in the regulation of peroxisomes. Furthermore, in vitro treatment of IPF fibroblasts with the profibrotic factors TGF-β1 or tumor necrosis factor alpha (TNF-α) was found to down-regulate peroxisomes via the AP-1 signaling pathway. Therefore, the molecular mechanisms by which reduced peroxisomal functions contribute to enhanced fibrosis were further studied. Direct down-regulation of PEX13 by RNAi induced the activation of Smad-dependent TGF-β signaling accompanied by increased ROS production and resulted in the release of cytokines (e.g., IL-6, TGF-β) and excessive production of collagen I and III. In contrast, treatment of fibroblasts with ciprofibrate or WY14643, PPAR-α activators, led to peroxisome proliferation and reduced the TGF-β–induced myofibroblast differentiation and collagen protein in IPF cells. Taken together, our findings suggest that compromised peroxisome activity might play an important role in the molecular pathogenesis of IPF and fibrosis progression, possibly by exacerbating pulmonary inflammation and intensifying the fibrotic response in the patients.Idiopathic pulmonary fibrosis (IPF) is a chronic, devastating, and lethal fibrotic disorder in human lung. IPF is characterized by a worsening of pulmonary function and persistent alterations of the lung parenchyma as a result of fibrotic foci formation by activated fibroblasts/myofibroblasts and excessive production and deposition of extracellular matrix components (ECM) (1–4). It is well accepted that transforming growth factor beta (TGF-β) signaling plays a critical role in IPF development. Inhibition of TGF-β signaling by blocking its downstream Smad3 gene expression protects against bleomycin-induced fibrosis in animal models (5, 6). In addition, there is increasing evidence that tumor necrosis factor alpha (TNF-α) also plays an important role in initiation and perpetuation of the fibrotic processes, possibly by activating TGF-β signaling pathway (7). However, the mechanisms by which TGF-β and TNF-α promote the fibrotic response in IPF are incompletely known.Peroxisomes are single membrane bounded ubiquitous organelles, present in all types of cells. Particularly, type II alveolar epithelial cells and club cells (Clara) in the lung have highly abundant peroxisomes (8). These organelles are involved in a variety of metabolic pathways, including degradation of reactive oxygen species (ROS) and bioactive lipid mediators (prostaglandins and leukotriens) and synthesis of antioxidant lipids (polyunsaturated fatty acids, plasmalogens, etc.) (9). Absence or dysfunction of peroxisomes results in increased cellular oxidative stress, leading to severe pathological consequences in many organ systems (10, 11). Lung is one of the organs with highest exposure to various forms of reactive oxygen and nitrogen species (ROS and RNS) due to oxygen and different environmental oxidants in the inspired air, causing oxidation of cellular DNA, proteins and lipids, consequently a direct lung injury (12). Studies have shown that the most severe phenotype of a peroxisome biogenesis disorder (e.g., Zellweger syndrome) is associated with progressive liver fibrosis or cirrhosis, leading to early death of the patients during childhood (11). Moreover, mice with peroxisome dysfunction caused by PEX11β knockout died during their first days of life and exhibit morphological alterations of the lungs (13). In contrast, treatment of rats with an agonist specific for peroxisome proliferator-activated receptor alpha (PPAR-α) significantly ameliorated tubulointerstitial renal fibrosis (14). Despite the fact that peroxisomal metabolism might play an important role in other tissue fibrosis, the role of peroxisomes in lung fibrosis onset and progression seen in IPF patients has never been reported (1, 15).Herein, using human IPF and control fibroblast cultures as well as a bleomycin-induced mouse lung fibrosis model, we demonstrate that peroxisomal biogenesis and metabolism is compromised in the lung and in fibroblasts of IPF patients, in which a down-regulation of peroxisomal proteins leads to activation and release of profibrotic factors such as TGF-β1 and collagen. In contrast, peroxisome proliferation by treatment with PPAR-α agonist (ciprofibrate, WY14643) significantly reduces the TGF-β1–induced myofibroblast differentiation in IPF fibroblast cultures.     

Improving Emergency Department Door to Doctor Time and Process Reliability: A Successful Implementation of Lean Methodology

The aim of this study is to determine the effectiveness of using lean management methods on improving emergency department door to doctor times at a tertiary care hospital.We performed a before and after study at an academic urban emergency department with 49,000 annual visits after implementing a series of lean driven interventions over a 20 month period. The primary outcome was mean door to doctor time and the secondary outcome was length of stay of both admitted and discharged patients. A convenience sample from the preintervention phase (February 2012) was compared to another from the postintervention phase (mid-October to mid-November 2013). Individual control charts were used to assess process stability.Postintervention there was a statistically significant decrease in the mean door to doctor time measure (40.0 minutes ± 53.44 vs 25.3 minutes ± 15.93 P < 0.001). The postintervention process was more statistically in control with a drop in the upper control limits from 148.8 to 72.9 minutes. Length of stay of both admitted and discharged patients dropped from 2.6 to 2.0 hours and 9.0 to 5.5 hours, respectively. All other variables including emergency department visit daily volumes, hospital occupancy, and left without being seen rates were comparable.Using lean change management techniques can be effective in reducing door to doctor time in the Emergency Department and improving process reliability.