Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease.

BACKGROUND: Alpha-1 Antitrypsin (AAT) deficiency (AATD), the most common genetic cause of emphysema presents with unexplained phenotypic heterogeneity in affected subjects. Our objectives to identify unique and shared AATD plasma biomarkers with chronic obstructive pulmonary disease (COPD) may explain AATD phenotypic heterogeneity. METHODS: The plasma or serum of 5,924 subjects from four AATD and COPD cohorts were analyzed on SomaScan V4.0 platform. Using multivariable linear regression, inverse variance random-effects meta-analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression we tested the association between 4,720 individual proteins or combined in a protein score with emphysema measured by 15th percentile lung density (PD15) or diffusion capacity (DLCO) in distinct AATD genotypes (Pi*ZZ, Pi*SZ, Pi*MZ) and non-AATD, PiMM COPD subjects. AAT SOMAmer accuracy for identifying AATD was tested using receiver operating characteristic curve analysis. FINDINGS: In PiZZ AATD subjects, 2 unique proteins were associated with PD15 and 98 proteins with DLCO. Of those, 68 were also associated with DLCO in COPD also and enriched for three cellular component pathways: insulin-like growth factor, lipid droplet, and myosin complex. PiMZ AATD subjects shared similar proteins associated with DLCO as COPD subjects. Our emphysema protein score included 262 SOMAmers and predicted emphysema in AATD and COPD subjects. SOMAmer AAT level <7.99 relative fluorescence unit (RFU) had 100% sensitivity and specificity for identifying Pi*ZZ, but it was lower for other AATD genotypes. INTERPRETATION: Using SomaScan, we identified unique and shared plasma biomarkers between AATD and COPD subjects and generated a protein score that strongly associates with emphysema in COPD and AATD. Furthermore, we discovered unique biomarkers associated with DLCO and emphysema in PiZZ AATD. FUNDING: This work was supported by a grant from the Alpha-1 Foundation to RPB. COPDGene was supported by Award U01 HL089897 and U01 HL089856 from the National Heart, Lung, and Blood Institute. Proteomics for COPDGene was supported by NIH 1R01HL137995. GRADS was supported by Award U01HL112707, U01 HL112695 from the National Heart, Lung, and Blood Institute, and UL1TRR002535 to CCTSI; QUANTUM-1 was supported by the National Heart Lung and Blood Institute, the Office of Rare Diseases through the Rare Lung Disease Clinical Research Network (1 U54 RR019498-01, Trapnell PI), and the Alpha-1 Foundation. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion.

Discovering the impact of reading coursework and discipline-specific mentorship on first-year teachers' self-efficacy: a latent class analysis.

Teacher self-efficacy is critical because it predicts teachers' future behavior and impacts teacher turnover. Most teachers begin their career with moderate to high self-efficacy for teaching, but often experience a sharp decline during the first year of teaching. After the first year, their self-efficacy begins to increase but rarely rises to the level it was prior to beginning teaching. Therefore, examining first-year teachers' self-efficacy is extremely important. Previous research generally depicts teachers as a homogeneous group, relying on variable-centered approaches and including self-efficacy as a scaling score, which may not be applicable at the individual level. Simply extending findings from the variable-centered analyses is insufficient. Therefore, the purpose of the present study is to examine the heterogeneous profiles of first-year teachers' self-efficacy from the 2011-2012 Schools and Staffing Survey and to investigate how self-efficacy profiles are related to teacher training at the individual level. Using latent class analyses, we found three statistically distinctive classes within self-efficacy: high, moderate, and low. Regardless of teaching assignments, teachers who completed reading content courses during preparation programs and received discipline-specific mentoring during their first year dominated a higher level of self-efficacy. We conclude that these two factors are essential to preparing and retaining high-quality teachers.

A genome-wide analysis of the response to inhaled ß2-agonists in chronic obstructive pulmonary disease.

Short-acting ß2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled ß2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.

Association of COPD candidate genes with computed tomography emphysema and airway phenotypes in severe COPD.

The principal determining factors influencing the development of the airway disease and emphysema components of chronic obstructive pulmonary disease (COPD) have not been clearly defined. Genetic variability in COPD patients might influence the varying degrees of involvement of airway disease and emphysema. Therefore, we investigated the genetic association of single nucleotide polymorphisms (SNPs) in COPD candidate genes for association with emphysema severity and airway wall thickness phenotypes. Polymorphisms in six candidate genes were analysed in 379 subjects of the National Emphysema Treatment Trial (NETT) Genetics Ancillary Study with quantitative chest computed tomography (CT) data. Genetic association with per cent of lung area below -950 HU (LAA950), airway wall thickness, and derived square root wall area (SRWA) of 10-mm internal perimeter airways were investigated. Three SNPs in EPHX1, five SNPs in SERPINE2 and one SNP in GSTP1 were significantly associated with LAA950. Five SNPs in TGFB1, two SNPs in EPHX1, one SNP in SERPINE2 and two SNPs in ADRB2 were associated with airway wall phenotypes in NETT. In conclusion, several COPD candidate genes showed evidence for association with airway wall thickness and emphysema severity using CT in a severe COPD population. Further investigation will be required to replicate these genetic associations for emphysema and airway wall phenotypes.

Impact of non-linear smoking effects on the identification of gene-by-smoking interactions in COPD genetics studies.

BACKGROUND: The identification of gene-by-environment interactions is important for understanding the genetic basis of chronic obstructive pulmonary disease (COPD). Many COPD genetic association analyses assume a linear relationship between pack-years of smoking exposure and forced expiratory volume in 1 s (FEV(1)); however, this assumption has not been evaluated empirically in cohorts with a wide spectrum of COPD severity. METHODS: The relationship between FEV(1) and pack-years of smoking exposure was examined in four large cohorts assembled for the purpose of identifying genetic associations with COPD. Using data from the Alpha-1 Antitrypsin Genetic Modifiers Study, the accuracy and power of two different approaches to model smoking were compared by performing a simulation study of a genetic variant with a range of gene-by-smoking interaction effects. RESULTS: Non-linear relationships between smoking and FEV(1) were identified in the four cohorts. It was found that, in most situations where the relationship between pack-years and FEV(1) is non-linear, a piecewise linear approach to model smoking and gene-by-smoking interactions is preferable to the commonly used total pack-years approach. The piecewise linear approach was applied to a genetic association analysis of the PI*Z allele in the Norway Case-Control cohort and a potential PI*Z-by-smoking interaction was identified (p=0.03 for FEV(1) analysis, p=0.01 for COPD susceptibility analysis). CONCLUSION: In study samples of subjects with a wide range of COPD severity, a non-linear relationship between pack-years of smoking and FEV(1) is likely. In this setting, approaches that account for this non-linearity can be more powerful and less biased than the more common approach of using total pack-years to model the smoking effect.

Polymorphisms in the superoxide dismutase-3 gene are associated with emphysema in COPD.

Superoxide dismutase-3 (SOD3) is a major extracellular antioxidant enzyme, and previous studies have indicated a possible role of this gene in chronic obstructive pulmonary disease (COPD). We hypothesized that polymorphisms in the SOD3 gene would be associated with COPD and COPD-related phenotypes. We genotyped three SOD3 polymorphisms (rs8192287 (E1), rs8192288 (I1), and rs1799895 (R213G)) in a case-control cohort, with severe COPD cases from the National Emphysema Treatment Trial (NETT, n = 389) and smoking controls from the Normative Aging Study (NAS, n = 472). We examined whether the single nucleotide polymorphisms (SNPs) were associated with COPD status, lung function variables, and quantitative computed tomography (CT) measurements of emphysema and airway wall thickness. Furthermore, we tried to replicate our initial findings in two family-based studies, the International COPD Genetics Network (ICGN, n = 3061) and the Boston Early-Onset COPD Study (EOCOPD, n = 949). In NETT COPD cases, the minor alleles of SNPs E1 and I1 were associated with a higher percentage of emphysema (%LAA950) on chest CT scan (p = .029 and p = .0058). The association with E1 was replicated in the ICGN family study, where the minor allele was associated with more emphysema (p = .048). Airway wall thickness was positively associated with the E1 SNP in ICGN; however, this finding was not confirmed in NETT. Quantitative CT data were not available in EOCOPD. The SNPs were not associated with lung function variables or COPD status in any of the populations. In conclusion, polymorphisms in the SOD3 gene were associated with CT emphysema but not COPD susceptibility, highlighting the importance of phenotype definition in COPD genetics studies.

The long-term effects of the Houston Child Advocates, Inc., program on children and family outcomes.

The objective of the study is to investigate the longitudinal effects of the Houston Child Advocates, Inc., program on children's outcomes. The treatment group consisted of children in the court system that were assigned Child Advocates volunteers, and the comparison children were chosen randomly from a similar population of children. The treatment group had significantly higher scores on the protective factor and family functioning measures and received more social services than those in the comparison group. Children in the treatment group also had significantly fewer placement changes and did better academically and behaviorally in school than children in the comparison group.

Polymorphic variation in surfactant protein B is associated with COPD exacerbations.

Exacerbations of chronic obstructive pulmonary disease (COPD) reduce quality of life and increase mortality. Genetic variation might explain the substantial variability seen in exacerbation frequency among COPD subjects with similar lung function. Polymorphisms in five candidate genes, previously associated with COPD susceptibility, were analysed in order to determine whether they demonstrated association with COPD exacerbations. A total of 88 single nucleotide polymorphisms (SNPs) in the genes microsomal epoxide hydrolase (EPHX1), transforming growth factor, beta-1 (TGFB1), serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 2 (SERPINE2), glutathione S-transferase pi (GSTP1) and surfactant protein B (SFTPB) were genotyped in 389 non-Hispanic white participants in the National Emphysema Treatment Trial. Exacerbations were defined as COPD-related emergency room visits or hospitalisations using the Centers for Medicare and Medicaid Services claims data. One or more exacerbations were experienced by 216 (56%) subjects during the study period. An SFTPB promoter polymorphism, rs3024791, was associated with COPD exacerbations. Logistic regression models, analysing a binary outcome of presence or absence of exacerbations, confirmed the association of rs3024791 with COPD exacerbations. Negative binomial regression models demonstrated association of multiple SFTPB SNPs (rs2118177, rs2304566, rs1130866 and rs3024791) with exacerbation rates. Polymorphisms in EPHX1, GSTP1, TGFB1 and SERPINE2 did not demonstrate association with COPD exacerbations. In conclusion, genetic variation in surfactant protein B is associated with chronic obstructive pulmonary disease susceptibility and exacerbation frequency.

Clinical determinants of exacerbations in severe, early-onset COPD.

Chronic obstructive pulmonary disease (COPD) exacerbations impair health. The present authors analysed participants in the Boston Early-Onset COPD Study for familial aggregation and propensity for COPD exacerbations. In the present study, two exacerbation outcomes, episodes of cough and phlegm, and frequent exacerbations were analysed with multivariable modelling and generalised estimating equations. In early-onset COPD probands, passive tobacco smoke exposure within the home was strongly associated with episodes of cough and phlegm. Chronic phlegm production was associated with both exacerbation phenotypes in probands. In first-degree relatives of early-onset COPD probands, chronic bronchitis, episodic wheezing, pneumonia and active smoking were associated with the episodes of cough and phlegm phenotype. In relatives, identical characteristics plus exertional dyspnoea were associated with frequent exacerbations. Exacerbation risk increased with declining lung function. Familial aggregation for episodes of cough and phlegm was observed in relatives with severe obstruction. In conclusion, passive smoke exposure increases morbidity in severe early-onset chronic obstructive pulmonary disease probands, and chronic obstructive pulmonary disease exacerbations correlate with chronic sputum production in probands and relatives. The familial aggregation of exacerbations suggests a genetic basis for susceptibility to chronic obstructive pulmonary disease exacerbations.

Genetic determinants of C-reactive protein in COPD.

Chronic obstructive pulmonary disease (COPD) is associated with a systemic inflammatory state, marked by elevations in serum inflammatory markers including C-reactive protein (CRP). The present study sought to determine epidemiological predictors of CRP levels, to estimate the genetic influence on CRP levels, and to identify genetic variants that affect CRP in a family-based study of COPD. CRP was measured by a high-sensitivity assay in participants from the Boston Early-Onset COPD Study. Predictors of CRP level were determined using multilevel linear models. Variance component analysis was used to estimate heritability and to perform genome-wide linkage analysis for CRP levels. Two variants in the surfactant protein B (SFTPB) gene were tested for association with CRP levels. Increased age, female sex, higher body mass index, greater smoking pack-yrs and reduced forced expiratory volume in one second were all associated with increased CRP levels. There was a significant genetic influence on CRP (heritability = 0.25). Genome-wide linkage analysis revealed several potentially interesting chromosomal regions, though no significant evidence for linkage was found. A short tandem repeat marker near SFTPB was significantly associated with CRP levels. There is a genetic influence on C-reactive protein levels in chronic obstructive pulmonary disease patients. Preliminary evidence suggests an association of the surfactant protein B gene with systemic inflammation in chronic obstructive pulmonary disease.

The protease inhibitor PI*S allele and COPD: a meta-analysis.

In many countries, the protease inhibitor (SERPINA1) PI*S allele is more common than PI*Z, the allele responsible for most cases of chronic obstructive pulmonary disease (COPD) due to severe alpha 1-antitrypsin deficiency. However, the risk of COPD due to the PI*S allele is not clear. The current authors located studies that addressed the risk of COPD or measured lung function in individuals with the PI SZ, PI MS and PI SS genotypes. A separate meta-analysis for each genotype was performed. Aggregating data from six studies, the odds ratio (OR) for COPD in PI SZ compound heterozygotes compared with PI MM (normal) individuals was significantly increased at 3.26 (95% confidence intervals (CI): 1.24-8.57). In 17 cross-sectional and case-control studies, the OR for COPD in PI MS heterozygotes was 1.19 (95%CI: 1.02-1.38). However, PI MS genotype was not associated with COPD risk after correcting for smoking. Furthermore, mean forced expiratory volume in one second, a measure of airflow obstruction and a defining feature of COPD, did not differ between PI MS and PI MM individuals. There were not enough cases to summarise the risk of COPD in PI SS homozygotes. In conclusion, the results show that the PI SZ genotype is a significant risk factor for chronic obstructive pulmonary disease. The risk of chronic obstructive pulmonary disease due to the PI MS genotype is not substantially elevated.

Chronic obstructive pulmonary disease in alpha1-antitrypsin PI MZ heterozygotes: a meta-analysis.

BACKGROUND: Severe alpha(1)-antitrypsin deficiency, usually related to homozygosity for the protease inhibitor (PI) Z allele, is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD). The risk of COPD in PI MZ heterozygous individuals is controversial. METHODS: A search of MEDLINE from January 1966 to May 2003 identified studies that examined the risk of COPD in PI MZ individuals and studies that measured forced expiratory volume in 1 second (FEV(1)) in heterozygotes. RESULTS: In 16 studies that reported COPD as a categorical outcome, the combined odds ratio (OR) for PI MZ versus PI MM (normal genotype) was 2.31 (95% CI 1.60 to 3.35). The summary OR was higher in case-control studies (OR 2.97; 95% CI 2.08 to 4.26) than in cross sectional studies (OR 1.50; 95% CI 0.97 to 2.31) and was attenuated in studies that adjusted for cigarette smoking (OR 1.61; 95% CI 0.92 to 2.81). In seven studies that reported FEV(1) as a continuous outcome there was no difference in mean FEV(1) between PI MM and PI MZ individuals. CONCLUSIONS: Case-control studies showed increased odds of COPD in PI MZ individuals, but this finding was not confirmed in cross sectional studies. Variability in study design and quality limits the interpretation. These results are consistent with a small increase in risk of COPD in all PI MZ individuals or a larger risk in a subset. Future studies that adjust for smoking and include other COPD related phenotypes are required to conclusively determine the risk of COPD in PI MZ heterozygotes.

Bronchogenic carcinoma complicating lung transplantation.

BACKGROUND: Malignancy is a well-recognized complication of solid-organ transplantation. Although a variety of malignancies have been reported in lung transplant recipients, a paucity of information exists regarding the incidence and clinical course of bronchogenic carcinoma in this patient population. METHODS: We conducted a retrospective cohort study of our lung transplant experience at the University of Pennsylvania. RESULTS: We identified 6 patients with bronchogenic carcinoma detected at the time of, or developing after, transplantation. The incidence of bronchogenic carcinoma was 2.4%. All patients with lung cancer had a history of smoking, with an average of 79 +/- 39 pack-years. A total of 5 patients had chronic obstructive pulmonary disease, and 1 had idiopathic pulmonary fibrosis. Lung cancers were all of non-small-cell histology and first developed in native lungs. Three patients had bronchogenic carcinoma at the time of surgery. The remaining 3 patients were diagnosed between 280 and 1,982 days post-transplantation. Of the 6 patients, 4 presented with a rapid course suggestive of an infectious process. The 1- and 2-year survival rates after diagnosis were 33% and 17%, respectively. CONCLUSION: Lung transplant recipients are at risk for harboring or developing bronchogenic carcinoma in their native lungs. Rapid progression to locally advanced or metastatic disease commonly occurs, at times mimicking an infection. Bronchogenic carcinoma should be considered in the differential diagnosis of pleuroparenchymal processes involving the native lung.

Comparison of the mechanical performance of trochanteric fixation devices.

The transtrochanteric surgical approach to the hip is commonly used, especially for revision hip surgery. Failure of the trochanter to heal can lead to hardware failure, persistent pain, and limp. Rigid internal fixation is needed in this approach to achieve an adequate rate of healing. Newer cable and cable grip systems have been designed to improve trochanteric fixation, but have not been compared to the older Charnley wire fixation techniques. In this study, an in vitro mechanical method previously used to test wire fixation methods was used to compare wire, cable, and cable grip fixation methods. A quasistatic mechanical distraction device was used to compare structural stiffness, load to clinical failure, energy to clinical failure, and maximum load resisted by the fixation devices. The cable grip system was found to be stiffer, to resist a larger load to mechanical failure at 1-cm displacement, and to absorb a greater amount of energy to clinical failure when compared with the other systems. These data suggest that use of the cable grip fixation method should result in improved clinical success compared with the Charnley wire technique.

Learning disabilities and learned helplessness: a heuristic approach.

This study investigated whether students with learning disabilities exhibited learned helpless behavior at a greater rate than their normal achieving peers when confronted with reading failure. Forty-five third grade students from a suburban elementary schools were participants in the study. Thirty of the subjects were classified as having a learning disability (LD) and the remaining 15 subjects were from regular education (RE) classrooms. Fifteen of the students with LD were placed in the treatment group and the remaining fifteen were placed in the control group. All the regular education students were placed in the treatment group. After randomly assigning the students with LD into either a treatment (stressed) group or a control (nonstressed) group, the stressed students were administered a reading instrument in order to measure how they dealt with failure. A one-way ANCOVA was conducted to determine whether significant differences existed between the groups based on their posttest scores. The results indicate that stressed students with LD have a significantly more difficult time recovering from stress than their regular education peers.

The versatility of the gastrocnemius muscle flap.

The gastrocnemius muscle rotation flap is a utilitarian procedure for management of soft-tissue defects about the knee. Ten patients underwent medial gastrocnemius muscle rotation flaps at our institution during a 24-month period. Four of the 10 patients underwent primary muscle rotation-plasty for reconstruction following tumor resection; 3 patients had soft-tissue defects following trauma; 2 patients had skin ischemia following total knee arthroplasty; and 1 patient had a soft-tissue defect from scar formation. All procedures were performed by an orthopaedic surgeon. At follow-up of 6 to 24 months, the soft-tissue coverage was maintained in all patients. All of the muscle rotation flaps survived. The gastrocnemius rotation flap provides reliable anterior knee soft-tissue coverage and can be performed by most orthopaedic surgeons.

Nicotinamide and tetracycline therapy of bullous pemphigoid.

BACKGROUND AND DESIGN: The combination of nicotinamide and tetracycline has been anecdotally reported to be effective in the treatment of bullous pemphigoid. We conducted a randomized, open-labeled trial comparing the combination of 500 mg of nicotinamide, three times daily, and 500 mg of tetracycline four times daily, with prednisone therapy in 20 patients with bullous pemphigoid. The study was divided between an 8-week acute phase with fixed drug dosages and a 10-month follow-up phase in which study medications were tapered based on patient response. RESULTS: Eighteen of 20 patients enrolled in the study were treated, two patients were unavailable for follow-up. Twelve patients were treated with the combination of nicotinamide and tetracycline and six patients were treated with prednisone. There were five complete responses, five partial responses, one nonresponder, and one patient with disease progression in the nicotinamide and tetracycline group compared with one complete response and five partial responses in the prednisone group. There were no statistically significant differences in response parameters between the two groups. All five patients in the nicotinamide and tetracycline group receiving long-term follow-up remained disease free during medication tapering, while three patients in the prednisone group had repeated disease flare-ups with steroid tapering. Adverse effects in the nicotinamide and tetracycline group included gastrointestinal upset (two patients) and transient renal failure (one patient). In the prednisone group, there was one occurrence each of hypertension, erosive gastritis, multiple decubitus ulcers, osteomyelitis, deep venous thrombosis, and death related to sepsis. Two patients required insulin therapy for hyperglycemia. CONCLUSIONS: The combination of nicotinamide and tetracycline appears to be a useful alternative to systemic steroids in the treatment of bullous pemphigoid.