Behavioral economic theory suggests that a reduction in substance use is most likely when there is an increase in rewarding substance-free activities. The goal of this randomized controlled clinical trial was to evaluate the incremental efficacy of a novel behavioral economic supplement (Substance-Free Activity Session, SFAS) to a standard alcohol brief motivational interviewing (BMI) session for heavy drinking college students.
Participants were 82 first-year college students (50% female, 81.7% White/European American, Mean age = 18.5 years, SD = .71) who reported two or more past-month heavy drinking episodes. After completing a baseline assessment and an individual alcohol-focused BMI, participants were randomized to either the SFAS or to a Relaxation Training (RT) control session. The SFAS was delivered in an MI style and attempted to increase the salience of delayed academic and career rewards and the patterns of behavior leading to those rewards.
The combination of an alcohol BMI plus the SFAS was associated with significantly greater reductions in alcohol problems compared to an alcohol BMI plus RT at the 1-month and 6-month follow-up assessments (p = .015, ηp2 = .07), an effect that was partially mediated by increases in protective behavioral strategies. BMI + SFAS was also associated with greater reductions in heavy drinking among participants who at baseline reported low levels of substance-free reinforcement or symptoms of depression.
These results are consistent with behavioral economic theory and suggest that a single session focused on increasing engagement in alternatives to drinking can enhance the effects of brief alcohol interventions.
alcohol; behavioral economics; binge drinking; college; motivational interventions; substance-free reinforcement
The inhibitory protein SOCS3 plays a key role in the immune and hematopoietic systems by regulating signaling induced by specific cytokines. SOCS3 functions by inhibiting the catalytic activity of Janus Kinases (JAKs) that initiate signaling within the cell. We determined the crystal structure of a ternary complex between murine SOCS3, JAK2 (kinase domain) and a fragment of the IL-6 receptor β-chain. The structure shows that SOCS3 binds JAK2 and receptor simultaneously, using two opposing surfaces. Whilst the phosphotyrosine-binding groove on the SOCS3 SH2 domain is occupied by receptor, JAK2 binds in a phospho-independent manner to a non-canonical surface. The kinase inhibitory region of SOCS3 occludes the substrate-binding groove on JAK2 and biochemical studies show it blocks substrate association. These studies reveal that SOCS3 targets specific JAK-cytokine receptor pairs and explains the mechanism and specificity of SOCS action.
Janus Kinases (JAKs) are essential mediators of almost all biological signalling events initiated by haemopoietic and immune cytokines. However, aberrant and/or prolonged JAK- induced signalling is detrimental and can give rise to a number of inflammatory and proliferative pathologies. For this reason the tyrosine kinase activity of the JAKs is carefully regulated at a number of different levels. Primarily this is achieved by: (1) Ensuring the catalytic domain is “switched off” under basal conditions and (2) Inhibiting the activity of JAK after it has been switched on. Whilst the first mode of inhibition is mediated by JAK’s own pseudokinase domain (JH2 domain) as well as the action of phosphatases, the second is achieved by the action of the SOCS (Suppressor of Cytokine Signalling) proteins, negative feedback inhibitors of JAK-mediated signalling. This review focuses on the mode of action of SOCS1 and SOCS3, the two most potent JAK inhibitors.
Janus Kinases; SOCS; cytokine signalling; JAK/STAT
Basic behavioral and neurobiological research has demonstrated that deficiencies in naturally occurring substance-free rewards are both a cause and a consequence of substance abuse that are due in part to the systematic discounting of delayed substance-free rewards. Existing brief motivational interventions (BMIs) for alcohol abuse do not target this mechanism of change. The goal of this uncontrolled pilot study was to evaluate a behavioral economic Substance-Free Activity Session (SFAS) to traditional alcohol BMIs. Participants were 13 college freshmen who reported two or more heavy drinking episodes (>5/4 drinks in an occasion for men/ women) in the past month. All participants completed a baseline assessment and a BMI that addressed alcohol use. In addition, participants received the SFAS, a 50-min individual session that attempts to increase engagement in constructive alternatives to drinking by enhancing the salience of delayed rewards (academic and career success) and the patterns of behavior (academic and extracurricular engagement) leading to these outcomes. At the 1-month follow-up assessment, participants reported significant reductions in heavy drinking, and moderate to large effect size reductions in weekly drinking and peak blood alcohol levels. The results of this pilot study provide preliminary support for the efficacy of this behavioral economic intervention session as a supplement to traditional alcohol BMIs.
Alcohol; behavioral economics; binge drinking; college; motivational interventions; substance-free reinforcement
The purposes of this study were: to describe chest CT findings in normal non-smoking controls and cigarette smokers with and without COPD; to compare the prevalence of CT abnormalities with severity of COPD; and to evaluate concordance between visual and quantitative chest CT (QCT) scoring
Volumetric inspiratory and expiratory CT scans of 294 subjects, including normal non-smokers, smokers without COPD, and smokers with GOLD Stage I-IV COPD, were scored at a multi-reader workshop using a standardized worksheet. There were fifty-eight observers (33 pulmonologists, 25 radiologists); each scan was scored by 9–11 observers. Interobserver agreement was calculated using kappa statistic. Median score of visual observations was compared with QCT measurements.
Interobserver agreement was moderate for the presence or absence of emphysema and for the presence of panlobular emphysema; fair for the presence of centrilobular, paraseptal, and bullous emphysema subtypes and for the presence of bronchial wall thickening; and poor for gas trapping, centrilobular nodularity, mosaic attenuation, and bronchial dilation. Agreement was similar for radiologists and pulmonologists. The prevalence on CT readings of most abnormalities (e.g. emphysema, bronchial wall thickening, mosaic attenuation, expiratory gas trapping) increased significantly with greater COPD severity, while the prevalence of centrilobular nodularity decreased. Concordances between visual scoring and quantitative scoring of emphysema, gas trapping and airway wall thickening were 75%, 87% and 65%, respectively.
Despite substantial inter-observer variation, visual assessment of chest CT scans in cigarette smokers provides information regarding lung disease severity; visual scoring may be complementary to quantitative evaluation.
Human interleukin-3 (hIL-3) is a polypeptide growth factor that regulates the proliferation, differentiation, survival and function of hematopoietic progenitors and many mature blood cell lineages. Although recombinant hIL-3 is a widely used laboratory reagent in hematology, standard methods for its preparation, including those employed by commercial suppliers, remain arduous owing to a reliance on refolding insoluble protein expressed in E. coli. In addition, wild-type hIL-3 is a poor substrate for radio-iodination, which has been a long-standing hindrance to its use in receptor binding assays. To overcome these problems, we developed a method for expression of hIL-3 in E. coli as a soluble protein, with typical yields of >3mg of purified hIL-3 per litre of shaking microbial culture. Additionally, we introduced a non-native tyrosine residue into our hIL-3 analog, which allowed radio-iodination to high specific activities for receptor binding studies whilst not compromising bioactivity. The method presented herein provides a cost-effective and convenient route to milligram quantities of a hIL-3 analog with wild-type bioactivity that, unlike wild-type hIL‑3, can be efficiently radio-iodinated for receptor binding studies.
Suppressor of Cytokine Signaling (SOCS)5 is thought to act as a tumour suppressor through negative regulation of JAK/STAT and epidermal growth factor (EGF) signaling. However, the mechanism/s by which SOCS5 acts on these two distinct pathways is unclear. We show for the first time that SOCS5 can interact directly with JAK via a unique, conserved region in its N-terminus, which we have termed the JAK interaction region (JIR). Co-expression of SOCS5 was able to specifically reduce JAK1 and JAK2 (but not JAK3 or TYK2) autophosphorylation and this function required both the conserved JIR and additional sequences within the long SOCS5 N-terminal region. We further demonstrate that SOCS5 can directly inhibit JAK1 kinase activity, although its mechanism of action appears distinct from that of SOCS1 and SOCS3. In addition, we identify phosphoTyr317 in Shc-1 as a high-affinity substrate for the SOCS5-SH2 domain and suggest that SOCS5 may negatively regulate EGF and growth factor-driven Shc-1 signaling by binding to this site. These findings suggest that different domains in SOCS5 contribute to two distinct mechanisms for regulation of cytokine and growth factor signaling.
We previously showed that metabolic tumor volume (MTV) on PET-CT predicts for disease recurrence and death in head and neck cancer (HNC). We hypothesized that increases in MTV over time would correlate with tumor growth and biology, and predict outcome. We sought to examine tumor growth over time in serial pre-treatment PET-CT scans.
Methods and Materials
From 2006–2009, 51 patients had two PET-CT scans prior to HNC treatment. MTV was defined as the tumor volume ≥50% of maximum SUV (SUVmax). MTV was calculated for the primary tumor, nodal disease, and composite (primary tumor + nodes). MTV and SUV velocity were defined as the change in MTV or SUVmax over time respectively. Cox regression analyses were used to examine correlations between SUV, MTV velocity, and outcome (disease progression and overall survival [OS]).
Median follow-up time was 17.5 months. Median time between PET-CT scans was 3 weeks. Unexpectedly, 51% of cases demonstrated a decrease in SUVmax (average −0.1cc/week) and MTV (average −0.3cc/week) over time. Despite the variability in MTV, primary tumor MTV velocity predicted disease progression (hazard ratio [HR] 2.94; p=0.01), and OS (HR 1.85; p=0.03).
Primary tumor MTV velocity appears to be a better prognostic indicator of disease progression and survival compared to nodal MTV velocity. However, substantial variability was found in PET-CT biomarkers between serial scans. Caution should be used when integrating PET-CT biomarkers into clinical protocols in HNC.
metabolic tumor volume; functional imaging; head and neck cancers; PETCT
We have previously reported that metabolic tumor volume (MTV) obtained from pre-treatment FDG PET/CT predicted outcome in patients with head-and-neck cancer (HNC). The purpose of this study is to validate these results on an independent dataset, determine if the primary tumor or nodal MTV drives this correlation, and explore the interaction with p16INK4a status as a surrogate marker for HPV.
Methods and Materials
The validation dataset in this study included 83 patients with squamous cell HNC who had a FDG PET/CT scan prior to definitive radiotherapy. MTV and SUVmax were calculated for the primary tumor, involved nodes, and the combination of both. The primary endpoint was to validate that MTV predicted progression-free survival and overall survival. Secondary analyses included determining the prognostic utility of primary tumor versus nodal MTV.
Similar to our prior findings, an increase in total MTV of 17 cm3 (difference between 75th and 25th percentile) was associated with a 2.1 fold increase in the risk of disease progression (p=0.0002), and a 2.0 fold increase in the risk of death (p=0.0048). SUVmax was not associated with either outcome. Primary tumor MTV predicted progression-free (HR=1.94; p<0.0001) and overall (HR=1.57; p<0.0001) survival, whereas nodal MTV did not. In addition, MTV predicted progression-free (HR=4.23; p<0.0001) and overall (HR=3.21; p=0.0029) survival in patients with p16INK4a positive oropharyngeal cancer.
This study validates our previous findings that MTV independently predicts outcomes in HNC. MTV should be considered as a potential risk stratifying biomarker in future studies of HNC.
Head-and-neck cancer; Positron emission tomography; metabolic tumor volume
The macrophage migration inhibitory factor (MIF) receptor (CD74) was cloned recently, but the signaling mechanism is not evident. We hypothesized that signaling requires an additional molecule such as CD44, which activates nonreceptor tyrosine kinases. We utilized the CD74- and CD44-deficient COS-7/M6 cell to create stable transfectants expressing CD74, CD44, and a truncated CD44 lacking its intracytoplasmic signaling domain. CD74 alone mediated MIF binding; however, MIF-induced ERK1 and ERK2 kinase phosphorylation required the coexpression of full-length CD44. MIF binding was associated with the serine phosphorylation of CD74 and CD44. Investigations that used siRNA or kinase inhibitors indicate that MIF-induced ERK1 and ERK2 activation through CD44 required the Src tyrosine kinase. Studies of CD74, CD44, and CD74-CD44 transformants and corresponding mutant cells showed that CD74 and CD44 were necessary for MIF protection from apoptosis. These data establish CD44 as an integral member of the CD74 receptor complex leading to MIF signal transduction.
Rationale and Objectives
There are limited data on, and controversies regarding gender differences in the airway dimensions of smokers. Multi-detector CT (MDCT) images were analyzed to examine whether gender could explain differences in airway dimensions of anatomically matched airways in smokers.
Materials and Methods
We used VIDA imaging software to analyze MDCT scans from 2047 smokers (M:F, 1021:1026) from the COPDGene® cohort. The airway dimensions were analyzed from segmental to subsubsegmental bronchi. We compared the differences of luminal area, inner diameter, wall thickness, wall area percentage (WA%) for each airway between men and women, and multiple linear regression including covariates (age, gender, body sizes, and other relevant confounding factors) was used to determine the predictors of each airway dimensions.
Lumen area, internal diameter and wall thickness were smaller for women than men in all measured airway (18.4 vs 22.5 mm2 for segmental bronchial lumen area, 10.4 vs 12.5 mm2 for subsegmental bronchi, 6.5 vs 7.7 mm2 for subsubsegmental bronchi, respectively p < 0.001). However, women had greater WA% in subsegmental and subsubsegmental bronchi. In multivariate regression, gender remained one of the most significant predictors of WA%, lumen area, inner diameter and wall thickness.
Women smokers have higher WA%, but lower luminal area, internal diameter and airway thickness in anatomically matched airways as measured by CT scan than do male smokers. This difference may explain, in part, gender differences in the prevalence of COPD and airflow limitation.
Airway dimensions; CT scan; Gender differences; Smoker
This study examined the association between parent and child change in physical activity during a family-based intervention for child weight gain prevention.
Daily step counts were recorded for parents and children in 83 families given a goal to increase activity by 2000 steps per day above baseline. Linear mixed effects models were utilized to predict child change in daily step counts from parental change in step counts.
Both maternal (p < .0001) and paternal (p < .0001) change in step counts for the current day strongly predicted child change in step counts for that day. On average, a child took an additional 2117.6 steps above baseline on days his or her mother met her goal versus 1175.2 additional steps when the mother did not meet her goal. The respective values were 1598.0 versus 1123.1 steps for fathers. Day of week moderated the maternal effect (p = 0.0019), with a larger impact on Saturday and Sunday compared to weekdays. A similar but non-significant pattern was observed for fathers.
Encouraging parents to increase physical activity, particularly on weekends, may be a highly effective way to leverage parental involvement in interventions to increase children's physical activity.
pediatric overweight; parent-child associations; daily step counts
CXCL12 (SDF-1α) and CXCR4 are critical for embryonic development and cellular migration in adults. These proteins are involved in HIV-1 infection, cancer metastasis, and WHIM disease. Sequestration and presentation of CXCL12 to CXCR4 by glycosaminoglycans (GAGs) is proposed to be important for receptor activation. Mutagenesis has identified CXCL12 residues that bind to heparin. However, the molecular details of this interaction have not yet been determined. Here we demonstrate that soluble heparin and heparan sulfate negatively affect CXCL12-mediated in vitro chemotaxis. We also show that a cluster of basic residues in the dimer interface is required for chemotaxis and is a target for inhibition by heparin. We present structural evidence for binding of an unsaturated heparin disaccharide to CXCL12 attained through solution NMR spectroscopy and x-ray crystallography. Increasing concentrations of the disaccharide altered the two-dimensional 1H-15N-HSQC spectra of CXCL12, which identified two clusters of residues. One cluster corresponds to β-strands in the dimer interface. The second includes the amino-terminal loop and the α-helix. In the x-ray structure two unsaturated disaccharides are present. One is in the dimer interface with direct contacts between residues His25, Lys27, and Arg41 of CXCL12 and the heparin disaccharide. The second disaccharide contacts Ala20, Arg21, Asn30, and Lys64. This is the first x-ray structure of a CXC class chemokine in complex with glycosaminoglycans. Based on the observation of two heparin binding sites, we propose a mechanism in which GAGs bind around CXCL12 dimers as they sequester and present CXCL12 to CXCR4.
Brief Motivational Interventions (BMI) and Computer-delivered interventions (CDI) have been successful in reducing drinking behaviors with mandated college students. However, research examining moderators of intervention effects have found mixed results. The current study sought to replicate and extend the research on moderators of intervention efficacy with mandated students. Baseline alcohol-related problems, readiness to change, gender, incident consequences, and participant responses to the event (personal attributions about the incident, aversiveness of the incident) were examined as moderators of intervention and booster condition efficacy on alcohol use and problems. Mandated students (N = 225) were randomized to complete either a BMI or CDI (Alcohol 101; Century Council, 1998), with or without a 1-month booster session, following a campus alcohol sanction. Outcomes were measured 3 months after baseline. Attributions moderated intervention condition such that participants low in personal attributions for their incident showed significantly less drinking following a CDI than a BMI. Men and individuals who reported low incident aversiveness showed higher drinks per occasion after receiving a booster, while individuals high in alcohol-related problems reported fewer heavy drinking days after completing a booster session. Findings suggest that identifying specific characteristics related to the precipitating event may inform intervention approaches in this high-risk population, however additional research is needed to offer concrete guidance to practitioners in the field.
Behavioral economic alcohol purchase tasks (APTs) are self-report measures of alcohol demand that assess estimated consumption at escalating levels of price. However, the relationship between estimated performance for hypothetical outcomes and choices for actual outcomes has not been determined. The present study examined both the correspondence between choices for hypothetical and actual outcomes, and the correspondence between estimated alcohol consumption and actual drinking behavior. A collateral goal of the study was to examine the effects of alcohol cues on APT performance.
Forty one heavy-drinking adults (56% male) participated in a human laboratory protocol comprising APTs for hypothetical and actual alcohol and money, an alcohol cue reactivity paradigm, an alcohol self-administration period, and a recovery period.
Pearson correlations revealed very high correspondence between APT performance for hypothetical and actual alcohol (ps < .001). Estimated consumption on the APT was similarly strongly associated with actual consumption during the self-administration period (r = .87, p <.001). Exposure to alcohol cues significantly increased subjective craving and arousal, and had a trend-level effect on intensity of demand, in spite of notable ceiling effects. Associations among motivational indices were highly variable, suggesting multidimensionality.
These results suggest there may be close correspondence both between value preferences for hypothetical alcohol and actual alcohol, and between estimated consumption and actual consumption. Methodological considerations and priorities for future studies are discussed.
Alcohol; Behavioral Economics; Purchase Task; Demand; Craving; Cue Reactivity
The 936-type lytic bacteriophages are the most frequently encountered species infecting lactococcal dairy starters. Infection by members belonging to this species has a significant negative impact on the cheese production process. Here we report the complete genome sequence of the bacteriophage CaseusJM1, a 936-type phage isolated from an Irish dairy plant.
Janus kinases (JAKs) are key effectors in controlling immune responses and maintaining hematopoiesis. SOCS3 (Suppressor of Cytokine Signaling-3) is a major regulator of JAK signaling and here we investigate the molecular basis of its mechanism of action. We found that SOCS3 bound and directly inhibited the catalytic domains of JAK1, JAK2 and TYK2, but not JAK3 via an evolutionarily conserved motif unique to JAKs. Mutation of this motif led to the formation of an active kinase that could not be inhibited by SOCS3. Surprisingly, we found that SOCS3 simultaneously bound JAK and the cytokine receptor to which it is attached, revealing how specificity is generated in SOCS action and explaining why SOCS3 inhibits only a subset of cytokines. Importantly, SOCS3 inhibited JAKs via a non-competitive mechanism, making it a template for the development of specific and effective inhibitors to treat JAK-based immune and proliferative diseases.
To explore the relationship between pathologic tumor volume and volume estimated from different tumor segmentation techniques on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in oral cavity cancer.
Materials and Methods
Twenty-three patients with squamous cell carcinoma of the oral tongue had PET-CT scans before definitive surgery. Pathologic tumor volume was estimated from surgical specimens. Metabolic tumor volume (MTV) was defined from PET-CT scans as the volume of tumor above a given SUV threshold. Multiple SUV thresholds were explored including absolute SUV thresholds, relative SUV thresholds, and gradient-based techniques.
Multiple MTV's were associated with pathologic tumor volume; however the correlation was poor (R2 range 0.29–0.58). The ideal SUV threshold, defined as the SUV that generates an MTV equal to pathologic tumor volume, was independently associated with maximum SUV (p=0.0005) and tumor grade (p=0.024). MTV defined as a function of maximum SUV and tumor grade improved the prediction of pathologic tumor volume (R2 = 0.63).
Common SUV thresholds fail to predict pathologic tumor volume in head and neck cancer. The optimal technique that allows for integration of PET-CT with radiation treatment planning remains to be defined. Future investigation should incorporate biomarkers such as tumor grade into definitions of MTV.
head-and-neck cancer; positron emission tomography; metabolic tumor volume
Many clinical research data integration platforms rely on the Entity–Attribute–Value model because of its flexibility, even though it presents problems in query formulation and execution time. The authors sought more balance in these traits.
Materials and Methods
Borrowing concepts from Entity–Attribute–Value and from enterprise data warehousing, the authors designed an alternative called the Dimensional Bus model and used it to integrate electronic medical record, sponsored study, and biorepository data. Each type of observational collection has its own table, and the structure of these tables varies to suit the source data. The observational tables are linked to the Bus, which holds provenance information and links to various classificatory dimensions that amplify the meaning of the data or facilitate its query and exposure management.
The authors implemented a Bus-based clinical research data repository with a query system that flexibly manages data access and confidentiality, facilitates catalog search, and readily formulates and compiles complex queries.
The design provides a workable way to manage and query mixed schemas in a data warehouse.
Data bus; data warehouse; EMR extract
Protective behavioral strategies (PBS) are specific cognitive-behavioral strategies designed to reduce alcohol consumption and resulting negative consequences. A host of studies have examined the cross-sectional relationship between such strategies and alcohol use in the high-risk population of United States college students, but prospective studies on the construct are lacking. The primary purposes of this study were to determine if PBS use prospectively predicted subsequent alcohol use/alcohol-related problems and if changes in PBS use were associated with less alcohol use and fewer problems.
Data were examined from 521 heavy drinking college students (60% male, 84% White, mean age = 18.9 years). Participants completed questionnaires assessing alcohol use, alcohol-related problems, and PBS use at baseline, 6-month, and 12-month follow-ups.
Analysis of residualized change scores indicated that increases in some PBS across time were associated with less alcohol use and fewer alcohol-related problems at follow-up. Findings regarding the prospective relationship between PBS use and subsequent alcohol use/problems were equivocal.
Results from the study suggest that PBS may have value in alcohol-related interventions among college students. Clinicians who help clients increase their use of PBS may help those clients increase the probability of drinking less and experiencing fewer alcohol-related problems in the future.
Alcohol; College Student; Protective Behavioral Strategies
Contingency management (CM) has not been thoroughly evaluated as a treatment for alcohol abuse or dependence, in part because verification of alcohol use reduction requires frequent in-person breath tests. Transdermal alcohol sensors detect alcohol regularly throughout the day, providing remote monitoring and allowing for rapid reinforcement of reductions in use.
The purpose of this study was to evaluate the efficacy of CM for reduction in alcohol use, using a transdermal alcohol sensor to provide a continuous measure of alcohol use. Participants were 13 heavy drinking adults who wore the Secure Continuous Remote Alcohol Monitoring (SCRAM) bracelet for three weeks and provided reports of alcohol and drug use using daily web-based surveys. In Week 1, participants were asked to drink as usual; in Weeks 2 and 3, they were reinforced on an escalating schedule with values ranging from $5-$17 per day on days when alcohol use was not reported or detected by the SCRAM.
Self-reports of percent days abstinent and drinks per week, and transdermal measures of average and peak transdermal alcohol concentration and area under the curve declined significantly in Weeks 2-3. A nonsignificant but large effect size for reduction in days of tobacco use also was found. An adjustment to the SCRAM criteria for detecting alcohol use provided an accurate but less conservative method for use with non-mandated clients.
Results support the efficacy of CM for alcohol use reductions and the feasibility of using transdermal monitoring of alcohol use for clinical purposes.
Contingency Management; Alcohol; Transdermal Monitoring
This study compared visuomotor speed and cognitive flexibility in emphysema patients treated either with standard multidisciplinary medical therapy (MT) or lung volume reduction surgery (LVRS), followed over a 2-year period.
MT patients (n=544) and 542 LVRS patients completed the Trail Making Test (TMT) Parts A and B prior to randomization (baseline). Testing was repeated at 1 and 2 years.
There were no differences on scores for TMT Part A and B between the LVRS and MT groups at baseline or at years 1 and 2. No significant difference between MT and LVRS was noted in terms of overall change in TMT Part A and B over 2 years. The MT group had a significant improvement on TMT-Part A at each followup time compared to baseline (P<.03) but the LVRS group did not. Both the MT and LVRS groups had a significant decline in performance (increase in time to completion) on TMT-Part B when comparing year 1 to baseline (P<.0001).
Emphysema patients who received LVRS or MT as treatment performed similarly on measures of visuomotor speed and flexibility at baseline and 1 and 2 year followup. Both groups showed improvement on visuomotor speed during the first year yet overall cognitive flexibility declined. By the second year neither group had any significant change from baseline. These findings suggest that improvement on visuomotor speed and flexibility, observed in a previous 6-month study of LVRS subjects, was not sustained at 1 and 2 year followup.
Lung volume reduction surgery; Medical therapy; Sequential skills
The so-called 936-type phages are the most frequently encountered lactococcal phage species in dairy fermentations, where they cause slow or even failed fermentations with concomitant economic losses. Several dairy phage population studies, performed in different geographical locations, have detailed their dominance in dairy phage populations, while various phage-resistance mechanisms have been assessed in a bid to protect against this virulent phage group. The impact of thermal and chemical treatments on 936 phages is an important aspect for dairy technologists and has been assessed in several studies, and has indicated that these phages have adapted to better resist such treatments. The abundance of 936 phage genome sequences has permitted a focused view on genomic content and regions of variation, and the role of such variable regions in the evolution of these phages. Here, we present an overview on detection and global prevalence of the 936 phages, together with their tolerance to industrial treatments and anti-phage strategies. Furthermore, we present a comprehensive review on the comparative genomic analyses of members of this fascinating phage species.
phage; lactic acid bacteria; Lactococcus; dairy; food fermentation
Rationale: The characterization of young adults who develop late-onset diseases may augment the detection of novel genes and promote new pathogenic insights.
Methods: We analyzed data from 2,500 individuals of African and European ancestry in the COPDGene Study. Subjects with severe, early-onset chronic obstructive pulmonary disease (COPD) (n = 70, age < 55 yr, FEV1 < 50% predicted) were compared with older subjects with COPD (n = 306, age > 64 yr, FEV1 < 50% predicted).
Measurements and Main Results: Subjects with severe, early-onset COPD were predominantly females (66%), P = 0.0004. Proportionally, early-onset COPD was seen in 42% (25 of 59) of African Americans versus 14% (45 of 317) of non-Hispanic whites, P < 0.0001. Other risk factors included current smoking (56 vs. 17%, P < 0.0001) and self-report of asthma (39 vs. 25%, P = 0.008). Maternal smoking (70 vs. 44%, P = 0.0001) and maternal COPD (23 vs. 12%, P = 0.03) were reported more commonly in subjects with early-onset COPD. Multivariable regression analysis found association with African American race, odds ratio (OR), 7.5 (95% confidence interval [CI], 2.3–24; P = 0.0007); maternal COPD, OR, 4.7 (95% CI, 1.3–17; P = 0.02); female sex, OR, 3.1 (95% CI, 1.1–8.7; P = 0.03); and each pack-year of smoking, OR, 0.98 (95% CI, 0.96–1.0; P = 0.03).
Conclusions: These observations support the hypothesis that severe, early-onset COPD is prevalent in females and is influenced by maternal factors. Future genetic studies should evaluate (1) gene-by-sex interactions to address sex-specific genetic contributions and (2) gene-by-race interactions.
chronic obstructive pulmonary disease; female; African Americans
Cachexia, whether assessed by body mass index (BMI) or fat-free mass index (FFMI), affects a significant proportion of patients with chronic obstructive pulmonary disease (COPD), and is an independent risk factor for increased mortality, increased emphysema, and more severe airflow obstruction. The variable development of cachexia among patients with COPD suggests a role for genetic susceptibility. The objective of the present study was to determine genetic susceptibility loci involved in the development of low BMI and FFMI in subjects with COPD. A genome-wide association study (GWAS) of BMI was conducted in three independent cohorts of European descent with Global Initiative for Chronic Obstructive Lung Disease stage II or higher COPD: Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-Points (ECLIPSE; n = 1,734); Norway-Bergen cohort (n = 851); and a subset of subjects from the National Emphysema Treatment Trial (NETT; n = 365). A genome-wide association of FFMI was conducted in two of the cohorts (ECLIPSE and Norway). In the combined analyses, a significant association was found between rs8050136, located in the first intron of the fat mass and obesity–associated (FTO) gene, and BMI (P = 4.97 × 10−7) and FFMI (P = 1.19 × 10−7). We replicated the association in a fourth, independent cohort consisting of 502 subjects with COPD from COPDGene (P = 6 × 10−3). Within the largest contributing cohort of our analysis, lung function, as assessed by forced expiratory volume at 1 second, varied significantly by FTO genotype. Our analysis suggests a potential role for the FTO locus in the determination of anthropomorphic measures associated with COPD.
chronic obstructive pulmonary disease genetics; chronic obstructive pulmonary disease epidemiology; chronic obstructive pulmonary disease metabolism; genome-wide association study