Circulating biomarkers of airflow limitation across the life span.

BACKGROUND: Airflow limitation is a hallmark of chronic obstructive pulmonary disease, which can develop through different lung function trajectories across the life span. There is a need for longitudinal studies aimed at identifying circulating biomarkers of airflow limitation across different stages of life. OBJECTIVES: This study sought to identify a signature of serum proteins associated with airflow limitation and evaluate their relation to lung function longitudinally in adults and children. METHODS: This study used data from 3 adult cohorts (TESAOD [Tucson Epidemiological Study of Airway Obstructive Disease], SAPALDIA [Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults], LSC [Lovelace Smoker Cohort]) and 1 birth cohort (TCRS [Tucson Children's Respiratory Study]) (N = 1940). In TESAOD, among 46 circulating proteins, we identified those associated with FEV1/forced vital capacity (FVC) percent (%) predicted levels and generated a score based on the sum of their z-scores. Cross-sectional analyses were used to test the score for association with concomitant lung function. Longitudinal analyses were used to test the score for association with subsequent lung function growth in childhood and decline in adult life. RESULTS: After false discovery rate adjustment, serum levels of 5 proteins (HP, carcinoembryonic antigen, ICAM1, CRP, TIMP1) were associated with percent predicted levels of FEV1/FVC and FEV1 in TESAOD. In cross-sectional multivariate analyses the 5-biomarker score was associated with FEV1 % predicted in all adult cohorts (meta-analyzed FEV1 decrease for 1-SD score increase: -2.9%; 95% CI: -3.9%, -1.9%; P = 2.4 × 10-16). In multivariate longitudinal analyses, the biomarker score at 6 years of age was inversely associated with FEV1 and FEV1/FVC levels attained by young adult life (P = .02 and .005, respectively). In adults, persistently high levels of the biomarker score were associated with subsequent accelerated decline of FEV1 and FEV1/FVC (P = .01 and .001). CONCLUSIONS: A signature of 5 circulating biomarkers of airflow limitation was associated with both impaired lung function growth in childhood and accelerated lung function decline in adult life, indicating that these proteins may be involved in multiple lung function trajectories leading to chronic obstructive pulmonary disease.

Systemic Markers of Lung Function and Forced Expiratory Volume in 1 Second Decline across Diverse Cohorts.

Rationale: Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by airway obstruction and accelerated lung function decline. Our understanding of systemic protein biomarkers associated with COPD remains incomplete. Objectives: To determine what proteins and pathways are associated with impaired pulmonary function in a diverse population. Methods: We studied 6,722 participants across six cohort studies with both aptamer-based proteomic and spirometry data (4,566 predominantly White participants in a discovery analysis and 2,156 African American cohort participants in a validation). In linear regression models, we examined protein associations with baseline forced expiratory volume in 1 second (FEV1) and FEV1/forced vital capacity (FVC). In linear mixed effects models, we investigated the associations of baseline protein levels with rate of FEV1 decline (ml/yr) in 2,777 participants with up to 7 years of follow-up spirometry. Results: We identified 254 proteins associated with FEV1 in our discovery analyses, with 80 proteins validated in the Jackson Heart Study. Novel validated protein associations include kallistatin serine protease inhibitor, growth differentiation factor 2, and tumor necrosis factor-like weak inducer of apoptosis (discovery ß = 0.0561, Q = 4.05 × 10-10; ß = 0.0421, Q = 1.12 × 10-3; and ß = 0.0358, Q = 1.67 × 10-3, respectively). In longitudinal analyses within cohorts with follow-up spirometry, we identified 15 proteins associated with FEV1 decline (Q < 0.05), including elafin leukocyte elastase inhibitor and mucin-associated TFF2 (trefoil factor 2; ß = -4.3 ml/yr, Q = 0.049; ß = -6.1 ml/yr, Q = 0.032, respectively). Pathways and processes highlighted by our study include aberrant extracellular matrix remodeling, enhanced innate immune response, dysregulation of angiogenesis, and coagulation. Conclusions: In this study, we identify and validate novel biomarkers and pathways associated with lung function traits in a racially diverse population. In addition, we identify novel protein markers associated with FEV1 decline. Several protein findings are supported by previously reported genetic signals, highlighting the plausibility of certain biologic pathways. These novel proteins might represent markers for risk stratification, as well as novel molecular targets for treatment of COPD.

Integrating decision-making preferences into ecosystem service conservation area identification: A case study of water-related ecosystem services in the Dawen River watershed, China.

The degradation of ecosystems and their services is threatening human wellbeing, making ecosystem service (ES) conservation an urgent necessity. In ES conservation planning, conservation area identification is crucial for the success of conservation initiatives. However, different decision-making preferences have not been fully considered and integrated in ES conservation area identification. This study takes the Dawen River watershed as the study area and considers three water-related ESs to be conserved. We aim to integrate the decision-making preferences of cost-effectiveness, ES sustainable supply, and ES social benefit into identifying ES conservation areas by using conservation cost, ecosystem health, and ES social importance as spatial constraints, respectively. We identified ES conservation area alternatives under the scenarios set according to different decision-making preferences. Specifically, ES conservation targets, i.e., the expected proportion of each ES in conservation areas, are designed to be met where there is low conservation cost (cost-oriented scenario), high ecosystem health (ES sustainable supply scenario), or high ES social importance (ES social benefit scenario). A balanced scenario considering all three decision-making preferences together is further established. The results show that under each scenario, the identified conservation areas can concurrently meet the conservation targets and decision-making preferences. The consideration of different decision-making preferences can greatly influence the spatial distributions of ES conservation areas. Moreover, a severe trade-off between conservation cost and ES social importance is observed under the ES social benefit scenario, and the balanced scenario can achieve a synergy of decision-making preferences. Our study provides a method to integrate the decision-making preference into ES conservation area identification, which can improve the rationality and practicality of ES conservation planning.

Testing of a novel questionnaire of Household Exposure to Wood Smoke.

Household air pollution from wood smoke (WS), contributes to adverse health effects in both low- and high-income countries. However, measurement of WS exposure has been limited to expensive in-home monitoring and lengthy face-to-face interviews. This paper reports on the development and testing of a novel, self-report nine-item measure of WS exposure, called the Household Exposure to Wood Smoke (HEWS). A sample of 149 individuals using household wood stoves for heating from western states in the U.S., completed the HEWS during the winter months (November to March) of 2013 through 2016 with 30 subjects having in-home particle monitoring. Hard copy or online surveys were completed. Cronbach's alpha (α), intraclass correlations (ICC), exploratory factor analysis (EFA) and tests of associations were done to evaluate reliability and validity of the HEWS. Based on initial analysis, only 9 of the 12 items were retained and entered in the EFA. The EFA did not support a unitary scale as the 9 items demonstrated a 3-factor solution (WS exposure duration, proximity, and intensity) with Cronbach's α of 0.79, 0.91, and 0.62, respectively. ICC was 0.86 of the combined items with single items ranging from 0.46 to 0.95. WS intensity was associated with symptoms and levoglucosan levels, while WS duration was associated with stove and flume maintenance. The three-dimensional HEWS demonstrated internal consistency and test-retest reliability, structural validity, and initial criterion and construct validity.

Cleaning the Flue in Wood-Burning Stoves Is a Key Factor in Reducing Household Air Pollution.

In experimental settings, replacing old wood stoves with new wood stoves results in reduced personal exposure to household air pollution. We tested this assumption by measuring PM2.5 and levoglucosan concentrations inside homes and correlated them with wood stove age. Methods: Thirty homes in the Albuquerque, NM area were monitored over a seven-day period using in-home particulate monitors placed in a common living area during the winter months. Real-time aerosol monitoring was performed, and filter samples were analyzed gravimetrically to calculate PM2.5 concentrations and chemically to determine concentrations of levoglucosan. A linear regression model with backward stepwise elimination was performed to determine the factors that would predict household air pollution measures. Results: In this sample, 73.3% of the households used wood as their primary source of heating, and 60% burned daily or almost daily. The mean burn time over the test week was 50 ± 38 h, and only one household burned wood 24/day (168 h). The average PM2.5 concentration (standard deviation) for the 30 homes during the seven-day period was 34.6 µg/m3 (41.3 µg/m3), and median (min, max) values were 15.5 µg/m3 (7.3 µg/m3, 193 µg/m3). Average PM2.5 concentrations in 30 homes ranged from 0−15 µg/m3 to >100 µg/m3. Maximum PM2.5 concentrations ranged from 100−200 µg/m3 to >3000 µg/m3. The levoglucosan levels showed a linear correlation with the total PM2.5 collected by the filters (R2 = 0.92). However, neither mean nor peak PM2.5 nor levoglucosan levels were correlated with the age (10.85 ± 8.54 years) of the wood stove (R2 ≤ 0.07, p > 0.23). The final adjusted linear regression model showed that average PM2.5 was associated with reports of cleaning the flue with a beta estimate of 35.56 (3.47−67.65) and R2 = 0.16 (p = 0.04). Discussion: Cleaning the flue and not the wood stove age was associated with household air pollution indices. Education on wood stove maintenance and safe burning practices may be more important in reducing household air pollution than the purchase of new stoves.

Looking back at experiences from 30 years with documentation and prevention of torture.

The author describes his experience in conducting monitoring visits to detention centres in different countries with an analytical perspective on the elements that perpetuate torture.

Genetic Associations and Architecture of Asthma-COPD Overlap.

BACKGROUND: Some people have characteristics of both asthma and COPD (asthma-COPD overlap), and evidence suggests they experience worse outcomes than those with either condition alone. RESEARCH QUESTION: What is the genetic architecture of asthma-COPD overlap, and do the determinants of risk for asthma-COPD overlap differ from those for COPD or asthma? STUDY DESIGN AND METHODS: We conducted a genome-wide association study in 8,068 asthma-COPD overlap case subjects and 40,360 control subjects without asthma or COPD of European ancestry in UK Biobank (stage 1). We followed up promising signals (P < 5 × 10-6) that remained associated in analyses comparing (1) asthma-COPD overlap vs asthma-only control subjects, and (2) asthma-COPD overlap vs COPD-only control subjects. These variants were analyzed in 12 independent cohorts (stage 2). RESULTS: We selected 31 independent variants for further investigation in stage 2, and discovered eight novel signals (P < 5 × 10-8) for asthma-COPD overlap (meta-analysis of stage 1 and 2 studies). These signals suggest a spectrum of shared genetic influences, some predominantly influencing asthma (FAM105A, GLB1, PHB, TSLP), others predominantly influencing fixed airflow obstruction (IL17RD, C5orf56, HLA-DQB1). One intergenic signal on chromosome 5 had not been previously associated with asthma, COPD, or lung function. Subgroup analyses suggested that associations at these eight signals were not driven by smoking or age at asthma diagnosis, and in phenome-wide scans, eosinophil counts, atopy, and asthma traits were prominent. INTERPRETATION: We identified eight signals for asthma-COPD overlap, which may represent loci that predispose to type 2 inflammation, and serious long-term consequences of asthma.

Racial and Ethnic Minorities Have a Lower Prevalence of Airflow Obstruction than Non-Hispanic Whites.

Racial and ethnic disparities in chronic obstructive pulmonary disease (COPD) are not well-studied. Our objective was to examine differences in limited COPD-related outcomes between three minority groups-African Americans (AAs), Hispanics, and American Indians (AIs) versus non-Hispanic Whites (NHWs), as the referent group, in separate cohorts. Separate cross-sectional evaluations were performed of three US-based cohorts of subjects at risk for COPD: COPDGene Study with 6,884 NHW and 3,416 AA smokers; Lovelace Smokers' Cohort with 1,598 NHW and 378 Hispanic smokers; and Mining Dust Exposure in the United States Cohort with 2,115 NHW, 2,682 Hispanic, and 2,467 AI miners. Prebronchodilator spirometry tests were performed at baseline visits using standard criteria. The primary outcome was the prevalence of airflow obstruction. Secondary outcomes were self-reported physician diagnosis of COPD, chronic bronchitis, and modified Medical Research Council dyspnea score. All minority groups had a lower prevalence of airflow obstruction than NHWs (adjusted ORs varied from 0.29 in AIs to 0.85 in AAs; p < 0.01 for all analyses). AAs had a lower prevalence of chronic bronchitis than NHWs. In our study, all minority groups had a lower prevalence of airflow obstruction but a greater level of self-reported dyspnea than NHWs, and covariates did not explain this association. A better understanding of racial and ethnic differences in smoking-related and occupational airflow obstruction may improve prevention and therapeutic strategies.

Effects of Wood Smoke Constituents on Mucin Gene Expression in Mice and Human Airway Epithelial Cells and on Nasal Epithelia of Subjects with a Susceptibility Gene Variant in Tp53.

BACKGROUND: Exposure to wood smoke (WS) increases the risk for chronic bronchitis more than exposure to cigarette smoke (CS), but the underlying mechanisms are unclear. OBJECTIVE: The effect of WS and CS on mucous cell hyperplasia in mice and in human primary airway epithelial cells (AECs) was compared with replicate the findings in human cohorts. Responsible WS constituents were identified to better delineate the pathway involved, and the role of a tumor protein p53 (Tp53) gene polymorphism was investigated. METHODS: Mice and primary human AECs were exposed to WS or CS and the signaling receptor and pathway were identified using short hairpin structures, small molecule inhibitors, and Western analyses. Mass spectrometric analysis was used to identify active WS constituents. The role of a gene variant in Tp53 that modifies proline to arginine was examined using nasal brushings from study participants in the Lovelace Smokers Cohort, primary human AECs, and mice with a modified Tp53 gene. RESULTS: WS at 25-fold lower concentration than CS increased mucin expression more efficiently in mice and in human AECs in a p53 pathway-dependent manner. Study participants who were homozygous for p53 arginine compared with the proline variant showed higher mucin 5AC (MUC5AC) mRNA levels in nasal brushings if they reported WS exposure. The WS constituent, oxalate, increased MUC5AC levels similar to the whole WS extract, especially in primary human AECs homozygous for p53 arginine, and in mice with a modified Tp53 gene. Further, the anion exchange protein, SLC26A9, when reduced, enhanced WS- and oxalate-induced mucin expression. DISCUSSION: The potency of WS compared with CS in inducing mucin expression may explain the increased risk for chronic bronchitis in participants exposed to WS. Identification of the responsible compounds could help estimate the risk of pollutants in causing chronic bronchitis in susceptible individuals and provide strategies to improve management of lung diseases. https://doi.org/10.1289/EHP9446.

An ecological perspective for understanding regional integration based on ecosystem service budgets, bundles, and flows: A case study of the Jinan metropolitan area in China.

Regional integration can contribute to co-occurring benefits of different parts of an urban agglomeration by managing these parts as a whole. However, current regional integration mainly focuses on the socioeconomic rather than the ecological dimension. To interpret regional ecological integration, we firstly selected six typical ecosystem services (ESs) to represent ecological benefits that potentially need to be improved by ecological integration for further analysis. Then we used ES budgets, bundles, and flows to investigate the potential, basic analysis unit, and occurring manners of ecological integration, respectively. Our results show that supply-demand mismatches were observed in all the ES types. Meanwhile, coexisting ES surpluses and deficits on the town scale were found in supporting biodiversity, soil retention, water yield, green space recreation, and crop yield, which indicates that their supply-demand mismatches can be mitigated with ecological integration. Furthermore, all the towns were classified into five spatial clusters with distinct ES budget bundles, which acted as the basic analysis unit of ecological integration. ES flows with three flow characteristic types were observed between different clusters, and all the clusters had ES provider-beneficiary relationships with each other. Based on the ES approach, we provided an ecological perspective for understanding regional integration, which has the potential to promote regional ecological sustainability.

Identifying key areas of imbalanced supply and demand of ecosystem services at the urban agglomeration scale: A case study of the Fujian Delta in China.

The coordinated supply and demand of ecosystem services (ESs) is important for ensuring regional sustainable development. However, research identifying key areas of imbalanced supply and demand of ESs at the urban agglomeration scale is limited. Therefore, in this study, using the Fujian Delta urban agglomeration of China as the research area, based on multi-source data, and analysis tools, such as ArcGIS, ENVI, and GeoDa, we constructed a research framework and indicator system for ESs supply and demand to determine the spatial change law, matching degree, and coupling coordination degree (CCD) of the ESs. On this basis, the key areas of imbalanced supply and demand of ESs were identified, and optimization strategies were proposed. The results showed that (1) there is obvious spatial heterogeneity between ESs supply and demand in the study area, and different degrees of spatial changes occurred with urbanization. Specifically, areas with large changes were concentrated in urban core areas and economic development zones. (2) The matching degree between ESs supply and demand is quite diverse and shows a trend of polarization. Under the influence of urbanization, some cities began facing ESs supply shortages. (3) Overall, the CCD between ESs supply and demand in the study area is in a state of mild incoordination, but with increasing urbanization, some cities have turned into a state of extreme incoordination. Our results indicate that the ESs supply and demand status in some cities at the urban agglomeration scale has become increasingly severe. Therefore, it is necessary to focus on certain "key areas" to formulate optimization strategies. For key areas with "low supply-high demand" and extreme incoordination, the population and land use intensity should be controlled to reduce the ESs demand level. Meanwhile, for key areas with "high supply-low demand" and extreme incoordination, the utilization efficiency of ecological resources should be improved to enhance the ESs supply capacity. The results of this study will help decision-makers optimize the relationship between ESs supply and demand in order to achieve the sustainable development of urban agglomeration.

ADAM15 expression is increased in lung CD8+ T cells, macrophages, and bronchial epithelial cells in patients with COPD and is inversely related to airflow obstruction.

BACKGROUND: A disintegrin and metalloproteinase domain-15 (ADAM15) is expressed by activated leukocytes, and fibroblasts in vitro. Whether ADAM15 expression is increased in the lungs of COPD patients is not known. METHODS: ADAM15 gene expression and/or protein levels were measured in whole lung and bronchoalveolar lavage (BAL) macrophage samples obtained from COPD patients, smokers, and non-smokers. Soluble ADAM15 protein levels were measured in BAL fluid (BALF) and plasma samples from COPD patients and controls. Cells expressing ADAM15 in the lungs were identified using immunostaining. Staining for ADAM15 in different cells in the lungs was related to forced expiratory volume in 1 s (FEV1), ratio of FEV1 to forced vital capacity (FEV1/FVC), and pack-years of smoking history. RESULTS: ADAM15 gene expression and/or protein levels were increased in alveolar macrophages and whole lung samples from COPD patients versus smokers and non-smokers. Soluble ADAM15 protein levels were similar in BALF and plasma samples from COPD patients and controls. ADAM15 immunostaining was increased in macrophages, CD8+ T cells, epithelial cells, and airway α-smooth muscle (α-SMA)-positive cells in the lungs of COPD patients. ADAM15 immunostaining in macrophages, CD8+ T cells and bronchial (but not alveolar) epithelial cells was related inversely to FEV1 and FEV1/FVC, but not to pack-years of smoking history. ADAM15 staining levels in airway α-SMA-positive cells was directly related to FEV1/FVC. Over-expressing ADAM15 in THP-1 cells reduced their release of matrix metalloproteinases and CCL2. CONCLUSIONS: These results link increased ADAM15 expression especially in lung leukocytes and bronchial epithelial cells to the pathogenesis of COPD.

Identification of novel epigenetic abnormalities as sputum biomarkers for lung cancer risk among smokers and COPD patients.

OBJECTIVES: Smoking is a common risk factor for chronic obstructive pulmonary disease (COPD) and lung cancer. Although COPD patients have higher risk of lung cancer compared to non-COPD smokers, the molecular links between these diseases are not well-defined. This study aims to identify genes that are downregulated by cigarette smoke and commonly repressed in COPD and lung cancer. MATERIALS AND METHODS: Primary human airway epithelial cells (HAEC) were exposed to cigarette-smoke-extract (CSE) for 10-weeks and significantly suppressed genes were identified by transcriptome array. Epigenetic abnormalities of these genes in lung adenocarcinoma (LUAD) from patients with or without COPD were determined using genome-wide and gene-specific assays and by in vitro treatment of cell lines with trichostatin-A or 5-aza-2-deoxycytidine. RESULTS: The ten most commonly downregulated genes following chronic CSE exposure of HAEC and show promoter hypermethylation in LUAD were selected. Among these, expression of CCNA1, SNCA, and ZNF549 was significantly reduced in lung tissues from COPD compared with non-COPD cases while expression of CCNA1 and SNCA was further downregulated in tumors with COPD. The promoter regions of all three genes were hypermethylated in LUAD but not normal or COPD lungs. The reduced expression and aberrant promoter hypermethylation of these genes in LUAD were independently validated using data from the Cancer Genome Atlas project. Importantly, SNCA and ZNF549 methylation detected in sputum DNA from LUAD (52% and 38%) cases were more prevalent compared to cancer-free smokers (26% and 15%), respectively (p < 0.02). CONCLUSIONS: Our data show that suppression of CCNA1, SNCA, and ZNF549 in lung cancer and COPD occurs with or without promoter hypermethylation, respectively. Detecting methylation of these and previously identified genes in sputum of cancer-free smokers may serve as non-invasive biomarkers for early detection of lung cancer among high risk smokers including COPD patients.

A millennium of population change in pre-modern Danish Ribe.

Denmark experienced major socioeconomic changes, including overall population growth, during the Viking, medieval and post-medieval periods from ca. AD 800 to 1800. Archaeological skeletons provide a unique perspective on the population structure of Ribe, a Danish town in Jutland, during the millennium that immediately precedes the industrialization of northern Europe. This skeletal study adds temporal depth to our understanding of an overall trend toward longer life as seen from historical records and in modern studies. Adult male and female mean age at death and mortality profiles during three time periods are based on 943 adult skeletons from three urban cemeteries that collectively represent a cross-section of this urban community. For both males and females, the mean age at death decreased slightly from the Viking (males 38.5 years, females 38.6 years) to the medieval (males 37.4 years, females 36.9 years) periods. This decline was followed by an increase in mean age at death for both sexes from the medieval to post-medieval (males 40.4 years, females 43.2 years) periods, a notable gain of 3.0 and 6.3 years for men and women, respectively.

Comparative Causal Analysis of the Effects of Long-Acting Muscarinic Antagonist Versus No Long-Acting Bronchodilator Use on Readmission or Mortality After Hospitalization for Chronic Obstructive Pulmonary Disease.

BACKGROUND: Retrospective observational studies may provide real-world evidence about long-acting muscarinic receptor antagonist (LAMA) effectiveness in reducing mortality or COPD-related readmission risk after a COPD hospitalization. Causal inference and competing risk statistical procedures aid in managing confounding and competing outcome events that complicate retrospective analyses. OBJECTIVE: To compare COPD-related readmission and mortality risk among patients receiving a LAMA versus patients receiving no long-acting bronchodilator ("no LABD") within 30 days post-discharge. METHODS: This retrospective observational analysis of patients (aged ≥ 40 years) hospitalized for COPD used claims data (years 2004-2012). Events occurring during the period from 31 days through 12 months post-discharge were compared. The hazard ratio (HR) for the combined outcome of COPD-related readmission or mortality was estimated using Cox regression. Confounding was addressed using inverse probability of treatment weighting (IPTW). The competing risk of non-COPD-related readmission was considered. RESULTS: 10,405 COPD patients were included (LAMA = 751, no LABD = 9654). IPTW achieved a balanced sample (10,518 LAMA, 10,405 no LABD). Unweighted HR (LAMA vs no LABD) for COPD-related readmission or death, adjusted for age, sex, comorbidities, and baseline utilization, was 1.00 [95% confidence interval (CI) 0.84, 1.20]. Weighted (IPTW) adjusted HR was 0.94 (95% CI 0.88, 1.00). Unweighted and weighted HRs further adjusted for competing risk were 0.97 (95% CI 0.82, 1.16) and 0.91 (0.86, 0.98), respectively. CONCLUSIONS: Bias by indication and comorbidities make the measurement of retrospective COPD treatment effectiveness difficult. Using IPTW and additionally considering the competing event risk, LAMA use was associated with a small reduction in risk for COPD-related readmission or death over the period from 31 days to 12 months post-discharge.

A problematic Israeli High Court dismissal of a torture complaint. A commentary by Hans Draminsky Petersen, MD.

It is not for the documenting medical experts (Shir, 2019), but for the court to decide whether the level of pain and suffering inflicted reaches the threshold of torture [while disregarding ill-treatment], i.e., the court upholds the prerogative to apply its own interpretation of the definition of torture, no matter existing medical evidence and disregarding the Istanbul Protocol. The criteria used to determine the level of FT's pain and suffering does not appear in the ruling. The ruling states that the burden of proof that the "means" were not reasonable [constituting torture] falls upon the petitioner (para 36). In the light of the above (1, a-h) this is in practice impossible for the petitioner to establish. This aligns with Shir's statement that no ISA interrogator has been indicted in 1200 torture complaints.

Plasma metabolomics and clinical predictors of survival differences in COPD patients.

BACKGROUND: Plasma metabolomics profile (PMP) in COPD has been associated with clinical characteristics, but PMP's relationship to survival has not been reported. We determined PMP differences between patients with COPD who died an average of 2 years after enrollment (Non-survivors, NS) compared to those who survived (S) and also with age matched controls (C). METHODS: We studied prospectively 90 patients with severe COPD and 30 controls. NS were divided in discovery and validation cohorts (30 patients each) and the results compared to the PMP of 30 S and C. All participants completed lung function tests, dyspnea scores, quality of life, exercise capacity, BODE index, and plasma metabolomics by liquid and gas chromatography / mass spectometry (LC/MS, LC/MS2, GC/MS). Statistically, we used Random Forest Analysis (RFA) and Support Vector Machine (SVM) to determine metabolites that differentiated the 3 groups and compared the ability of metabolites vs. clinical characteristics to classify patients into survivors and non-survivors. RESULTS: There were 79 metabolites statistically different between S and NS [p < 0.05 and false discovery rate (q value) < 0.1]. RFA and SVM classification of COPD survivors and non-survivors had a predicted accuracy of 74 and 85% respectively. Elevation of tricyclic acid cycle intermediates branched amino acids depletion and increase in lactate, fructose and xylonate showed the most relevant differences between S vs. NS suggesting alteration in mitochondrial oxidative energy generation. PMP had similar predictive power for risk of death as information provided by clinical characteristics. CONCLUSIONS: A plasma metabolomic profile characterized by an oxidative energy production difference between survivors and non-survivors was observed in COPD patients 2 years before death.

Outcomes of human adenovirus infection and disease in a retrospective cohort of pediatric solid organ transplant recipients.

Information about HAdV infection in SOT recipients is limited. We aimed to describe HAdV infection epidemiology and outcomes in a single-center retrospective cohort during the era of PCR availability. SOT recipients transplanted at the CHOP 2004-2013 were followed up for 180 days post-transplant. HAdV infection was defined as a positive HAdV PCR from a clinical specimen. HAdV disease was defined by organ-specific radiologic and/or laboratory abnormalities. No HAdV surveillance protocols were employed during the study period; testing was solely per clinician discretion. Progression of HAdV infection was defined as HAdV disease or ≥1-log viral load increase since a corresponding site's first positive specimen. Of the assembled 425 SOT recipients, 227 (52.6%) had ≥1 HAdV PCR. Twenty-four (10.6%) had ≥1 HAdV-positive PCR. HAdV-positive subjects were younger than uninfected subjects (2.0 years vs 6.5, P = 0.001). Infection incidence rates were highest in liver recipients (15.3%), followed by heart (8.6%), kidney (8.3%), and lung (4.2%). Four subjects (16.7%) met HAdV disease criteria at virus detection. Five subjects (20.8%) had progression of HAdV infection. All-cause mortality rates in positive and negative subjects were 0% and 3.9%, respectively. HAdV infection was infrequently detected in SOT recipients. Over one-third of HAdV-positive patients met disease criteria at detection or had infection progression, but none died. This low all-cause mortality raises questions about benefits of HAdV surveillance. Larger multicenter studies are needed to assess incidence variance by center and comparative effectiveness of therapeutic interventions.

Assessing the level of credibility of allegations of physical torture.

BACKGROUND: No means exists to classify the overall credibility of physical torture allegations, which relies on qualitative forensic medical criteria. OBJECTIVES: To develop procedures for processing physical data from torture allegations in order to achieve robust credibility assessments. To assess inter-observer variation in semi-quantitative evaluations. To analyse the importance of physical aspects for the overall assessment of allegations of torture. To assess the correlation between a quantitative description of physical aspects of torture and the appraisal of credibility based on the semi-quantitative model. METHODS: We developed a semi-quantitative model to assess credibility of physical torture allegations and a model to describe allegations quantitatively. Information about physical aspects of ill-treatment in 202 extensive reports made by psychologists (part of a Basque Country Governmental project) was appraised individually and jointly by the two authors in the semi-quantitative model. Inter-observer variation was appraised. The assessed credibility based on physical details was compared with the psychologists' overall assessments and with the quantitative scoring of physical data. FINDINGS: The inter-observer agreement was substantial with kappa values of 0.64-0.77. Peer-reviewing revealed an error; using the defined criteria in the models facilitated achievement of common opinions. Comparison of credibility assessments found by different means suggests that physical data may be given a low priority in the overall assessment of torture allegations. There was a strong correlation (r=0,86, p<0.001) between the semi-quantitative credibility assessment and the quantitative scoring of physical aspects of torture, reinforcing the validity of both means. CONCLUSION: Peer-reviewing of physical aspects of torture based on a qualitative /semi-quantitative /quantitative multi-step analysis leads to robust assessments of credibility. A procedure is needed on how to merge the credibility assessments of the psychological and the physical data into an overall conclusion. We suggest that the highest level of the two evaluations should constitute the overall credibility assessment. LIMITATIONS: The examinations were done years after the detentions, they were not focused on physical details and the data we used was retrieved retrospectively.

Outcomes of Human Adenovirus Infection and Disease in a Retrospective Cohort of Pediatric Hematopoietic Cell Transplant Recipients.

BACKGROUND: Human adenoviruses (HAdVs) are associated with significant morbidity and death after hematopoietic cell transplantation (HCT). In this study, we sought to determine the incidence of HAdV infection among pediatric HCT recipients in the polymerase chain reaction (PCR) testing era, identify risk factors for viremia among patients undergoing HAdV surveillance, and assess the effectiveness of preemptive cidofovir. METHODS: A single-center retrospective cohort of patients who underwent a transplant within a 10-year period was assembled. The incidence of and outcomes of patients with HAdV infection and disease were determined by PCR results and chart review. A Cox regression model was used for surveilled allogeneic HCT recipients to identify factors associated with viremia. We also used a discrete-time failure model with inverse probability treatment weights to assess the effectiveness of preemptive cidofovir for infection. RESULTS: Among 572 HCT recipients, 76 (13.3%) had ≥1 sample that was HAdV PCR positive (3.5% of autologous HCT recipients and 19.7% of allogeneic HCT recipients). Among 191 allogeneic HCT recipients under surveillance, 58 (30.4%) had HAdV detected from any source, and 50 (26.2%) specifically had viremia. The mortality rate was higher in allogeneic HCT recipients with HAdV infection versus those without infection (25.9% vs 11.3%; P = .01). Factors associated with infection included an age of 6 to 12 years, an absolute lymphocyte count of <200 cells/µL, recent prednisone exposure, and recent bacteremia. Preemptive cidofovir was not associated with a reduced risk of infection progression (odds ratio, 0.96 [95% confidence interval, 0.30-3.05]). CONCLUSIONS: HAdV infection is common and associated with an increased rate of death after allogeneic HCT. Using prediction models that incorporate factors associated with HAdV might help target surveillance. Preemptive cidofovir therapy was not protective in a subset of HAdV-positive patients. Larger observational or randomized investigations are necessary, because the utility of surveillance requires effective preemptive therapies.