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Rationale: Serum Immunoglobulin G (IgG) deficiency is associated with morbidity in chronic obstructive pulmonary disease (COPD) but it is unclear whether concentrations in the lower end of the normal range still confer risk., Objectives: To determine if levels above traditional cutoffs for serum IgG deficiency are associated with exacerbations among current and former smokers with or at risk for COPD., Measurements and Main Results: Former and current smokers in SPIROMICS (n=1,497) were studied, n=1,026 with and n=471 at risk for COPD. In a subset (n=1,031), IgG subclasses were measured. Associations between total IgG or subclasses and prospective exacerbations were evaluated with multivariable models adjusting for demographics, current smoking, smoking history, FEV 1 % predicted, inhaled corticosteroids, and serum IgA., Results: The 35th percentile (1225 mg/dL in this cohort) of IgG was the best cutoff by Akaike Information Criterion (AIC). Below this, there was increased exacerbation risk (IRR 1.28, 95% CI 1.08-1.51). Among subclasses, IgG1 and IgG2 below 35 th percentile (354 and 105 mg/dL, respectively) were both associated with increased risk of severe exacerbation (IgG1: IRR 1.39, 95% CI 1.06-1.84; IgG2: IRR 1.50, 95% CI 1.14-1.1.97). These associations remained significant when additionally adjusting for history of exacerbations., Conclusions: Lower serum IgG is prospectively associated with exacerbations in individuals with or at risk for COPD. Among subclasses, lower IgG1 and IgG2 are prospectively associated with severe exacerbations. The optimal IgG cutoff was substantially higher than traditional cutoffs for deficiency, suggesting subtle impairment of humoral immunity may be associated with exacerbations.

The accelerated weathering of flax and miscanthus fibers possessing distinct chemical compositions was investigated. The chosen fibers included raw, extractive-free (EF) and delignified samples (x3), alone and used as fillers in a stabilized polypropylene blue matrix (PP). Modifications in both color and the chemical composition of the fibers throughout the weathering process under ultraviolet (UV) light were meticulously tracked and analyzed by spectrophotometry and attenuated total reflectance with Fourier-transform infrared spectroscopy (ATR-FTIR). The inherent nature and composition of the selected fibers led to varied color-change tendencies. Raw and EF flax fibers exhibited lightening effects, while raw and EF miscanthus fibers demonstrated darkening effects. Extractives exhibited negligible influence on the color alteration of both flax and miscanthus fibers. This disparity between the fibers correlates with their respective lignin content and type, and the significant formation of carbonyl (C=O) groups in miscanthus. Better stability was noted for delignified flax fibers. A comparative study was achieved by weathering the PP matrix containing these various fibers. Contrary to the weathering observations on individual fibers, it was noted that composites containing raw and EF flax fibers exhibited significant color degradation. The other fiber-containing formulations showed enhanced color stability when compared to the pure PP matrix. The study highlights that the UV stability of composites depends on their thermal history. As confirmed by thermogravimetric analysis (TGA), fiber degradation during extrusion may affect UV stability, a factor that is not apparent when fibers alone are subjected to UV aging.

Pathogenic Variants (PV) in major cancer predisposition genes are only identified in approximately 10% of patients with Hereditary Breast and Ovarian Cancer (HBOC) syndrome. Next Generation Sequencing (NGS) leads to the characterization of incidental variants in genes other than those known to be associated with HBOC syndrome. The aim of this study was to determine if such incidental PV were specific to a phenotype. The detection rates of HBOC-associated and incidental PV in 1812 patients who underwent genetic testing were compared with rates in control groups FLOSSIES and ExAC. The rates of incidental PV in the PALB2, ATM and CHEK2 genes were significantly increased in the HBOC group compared to controls with, respective odds ratios of 15.2 (95% CI = 5.6-47.6), 9.6 (95% CI = 4.8-19.6) and 2.7 (95% CI = 1.3-5.5). Unsupervised Hierarchical Clustering on Principle Components characterized 3 clusters: by HBOC (P = 0.01); by ExAC and FLOSSIES (P = 0.01 and 0.02 respectively); and by HBOC, ExAC and FLOSSIES (P = 0.01, 0.04 and 0.04 respectively). Interestingly, PALB2 and ATM were grouped in the same statistical cluster defined by the HBOC group, whereas CHEK2 was in a different cluster. We identified co-occurrences of PV in ATM and BRCA genes and confirmed the Manchester Scoring System as a reliable PV predictor tool for BRCA genes but not for ATM or PALB2. This study demonstrates that ATM PV, and to a lesser extent CHEK2 PV, are associated with HBOC syndrome. The co-occurrence of ATM PV with BRCA PV suggests that such ATM variants are not sufficient alone to induce cancer, supporting a multigenism hypothesis., (© 2022. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Rationale: In the IMPACT (Informing the Pathway of COPD Treatment) trial, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy reduced exacerbation risk versus FF/VI and UMEC/VI and mortality risk versus UMEC/VI. However, pneumonia incidence was higher in the inhaled corticosteroid (FF)-containing arms, raising questions about the relative benefit of exacerbation reduction compared with the increased risk of pneumonia. Objectives: Determine benefit-risk of the three treatments by evaluating time-to-first and rates of composite exacerbation or pneumonia outcomes. Methods: We evaluated time-to-first (prespecified) and rates ( post hoc ) of investigator-reported pneumonia, serious pneumonia leading to hospitalization or death, and the composite endpoints of 1 ) moderate (required antibiotics/corticosteroids)/severe (hospitalized) exacerbation or pneumonia and 2 ) severe exacerbation or serious (hospitalized) pneumonia. Analyses were repeated for radiographically confirmed pneumonia ( post hoc ). Results: Moderate/severe exacerbations occurred in 47%, 49%, and 50% of patients randomized to FF/UMEC/VI, FF/VI and UMEC/VI, and pneumonias in 8%, 7%, and 5%, respectively. FF/UMEC/VI reduced the risk of combined moderate/severe exacerbation or pneumonia (time-to-first) versus FF/VI (hazard ratio, 0.87 [95% confidence interval (CI), 0.82-0.92]) and UMEC/VI (0.87 [0.81-0.94]), as well as the risk of combined severe exacerbation or serious pneumonia versus UMEC/VI (0.83 [0.72-0.96]). FF/UMEC/VI reduced the rate of combined moderate/severe exacerbation or pneumonia (rate ratio, 0.78 [0.72-0.84]) and combined severe exacerbation or serious pneumonia (rate ratio, 0.76 [0.65-0.89]) versus UMEC/VI. Results were similar for radiographically confirmed pneumonia endpoints. Conclusions: Despite higher incidence of pneumonia in FF-containing arms, these composite exacerbation/pneumonia outcomes support a favorable benefit-risk profile of FF/UMEC/VI versus FF/VI and UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease and a history of exacerbations.

Background: COPD is a leading cause of mortality., Research Question: We hypothesized that applying machine learning to clinical and quantitative CT imaging features would improve mortality prediction in COPD., Study Design and Methods: We selected 30 clinical, spirometric, and imaging features as inputs for a random survival forest. We used top features in a Cox regression to create a machine learning mortality prediction (MLMP) in COPD model and also assessed the performance of other statistical and machine learning models. We trained the models in subjects with moderate to severe COPD from a subset of subjects in Genetic Epidemiology of COPD (COPDGene) and tested prediction performance in the remainder of individuals with moderate to severe COPD in COPDGene and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We compared our model with the BMI, airflow obstruction, dyspnea, exercise capacity (BODE) index; BODE modifications; and the age, dyspnea, and airflow obstruction index., Results: We included 2,632 participants from COPDGene and 1,268 participants from ECLIPSE. The top predictors of mortality were 6-min walk distance, FEV 1 % predicted, and age. The top imaging predictor was pulmonary artery-to-aorta ratio. The MLMP-COPD model resulted in a C index ≥ 0.7 in both COPDGene and ECLIPSE (6.4- and 7.2-year median follow-ups, respectively), significantly better than all tested mortality indexes (P < .05). The MLMP-COPD model had fewer predictors but similar performance to that of other models. The group with the highest BODE scores (7-10) had 64% mortality, whereas the highest mortality group defined by the MLMP-COPD model had 77% mortality (P = .012)., Interpretation: An MLMP-COPD model outperformed four existing models for predicting all-cause mortality across two COPD cohorts. Performance of machine learning was similar to that of traditional statistical methods. The model is available online at: https://cdnm.shinyapps.io/cgmortalityapp/., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

A study was conducted with occupational health services to describe the progress of occupational pregnancies in the health sector. Compared to female administrative employees and workers, health sector employees were particularly exposed to more than five risks for pregnancy. Workplace adaptations observed are infrequent and work stoppages are particularly numerous. This justifies effective monitoring of pregnancies for personnel in this sector., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Objectives: To describe the follow-up of pregnancies at work and exposures to pregnancy occupational hazards., Methods: A cross-sectional study was performed between January and December 2014 in occupational health services of Languedoc-Roussillon region. Eligible workers were interviewed by occupational health physicians (OHPs) after delivery and at the time of returning to work (exposure, anticipation, prevention, communication, sick leave). Occupational skill levels were classified according to the French standard classification of occupations (version 2003) from the French National Institute of Statistics. Socioeconomic deprivation was assessed using the Evaluation of Deprivation and Inequalities in Health Examination (EPICES) individual scale., Results: A total of 1347 workers were recruited. The mean age was at 30.7±4.5 years. Among pregnant workers, there were 54.2% of employees, 30.7% of intermediate occupations, 10.4% of managers and, 4.7% of manual workers. Twenty-two percent of workers were classed as deprived. Also, 43.2% of workers were exposed to three or more occupational hazards during pregnancy. Only 17.7% of workers had medical visits with OHP during pregnancy and 14.7% benefited from workstation adjustments. In contrast, the level of sick leaves was high (74.2%)., Conclusion: Our results argue for the need to follow pregnancies at work. However, the low level of prevention activities and the high level of sick leaves raise the question of the management of pregnant women at work., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Background: This study aimed to investigate the association between exposure to occupational hazards for pregnancy and sick leave (SL) in pregnant workers., Methods: A cross-sectional study was performed in French occupational health services in 2014. Occupational hazards for pregnancy were assessed by occupational health physicians (OHPs). After delivery and at the time of returning to work, 1,495 eligible workers were interviewed by OHPs. Information on SL was self-reported. Risk ratios (RRs) were calculated from multivariable analyses based on a generalized linear model with a Bernoulli distribution and a log link adjusted for selected confounders for binary outcomes or zero-inflated negative binomial regression for count outcomes., Results: Among recruited workers, 74.9% presented "at least one SL" during pregnancy. After adjustment, the cumulative index of occupational hazards (0, 1-2, 3-4, ≥ 5 risks) for pregnancy was significantly associated with "at least one SL" during pregnancy in a dose-response relationship. This gradient was also observed with "early SL" (<15 week gestation): from 1 to 2 risks, RR = 1.48 (95% confidence intervals (CIs): 0.92-2.38); from 3 to 4 risks, RR = 2.03 (95% CI: 1.25-3.30); equal to or higher than five risks, RR = 2.90 (95% CI: 1.89-4.44); with "duration of absence" (adjusted mean): from 1 to 2 risks, m = 38.6 days; from 3 to 4 risks, m = 46.8 days; equal to or higher than five risks, m = 53.8 days. We also found that deprivation, pregnancy at risk, assisted reproductive therapy, work-family conflicts, home-work commuting felt as difficult and young age are associated with a higher risk of SL., Conclusions: Our results support the assertion that pregnant workers exposed to occupational hazards for pregnancy without medical complications are also at risk of taking SL during pregnancy. More prevention in the workplace for pregnant workers exposed to occupational hazards could reduce SL.

Background: Recent global economic difficulties have widened social inequalities, but their impact on pregnant workers is not known., Aims: To investigate the association between deprivation, exposure to occupational hazards and adverse perinatal outcomes in pregnant workers., Methods: A cross-sectional study performed in 2014 in French occupational health services. Eligible workers were women who had worked during their pregnancy and had a medical visit by occupational health physicians (OHPs) after delivery and at the time of returning to work. Deprivation was measured using the EPICES scale (Evaluation of Precariousness and Inequalities in Health Examination Centres). Information on birth outcomes was self-reported. Occupational risks for pregnancy were assessed by OHPs. Jobs were coded by the occupational health team using standardized French nomenclature. The groups (deprivation/no deprivation) were compared using univariate (chi-squared test) and multivariate Poisson regression analyses., Results: Of 1402 pregnant workers, 293 (21%) were classed as deprived. This group more frequently encountered occupational hazards, particularly for physical exposures (P < 0.001), and had a higher risk of cumulated occupational hazards of three or more for pregnancy [adjusted relative risk (RRa) = 4.2; 95% confidence interval (CI) 2.2-7.9]. Our findings suggest that deprivation and exposure to three or more occupational hazards during pregnancy cumulatively increased the risk of pre-term birth (RRa = 3.9; 95% CI 1.2-12.4)., Conclusions: Our data suggest that deprived pregnant workers are an occupationally vulnerable group., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The pneumococcal conjugate vaccine (PCV) was developed to overcome the limitations of the pneumococcal polysaccharide vaccine, which produces poor immunogenicity in infants younger than 2 years. As many countries have included PCVs in national immunization programs for children, the incidence of invasive pneumococcal disease caused by vaccine type Streptococcus pneumoniae has declined markedly, not only among the vaccinated pediatric population, but also among unvaccinated adults. In this review, we present a concise overview of the indirect effects of mass pediatric PCV immunization on unvaccinated adults., Competing Interests: No conflicts of interest

Aim: To examine the quality of manual job coding carried out by occupational health teams with access to a software application that provides assistance in job and business sector coding (CAPS). Methods: Data from a study conducted in an Occupational Health Service were used to examine the first-level coding of 1,495 jobs by occupational health teams according to the French job classification entitled “PSC- Professions and socio-professional categories” (INSEE, 2003 version). A second level of coding was also performed by an experienced coder and the first and second level codes were compared. Agreement between the two coding systems was studied using the kappa coefficient (κ) and frequencies were compared by Chi2 tests. Results: Missing data or incorrect codes were observed for 14.5% of social groups (1 digit) and 25.7% of job codes (4 digits). While agreement between the first two levels of PCS 2003 appeared to be satisfactory (κ=0.73 and κ=0.75), imbalances in reassignment flows were effectively noted. The divergent job code rate was 48.2%. Variation in the frequency of socio-occupational variables was as high as 8.6% after correcting for missing data and divergent codes. Conclusions: Compared with other studies, the use of the CAPS tool appeared to provide effective coding assistance. However, our results indicate that job coding based on PSC 2003 should be conducted using ancillary data by personnel trained in the use of this tool.

The aim of this study was to better define the clinical and biopathological features of patients with desmoplastic/nodular medulloblastoma (DNMB) and to further characterize this subgroup. 17 children aged < 5 years, with initial DNMB treated according to the HIT-SKK protocol, were evaluated. A retrospective central radiological review, a pathological and immunohistochemical study, and array-CGH and sequencing of germline SUFU and PTCH1 genes were performed. 15 histologically reviewed cases were confirmed as DNMB including three cases of medulloblastoma with extensive nodularity. Median age at diagnosis was 26 months. Radiology showed five cases with a vermis location and one with T2 hyperintensity. All cases showed a SHH immunoprofile. A 9q deletion was found in 6 cases, a MYCN-MYCL amplification in 1 case, and a SUFU germline mutation in 1 case (/9). The presence of SUFU and PTCH1 germline mutations agreed with previous reports. At 3 years, progression-free survival and overallsurvival rates were 72 ± 15% and 85 ± 10%, respectively. The rate of recurrence was relatively high (4 patients). This may have been because chemotherapy was delayed in two cases. Age > 3 years, and residual tumor may also have been an explanation for recurrence.

Objectives: The aim of this study was to perform a systematic review and to use a meta-analytical approach to assess quantitatively the risk of adverse pregnancy outcomes in hairdressers and cosmetologists., Methods: A systematic literature search up to 1 February 2012 was carried out using major bibliographic databases, grey literature, contacts with research teams working on the subject, review papers and reference lists of selected articles. Observational studies reporting measures of effects in relation with body care (hairdressers, cosmetologists, etc.) and reproductive disorders were included. Study quality was assessed by three reviewers. The estimated risk ratios (RR) from all studies reporting on identical outcomes were combined using an average of logarithm transformation of estimated RR weighted by their inverted variance. Statistical heterogeneity across studies was assessed using Cochran's Q test. To explore the sources of heterogeneity, several sensitivity analyses and subgroup analyses were conducted based on study quality, country, study period, alcohol consumption, smoking habit, jobs and control populations., Results: Nineteen studies were selected and reviewed in-depth. The combined risk ratios (RRcs) of five reproductive outcomes were calculated and found to be significantly increased for four outcomes: time to pregnancy, which had an RRc of 1.11 (95% CI: 1.03-1.19); premature birth, which had an RRc of 1.05 (95% CI: 0.99-1.11); small for gestational age, which had an RRc of 1.24 (95 CI%: 1.10-1.41); low birth weight, which had an RRc of 1.21 (95% CI: 1.06-1.39); and embryonic and fetal losses, which had an RRc of 1.19 (95% CI: 1.03-1.38)., Conclusions: This work confirms a weak increase in risk of some reproductive disorders in female hairdressers/cosmetologists. However, the evidence level is rather weak, and a causal association between job and reproductive outcomes cannot be asserted.

PTEN plays a well-established role in the negative regulation of the PI3K pathway, which is frequently activated in several cancer types, including breast cancer. A nuclear function in the maintenance of chromosomal stability has been proposed for PTEN but is yet to be clearly defined. In order to improve understanding of the role of PTEN in mammary tumorigenesis in terms of a possible gene dosage effect, its PI3K pathway function and its association with p53, we undertook comprehensive analysis of PTEN status in 135 sporadic invasive ductal carcinomas. Four PTEN status groups were defined; complete loss (19/135, 14%), reduced copy number (19/135, 14%), normal (86/135, 64%) and complex (11/135, 8%). Whereas the PTEN complete loss status was significantly associated with estrogen receptor (ER) negativity (p=0.006) and in particular the basal-like phenotype (p<0.0001), a reduced PTEN copy number was not associated with hormone receptor status or a particular breast cancer subtype. Overall, PI3K pathway alteration was suggested to be involved in 59% (79/134) of tumors as assessed by human epidermal growth factor receptor 2 overexpression, PIK3CA mutation or a complete loss of PTEN. A complex PTEN status was identified in a tumor subgroup which displayed a specific, complex DNA profile at the PTEN locus with a strikingly similar highly rearranged pan-genomic profile. All of these tumors had relapsed and were associated with a poorer prognosis in the context of node negative disease (p=1.4 × 10(-13) ) thus may represent a tumor subgroup with a common molecular alteration which could be targeted to improve clinical outcome., (Copyright © 2013 UICC.)

Nephroblastoma (Wilms' tumor; WT) is the most common renal tumor of childhood. To date, several genetic abnormalities predisposing to WT have been identified in rare overgrowth syndromes. Among them, abnormal methylation of the 11p15 region, GPC3 and DIS3L2 mutations, which are responsible for Beckwith-Wiedemann, Simpson-Golabi-Behmel and Perlman syndromes, respectively. However, the underlying cause of WT remains unknown in the majority of cases. We report three unrelated patients who presented with WT in addition to a constitutional 9q22.3 microdeletion and dysmorphic/overgrowth syndrome. The size of the deletions was variable (ie, from 1.7 to 8.9 Mb) but invariably encompassed the PTCH1 gene. Subsequently, we identified a somatic PTCH1 nonsense mutation in the renal tumor of one patient. In addition, by array comparative genomic hybridization method, we analyzed the DNA extracted from the blood samples of nine patients with overgrowth syndrome and WT, but did not identify any deleterious chromosomal imbalances in these patients. These findings strongly suggest that patients with constitutional 9q22.3 microdeletion have an increased risk of WT, and that PTCH1 have a role in the pathogenesis of nephroblastomas.

Following the French health and environment action plan, the French Agency for Environmental and Occupational Health and Safety set up a workgroup to standardise a method of deriving toxicity reference values (TRVs). Over the last few decades, there has been increasing concern about the effect of exposure to chemicals on reproductive function, leading the group to take an interest in reprotoxic effects. This article presents the recommendations of the workgroup regarding specific reprotoxic effects. Abnormal development of foetuses and infants, together with impairment of reproduction were considered to be critical effects. Where critical windows of exposure were concerned, quantitative analysis suggested the need for several types of toxicity reference value, as a function of exposure duration: reprotoxic effects may result from acute or chronic exposure at any time of life, whilst developmental effects may occur after exposure during the pregnancy or during the lactation period. The choice of a critical study is based on epidemiological or toxicological quality criteria. The working group recommends the use of the benchmark dose approach in estimating the critical dose. Finally, the working group considered the application of uncertainty factors typically used to take into account the variability between animal and human, between different individuals, and the availability of the data.

European regulations (transcribed into French law) aimed at protecting employees from chemicals toxic to reproduction enable classification and labelling of such substances, if they are liable to cause an alteration of male or female reproductive functions or capacity, or to induce non-hereditary harmful effects on their offspring. Three categories can be used to classify these substances in two areas, namely their impairment of fertility and their effects on development. This classification is rarely based on epidemiological study results, but most often on those of experimental toxicological studies conducted by substance manufacturers. These reproduction toxicological studies are only compulsory above a certain tonnage placed on the market. The high level of this tonnage means that these tests are effectively only conducted on rare occasions. It is reckoned that there is no reproduction experimental data for over 95% of substances newly placed on the market. These products therefore appear to be reproduction non-toxic only because they have not been tested. This is a major fault in the current labelling system, which does not allow non-toxic products to be differentiated from non-tested products. The future EU regulatory framework for Registration, Evaluation and Authorisation of CHemicals (REACH) will only slightly enhance information in this area. It can be estimated that over 80% of chemical products will not be exhaustively tested for reproduction and nearly 75% will not be tested to any degree.

Loss of heterozygosity (LOH) on the long arm of human chromosome 16 is a common genetic alteration observed in both invasive ductal and invasive lobular breast carcinomas. We have generated a high-resolution integrated map encompassing the smallest region of LOH overlap within chromosome 16q22.1 (SRO2). Southern hybridization experiments using more than 140 probes resulted in the assembly of 152 bacterial large-insert clones into a 2.8-Mb contig covering SRO2. The structure of the contig was verified by long-range mapping using total human genomic DNA, and the contig orientation was determined by fluorescence in situ hybridization. A total of 68 transcripts have been identified in the map. One of the genes residing within SRO2 is the E-cadherin gene, CDH1, which has previously been shown to be mutated in lobular breast carcinomas, resulting in loss of E-cadherin expression. In most cases of ductal carcinoma, which is the major mammary cancer type, E-cadherin is normally expressed, suggesting that other genes within 16q22.1 are involved in the development of this tumor subtype. The high-resolution map presented in this study provides a valuable resource for identification of tumor suppressor genes expected to be involved in the etiology of breast carcinomas.

Infectious embolic retinopathy occurring secondary to a bacterial endocarditis is described in a 38-year-old woman with known aortic disease. The infectious organism was a haemophilus parainfluenzae confirmed by serial blood cultures and characterized by an embolic power equal to fungal infection. After four-weeks period of appropriate and intensive antibiotic therapy, blood cultures became negative but new emboli were observed in the fundus. This report describes ocular lesions rarely observed in endogenous bacterial retinitis. The delay between the bacterial endocarditis and the occurrence of the retinitis emphasizes the need for a long-term follow-up. Ophthalmologic examination can be acline for changing the heart valve.