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Objective: Timing and accumulation of work-related exposures may influence later life health. This study evaluates the association between women's work patterns and physical functioning. Method: Work history and physical functioning information was collected at baseline for U.S. women ages 50 to 79 years in the Women's Health Initiative Observational Study (N = 75,507). We estimated life course workforce participation patterns using latent class analysis. Associations between work patterns and physical limitations were explored using modified Poisson regression. Results: Compared with working continuously, women who left the workforce early had 8% increased risk and women who worked intermittently had 5% reduced risk of physical limitations later in life. The negative association with intermittent workforce participation was stronger for women with substantively complex work (9% reduced risk) than for women with nonsubstantively complex work (2% reduced risk). Discussion: Life course work patterns and characteristics may contribute to physical functioning later in life among women.

Glyphosate is the most widely used pesticide in the world. (1) It is also, arguably, the most controversial. Since being classified as 'probably carcinogenic to humans' by the International Agency [...]

BackgroundWomen comprise nearly half of the labor force in our society, but the impact of the occupational psychical activity on women's heart health in later life was unclear. We conducted a case-cohort study to assess the association of occupational physical activity (OPA), alone and jointly with leisure-time physical activity (LTPA) and risk of coronary heart disease (CHD).MethodsWe included women enrolled in Women's Health Initiative Observational Study who provided an occupational history at baseline and were followed until 2013 for the first occurrence of myocardial infarction or death from CHD (mean age ± SD = 63.4 ± 7.2). A total of 5,243 women free of CHD at baseline were randomly selected into a subcohort and 3,421 CHD events were adjudicated during follow-up. Through linkage of Standard Occupational Classification codes to the Occupational Information Network, we assessed cumulative and most recent exposure of OPA. LTPA was assessed through Women's Health Initiative's physical activity questionnaire. Weighted Cox proportional hazard models were used to evaluate CHD risk.ResultsAfter adjustment for demographic and socioeconomic factors, levels of OPA were not associated with CHD risk. Compared with women with low OPA and high LTPA, women with moderate to high cumulative OPA and low LTPA had relative high CHD risk (hazard ratio [HR]: 1.54, 95% confidence interval [CI]: 1.26, 1.88 for moderate OPA and HR: 1.46. 95% CI: 1.20, 1.78 for high OPA).DiscussionResults from this study suggest no overall association between lifetime OPA and CHD risk in women, but the impact of OPA varies by LTPA levels.

Women make up almost half of the labor force with older women becoming a growing segment of the population. Work characteristics influence physical functioning and women are at particular risk for physical limitations. However, little research has explored the effects of work characteristics on women's physical functioning. U.S. women between the ages of 50 and 79 were enrolled in the Women's Health Initiative Observational Study between 1993 and 1998. Women provided job titles and years worked at their three longest-held jobs (n = 79,147). Jobs were linked to characteristics in the Occupational Information Network. Three categories of job characteristics related to substantive complexity, physical demand, and social collaboration emerged. The association between job characteristics and physical limitations in later life, measured using a SF-36 Physical Functioning score

Respiratory virus infections are related to over 80% of childhood asthma exacerbations. They enhance pro-inflammatory mediator release, especially for sensitized individuals exposed to pollens/molds. Using a time-series study design, we investigated possible effect modification by respiratory virus infections of the associations between aeroallergens/PM2.5 and asthma exacerbation rates. Outpatient, emergency department (ED), and inpatient visits for asthma exacerbation among children with asthma (28,540/24,444 [warm/cold season]), as well as viral infection counts were obtained from electronic health records of the Children's Hospital of Philadelphia from 2011 to 2016. Rate ratios (RRs, 90th percentile vs. 0) for late-season grass pollen were 1.00 (0.85–1.17), 1.04 (0.95–1.15), and 1.12 (0.96–1.32), respectively, for respiratory syncytial virus (RSV) counts within each tertile. However, similar trends were not observed for weed pollens/molds or PM2.5. Overall, our study provides little evidence supporting effect modification by respiratory viral infections. [ABSTRACT FROM AUTHOR]

BackgroundGenome-wide association studies (GWAS) in European populations have identified genetic risk variants associated with multiple myeloma.MethodsWe performed association testing of common variation in eight regions in 1,318 patients with multiple myeloma and 1,480 controls of European ancestry and 1,305 patients with multiple myeloma and 7,078 controls of African ancestry and conducted a meta-analysis to localize the signals, with epigenetic annotation used to predict functionality.ResultsWe found that variants in 7p15.3, 17p11.2, 22q13.1 were statistically significantly (P < 0.05) associated with multiple myeloma risk in persons of African ancestry and persons of European ancestry, and the variant in 3p22.1 was associated in European ancestry only. In a combined African ancestry-European ancestry meta-analysis, variation in five regions (2p23.3, 3p22.1, 7p15.3, 17p11.2, 22q13.1) was statistically significantly associated with multiple myeloma risk. In 3p22.1, the correlated variants clustered within the gene body of ULK4 Correlated variants in 7p15.3 clustered around an enhancer at the 3' end of the CDCA7L transcription termination site. A missense variant at 17p11.2 (rs34562254, Pro251Leu, OR, 1.32; P = 2.93 × 10-7) in TNFRSF13B encodes a lymphocyte-specific protein in the TNF receptor family that interacts with the NF-κB pathway. SNPs correlated with the index signal in 22q13.1 cluster around the promoter and enhancer regions of CBX7 CONCLUSIONS: We found that reported multiple myeloma susceptibility regions contain risk variants important across populations, supporting the use of multiple racial/ethnic groups with different underlying genetic architecture to enhance the localization and identification of putatively functional alleles.ImpactA subset of reported risk loci for multiple myeloma has consistent effects across populations and is likely to be functional. Cancer Epidemiol Biomarkers Prev; 25(12); 1609-18. ©2016 AACR.

BackgroundReasons for the highly variable and often poor protection conferred by the Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccine are multifaceted and poorly understood.ObjectivesWe aimed to determine whether early-life exposure to PCBs (polychlorinated biphenyls) and DDE [1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene] reduces 6-month infant BCG vaccine response.MethodsData came from families participating in a prospective birth cohort in eastern Slovakia. At birth, maternal and cord blood were collected for chemical analyses, and infants were immunized with BCG. Blood was collected from infants for chemical analyses and to determine 6-month BCG-specific immunoglobulin (Ig) G and IgA levels. Multivariable linear regression models were fit to examine chemical-BCG associations among approximately 500 mother-infant pairs, with adjustment for confounders.ResultsThe median 6-month infant concentration of the prevalent congener PCB-153 was 113 ng/g lipid [interquartile range (IQR): 37-248], and 388 ng/g lipid (IQR: 115-847) for DDE. Higher 6-month infant concentrations of PCB-153 and DDE were strongly associated with lower 6-month BCG-specific antibody levels. For instance, BCG-specific IgG levels were 37% lower for infants with PCB-153 concentrations at the 75th percentile compared to the 25th percentile (95% CI: -42, -32; p < 0.001). Results were similar in magnitude and precision for DDE. There was also evidence of PCB-DDE additivity, where exposure to both compounds reduced anti-BCG levels more than exposure to either compound alone.ConclusionsThe associations observed in this study indicate that environmental exposures may be overlooked contributors to poorer responses to BCG vaccine. The overall association between these exposures and tuberculosis incidence is unknown.CitationJusko TA, De Roos AJ, Lee SY, Thevenet-Morrison K, Schwartz SM, Verner MA, Palkovicova Murinova L, Drobná B, Kočan A, Fabišiková A, Čonka K, Trnovec T, Hertz-Picciotto I, Lawrence BP. 2016. A birth cohort study of maternal and infant serum PCB-153 and DDE concentrations and responses to infant tuberculosis vaccination. Environ Health Perspect 124:813-821; http://dx.doi.org/10.1289/ehp.1510101.

Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 × 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 × 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.

PurposeRelationships of farm history and insecticide exposure at home or work with lymphohematopoietic (LH) neoplasm risk were investigated in a large prospective cohort of US women.MethodsIn questionnaires, women self-reported history living or working on a farm, personally mixing or applying insecticides, insecticide application in the home or workplace by a commercial service, and treating pets with insecticides. Relationships with non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, plasma cell neoplasms, and myeloid leukemia were investigated using Cox proportional hazard models. Age and farming history were explored as effect modifiers.ResultsThe analysis included 76,493 women and 822 NHL cases. Women who ever lived or worked on a farm had 1.12 times the risk of NHL (95% confidence interval [CI] = 0.95-1.32) compared to those who did not. Women who reported that a commercial service ever applied insecticides in their immediate surroundings had 65% higher risk of CLL/SLL (95% CI = 1.15-2.38). Women aged less than 65 years who ever applied insecticides had 87% higher risk of DLBCL (95% CI = 1.13-3.09).ConclusionsInsecticide exposures may contribute to risk of CLL/SLL and DLBCL. Future studies should examine relationships of LH subtypes with specific types of household insecticides.

Autoimmune conditions and immune system-related genetic variations are associated with risk of non-Hodgkin lymphoma (NHL). In a pooled analysis of 8,692 NHL cases and 9,260 controls from 14 studies (1988-2007) within the International Lymphoma Epidemiology Consortium, we evaluated the interaction between immune system genetic variants and autoimmune conditions in NHL risk. We evaluated the immunity-related single nucleotide polymorphisms rs1800629 (tumor necrosis factor gene (TNF) G308A), rs1800890 (interleukin-10 gene (IL10) T3575A), rs6457327 (human leukocyte antigen gene (HLA) class I), rs10484561 (HLA class II), and rs2647012 (HLA class II)) and categorized autoimmune conditions as primarily mediated by B-cell or T-cell responses. We constructed unconditional logistic regression models to measure associations between autoimmune conditions and NHL with stratification by genotype. Autoimmune conditions mediated by B-cell responses were associated with increased NHL risk, specifically diffuse large B-cell lymphoma (odds ratio (OR) = 3.11, 95% confidence interval (CI): 2.25, 4.30) and marginal zone lymphoma (OR = 5.80, 95% CI: 3.82, 8.80); those mediated by T-cell responses were associated with peripheral T-cell lymphoma (OR = 2.14, 95% CI: 1.35, 3.38). In the presence of the rs1800629 AG/AA genotype, B-cell-mediated autoimmune conditions increased NHL risk (OR = 3.27, 95% CI: 2.07, 5.16; P-interaction = 0.03) in comparison with the GG genotype (OR = 1.82, 95% CI: 1.31, 2.53). This interaction was consistent across major B-cell NHL subtypes, including marginal zone lymphoma (P-interaction = 0.02) and follicular lymphoma (P-interaction = 0.04).

Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10(-15)) and HLA-B (rs2922994, P=2.43 × 10(-9)) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10(-13) and 3.63 × 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.

Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [OR(per-allele)] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (OR(per-allele) = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.

Specific associations for lymphoma in the general population suggest that chronic immune dysfunction/dysregulation may be associated with the development of B-cell non-Hodgkin lymphoma (NHL). Furthermore, polymorphisms in several cytokine genes have been associated with increased lymphoma risk, most consistently with genes for TNF and IL10. To evaluate the hypothesis that prediagnostic circulating cytokine levels would be associated with increased B-cell lymphoma risk, we conducted a nested case-control study within the Women's Health Initiative Observational Study cohort involving 491 B-cell NHL cases and 491 controls. Levels of eleven cytokines, including IL1β, IL2, IL4, IL5, IL6, IL10, IL12, IL13, TNF, IFNγ and GM-CSF, were measured using a Luminex suspension bead-based multiplexed array in prediagnostic serum samples collected a median of 6 years prior to the lymphoma diagnosis. We observed a modestly increased risk of all B-cell NHL in women with increased levels of the cytokines TNF and IL10 (OR1.22, CI 1.07-1.38 and OR 1.09, CI 1.04-1.15, respectively, per doubling in the serum cytokine concentration) and this association showed some variation according to histologic subtype. The increased risk was strongest for those neoplasms diagnosed in close proximity to the blood draw for some histologic subtypes but not others, suggesting a component of reverse causation. Further study will be required to better understand how genetic polymorphisms in TNF and IL10 genes may interact with circulating cytokine levels and states of chronic immune dysfunction/stimulation to contribute to the risk of B-cell NHL.

BackgroundWe hypothesized that poor control of Epstein-Barr virus (EBV) infection, leading to reactivation of the virus, increases the risk of non-Hodgkin lymphoma (NHL) in the general population of primarily immunocompetent persons.MethodsWe conducted a case-control study nested within the Women's Health Initiative Observational Study cohort in which we measured antibodies to EBV antigens [immunoglobulin G (IgG) to viral capsid antigen (VCA), nuclear antigen (EBNA1), and early antigen-diffuse (EA-D)] and EBV DNA load in prediagnostic samples of 491 B-cell NHL cases and 491 controls.ResultsWe found no association with established EBV infection, based on seropositivity for VCA. Seropositivity for EBNA1 was associated with decreased risk of B-cell NHL, overall [OR = 0.5; 95% confidence interval (CI), 0.3-0.8] and for each of the histologic subtypes examined. Increased risk of chronic lymphocytic leukemia (CLL) and related subtypes was observed with higher levels of EBV DNA and antibody to EA-D, both markers reflective of reactivation. These associations were strongest for cases with the shortest time interval between blood draw and diagnosis.ConclusionsIn balance, these results do not provide strong evidence of EBV playing a causal role in B-cell NHL in general population women. The associations we observed may reflect increased risk of NHL with underlying immune impairment or could be due to reverse causation.ImpactFurther characterization of the subtype-specific association with CLL is warranted. Exclusion of cases with preclinical disease markers (such as monoclonal B-lymphocytosis for CLL) may help rule out reverse causation in future studies.

Genome-wide association studies (GWAS) have previously identified 13 loci associated with risk of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL). To identify additional CLL susceptibility loci, we conducted the largest meta-analysis for CLL thus far, including four GWAS with a total of 3,100 individuals with CLL (cases) and 7,667 controls. In the meta-analysis, we identified ten independent associated SNPs in nine new loci at 10q23.31 (ACTA2 or FAS (ACTA2/FAS), P=1.22×10(-14)), 18q21.33 (BCL2, P=7.76×10(-11)), 11p15.5 (C11orf21, P=2.15×10(-10)), 4q25 (LEF1, P=4.24×10(-10)), 2q33.1 (CASP10 or CASP8 (CASP10/CASP8), P=2.50×10(-9)), 9p21.3 (CDKN2B-AS1, P=1.27×10(-8)), 18q21.32 (PMAIP1, P=2.51×10(-8)), 15q15.1 (BMF, P=2.71×10(-10)) and 2p22.2 (QPCT, P=1.68×10(-8)), as well as an independent signal at an established locus (2q13, ACOXL, P=2.08×10(-18)). We also found evidence for two additional promising loci below genome-wide significance at 8q22.3 (ODF1, P=5.40×10(-8)) and 5p15.33 (TERT, P=1.92×10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism.

B-cell activation biomarkers have been associated with increased risk of non-Hodgkin lymphoma (NHL) in HIV-infected populations. However, whether a similar association may exist in general populations has not been established. We conducted a case-control study within the Women's Health Initiative Observational Study cohort to measure the B-cell activation biomarkers sCD23, sCD27, sCD30, sCD44, and CXCL13 in serum samples collected an average of 6 years before NHL diagnosis in 491 cases and 491 controls. Using logistic regression to estimate odds ratios, we observed strong associations between NHL and markers for all B-cell NHL and for major subtypes. Women with marker levels in the highest-versus-lowest quartile categories of CD23, CD27, CD30, or CXCL13 were at 2.8- to 5.5-fold increased risk of B-NHL. In addition, there were significant trends of risk with increasing levels of these markers present. Associations were strongest for cases with shortest lag times between blood draw and diagnosis (

ObjectivesWe hypothesized that intentional weight loss may be associated with development of lymphohematopoietic cancers, based on observations of immune suppression following weight loss in short-term studies.MethodsAt the baseline of the Women's Health Initiative Observational Study (1994-1998), participants reported information about intentional weight loss episodes in the past 20 years. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) among 81,219 women for associations between past intentional weight loss and risk of developing non-Hodgkin lymphoma (NHL), leukemia, and multiple myeloma during an average 9.9 years of follow-up.ResultsThe risk of NHL was associated with having lost a large maximum amount of weight (> or =50 pounds, HR = 1.68, 95% CI 1.13-2.50). NHL risk also varied by the frequency of intentional weight loss; women had increased risk if they lost 50 pounds or more > or =3 times (HR = 1.97, 95% CI 0.93-4.16; p trend by frequency = 0.09) or 20-49 pounds > or =3 times (HR = 1.55, 95% CI 1.00-2.40; p trend = 0.05), but there was no risk associated with smaller amounts of weight loss (10-19 pounds > or =3 times, HR = 0.78, 95% CI 0.46-1.33). These associations persisted with adjustment for body mass index at different ages. We observed non-significant associations of similar magnitude for multiple myeloma, but past intentional weight loss episodes were not associated with leukemia.ConclusionFurther assessment of intentional weight loss as a possible risk factor for lymphomas may provide insight into the etiology of these cancers.