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We investigated the feasibility of a semiautomatic approach for assessments of the fetal heart (fetal intelligent navigation echocardiography [FINE]) in cases of optimal and unfavorable fetal spine positions. In this study, a total of 1693 spatiotemporal image correlation volumes of first‐, second‐, and third‐trimester fetuses were evaluated by experts using the FINE approach. The data were analyzed regarding proper reconstruction of the diagnostic cardiac planes depending on the fetal spine position. A total of 1531 volumes were included. The volumes were divided into 4 groups depending on the fetal spine position: 5–7 o'clock, 4 + 8 o'clock, 3 + 9 o'clock, and 2 + 10 o'clock. In total, 93.2% of the diagnostic planes were displayed properly. Between 5 and 7 o'clock, 94.9% of the diagnostic planes were displayed properly. The correct depiction rates in the other groups were 92.4% (4 + 8 o'clock; n = 538; P= 0.0027), 88.3% (3 + 9 o'clock; n = 156; P< .0001), and 87.3% (2 + 10 o'clock; n = 41; P= .0139). In total, the highest dropout rates were found in the sagittal planes: ductal arch, 13.9%; aortic arch, 10.5%; and venae cavae, 12.0%. Based on our results, the FINE technique is an effective method, but its feasibility depends on the fetal position. The use of this semiautomatic work flow–based approach supports evaluation of the fetal heart in a standardized manner. Semiautomatic evaluation of the fetal heart might be useful in facilitating the detection of fetal cardiac anomalies.

To investigate the interobserver and intraobserver variability and corresponding learning curve in a semiautomatic approach for a standardized assessment of the fetal heart (fetal intelligent navigation echocardiography [FINE]). A total of 30 stored spatiotemporal image correlation volume data sets of second‐trimester fetuses were evaluated by 3 physicians with different levels of expertise in fetal echocardiography by using the FINE approach. Data were analyzed regarding the examination time and proper reconstruction of the diagnostic cardiac planes. The completions and numbers of correct depictions of all diagnostic planes were evaluated by a blinded expert (time t0). To determine interobserver and intraobserver variability, the volumes were reassessed after a 4‐week training interval (time t1). All operators were able to perform the investigation on all 30 volumes. At t0, the interobserver variability between the beginner and both the advanced (P= .0013) and expert (P< .0001) examiners was high. Focusing on intraobserver variability at t1, the beginner showed a marked improvement (P= .0087), whereas in advanced and expert hands, no further improvement regarding proper achievement of all diagnostic planes could be noticed (P> .999; P= .8383). The beginner also showed improvement in the mean investigation time (t0, 82.8 seconds; t1, 73.4 seconds; P= .0895); nevertheless, the advanced and expert examiners were faster in completing the examination (t1, advanced, 20.9 seconds; expert, 28.3 seconds; each P< .0001). Based on our results, the FINE technique is a reliable and easily learned method. The use of this semiautomatic work flow–based approach supports evaluation of the fetal heart in a standardized and time‐saving manner. A semiautomatic evaluation of the fetal heart might be useful in facilitating the detection of fetal cardiac anomalies.

The aim of this study was to evaluate the feasibility of sonographic assessment of the embryonic/fetal neural tube in nonviable pregnancies and to determine the defect incidence. Prospective analysis of transvaginally acquired 3‐dimensional (3D) multiplanar and 3D surface‐rendered volume sets of 340 cases of missed abortion between March 2010 and September 2015 was performed. Data regarding karyotype and postmortem examination as well as demographic features and the outcomes of subsequent pregnancies were evaluated. In 223 cases, an embryo/fetus was detected and considered suitable for further evaluation: in 37 of 223 (16.6%) embryos/fetuses, a neural tube defect was present: 27 of 37 cephaloceles, 5 of 37 anencephalies/exencepahlies, 3 of 37 spina bifidas, 1 of 37 caudal regression syndrome, and 1 of 37 iniencephaly. Additional alterations were not observed. In 7 of 37 cases karyotyping was carried out and showed no aneuploidy. Eight subsequent pregnancies had a favorable outcome, with 1 ending in an intrauterine fetal death during the 22nd week of gestation. Maternal folic acid supplementation was provided for all subsequent pregnancies. No neural tube defects occurred. Sonographic 3D evaluation of complete neural tube closure in embryonic/fetal demise is technically feasible and can be achieved in embryos with a crown‐rump length greater than 8 mm. In 26 of 37 cases a defective closure site could be allocated to high‐risk areas known for early embryonic demise. Regardless of the etiology of different neural tube defects, high‐dose folic acid prophylaxis must be recommended in all cases. Sonographic evaluation of the neural tube, including 3D surface‐rendered images, should be offered to every woman with a missed abortion because of the impact on subsequent pregnancies.

(Abstracted from J Clin Oncol2022; doi: 10.1200/JCO.21.01900)Ovarian cancer is the deadliest gynecologic cancer because of its nonspecific symptom presentation and lack of early detection or prevention strategies. Chronic inflammation has been demonstrated to play a key role in the molecular mechanisms driving ovarian cancer.

In the present work, the steady-state behavior of a Chemical Looping Combustion process of interconnected fluidized bed reactors is simulated. The simulations have been carried out in two different scales, 50 kWthand 100 MWth. Attrition model derived from small scale laboratory experiments has been employed for the prediction of the process behavior in terms of attrition and Oxygen Carrier loss. Information on Oxygen Carrier characteristics and reaction kinetics were taken from literature. Realistic circulation mass flows of Oxygen Carrier particles are obtained and Oxygen Carrier losses are quantified. The large scale process looses significantly more Oxygen Carrier than the small scale process based on the same amount of thermal energy produced. Incomplete conversion in the air reactor could be identified as a critical point. Another issue is the fuel gas bypassing the Oxygen Carrier particles through bubbles in the large scale process which leads to lowered fuel conversions. The simulations indicate that a similar performance of a pilot scale and a large scale process is not guaranteed due to the scale-up effect on fluid dynamics. Furthermore, the simulations allow an assessment of the influence of the quality of the solids recovery system on the Oxygen Carrier loss. The distribution of the losses between possible origins is investigated and different changes in the solids recovery system are discussed regarding their potential to decrease the Oxygen Carrier loss. For example, the addition of a second-stage cyclone after the air reactor of the large scale process reduces the Oxygen Carrier loss significantly.

Reduction of premature mortality is a UN Sustainable Development Goal. Unlike other high-income countries, age-adjusted mortality in the USA plateaued in 2010 and increased slightly in 2015, possibly because of rising premature mortality. We aimed to analyse trends in mortality in the USA between 1999 and 2014 in people aged 25–64 years by age group, sex, and race and ethnicity, and to identify specific causes of death underlying the temporal trends.

IMPORTANCE: A growing proportion of US smokers now smoke fewer than 10 cigarettes per day (CPD), and that proportion will likely rise in the future. The health effects of smoking only a few CPD over one’s lifetime are less understood than are the effects of heavier smoking, although many smokers believe that their level is modest. OBJECTIVE: To evaluate the associations of long-term smoking of fewer than 1 or 1 to 10 CPD (low intensity) with all-cause and cause-specific mortality compared with never smoking cigarettes. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of 290 215 adults in the National Institutes of Health–AARP (formerly known as the American Association of Retired Persons) Diet and Health Study who were aged 59 to 82 years in calendar years 2004-2005 (baseline). Data were gathered with a questionnaire assessing lifetime cigarette smoking history. Hazard ratios (HRs) and 95% CIs were determined for all-cause mortality and cause-specific mortality through the end of 2011. Hazard ratios and 95% CIs were estimated using Cox proportional hazards regression models using age as the underlying time metric and adjusted for sex, race/ethnicity, educational level, physical activity, and alcohol intake. Data analysis was conducted from December 15, 2015, to September 30, 2016. EXPOSURES: Current and historical smoking intensity during 9 previous age periods (from &lt;15 years to ≥70 years) over the lifetime assessed on the 2004-2005 questionnaire. MAIN OUTCOMES AND MEASURES: All-cause and cause-specific mortality among current, former, and never smokers. RESULTS: Of the 290 215 cohort participants who completed the 2004-2005 questionnaire, 168 140 were men (57.9%); the mean (SD) age was 71 (5.3) years (range, 59-82 years). Most people who smoked fewer than 1 or 1 to 10 CPD at baseline reported smoking substantially higher numbers of CPD earlier in their lives. Nevertheless, 159 (9.1%) and 1493 (22.5%) of these individuals reported consistently smoking fewer than 1 or 1 to 10 CPD in each age period that they smoked, respectively. Relative to never smokers, consistent smokers of fewer than 1 CPD (HR, 1.64; 95% CI, 1.07-2.51) and 1 to 10 CPD (HR, 1.87; 95% CI, 1.64-2.13) had a higher all-cause mortality risk. Associations were similar in women and men for all-cause mortality and were observed across a range of smoking-related causes of death, with an especially strong association with lung cancer (HR, 9.12; 95% CI, 2.92-28.47, and HR, 11.61; 95% CI, 8.25-16.35 for &lt;1 and 1-10 CPD, respectively). Former smokers who had consistently smoked fewer than 1 or 1 to 10 CPD had progressively lower risks with younger age at cessation. For example, the HRs for consistent smokers of fewer than 1 and 1 to 10 CPD who quit at 50 years or older were 1.44 (95% CI, 1.12-1.85) and 1.42 (95% CI, 1.27-1.59), respectively. CONCLUSIONS AND RELEVANCE: This study provides evidence that individuals who smoke fewer than 1 or 1 to 10 CPD over their lifetime have higher mortality risks than never smokers and would benefit from cessation. These results provide further evidence that there is no risk-free level of exposure to tobacco smoke.

IMPORTANCE: Leisure-time physical activity has been associated with lower risk of heart-disease and all-cause mortality, but its association with risk of cancer is not well understood. OBJECTIVE: To determine the association of leisure-time physical activity with incidence of common types of cancer and whether associations vary by body size and/or smoking. DESIGN, SETTING, AND PARTICIPANTS: We pooled data from 12 prospective US and European cohorts with self-reported physical activity (baseline, 1987-2004). We used multivariable Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals for associations of leisure-time physical activity with incidence of 26 types of cancer. Leisure-time physical activity levels were modeled as cohort-specific percentiles on a continuous basis and cohort-specific results were synthesized by random-effects meta-analysis. Hazard ratios for high vs low levels of activity are based on a comparison of risk at the 90th vs 10th percentiles of activity. The data analysis was performed from January 1, 2014, to June 1, 2015. EXPOSURES: Leisure-time physical activity of a moderate to vigorous intensity. MAIN OUTCOMES AND MEASURES: Incident cancer during follow-up. RESULTS: A total of 1.44 million participants (median [range] age, 59 [19-98] years; 57% female) and 186 932 cancers were included. High vs low levels of leisure-time physical activity were associated with lower risks of 13 cancers: esophageal adenocarcinoma (HR, 0.58; 95% CI, 0.37-0.89), liver (HR, 0.73; 95% CI, 0.55-0.98), lung (HR, 0.74; 95% CI, 0.71-0.77), kidney (HR, 0.77; 95% CI, 0.70-0.85), gastric cardia (HR, 0.78; 95% CI, 0.64-0.95), endometrial (HR, 0.79; 95% CI, 0.68-0.92), myeloid leukemia (HR, 0.80; 95% CI, 0.70-0.92), myeloma (HR, 0.83; 95% CI, 0.72-0.95), colon (HR, 0.84; 95% CI, 0.77-0.91), head and neck (HR, 0.85; 95% CI, 0.78-0.93), rectal (HR, 0.87; 95% CI, 0.80-0.95), bladder (HR, 0.87; 95% CI, 0.82-0.92), and breast (HR, 0.90; 95% CI, 0.87-0.93). Body mass index adjustment modestly attenuated associations for several cancers, but 10 of 13 inverse associations remained statistically significant after this adjustment. Leisure-time physical activity was associated with higher risks of malignant melanoma (HR, 1.27; 95% CI, 1.16-1.40) and prostate cancer (HR, 1.05; 95% CI, 1.03-1.08). Associations were generally similar between overweight/obese and normal-weight individuals. Smoking status modified the association for lung cancer but not other smoking-related cancers. CONCLUSIONS AND RELEVANCE: Leisure-time physical activity was associated with lower risks of many cancer types. Health care professionals counseling inactive adults should emphasize that most of these associations were evident regardless of body size or smoking history, supporting broad generalizability of findings.

(Abstracted from J Natl Cancer Inst2018; doi: 10.1093/jnci/djy100)The most fatal gynecologic cancer is ovarian cancer. This is largely due to its delayed symptom presentation and lack of early detection strategies.

IMPORTANCE: The 2008 Physical Activity Guidelines for Americans recommended a minimum of 75 vigorous-intensity or 150 moderate-intensity minutes per week (7.5 metabolic-equivalent hours per week) of aerobic activity for substantial health benefit and suggested additional benefits by doing more than double this amount. However, the upper limit of longevity benefit or possible harm with more physical activity is unclear. OBJECTIVE: To quantify the dose-response association between leisure time physical activity and mortality and define the upper limit of benefit or harm associated with increased levels of physical activity. DESIGN, SETTING, AND PARTICIPANTS: We pooled data from 6 studies in the National Cancer Institute Cohort Consortium (baseline 1992-2003). Population-based prospective cohorts in the United States and Europe with self-reported physical activity were analyzed in 2014. A total of 661 137 men and women (median age, 62 years; range, 21-98 years) and 116 686 deaths were included. We used Cox proportional hazards regression with cohort stratification to generate multivariable-adjusted hazard ratios (HRs) and 95% CIs. Median follow-up time was 14.2 years. EXPOSURES: Leisure time moderate- to vigorous-intensity physical activity. MAIN OUTCOMES AND MEASURES: The upper limit of mortality benefit from high levels of leisure time physical activity. RESULTS: Compared with individuals reporting no leisure time physical activity, we observed a 20% lower mortality risk among those performing less than the recommended minimum of 7.5 metabolic-equivalent hours per week (HR, 0.80 [95% CI, 0.78-0.82]), a 31% lower risk at 1 to 2 times the recommended minimum (HR, 0.69 [95% CI, 0.67-0.70]), and a 37% lower risk at 2 to 3 times the minimum (HR, 0.63 [95% CI, 0.62-0.65]). An upper threshold for mortality benefit occurred at 3 to 5 times the physical activity recommendation (HR, 0.61 [95% CI, 0.59-0.62]); however, compared with the recommended minimum, the additional benefit was modest (31% vs 39%). There was no evidence of harm at 10 or more times the recommended minimum (HR, 0.69 [95% CI, 0.59-0.78]). A similar dose-response relationship was observed for mortality due to cardiovascular disease and to cancer. CONCLUSIONS AND RELEVANCE: Meeting the 2008 Physical Activity Guidelines for Americans minimum by either moderate- or vigorous-intensity activities was associated with nearly the maximum longevity benefit. We observed a benefit threshold at approximately 3 to 5 times the recommended leisure time physical activity minimum and no excess risk at 10 or more times the minimum. In regard to mortality, health care professionals should encourage inactive adults to perform leisure time physical activity and do not need to discourage adults who already participate in high-activity levels.

To assess the independent effect of waist circumference on mortality across the entire body mass index (BMI) range and to estimate the loss in life expectancy related to a higher waist circumference.

Double inlet left ventricle as a rare cardiac malformation comprises a broad spectrum of anatomic variants making its correct antenatal diagnosis challenging. We report on echocardiographic findings of three fetuses found to have a less frequent morphologic subgroup of double inlet left ventricle, namely Holmes heart, characterized by a single (left) ventricle connected to both atrioventricular orifices and normally related arteries. We addressed the pre‐ and perinatal management as well as additional abnormalities and discussed our experiences together with what is known from current literature.

The objective of this study was to fine-map common pancreatic cancer susceptibility regions.

Insulin-like growth factor-1 (IGF-1), insulin, and IL-6 are dysregulated in multiple myeloma pathogenesis and may also contribute to multiple myeloma etiology. To examine their etiologic role, we prospectively analyzed concentrations of serologic markers in 493 multiple myeloma cases and 978 controls from 8 cohorts in the Multiple Myeloma Cohort Consortium. We computed odds ratios (ORs) and 95% confidence intervals (CIs) for multiple myeloma per 1-SD increase in biomarker concentration using conditional logistic regression. We examined heterogeneity by time since blood collection (≤ 3, 4- ≤ 6, and > 6 years) in stratified models. Fasting IGF binding protein-1 concentration was associated with multiple myeloma risk within 3 years (OR, 95% CI per 1-SD increase: 2.3, 1.4-3.8, P= .001) and soluble IL-6 receptor level was associated within 6 years after blood draw (OR ≤ 3 years, 95% CI, 1.4, 1.1-1.9, P= .01; OR4- ≤ 6 years, 95% CI, 1.4, 1.1-1.7, P= .002). No biomarker was associated with longer-term multiple myeloma risk (ie, > 6 years). Interactions with time were statistically significant (IGF binding protein-1, P-heterogeneity = .0016; sIL6R, P-heterogeneity = .016). The time-restricted associations probably reflect the bioactivity of tumor and microenvironment cells in transformation from monoclonal gammopathy of undetermined significance or smoldering multiple myeloma to clinically manifest multiple myeloma.

Many common genetic variants have been associated with non-Hodgkin lymphoma (NHL), but individual study results are often conflicting. To confirm the role of putative risk alleles in B-cell NHL etiology, we performed a validation genotyping study of 67 candidate single nucleotide polymorphisms within InterLymph, a large international consortium of NHL case-control studies. A meta-analysis was performed on data from 5633 B-cell NHL cases and 7034 controls from 8 InterLymph studies. rs3789068 in the proapoptotic BCL2L11 gene was associated with an increased risk for B-cell NHL (odds ratio = 1.21, P random = 2.21 × 10−11), with similar risk estimates for common B-cell subtypes. PRRC2A rs3132453 in the HLA complex class III region conferred a reduced risk of B-cell NHL (odds ratio = 0.68, P random = 1.07 × 10−9) and was likewise evident for common B-cell subtypes. These results are consistent with the known biology of NHL and provide insights into shared pathogenic components, including apoptosis and immune regulation, for the major B-cell lymphoma subtypes.

Many common genetic variants have been associated with non-Hodgkin lymphoma (NHL), but individual study results are often conflicting. To confirm the role of putative risk alleles in B-cell NHL etiology, we performed a validation genotyping study of 67 candidate single nucleotide polymorphisms within InterLymph, a large international consortium of NHL case-control studies. A meta-analysis was performed on data from 5633 B-cell NHL cases and 7034 controls from 8 InterLymph studies. rs3789068 in the proapoptotic BCL2L11gene was associated with an increased risk for B-cell NHL (odds ratio = 1.21, Prandom = 2.21 × 10−11), with similar risk estimates for common B-cell subtypes. PRRC2Ars3132453 in the HLA complex class III region conferred a reduced risk of B-cell NHL (odds ratio = 0.68, Prandom = 1.07 × 10−9) and was likewise evident for common B-cell subtypes. These results are consistent with the known biology of NHL and provide insights into shared pathogenic components, including apoptosis and immune regulation, for the major B-cell lymphoma subtypes.

We show how to use reports of cancer in family members to discover additional genetic associations or confirm previous findings in genome-wide association (GWA) studies conducted in case-control, cohort, or cross-sectional studies. Our novel family history–based approach allows economical association studies for multiple cancers, without genotyping of relatives (as required in family studies), follow-up of participants (as required in cohort studies), or oversampling of specific cancer cases (as required in case-control studies). We empirically evaluate the performance of the proposed family history–based approach in studying associations with prostate and ovarian cancers, using data from GWA studies previously conducted within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The family history–based method may be particularly useful for investigating genetic susceptibility to rare diseases for which accruing cases may be very difficult, by using disease information from nongenotyped relatives of participants in multiple case-control and cohort studies designed primarily for other purposes.

In chemical looping combustion of solid fuels the well‐mixed solids flow from the fuel reactor consisting of char, ash, and oxygen carrier particles cannot be completely separated into its constituents before it enters the air reactor. The slip of carbon will thus lead to char oxidation in the wrong reactor. Process simulation was applied to investigate the carbon stripping process in chemical looping combustion of solid fuels. Depending on the fuel choice, without carbon stripping CO2capture rates below 50 % are calculated for 4 min of solids residence time in the fuel reactor. In a process with carbon stripper, however, CO2capture rates exceeding 90 % can be achieved for both fuels investigated in this work.

AbstractObjectiveThe aim of this study is to evaluate the cumulative detection rate of foetal echocardiography during gestation and in the early neonatal period, with a special emphasis on early foetal echocardiography.MethodsWe conducted a retrospective survey of all singleton pregnancies from 1993 to 2007, with complete sequential echocardiography from 11 plus 0 to 13 plus 6 weeks of gestation. It was mandatory to have at least one foetal echocardiography in the second or third trimester and one postnatally.ResultsOur study included 3521 pregnancies, in which 77 cases were diagnosed with congenital heart disease. Of them, 66 were detected in the first trimester – 11 plus 0 to 11 plus 6 weeks: 22 cases; 12 plus 0 to 12 plus 6 weeks: 23 cases; 13 plus 0 to 13 plus 6 weeks: 21 cases – with an 85.7% detection rate of congenital heart disease in early foetal echocardiography. In the second trimester, seven cases were found, with a detection rate of 9.1%. The third trimester reported two cases, with a detection rate of 2.6%. Postnatally, two (2.6%) cases were detected. The overall in utero detection rate of congenital heart disease was 97.4%.ConclusionsFoetal echocardiography performed at the time of anomaly screening in the first trimester results in high detection rates of congenital heart disease. Cardiac pathology may evolve, and further examinations at later stages of pregnancy could improve the detection rate of congenital heart disease.

Germ-line genetic variation may affect clinical outcomes of cancer patients. We applied a candidate-gene approach to evaluate the effect of putative markers on survival of patients with pancreatic cancer. We also examined gene-radiotherapy and gene-chemotherapy interactions, aiming to explain interindividual differences in treatment outcomes.

The ductus arteriosus (DA) is a small vessel with major functional importance for the integrity of the fetal circulation. Technical advances in prenatal diagnostics facilitate appropriate echocardiographic estimation of the ductal flow and its abnormalities. Despite the emerging knowledge of its embryological background and developmental processes during advancing gestation we still have to face unresolved questions regarding the identification and optimal surveillance of fetuses at risk of premature closure of the ductus. Prenatal administration of tocolytics such as indomethacin should be monitored by close Doppler sonographic scans to follow the ductal circulation. Understanding the transcriptional regulation of normal DA development, maturation, and closure of the arterial duct as well as the hemodynamic changes during pregnancy and after delivery may provide additional targets for rational drug design to either close or open the DA, both antenatally and postnatally.

Genome-wide association and candidate gene studies implicate different genetic variants within the 6p21 chromosomal region with different non-Hodgkin lymphoma (NHL) subtypes. Complementing these efforts, we conducted human leukocyte antigen (HLA) class I and class II genotyping among 610 NHL cases and 555 controls of non-Hispanic white descent from a US multicenter study. Allele-disease associations were assessed by logistic regression for NHL and its subtypes. Statistically significant associations between HLAand NHL subtypes include HLA-DRB1*0101 for follicular lymphoma (odds ratio [OR] = 2.14, P< .001), HLA-DRB1*0401 for diffuse large B-cell lymphoma (DLBCL; OR = 0.45, P= .006), and HLA-DRB1*13and follicular lymphoma (OR = 0.48, P= .008). We further observed significant heterozygote advantage for HLAclass I alleles and NHL, and particularly DLBCL (Ptrend = .01 for elevated risk with increasing number of homozygous alleles). Our results support a role for HLAin the etiology of NHL and its subtypes.

Ethylen ist der bedeutendste Baustein der industriellen organischen Chemie. Seine Folgechemie ist äußerst vielfältig und die aus Ethylen hergestellten Produkte sind ein ständiger Bestandteil unseres täglichen Lebens. Derzeit ist Ethylen fast ausschließlich über thermische Crackprozesse von Kohlenwasserstoffen zugänglich. Die immer stärker ins Bewusstsein tretende natürliche Begrenzung der Erdölvorräte und damit des Hauptrohstoffs für die Basischemikalie Ethylen hat das Interesse an alternativen Zugangsrouten neu belebt. Diese Übersicht betrachtet die bekannten Synthesewege und beschreibt einen Prozess zur Herstellung von Ethylen, der sich auch für kleinere Produktionsmaßstäbe eignet.

Caspases play a critical role in regulation of apoptosis, cell differentiation, inflammation, and innate immunity, and several are mutated or have altered expression in non-Hodgkin lymphoma (NHL). To study the impact of genetic variation in caspases on NHL risk, we analyzed tag single nucleotide polymorphisms (SNPs) in 12 caspase and related genes in 3 population-based case-control studies (1946 cases and 1808 controls). Gene-based analysis, adjusting for the number of tagSNPs genotyped in each gene, showed significant associations for CASP8, CASP9, and CASP1. SNP-based analysis showed that CASP8 rs6736233 (odds ratio (OR) CG = 1.21; ORCC = 2.13; P trend = .011); CASP9 rs4661636 (ORCT = 0.89; ORTT = 0.77; P trend = .011); and CASP1 rs1785882 (ORAT = 1.12; ORAA = 1.30; P trend = .0054) were significantly associated with NHL risk and consistent across studies. It is noteworthy that genetic variants in CASP8 were associated with risk of all major NHL subtypes. Our findings suggest that genetic variation in caspases may play an important role in lymphomagenesis.

Organochlorine exposure was linked to non-Hodgkin lymphoma (NHL) risk. To determine whether this relation is modified by immune gene variation, we genotyped 61 polymorphisms in 36 immune genes in 1172 NHL cases and 982 controls from the National Cancer Institute–Surveillance, Epidemiology, and End Results (NCI-SEER) study. We examined 3 exposures with elevated risk in this study: PCB180 (plasma, dust measurements), the toxic equivalency quotient (an integrated functional measure of several organochlorines) in plasma, and α-chlordane (dust measurements, self-reported termiticide use). Plasma (100 cases, 100 controls) and dust (682 cases, 513 controls) levels were treated as natural log-transformed continuous variables. Unconditional logistic regression was used to calculate β coefficients and odds ratios, stratified by genotype. Associations between all 3 exposures and NHL risk were limited to the same genotypes for IFNG (C−1615T) TT and IL4 (5′-UTR, Ex1-168C>T) CC. Associations between PCB180 in plasma and dust and NHL risk were limited to the same genotypes for IL16 (3′-UTR, Ex22+871A>G) AA, IL8 (T−251A) TT, and IL10 (A−1082G) AG/GG. This shows that the relation between organochlorine exposure and NHL risk may be modified by particular variants in immune genes and provides one of the first examples of a potential gene-environment interaction for NHL.

Understanding patterns of etiologic commonality and heterogeneity for non-Hodgkin lymphomas may illuminate lymphomagenesis. We present the first systematic comparison of risks by lymphoma subtype for a broad range of putative risk factors in a population-based case-control study, including diffuse large B-cell (DLBCL; N = 416), follicular (N = 318), and marginal zone lymphomas (N = 106), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; N = 133). We required at least 2 of 3 analyses to support differences in risk: (1) polytomous logistic regression, (2) homogeneity tests, or (3) dichotomous logistic regression, analyzing all 7 possible pairwise comparisons among the subtypes, corresponding to various groupings by clinical behavior, genetic features, and differentiation. Late birth order and high body mass index (≥ 35) kg/m2) increased risk for DLBCL alone. Autoimmune conditions increased risk for marginal zone lymphoma alone. The tumor necrosis factor G-308A polymorphism (rs1800629) increased risks for both DLBCL and marginal zone lymphoma. Exposure to certain dietary heterocyclic amines from meat consumption increased risk for CLL/SLL alone. We observed no significant risk factors for follicular lymphoma alone. These data clearly support both etiologic commonality and heterogeneity for lymphoma subtypes, suggesting that immune dysfunction is of greater etiologic importance for DLBCL and marginal zone lymphoma than for CLL/SLL and follicular lymphoma.

To evaluate the hypothesis that host germ line variation in immune genes is associated with overall survival in diffuse large B-cell lymphoma (DLBCL), we genotyped 73 single nucleotide polymorphisms (SNPs) from 44 candidate genes in 365 DLBCL patients diagnosed from 1998 to 2000. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of SNPs with survival after adjusting for clinical factors. During follow-up, 96 (26%) patients died, and the median follow-up was 57 months for surviving patients. The observed survival of this cohort was consistent with population-based estimates conditioned on surviving 12 months. An IL10 haplotype (global P = .03) and SNPs in IL8RB (rs1126580; HRAG/GG = 2.11; CI, 1.28-3.50), IL1A (rs1800587; HRCT/TT = 1.90; CI, 1.26-2.87), TNF (rs1800629; HRAG/GG = 1.44; CI, 0.95-2.18), and IL4R (rs2107356; HRCC/CT = 1.97; CI, 1.01-3.83) were the strongest predictors of overall survival. A risk score that combined the latter 4 SNPs with clinical factors was strongly associated with survival in a Cox model (P = 6.0 × 10−11). Kaplan-Meier 5-year survival estimates for low, intermediate-low, intermediate-high, and high-risk patients were 94%, 79%, 60%, and 48%, respectively. These data support a role for germ line variation in immune genes, particularly genes associated with a proinflammatory state, as predictors of late survival in DLBCL.

Animal studies suggest that prenatal exposure to the synthetic estrogen diethylstilbestrol (DES) causes epigenetic changes that may be transmitted to the next generation. Specifically, these studies show an elevated incidence of reproductive tumors in the female offspring of prenatally-exposed mice.

The data in this paper show that 2,2,4,4,6-pentachloro-5-cyclohexene-1,3-dione (2, also named pentachlororesorcinol and PCR), a humic acid model, reacts with several chemicals related to drinking water chlorination, for example, NH2Cl, NaOCl, and NH3, leading to the formation of several unusual chlorinated organic products, most of which have never been reported in the literature. The syntheses and confirmation of structures are discussed in detail.

Measurement of soil strength with sophisticated parameters is tedious and expensive. Therefore, we developed two straightforward methods to determine this parameter down to about 80 cm, based on the classical measurements of bulk density and penetration resistance as a function of depth. They were applied to three profiles of arable Luvisols, all developed from glacial till. For each method, a procedure was worked out that allows expression of the results in terms of a normal (NC) or precompacted (PC) state. We defined the NC state as that observed in packing characteristics of virgin soils like forests and meadows, and the PC state as the packing characteristics that exist in the topsoil of agricultural soils and intensely grazed areas. Bulk density data were used to examine the packing characteristics and overburden pressures with the assumption that the horizon was in a NC state below 80 cm. For penetration resistance, we assumed a linear increase in penetration resistance with depth to represent the hydrostatic stress distribution in the NC state and deviations of measured values from this line as the PC state. The upper approximately 60 cm of all three soils were compacted, which is proofed both for the penetration resistance and for the bulk density data. For both approaches, the dimensionless coefficient of “stresses at rest,” K0, was calculated following the line of thought used in engineering soil mechanics (K0= σx/σz, where σxand σzare the horizontal and vertical stresses, respectively). The K0values are highest in the precompacted soil horizons and decrease with depth.

Recent gene-expression data have suggested that host immune genetic signatures may predict outcomes in patients with follicular lymphoma. We evaluated the hypothesis that germ line common variation in candidate immune genes is associated with survival. Cox models were used to estimate hazard ratios (HR) and corresponding 95% confidence intervals for individual SNPs after accounting for age, clinical, and other demographic factors. The median age at diagnosis of the 278 patients was 57 years, and 59 (21%) of the patients died during follow-up, with a median follow-up of 59 months (range, 27-78 months) for surviving patients. SNPs in IL8(rs4073; HRTT= 2.14, 1.26-3.63), IL2(rs2069762; HRGT/TT= 1.80, 1.06-3.05), IL12B(rs3212227; HRAC/CC= 1.83, 1.06-3.06), and IL1RN(rs454078; HRAA= 1.93, 1.11-3.34) were the most robust predictors of survival. A summary score of the number of deleterious genotypes from these genes was strongly associated with survival (P= .001). A risk score that combined the 4 SNPs with the clinical and demographic factors was even more strongly associated with survival (P< .001); the 5-year Kaplan-Meier survival estimates were 96% (93%-100%), 72% (62%-83%), and 58% (48%-72%) for groups at low, intermediate, and high risk, respectively. Common variation in host immune genes warrants further evaluation as a promising class of prognostic factors in follicular lymphoma.

A role for genetic susceptibility in non-Hodgkin lymphoma (NHL) is supported by the accumulating evidence of common genetic variations altering NHL risk. However, the pattern of NHL heritability remains poorly understood. We conducted a pooled analysis of 10 211 NHL cases and 11 905 controls from the International Lymphoma Epidemiology Consortium (InterLymph) to evaluate NHL risk among those with hematopoietic malignancies in first-degree relatives. Odds ratios (ORs) and 95% confidence intervals (CIs) of NHL and its subtypes were estimated from unconditional logistic regression models with adjustment for confounders. NHL risk was elevated for individuals who reported first-degree relatives with NHL (OR = 1.5; 95% CI = 1.2-1.9), Hodgkin lymphoma (OR = 1.6; 95% CI = 1.1-2.3), and leukemia (OR = 1.4; 95% CI = 1.2-2.7). Risk was highest among individuals who reported a brother with NHL (OR = 2.8; 95% CI = 1.6-4.8) and was consistent for all NHL subtypes evaluated. If a first-degree relative had Hodgkin lymphoma, NHL risk was highest if the relative was a parent (OR = 1.7; 95% CI = 1.0-2.9). If a first-degree relative had leukemia, NHL risk was highest among women who reported a sister with leukemia (OR = 3.0; 95% CI = 1.6-5.6). The pattern of NHL heritability appeared to be uniform across NHL subtypes, but risk patterns differed by specific hematopoietic malignancies and the sex of the relative, revealing critical clues to disease etiology.

We previously reported a lower risk of non-Hodgkin lymphoma (NHL) associated with high consumption of vitamin B6 and methionine, dietary determinants of one-carbon metabolism. Evidence has linked genetic variants involved in one-carbon metabolism to NHL. We investigated 30 polymorphisms in 18 genes for their main effect on NHL among 1141 incident cases and 949 population-based controls and examined gene-nutrient interactions in a subgroup of 386 cases and 319 controls who provided detailed food-frequency information. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for age, sex, and race. We observed a decreased risk of NHL overall with BHMT Ex8+453A>T and increased risk with CBS Ex13+41C>T, FPGS Ex15-263T>C, and SHMT1 Ex12+138C>T and Ex12+236C>T. Furthermore, significant gene-nutrient interactions limited the protective association comparing high versus low vitamin B6 to FPGS Ex15-263T>C CC (OR = 0.22; 95% CI = 0.10-0.52), MTHFS IVS2-1411T>G TT/TG (OR = 0.54; 95% CI = 0.36-0.81), and MTR Ex26-20A>G AA (OR = 0.55; 95% CI = 0.35-0.86) genotypes, and the protective association of methionine to FTHFD Ex10-40G>T GG (OR = 0.63; 95% CI = 0.44-0.91), MTHFR Ex8-62A>C CC (OR = 0.13; 95% CI = 0.04-0.39), and MTRR Ex5+136T>C TT (OR = 0.67; 95% CI = 0.47-0.97) genotypes. Warranting replication, our finding of gene-nutrient interactions in one-carbon metabolism supports their etiologic involvement in lymphomagenesis.

Wettability of soil affects a wide variety of processes in soils like infiltration, percolation, preferential flow, and surface runoff. Even though efforts have been made to determine contact angles and surface tension or energy of smooth surfaces, the determination on granular materials like soil particles remains unsolved. One objective of this study was to test the consistency of contact angles (CA) measured with the newly modified and easy-to-apply Wilhelmy plate method by using solid particles and liquids with defined variations of surface tension. A second objective was to derive basic physical surface properties for the irregularly shaped and chemically heterogeneous soil particles. Advancing contact angles were determined by using model soils varying in texture from clay to coarse sand to check the impact of grain size on the CA measurements. Varying the solid-surface tension with dichlorodimethlylsilane treatments provided for pure-water wetting stages ranging from wettable to extremely hydrophobic. The surface tensions of the liquids were varied from 72 mN m–1 to 25 mN m–1 by using water or water-ethanol mixtures. The surface tensions of the model soils were determined with the zero degree–contact angle method following Zisman's critical–surface tension concept. Results show that the measured CA varied continuously with the variations of the surface tension of the liquid and the solid phase, respectively. A general interpretation of the results is possible by using the concept of the Equation of State Approach.

Chromosomal translocations, insertions, and deletions are common early events in non-Hodgkin lymphoma (NHL) carcinogenesis, and implicated in their formation are endogenous processes involved in antigen-receptor diversification, such as V(D)J recombination. DNA repair genes respond to the double- and single-strand breaks induced by these processes and may influence NHL etiology. We examined 34 genetic variants in 19 genes within or related to 5 DNA repair pathways among 1172 cases and 982 matched controls who participated in a population-based NHL study in Los Angeles, Seattle, Detroit, and Iowa from 1998 to 2000. Cases were more likely than controls to have the RAG1820 R/R (odds ratio [OR] = 2.7; 95% confidence interval [CI] = 1.4 to 5.0) than Lys/Lys genotypes, with evidence of a gene dosage effect (Ptrend < .001), and less likely to have the LIG4(DNA ligase IV) 9 Ile/Ile (OR = 0.5; 95% CI = 0.3 to 0.9) than T/T genotype (Ptrend = .03) in the nonhomologous end joining (NHEJ)/V(D)J pathway. These NHEJ/V(D)J-related gene variants represent promising candidates for further studies of NHL etiology and require replication in other studies.

Because of conflicting findings about the relationship between ultraviolet (UV) radiation and the risk of non-Hodgkin lymphoma (NHL), we evaluated the risk of several indicators related to UV, including two not previously studied: dietary vitamin D, and ambient UV levels by residential location.As part of a case–control study conducted in four Surveillance, Epidemiology, and End Results (SEER) registries, we collected UV information from a self-administered questionnaire and computer-assisted personal interview with 551 NHL cases and 462 controls. We estimated the relative risk (RR) and 95% confidence intervals (CI) from unconditional logistic regression models.Eye color, a marker of host susceptibility to UV, showed a decreasing risk gradient for lightest eyes (0.47) compared to darkest. Relative risks were in the range of 0.73–0.78 for participants reporting more hours in the mid-day summer sun. Use of sunlamps or tanning booths was associated with decreased risk (RR = 0.88), as was estimated overall ambient UV (RR = 0.76 per 50 RB-units) overall. Vitamin D intake from diet and supplements was not related to risk. Results were thus consistent for the various indicators, although some estimated risks were not statistically significant. Effects were generally similar for diffuse large B-cell (DLBCL) and follicular lymphomas.These data suggest a slight protective effect of sunlight against NHL, and they agree with geographic patterns of NHL incidence observed in the US.

Evidence supporting the contribution of oxidative stress to key pathways in cancer, such as inflammation and DNA damage, continues to mount. We investigated variations within genes mediating oxidative stress to determine whether they alter risk for non-Hodgkin lymphoma (NHL). Thirteen single nucleotide polymorphisms (SNPs) from 10 oxidative stress genes (AKR1A1, AKR1C1, CYBA, GPX, MPO, NOS2A, NOS3, OGG1, PPARG and SOD2) were genotyped in 1172 NHL cases and 982 population-based controls from a USA multicenter case–control study. For NHL and five subtypes (diffuse large B-cell, follicular, marginal zone, small lymphocytic and T-cell), SNP associations were calculated. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for sex, age (<45, 45–64, 65+ years), race (white, black, other) and study site. Overall, the oxidative stress pathway was associated significantly with the B-cell NHL subtype, diffuse large B-cell lymphoma (DLBCL) (global P-value = 0.003). Specifically, for nitric oxide synthase (NOS2A Ser608Leu, rs2297518) Leu/Leu homozygotes, there was a 2-fold risk increase for NHL (OR = 2.2, 95% CI = 1.1–4.4) (referent = Ser/Ser and Ser/Leu). This risk increase was consistent by cell lineage (B- and T-cell NHL) and pronounced for the two most common subtypes, diffuse large B-cell (OR = 3.4, 95% CI = 1.5–7.8) and follicular lymphoma (OR = 2.6, 95% CI = 1.0–6.8). In an analysis of manganese superoxide dismutase (SOD2 Val16Ala, rs1799725) Ala/Ala homozygotes, we observed moderately increased risks for B-cell lymphomas (OR = 1.3, 95% CI = 1.0–1.6; referent = Val/Val and Val/Ala) that was consistent across the B-cell subtypes. Genetic variations that result in an increased generation of reactive oxygen species appear to increase risk for NHL and its major subtypes, particularly DLBCL. Independent replication of our findings are warranted and further evaluation of oxidative stress in the context of inflammation, DNA repair and the induction of the NF-κB pathway may further reveal important clues for lymphomagenesis.

Animal studies suggest that lymphomagenesis can be induced by exposure to carcinogenic aromatic and heterocyclic amines found in diet, cigarette smoke and the environment, but human epidemiologic investigations of these exogenous exposures have yielded conflicting results. As part of our evaluation of the role of aromatic and heterocyclic amines, which are metabolized by N-acetyltransferase (NAT) enzymes, in the etiology of non-Hodgkin lymphoma (NHL), we examined NHL risk in relation to genetic variation in NAT1and NAT2and exposure to cigarette smoke and dietary heterocyclic amines and mutagens. We genotyped 10 common single nucleotide polymorphisms (SNPs) in NAT1and NAT2among 1136 cases and 922 controls from a population-based case–control study in four geographical areas of the USA. Relative risk of NHL for NAT1and NAT2genotypes, NAT2acetylation phenotype, and exposure to cigarette smoke and dietary heterocyclic amines and mutagens was estimated using odds ratios (ORs) and 95 confidence intervals (CIs) derived from unconditional logistic regression models. We observed increased risk of NHL among individuals with the NAT11010genotype compared with individuals with other NAT1genotypes (OR1.60, 95 CI1.04–2.46, P0.03). We also observed increased NHL risk in a dose-dependent model among NAT2intermediate- and rapid-acetylators compared with slow-acetylators, although only the trend was statistically significant (intermediate OR1.18, 95 CI0.97–1.44, P0.1; rapid OR1.43, 95 CI0.97–2.14, P0.07; Pfor linear trend 0.03). Compared with non-smokers, NHL risk estimates for current cigarette smoking were increased only among NAT2intermediaterapid-acetylators (OR2.44, 95 CI1.15–5.20, P0.02). Our data provide evidence that NAT1and NAT2genotypes are associated with NHL risk and support a contributory role for carcinogenic aromatic andor heterocyclic amines in the multi-factorial etiology of NHL.

Nitrate and nitrite are precursors in the in vivo formation of N-nitroso compounds, potent animal carcinogens.

Depth-dependent soil bulk density (BDS) is usually affected by soil-specific factors like texture, structure, clay mineralogy, soil organic-matter content, soil moisture content, and composition of soil solution and is also affected by external factors like overburden-stress history or hydrological fluxes. Generally, the depth-dependent BDS cannot be predicted or extrapolated precisely from a limited number of sampling depths. In the present paper, an easy method is proposed to estimate the state of soil mechanical stress by analyzing the packing characteristics of the profile using soil bulk-density data. Results for homogeneous loess profiles exposed to the site-specific climatic conditions show that the depth-dependent relation of void ratio vs. weight of overburden soil can be described systematically so that deviations from the noncompacted reference state can be detected. We observed that precompaction increased from forest soils (reference) to agricultural soils with decreasing depth.

ObjectiveA recent study suggested that risk of bladder cancer may be higher in women than in men who smoked comparable amounts of cigarettes. We pooled primary data from 14 case–control studies of bladder cancer from Europe and North America and evaluated differences in risk of smoking by gender.

Non-Hodgkin Lymphoma (NHL) incidence has risen dramatically over past decades, but the reasons for most of this increase are not known. Meat cooked well-done using high-temperature cooking techniques produces heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (B[a]P). This study was conducted as a population-based case–control study in Iowa, Detroit, Seattle and Los Angeles and was designed to determine whether meat, meat-cooking methods, HCAs or PAHs from meat were associated with NHL risk. This study consisted of 458 NHL cases, diagnosed between 1998 and 2000, and 383 controls. Participants completed a 117-item food frequency questionnaire (FFQ), with graphical aids to assess the meat-cooking method and doneness level, which was linked to a HCA and B[a]P database. Logistic regression, comparing the fourth to the first quartile, found no association between red meat or processed meat intake and risk for NHL [odds ratio (OR) and 95% confidence interval (CI): 1.10 (0.67–1.81) and 1.18 (0.74–1.89), respectively]. A marginally significant elevated risk for NHL was associated with broiled meat [OR and 95% CI: 1.32 (0.99–1.77); P trend = 0.09], comparing those who consumed broiled meat with those who did not. The degree to which meat was cooked was not associated with the risk for NHL, although one of the HCAs, DiMeIQx (2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline), was associated with an inverse risk. Fat intake was associated with a significantly elevated risk for NHL [OR and 95% CI: 1.60 (1.05–2.45); P trend = 0.12]; in contrast, animal protein was inversely associated with risk for NHL [OR and 95% CI: 0.39 (0.22–0.70); P trend = 0.004]. Overall, our study suggests that consumption of meat, whether or not it is well-done, does not increase the risk of NHL. Furthermore, neither HCAs nor B[a]P from meat increase the risk of NHL.

Because the causes of most lymphoid neoplasms remain unknown, comparison of incidence patterns by disease subtype may provide critical clues for future etiologic investigations. We therefore conducted a comprehensive assessment of 114 548 lymphoid neoplasms diagnosed during 1992-2001 in 12 Surveillance, Epidemiology, and End Results (SEER) registries according to the internationally recognized World Health Organization (WHO) lymphoma classification introduced in 2001. Cases coded in International Classification of Diseases for Oncology, Second Edition (ICD-O-2), were converted to ICD-O-3 for WHO subtype assignment. Age-specific and age-adjusted rates were compared by sex and race (white, black, Asian). Age-adjusted trends in incidence were estimated by sex and race using weighted least squares log-linear regression. Diverse incidence patterns and trends were observed by lymphoid neoplasm subtype and population. In the elderly (75 years or older), rates of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma increased 1.4% and 1.8% per year, respectively, whereas rates of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) declined 2.1% per year. Although whites bear the highest incidence burden for most lymphoid neoplasm subtypes, most notably for hairy cell leukemia and follicular lymphoma, black predominance was observed for plasma cell and T-cell neoplasms. Asians have considerably lower rates than whites and blacks for CLL/SLL and Hodgkin lymphoma. We conclude that the striking differences in incidence patterns by histologic subtype strongly suggest that there is etiologic heterogeneity among lymphoid neoplasms and support the pursuit of epidemiologic analysis by subtype.

Abstract Background: Recent reports suggest that obesity, or conditions associated with obesity, might be risk factors for non-Hodgkin lymphoma (NHL), a cancer with dramatically increasing incidence in western countries over the last several decades. Physical inactivity increases the risk of obesity and of type 2 diabetes, but there are few data on the association of physical activity with risk of NHL.

Abstract

Geocoding is often used in epidemiologic studies to map residences with geographic information systems (GIS). The accuracy of the method is usually not determined.