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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. Additionally, 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 (<3 years). However, there were also significant associations for cases with the longest prediagnostic lag (9–13 years). Taken together, our findings indicate a prominent role for B-cell activation among postmenopausal women in the etiology of B-cell NHL and/or in processes reflective of early disease development, as early as 9 years before diagnosis.
One factor that is a well-known cause of NHL is altered immunity – as evidenced by increased rates of NHL among persons with AIDS, transplant recipients, and autoimmune disease patients (1–3). However, the importance of subclinical immune dysregulation in development of NHL in cases occurring in the general population, who comprise the majority of cases, is unclear.
The risk of developing NHL of the B-cell type is markedly increased in HIV/AIDS, particularly for aggressive subtypes such as diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. B-cell hyperactivation is commonly seen in persons with HIV, and several studies indicate that those patients with the most marked B-cell activation are at increased risk of developing NHL. For example, increased serum/plasma levels of molecules involved in B-cell activation, including soluble sCD23 (4–7), sCD27 (7,8), sCD30 (9), sCD44 (10), and CXCL13 (11,12), have been associated with subsequent development of AIDS-related NHL. B-cell activation is characterized by lymphocyte proliferation, class switch recombination, and somatic hypermutation, all of which are prone to resultant errors in DNA that may lead to lymphomagenesis.
Recently, reports from two prospective cohort studies of the general population (presumably immunocompetent persons) found that increased levels of sCD30 were associated with increased risk of NHL, when measured in blood samples collected up to 6–10 years before diagnosis (13,14). sCD27 was also associated with increased NHL risk in one of these cohorts (15). Taken together, these studies provide the first evidence that lymphomagenesis in the general population may result from relatively increased levels of B-cell activation in a manner similar to that observed in HIV-positive persons.
We investigated the risk of B-cell NHL associated with biomarkers, measured in prediagnostic serum, that are indicative of an immune stimulatory host environment, including levels of a cytokine-like molecule (sCD23), soluble cytokine receptors (sCD27, sCD30), a molecule involved in lymphocyte activation (sCD44), and a B-cell stimulatory chemokine (CXCL13). We hypothesized that chronic B-cell activation, as evidenced by elevated serum levels of these molecules, increases the risk of B-cell NHL among immunocompetent persons, similar to the risks observed in HIV-positive populations. We further hypothesized that the increased risk would apply across a range of histologic subtypes, including more indolent subtypes less commonly encountered in HIV. We investigated our hypothesis in the Women's Health Initiative (WHI) Observational Study (OS) cohort using biologic samples collected an average of 6 years before NHL diagnosis.
The study was designed as a nested case-control study in the WHI OS. All study activities were approved by Human Subjects review by the FHCRC IRB (IR #6897).
The design of the WHI OS has been published previously (16). The OS includes 93,676 community-dwelling, postmenopausal women enrolled between 1994 and 1998 at 40 clinical centers distributed widely throughout the U.S., including targeted enrollment of minority women. Participants in the OS were screened for the WHI clinical trials but were determined to be ineligible or were unwilling to participate, or were recruited through a direct invitation for screening into the OS only. All participants of the WHI OS gave written informed consent.
Patient charts of women who reported a cancer diagnosis on an annually mailed questionnaire were reviewed by coders trained in Surveillance, Epidemiology, and End-Results (SEER) program guidelines to classify pathology findings according to the ICD-O-3 coding (17). We included B-cell NHL cases that were diagnosed before April 2009. Of 615 incident cases, 493 met the criteria for our study. Excluded were women with cancer history (except non-melanoma skin cancer) at enrollment (n=88) or incident cancer during follow-up but prior to the B-cell NHL diagnosis (n=34). Two additional cases were eliminated because we did not find a matched control (one DLBCL and one follicular lymphoma, see below); therefore, the final number of cases in our study was 491. Our overall case group included any subtype of B-cell NHL, and subtypes were further grouped based on the World Health Organization and the International Lymphoma Epidemiology Consortium (InterLymph) guidelines (18,19), including 142 chronic lymphocytic leukemia/small lymphocytic lymphoma/prolymphocytic leukemia (CLL/SLL/PLL; 28.8% of cases), 138 DLBCL (28.2%), and 102 follicular lymphoma (20.9%); any case not included in one of these subtypes was classified as 'other' B-cell NHL (N=109, 22.2%).
We selected one control for each case from OS cohort members who had never been diagnosed with cancer (except non-melanoma skin cancer) at the time of case diagnosis. Each control was selected using stratified random sampling from the pool of eligible non-cases living at the time of case diagnosis, and was individually matched to its case by birthdate (±1 year), US region (Northeast, South, Midwest, West), and date of enrollment blood draw (±3 months). We successfully matched 491 control participants to the cases (we excluded 2 cases for whom a successful match was not found).
We measured serum levels of soluble receptor molecules (sCD23, sCD27, sCD30, sCD44) and CXCL13 by enzyme-linked immunosorbent assay (ELISA). Assays were carried out according to the manufacturers' protocols for sCD23, sCD30, and sCD44 (Bender MedSystems, Burlingame, CA), CXCL13 (Quantikine™, R&D Systems, Minneapolis, MN), and sCD27 using the PeliKine-compact ELISA Kit and Toolset (CLB/Sanquin, RDI/Fitzgerald, Concord, MA). Case and control serum samples were placed in random order, with matched case/control pairs located next to each other. Several precautions were taken to minimize interassay variation (i.e., variation between runs for each analyte). We purchased all of the ELISAs used in the study for a given analyte from a single lot, to eliminate lot-to-lot variation. We included a standard curve for each ELISA plate; therefore, the values of the study specimens were calculated from a standard curve run on the same plate as the specimens. Additionally, replicate laboratory controls were included in every plate, allowing us to monitor interassay coefficients of variation (CVs), which were <5% based on replicates from three plates selected from the first, middle, and last third of assay plates run. The WHI also included 50 blinded duplicate pairs (100 samples), interspersed randomly among the study samples. Overall CVs based on the blind duplicate samples ranged from 7.0% (sCD30) to 11.7% (sCD23).
All analyses were performed using the SAS system, version 9.1 (SAS Institute, Cary, NC). The immune markers were analyzed as continuous variables as well as categorical variables with cutpoints for each assay set at the quartiles of the control distributions. All of the immune marker variables had non-normal distributions with right-skewing. We transformed these variables using the natural log in order to reduce the influence of extreme values in regression analyses.
We generated odds ratios (ORs) and 95% confidence intervals (CIs) as estimates of relative risks of B-cell NHL associated with higher- versus lower levels of each marker, using conditional logistic regression (20). Statistical significance of the odds ratios was evaluated using the Wald χ2–square test. Initially, each specific marker was modeled separately. Relative risks associated with each continuous marker variable were estimated per unit increase in the analyte level based on a log-linear model for the OR, corresponding to a 2.72-fold increase of the untransformed analyte level. Risks associated with marker level categories based on quartiles were estimated using the lowest category as the referent. We conducted tests for trend across quartiles using a continuous variable with assigned values equal to the intra-category median analyte level among controls. We also created a variable reflecting the number of "high" marker levels for each woman, calculated as the number of markers (out of 5 total) for which a subject had levels in the highest quartile category. We analyzed the number of high marker levels as a set of indicator variables for each possibility (1 through 5, using 0 as the referent).
We tested for etiologic heterogeneity by fitting unconditional polytomous logistic regression models for major subtypes of B-cell NHL, including DLBCL (N=138), follicular lymphoma (N=102), CLL/SLL/PLL (N=142), and 'other' B-cell NHL (N=109), and testing for heterogeneity of risk estimates between each pair of NHL subtypes.
To describe the patterns of association between immune biomarkers and B-cell NHL according to the number of years between blood sample collection and NHL diagnosis ("prediagnostic lag"), we classified NHL cases according to prediagnostic lag increments of <3, 3–5, 6–8, and 9–13 years, chosen to maximize the range between the shortest and longest lags, while including at least 90 cases in each group. We tested whether there was heterogeneity in the associations between the immune markers and NHL according to the length of the prediagnostic lag by fitting unconditional polytomous logistic regression models with NHL categorized in these lag increments, and computing p-values for heterogeneity of risk estimates between specific lag increments. We also evaluated risk estimates according to the prediagnostic lag for DLBCL, follicular lymphoma, and CLL/SLL/PLL subtypes, separately, for the continuous marker measures and the trend variables only (due to sample size limitations in these subtype-specific analyses).
All estimates were adjusted for the matching factors – age, region, and date of blood draw. We also evaluated a set of potential confounders, selected a priori, including race/ethnicity (coded as indicator variables for Black or African American and Other, with White, not Hispanic as the referent), education (coded as grouped linear with 7 categories, as shown in Table 2), body mass index (BMI, coded as continuous), and smoking status (coded as indicator variables for Former and Current, with Never as the referent). Potential confounding was evaluated by the change in the effect estimate for a specific marker when including the covariate in the model compared to the model without the covariates; changes in risk estimates greater than 10 percent were considered as evidence of possible confounding. Certain medical conditions and medications may influence circulating levels of the immune markers we are studying and may also increase risk of NHL. To further evaluate the magnitude of the main associations of interest among otherwise apparently immunocompetent subjects, we conducted subanalyses of the main effects by excluding subjects who reported at baseline that they had ever been diagnosed with certain conditions or taken medications known to be characterized by/cause altered immune status (such as inflammation). Specifically, we excluded subjects who reported a history of systemic lupus erythematosus, rheumatoid arthritis, glucocorticosteroid medications, disease-modifying antirheumatic drugs, colitis, diverticulitis, pancreatitis, kidney stones, gallbladder disease, stomach ulcer, goiter, and asthma.
Our study population of postmenopausal women (Table 1) were mostly 60 years and older at the study baseline (>80% of cases and controls), of white, not Hispanic race/ethnicity (91% of cases and 85% of controls), and educated beyond high school (approximately 80% of cases and controls). Approximately half of the women never smoked, and approximately 60% were classified as overweight or obese (BMI ≥25.0 kg/m2).
The levels of the immune markers we studied (Table 2) differed significantly by age, in that older women had higher levels (sCD27, sCD30, sCD44, CXCL13). Black or African American subjects had lower levels of sCD30 than white or other race/ethnicity groups. Smoking status was a significant predictor of sCD23 and sCD27 levels, with opposite patterns (current smokers had the lowest levels of sCD23 and the highest levels of sCD27). There were some differences of immune marker levels by education, but with no clear pattern. Body mass index was associated with sCD23 (p=0.0002) and sCD44 (p=0.07), with marker levels increasing by BMI category and notably low levels for the small number of underweight controls (N=10). CXCL13 levels were also significantly associated with BMI; however, the only apparent variability in the marker was that underweight women had higher levels than the rest of the BMI categories. The five markers were all significantly correlated with eachother (not shown in tables), with Spearman rank correlation coefficients ranging from r=0.26 (sCD23 with CXCL13) to r=0.59 (sCD27 with sCD30).
Each of the immune markers was significantly associated with increased risk of B-cell NHL, all types combined (Table 3). There was no evidence of confounding by the a priori covariates (race/ethnicity, education, BMI, and smoking status) in any of our analyses of all B-NHL, NHL subtypes, or NHL cases grouped by years since blood draw; therefore, we present risk estimates adjusted for the matching factors only (age, region, blood draw date). The continuous marker variables were all associated with NHL risk, with 2.07 to 5.94-fold increases in risk for each unit increase on the natural log scale (Table 3). When all five markers were modeled together in continuous form (not shown in tables), the risk estimates for B-cell NHL were reduced somewhat but remained increased, with the exception of sCD44 for which the association was reversed (sCD23, OR=1.71 [95% CI: 1.44–2.04]; sCD27, OR=2.64 [(95% CI: 1.43–4.87]; sCD30, OR=1.45 [95% CI: 0.95–2.21]; sCD44, OR=0.42 [95% CI: 0.2–0.92]; CXCL13, OR=1.51 [95% CI: 1.09–2.08]). 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 NHL, and there were significant trends of risk by increasing categories of these markers. CD44 was significantly associated with NHL in each quartile category; however, the risk did not increase across categories (p-trend=0.39). Women with a high level (highest quartile) for any one of the 5 markers had 1.9-fold increased risk of B-cell NHL (95% CI: 1.3–2.8) compared to women without high levels for any of the markers, and the relative risk increased with each additional number of high marker levels (2 high, OR=2.1 [95% CI: 1.4–3.2]; 3 high, OR=2.5 [95% CI: 1.5–4.2]; 4 high, OR=5.5 [95% CI: 3.1–9.7]; 5 high, OR=10.0 [95% CI: 5.0–20.2]).
We saw increased risks associated with CD23, CD27, CD30, and CXCL13 for all the NHL subtypes examined (Table 3); however, there were some significant differences between subtypes in the magnitude of risk estimates (p<0.05 for tests of heterogeneity between subtypes in polytomous regression analyses). sCD23 was more strongly associated with CLL/SLL/PLL than with DLBCL or follicular lymphoma for the continuous measure, the highest-versus-lowest quartile, and the trend variable, and in turn, sCD23 was more strongly associated with follicular lymphoma than DLBCL. For example, each per-unit increase in the continuous sCD23 measure (on the natural log scale) was associated with 4.99-fold increased risk of CLL/SLL/PLL, which was significantly greater than the 1.97-fold increased risk estimated for follicular lymphoma (p-heterogeneity < 0.0001), and this risk estimate for follicular lymphoma was significantly greater than the 1.30-fold risk associated with DLBCL (p-heterogeneity < 0.005). sCD27 associations were stronger for CLL/SLL/PLL than follicular lymphoma for the quartile variables. The relative risk estimate associated with the sCD30 continuous measure was significantly higher for follicular lymphoma than CLL/SLL/PLL, and the trend across quartiles was stronger for follicular lymphoma or DLBCL than for CLL/SLL/PLL. sCD44 results were stronger for the highest-versus-lowest quartile for DLBCL than CLL; however, there was no clear risk trend across quartiles for DLBCL. CXCL13 associations were stronger for DLBCL and follicular lymphoma than for CLL/SLL/PLL for the continuous measure and the highest-versus-lowest quartile, and the trend across quartiles was stronger for DLBCL than for CLL/SLL/PLL. Similar to observed associations for the three subtypes examined, the risk of 'other' B-cell NHL was significantly elevated by continuous marker levels of sCD23 (OR=1.50, 95% CI: 1.20–1.89), sCD27 (OR=5.23, 95% CI: 3.04–9.01), sCD30 (OR=2.02, 95% CI: 1.32–3.10), and CXCL13 (OR=2.66, 95% CI: 1.93–3.68), but not sCD44 (OR=1.94, 95% CI: 0.89–4.25).
In polytomous regression analyses with B-NHL cases grouped by the lag time between (prediagnostic) blood draw and diagnosis (Table 4), CD23, CD27, CD30, and CXCL13 were all significantly associated with increased risk of NHL when measured in samples collected as early as 9–13 years before diagnosis, whereas CD44 was associated with NHL risk (albeit inconsistently) only when measured in samples collected within 8 years of the diagnosis. Nevertheless, there was significant heterogeneity in the results by the length of the prediagnostic lag (based on p<0.05 for tests of heterogeneity between cases grouped by lag time in polytomous regression analyses) that indicated generally decreasing strength of associations with increasing time between blood draw and NHL diagnosis. The continuous measure for each marker was more strongly associated with NHL cases with <3 years prediagnostic lag than for cases with 9–13 years lag; for example, sCD30 was associated with 4.08-fold increased risk of NHL for cases with <3 years prediagnostic lag, versus 2.03-fold increased risk for cases with 9–13 years lag (p-heterogeneity = 0.009). The most consistent pattern of risk decreases by increasing lag time were observed for sCD23 and sCD27, for which the continuous marker measure was more strongly associated with NHL cases whose blood samples were collected in the <3 years before diagnosis than for any longer lag, and the trend across quartiles was less strong for cases with 9–13 years lag than for cases with any shorter lag. Similar results were seen for sCD30, CD44, and CXCL13 with statistical significance for some, but not all pairwise lag increment comparisons.
Of the subtypes examined, CLL/SLL/PLL was most strongly associated with sCD23. The continuous sCD23 measure was significantly associated with CLL/SLL/PLL within each prediagnostic lag category (lags of <3 years and 9–13 years are shown in Figure 1); however, the association was significantly stronger for CLL/SLL/PLL cases with blood draw <3 years before diagnosis (OR=14.5, 95% CI: 8.10–25.8) than for longer lags (for example, for cases with 9–13 years lag, OR=4.62, 95% CI: 2.81–7.62; p-heterogeneity = 0.0003). The trend of increasing risk across quartiles of sCD23 was significant for CLL/SLL/PLL cases within each prediagnostic lag increment, although the trend was significantly stronger for cases with <3 years lag compared to those with 9–13 years lag (p-heterogeneity = 0.04). Similar heterogeneity by prediagnostic lag was seen for sCD27 and sCD30 associations with CLL/SLL/PLL (Figure 1). DLBCL associations with each immune marker tended to drop off with a longer lag between blood draw and diagnosis (Figure 2). There were no statistically significant associations with the continuous marker measures for DLBCL cases with 9–13 years lag since blood draw, and no indication of a trend across quartiles for the 9–13 years lag, except for CXCL13 (p-trend = 0.07). For example, the association with sCD44 was significantly stronger for DLBCL cases with blood draw <3 years before diagnosis (OR=8.74, 95% CI: 1.95–39.2) than for 9–13 years lag (OR=1.08, 95% CI: 0.26–4.51; p-heterogeneity = 0.04). DLBCL associations with CXCL13 were not significantly different between lag increments. There was no significant heterogeneity by length of the prediagnostic lag for any of the immune marker associations with follicular lymphoma (Figure 3). Nevertheless, associations did decrease slightly with longer lags for sCD23, sCD27, and sCD30. For example, there was 7.71-fold increased risk associated with the continuous sCD30 measure for follicular lymphoma cases with <3 years prediagnostic lag (95% CI: 3.61–16.5) and 4.53-fold increased risk observed for cases with 9–13 years lag (95% CI: 2.01–10.2), and the trend of increasing risk across quartile categories was significant for all lag increments except 9–13 years.
The associations we observed were robust to exclusion of study subjects reporting immune-related medical conditions or medications at baseline (not shown in tables). For example, in these analyses (n=346 cases, 349 controls), risk of B-cell NHL was significantly elevated for the continuous measure, the highest-versus-lowest quartile, and the trend variable for sCD23, sCD27, sCD30, and CXCL13, with risk estimates for the highest-versus-lowest quartiles ranging from 2.5 for sCD30 (95% CI: 1.5–4.2) to 6.3 for sCD23 (95% CI: 3.4–11.8).
Our research was inspired by previous prospective studies that have found these and other immune biomarkers of B-cell activation to be associated with risk of NHL among HIV patients (5–7,9–11,21). Based on the findings of the studies among immune compromised patients, we hypothesized that a B-cell stimulatory host environment increases the risk of B-cell NHL among immunocompetent persons. The prospective design of the WHI OS and the banked samples offered a valuable resource to identify markers of subclinical B-cell activation associated with NHL incidence in a sizable study. We found strong associations between B-cell NHL and sCD23, sCD27, sCD30, and CXCL13, with risks that increased significantly by increasing levels of the markers.
The markers we studied are all indicative of, or involved in B-cell activation. CD23 is an Fc receptor for IgE that is upregulated on activated B cells. Its soluble form, sCD23, is released from activated B cells and can itself induce further B-cell stimulation, including enhancement of Ig class switch recombination (22). CD27 and CD30 are both members of the TNF-receptor superfamily (23,24). CD27 interacts with other molecules to provide co-stimulatory signaling in the activation of both T- and B cells to proliferate and produce cytokines or immunoglobulins.(8) CD30 is preferentially expressed by activated type-2 T cells which produce cytokines that support or enhance B-cell activation and/or differentiation (25). Higher levels of both sCD27 and sCD30 have been found in persons with immune system activation, such as those with autoimmune disorders, hepatitis B and C viruses, and HIV (26,27). CXCL13 is a chemokine that plays a central role in the homeostatic trafficking of B cells, through interactions with its only known receptor, CXCR5, which is commonly expressed on resting B cells (28). The markers we studied are correlated, which was not unexpected, given their related roles in immune activation. Regardless of these correlations and the possibility of one marker serving as a surrogate for a true association with a related molecule, an association with any of the markers we studied would suggest a role of B-cell activation in development of B-cell NHL. Furthermore, even surrogate markers may be useful in development of screening tests for NHL. There remains the possibility that these markers may be predictive of other types of cancer (or other diseases) in addition to NHL, and the specificity of the associations to NHL would need to be examined before the utility of the markers for screening could be determined.
An important question in studies such as ours is whether the markers (or B-cell activation, in general) are etiologically associated with the disease in question (i.e., causal) or whether they are simply elevated in response to as-yet undiagnosed disease (i.e., reverse causation). While this is impossible to determine in an observational study, we assumed that if risk estimates were stronger for cases with a short lag between blood draw and diagnosis than for those with longer lags, this was likely indicative of elevations in the marker due to undiagnosed disease. Some of these molecules, such as sCD27, have been previously associated with lymphoma tumor load (29), providing a basis for speculation that associations we observed may reflect undiagnosed B-NHL or a precursor lesion. We did observe the strongest associations for cases with the shortest prediagnosis lag (<3 years). However, there were also relatively strong, significant associations for cases with the longest lag (9–13 years), suggesting either an etiologic role of B-cell activation, correlation with another etiologic process (i.e. association due to confounding), or a prolonged occult phase of B-NHL. Theoretically, the same molecule could play a causal role in NHL development, as well as be subsequently upregulated after tumor formation, and our results may reflect both scenarios.
The presence of a consistent association of these markers with B-cell NHL across histologic subtypes and over a number of years argues that these associations cannot be attributed to undiagnosed disease in all instances. There is currently no evidence that most lymphoma subtypes, including DLBCL or follicular lymphoma, are preceded by significant circulating subclinical clonal lymphocyte expansions. However, specific associations that we note with a short time lag may reflect undiagnosed disease, particularly for CLL/SLL. It is now well established that CLL/SLL is preceded in virtually all instances by small, preclinical clonal lymphocyte expansions termed "monoclonal B-cell lymphocytosis" (MBL) (30,31). CD23 is known to be expressed by the neoplastic lymphocytes in CLL/SLL, and increased levels of sCD23 have been associated with CLL/SLL diagnosis and may be of prognostic significance (32,33). It is therefore likely that the marked elevation in risk of CLL/SLL associated with increased sCD23 close to the time of diagnosis reflects the presence of preclinical disease in these patients. The same may also apply to the associations with sCD27, as CD27 has also been shown to be expressed on clonal lymphocytes in both MBL and CLL/SLL (33). However, even if this is the case it does not necessarily imply that weaker associations observed with a longer time lag reflect undiagnosed disease, even for CLL/SLL. At this time it is not well-documented whether MBL populations may precede a clinical diagnosis of CLL/SLL by as much as 9 years, and it is also unclear whether very small MBL populations would contribute significantly to circulating levels of these markers.
Our study is the largest to date of the biomarkers we studied in relation to risk of NHL and was well-powered, as evidenced by narrow confidence intervals for our main analyses (confidence interval widths of <3). Nevertheless, B-cell NHL is quite heterogeneous, and we had adequate power for separate analyses of only the more common NHL subtypes. Our results provide evidence that the association with B-cell activation is not limited to the aggressive forms of NHL that predominate in HIV, based on similar associations we observed with indolent lymphomas such as follicular lymphoma and CLL/SLL. In our study, follicular lymphoma was the subtype with the most consistent associations regardless of the lag time between blood draw and diagnosis. We also observed the strongest associations for sCD30 with follicular lymphoma, as did Purdue et al (13). However, we had only 15 follicular lymphoma cases with 9–13 years between blood draw and NHL diagnosis, limiting our power to detect differences by lag time. Much larger samples will be needed to further characterize the heterogeneity by both NHL subtype and the lag between blood draw and diagnosis.
Our findings indicate a prominent role for B-cell activation in the etiology of B-cell NHL and/or in processes reflective of early disease. Our study population consisted of post-menopausal women who were primarily of white race and well-educated, and the generalizability of our findings to the general population is unknown. Further investigation of this biologic pathway in prospective studies is warranted, both for increasing understanding of NHL etiology and well as for development of diagnostic/predictive markers.
The authors thank the WHI investigators and staff for their dedication, and the study participants for making the program possible. A listing of WHI investigators can be found at http://www.whiscience.org/publications/WHI_investigators_shortlist.pdf.
This WHI ancillary study was funded through a contract with the National Heart, Lung, and Blood Institute under the Broad Agency Announcement mechanism ("Markers of B-Cell Stimulation as Potential Predictors of Non-Hodgkin Lymphoma", BA13). The work was carried out, in part, in the facilities of the UCLA AIDS Institute, which were supported, in part, by funds from the James B. Pendleton Charitable Trust and the McCarthy Family Foundation. The WHI program is supported by contracts from the National Heart, Lung and Blood Institute, NIH.
Conflicts of interest: None
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Double rifle
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A double-barreled rifle or double rifle is a type of sporting rifle with two barrels instead of one, available in either "side-by-side" or "over-and-under" barrel configurations (the former being traditional). It is basically identical to a side-by-side or double barreled shotgun, only with rifle barrels instead of shotgun tubes.
Double rifles are one of the family of combination guns. In general, double rifles are much more expensive than the more common magazine-fed, bolt-action repeater rifles. They are usually targeted at serious "professional" or big-game hunters, and also tend to be expensively finished; this aspect, their cachet and their high price is another parallel with double barrel shotguns, many of which run in the thousands, or even tens of thousands, of dollar range. Although a double rifle can be made in any caliber, traditionally, they are manufactured as large-bore hunting rifles, in cartridges like the .300 H&H Magnum and other large calibers, up to .500 Nitro Express and larger. They are considered the classic African safari "stopping gun", a powerful rifle intended for quickly stopping an enraged and charging animal (for example, a Cape Buffalo that has been shot but only wounded), due to their powerful loadings, instinctive handling and quick follow-up shots, and almost 100% reliability rate. Because of the usual nature of their use, most double rifles use "iron sights", which are more ideal for close-range, fast shooting, unlike bolt-action rifles, which are frequently given telescopic sights for improved long-range accuracy. Also, because they do not have the lengthy action of a bolt-action rifle, a double can have just as long a barrel (to maximize velocity for a particular loading) and yet be significantly shorter in overall length (as well as having quick and balanced shotgun-like handling), thus making it better to use in close brush and cover.
While double rifles originated as muzzleloaders able to make a rapid second shot without reloading (crucial for big game), modern double-rifles are breechloaders, with "break open" actions, where the barrels are pivoted on the stock; releasing a catch causes the barrels to hinge downward, exposing the chambers and (usually) ejecting the cartridges. Each barrel accepts a single round only. Early double rifles used manually cocked external hammers, from the days of black-powder and muzzle-loading, well into the days of the breechloader, due to the need for absolute simplicity and reliability. However, most now feature internal, self-cocking strikers that cock upon closing the action. In either configuration, the gun can either feature twin triggers fore and aft (one for each barrel), or a single trigger and a selector switch that selects which barrel the user wishes to fire.
While double barrel rifles were invented to give more firepower than a single-barrel muzzle-loading rifle, modern magazine-fed rifles are able to hold more ammunition than a double rifle. However, no matter what sort of repeating rifle one uses, there is always a possibility of it jamming, and a double barrel can make a follow-up shot faster than a bolt action; semi-automatic guns are very rare for big-game hunting, due to higher possibility of failure, and the difficulty of designing an action strong enough to withstand the powerful cartridges typically used. Another advantage of a double rifle is that the two chambers can hold different loads, each selected for a different sort of game or different field conditions. For example, one barrel can be loaded with a cartridge with a very heavy bullet for close-range stopping power or shooting through brush, while the other is loaded with a lighter, faster bullet ideal for smaller game or targets at distance in the open. This is similar in concept to other combination guns that take the idea further and provide barrels firing completely different calibers, or even one shotgun barrel and one rifle barrel. A magazine fed rifle can only fire the round chambered without reloading or switching to a different gun. However, this capability is rarely used in the field, as most of these guns are reserved for close-range stopping power, and in an emergency situation, one wants both rounds to behave the same and give maximum stopping power. A typical double rifle exists only to give two very powerful, 100% reliable shots at a selected target at relatively close range.
Manufacturers of double rifles[edit]
- Holland & Holland
- Heym
- Hartmann & Weiss
- Westley Richards
- Blaser
- Merkel
- Verney-Carron, French, imported by Verney-Carron US
- Aya, Spanish
- James Purdey and Sons
- John Rigby and Company
- B. Searcy & Co., USA
- Anderson Wheeler
- Fausti
- Baikal
- Davide Pedersoli
- Merkel


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Stories from Kandahar, the Afghan province Canada left behindToday, Panjwai district centre is a short strip of bread nailed to wooden beams, meat hanging on hooks, stalls selling seasonal fruit: mangoes from Pakistan and oblong cantaloupes from nearby fields. Here, Haji Mahmood, a tribal elder, explained how ... OpenCanada.org, 5 days ago
15 images for panjwai district
Canada promotes first female combat general
courtesy of National Defence / Government of Canada shows Colonel Jennie Carignan patrolling in Nakhonay, District of Panjwai, Afghanistan, in February 2010 A Canadian woman who fought insurgents in Afghanistan became the country's first female ...MSN News Canada, 1 month ago
Book Review: Afghanistan, Pakistan and India: A Paradigm Shift
By Khan Wali Khan Basharmal Shaida Mohammad Abdali serves Afghanistan as its ambassador to India, as well as serving as a non-resident ambassador to Nepal, Bhutan and the Maldives. He previously held the position of Deputy National Security ...South Asia Monitor, 2 days ago
Feature: Farmers switch nefarious poppy cultivation for grapes as security situation in S. Afghanistan improves
"I am delighted to embark on this new journey of producing grapes to sell to make a living for my family rather than having to produce poppy plants for the drug trade," Ajab Khan, a farmer in the southern Kandahar province, told Xinhua. While ...China.org.cn, 1 week ago
Appointment of the new Taliban leader may open the way to the return of Al Qaeda in Afghanistan
The latest developments in Afghanistan demonstrate not only the negative perspectives for national security but also trigger fears about a possible return to a situation similar to that before 9/11. In fact, despite the killing of the Taliban leader ...ESISC, 1 week ago What has the appointment of Taliban's new leader meant for Afghans? Huffington Post, 1 month ago Afghanistan sees Taliban leader as rigid conservative uninterested in peace Yahoo! UK and Ireland, 1 month ago Mullah Haibatullah: Why has Taliban chosen a scholar over a warrior? Oneindia, 2 months ago
U.S. troop cut won't impact mission in Afghanistan: U.S. general
. U.S. Army soldiers from the 2nd Platoon, B battery 2-8 field artillery, fire a howitzer artillery piece at Seprwan Ghar forward fire base in Panjwai district By Phil Stewart KABUL (Reuters) - President Barack Obama's decision to withdraw roughly ...Investing.com, 2 weeks ago Retired generals, diplomats urge Obama to keep Afghanistan troop level Business Insider, 1 month ago
Malaysian police say the Islamic State has carried out its first successful attack in the country. Inspector-General of Police Khalid Abu Bakar told CNN that a grenade attack on June 28 at a nightspot near Kuala Lumpur, the country's capital, was ...Malaysia Chronicle, 2 weeks ago
Gunman kills family of seven in Kandahar
Array AT-KABUL : A family of seven including three women was shot dead by an anti-government armed militant in southern Kandahar province, local officials said on Saturday. The shooting took place late Friday in the Shahwali Kot district ...Afghanistan Times, 3 weeks ago
Liberal MP's flyer wrongly claims government restored lifelong pensions for veterans
'Personally, I think he's trying to pull the wool over people's eyes,' father of Afghan veteran says A Liberal MP has sent flyers to his constituents touting the government's record on the veterans file, claiming it has already restored lifetime ...CBC, 1 month ago
14-year-old detained for suicide attack in Afghanistan's Kandahar province
A 14-year-old boy has been detained by Afghan Border Police forces before he managed to carry out a suicide attack on senior government officials in southern Kandahar province. The local government officials said the boy was encouraged to target the district ...Sify, 1 month ago
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What is bullying?
- Bullying is an intentional act. The child who bullies wants to harm the victim; it is no accident.
- Bullying involves repeated occurrences. Bullying is not generally considered a random act nor a single incident. Rather, a child is repeatedly picked on by another child or is the target of harassment from a whole group of children. It is the repeated nature of bullying that causes anxiety and apprehension in victims, such that the anticipation of bullying becomes as problematic as the bullying itself.
- Bullying is characterized by a power difference; an unfair fight where the child who bullies has some advantage or power over the child who is victimized. Bullying is not the same as "playing around," it is about the abuse of power.
Practical Expert Advice
My Child is Being Bullied
How to Make a Difference at School
Myths & Facts about Bullies & Victims
|Bullies are rejected by their peers and have no friends.
|Many bullies have high status in the classroom and lots of friends.
|Bullies have low self-esteem.
|High self-esteem can sometimes encourage bullies.
|Being a victim builds character.
|Bullying experiences increase children's vulnerabilities.
|Many childhood victims of harassment become violent as teens.
|Victims of bullying are more likely to suffer in silence than to retaliate.
|There is a victim personality.
|There are usually a combination of situational and social risk factors apart from certain personality traits that make children vulnerable.
|Bullying involves only perpetrators and victims.
|Bullying incidents are typically public events that have witnesses.
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It is no fun to be on the receiving end of bullying. The immediate effects-physical injury, humiliation, helplessness,...Source: Pearson Allyn Bacon Prentice Hall
Four Strategies for Teachers and Parents to Pass on to Kids who Witness Bullying
Parents and teachers are sometimes unsure of what to say when a child or youth asks, "What should I do if I see...Source: Bullying Special Edition Contributor
Adjustment Problems Associated with Bullying
Experts currently recognize roughly three categories of students involved with bullying: bullies, passive victims, and...Source: Pearson Allyn Bacon Prentice Hall
Stopping Bullying Behaviors: Advice for Parents and Caregivers
Every day in our schools (and communities) children are teased, threatened, and tormented by bullies. Bullying has been...Source: Substance Abuse and Mental Health Services Administration
Why Don't Kids Report Bullying?
There is good evidence that young people often do not report bullying to adults. They are adept at hiding...Source: Committee for Children
Is my child bullied?
Possible warning signs:
- Numerous lost belongings
- Frequent injuries or damage to clothes or property
- Spends time primarily with younger students (may indicate a problem with peers)
- Avoids recess (i.e., playground) before, during and/or after school
- Arrives to school late or just at the starting bell
- Appears to be alone most of the time at school
- Obtains an excessive or insufficient amount of sleep


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We really enjoyed our meal, but the only negative was that we had a 9:45p dinner reservation, and when we got to dessert they said we couldn't get anything because the kitchen was closed. Really? We just wanted anything sweet at that point, and they said there was nothing available.
With that aside, here are some of the things we loved:
-Cotton candy bacon (must get)
-Tuna with jalapeño appetizer (we got 2!)
-Black kale salad
-Wagyu strip
The side dishes were great too - mac and cheese, brussels sprouts, sweet potatoes, and creamed spinach.
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Sen. Elizabeth Warren (D-Mass.) is relishing her role as one of Hillary Clinton's most effective attack dogs against Donald Trump.
Warren's criticism of Trump in tweets and speeches has gotten under the Republican presidential nominee's skin, provoking angry outbursts from the billionaire businessman.
She's has shown a talent for irking Trump — mainly on Twitter — and moving him off message, which is something Trump's GOP primary foes struggled to do.
Scott Ferson, a Boston-based Democratic strategist who voted for Clinton in the primary, said Warren's attacks were effective because she knows where to aim and has the credibility to back it up.
"She knows how to hit Trump where he lives," said Ferson. "I would have hated to be Elizabeth Warren's younger brother."
The liberal stalwart homed in on Trump's business background and derogatory comments about women, labeling him a con artist who's bilked his way into striking distance of the White House.
Soon after Trump announced Indiana Gov. Mike Pence as his running mate, Warren tweeted that the duo was a perfect match: "Two small, insecure, weak men who use hate & fear to divide our country & our people."
Trump changed the subject and countered that Warren was a "fraud" who lied about having Native American ancestry. Warren shot back with comments about the lawsuits he faces over Trump University while defending her own credentials.
"It might blow your mind that a woman worked hard & earned a good job on her own," she tweeted, "but it's not the 1800s. It happens."
Warren also joined a chorus of Democrats calling for Trump to publicly release his tax returns, implying that the real estate mogul is hiding a bombshell.
"Maybe he's just a lousy businessman who doesn't want you to find out he's worth a whole lot less than he claims. We really can't know for sure," Warren said in a video for progressive nonprofit MoveOn.org.
And when Warren campaigned with Clinton for the first time, on June 27, she used the stage to knock Trump's ethics.
"What kind of a man roots for people to lose their jobs, lose their homes, lose their life savings? I'll tell you what kind of a man: a small, insecure money-grubber who fights for no one other than himself," she said. "What kind of a man? A nasty man who will never become president of the United States."
Democratic strategist Craig Varoga said Warren "expresses well thought-out plans in pithy sound bites."
Trump has trouble with people attacking him, "especially a well-educated, forceful woman," Varoga added.
Warren, a former law professor, has spent her career advocating for and proposing economic policies aimed at reining in Wall Street and big corporations and helping the middle class and the poor.
Her authenticity and credibility on economic issues could help energize people who backed Sen. Bernie Sanders (I-Vt.) during the Democratic primary and persuade undecided voters to vote for Clinton.
"She's uniquely suited to talk about economic solutions to the problems that both Trump and Sanders have identified and talked about so far," such as bad trade deals and the struggles of the middle class, Varoga said.
Warren targeted Trump even before endorsing Clinton, and she continued as the presumptive nominee deliberated about choosing a running mate.
But Warren is unlikely to stop attacking Trump and pushing her economic message just because she won't be the vice presidential nominee, say allies on the left.
"She's motivated by a policy agenda she believes in," said Adam Green, co-founder of the Progressive Change Campaign Committee. "She's not motivated by a desire to audition for a title."
Ferson agreed, noting Warren's past tension with Clinton gives her no reason to stick her neck out.
"She is really, really afraid of what Donald Trump will do if he becomes president," said Ferson. "Elizabeth Warren has no reason from a personal standpoint to help Hillary Clinton."
Warren energizes progressives and Democrats as a whole because "she is fearlessly willing to speak truth to power," said Neil Sroka, communications director at Democracy for America. His group and MoveOn had partnered on the "Run Warren Run" campaign from December 2014 to June 2015 to encourage the senator to run for president.
Warren's comments resonate with progressives and people across the political spectrum because she has a plain, easy-to-understand way of speaking and "her integrity is self-evident," said MoveOn Communications Director Nick Berning.
She can also appeal to undecided voters who may be attracted to Trump's economic message because she provides more substance, experts said.
Warren's progressive credentials give Clinton a much-needed bridge to the left wing of her party.
Though Warren criticized Clinton's economic stances long before she joined the Senate in 2013 and held out on an endorsement in 2016 until the former first lady had clinched the nomination, she's insisted Clinton is the best person to fight for middle- and working-class families.
"For 25 years … the right wing has been throwing everything they possibly can at her. What she's done is she gets back up, and she gets back in the fight," Warren told MSNBC upon endorsing Clinton on June 9.
"You also have to be willing to throw a punch, and there are a lot of things people say about Hillary Clinton, but nobody says she doesn't know how to throw a punch," she said.
Warren is the "best person to raise money, excite the base and maximize turnout for the base," said Ferson. "There's no one who provides that excitement in the way that Elizabeth Warren does."
By Naomi Jagoda and Sylvan Lane
By Ayesha Rascoe and Roberta Rampton
WASHINGTON (Reuters) – The dark vision of America under siege described by Donald Trump in his acceptance speech for the Republican presidential nomination does not mesh with reality, U.S. President Barack Obama said on Friday.
Obama noted that the "birds were chirping and the sun was out" for most Americans after Trump's Thursday night speech, which expounded on the threats to America from illegal immigrants, Islamic State militants, and race-related violence.
"This idea that America is somehow on the verge of collapse, this vision of violence and chaos everywhere, doesn't really jibe with the experience of most people," Obama said at a White House news conference after meeting with Mexican President Enrique Pena Nieto.
Obama said the violent crime rate in America has been lower during his 7-1/2 years in office than any time during the last three or four decades, despite an "uptick" in murders in some cities this year, and the recent high-profile killings of black men and police officers.
The timing of Obama's quickly arranged short meeting with Pena Nieto presented both leaders with a convenient platform from which to criticize Trump.
Just three weeks ago, Obama – who has six months left in the White House – invited the Mexican president to visit one last time before the U.S. president leaves on Jan. 20.
Trump has pledged to build a wall at the Mexico border to keep out illegal immigrants and drugs, and to force Mexico to pay for it.
The New York businessman has also promised to slap tariffs on some U.S. products made in Mexico, and seek radical changes or even discard the North American Free Trade Agreement (NAFTA) between the United States, Mexico and Canada.
Pena Nieto was first to mention Trump, but said he respected both Trump and presumptive Democratic presidential nominee Hillary Clinton, and would work with constructively and in good faith with whoever wins the Nov. 8 election.
In March, Pena Nieto likened Trump's "strident tone" to the ascent of dictators Adolf Hitler and Benito Mussolini. But he said on Friday that he had never pointed the finger at any of the candidates, saying that anything he had said had been taken out of context.
And he stressed that the two nations' futures were closely bound.
"The closeness between the United States and Mexico is more than a relationship between governments. It's a solid and unbreakable relationship between millions of people who live in both nations," Pena Nieto said.
Obama said the rate of illegal immigration is down from past decades, and praised Mexico for helping to address a flood of migrants fleeing Central America and for work on drug trafficking.
"A Mexico that has a healthy economy, a Mexico that can help us build stability and security in Central America, that's going to do a lot more to solve any migration crisis or drug trafficking problem than a wall," Obama said.
Obama and Pena Nieto praised the 12-nation Trans-Pacific Partnership (TPP) trade deal as addressing some of the criticisms of NAFTA. Both Trump and Clinton have said they oppose the TPP, which has yet to be ratified by the U.S. Congress.
"There are going to be different visions about where we should go as a country," Obama said, running down a list of economic issues facing the nation.
"But we're not going to make good decisions based on fears that don't have a basis in fact," he said.
(Additional reporting by Doina Chiacu, David Alexander and Eric Walsh in Washington, and Dave Graham, Ana Isabel Martinez, Adriana Barrera and Michael O'Boyle in Mexico City; Editing by Jonathan Oatis)
In a Facebook post that had garnered more than 49,000 shares at the time of this story's publication, Davenport described an event when her train was stalled at South Station. A conductor, who had asked a group of black teenagers to quiet down, called on MBTA police after the teens "mouthed off," according to Davenport.
When the MBTA police arrived, they asked the teens to de-board. The teens obliged. The officers then ordered a 16-year-old boy to leave, as well.
The 16-year-old wasn't part of the group—he told the police this, Davenport wrote, but they still ordered him off.
As I begin to put my headphones back on the police reenter the car. They look at the boy and say,
"We said everyone in the group has to get off."
The boy says,
"I don't know them."
The police say,
"It's an order. Everyone in the group has to get off."
I collect my bags. The police looks at me and says,
"Not you. You're not in the group."
The police places his hand on the boys shoulder and guides him off the train. In a moment of temporary rage blindness I stand up and scream,
"He doesn't fucking know those kids."
The police looks at me and says,
"Is that true?"
To which I say,
"Yes, and it was true when he said it too."
The police release the boy and he sits down across from me again. We share a moment of blankness and then tears well in both of our eyes. He waves me over to the seat next to him. He says,
"That was because I am black. Wasn't it?"
I nod. He looks down sheepishly at his shirt and says quietly,
"I'm just happy they didn't hurt me. That would kill my mom. And she is not someone you want to mess with."
I say the only thing I can think,
"I'm so sorry."
He says,
"With all that's going on in the world I am so scared all the time."
In a statement, MBTA Transit Police Superintendent Richard Sullivan said that he took immediate steps to understand what transpired on the stalled train at South Station. He said he reviewed public safety cameras and audio tapes and also spoke with MBTA employees and the "MBTA passenger who raised the matter."
"My preliminary findings suggest our officers conducted themselves with a calm and professional demeanor," Sullivan said in the statement. Those preliminary findings "suggest TPD officers requested a disorderly group of young people exit from the train with the understanding and explicit directions they would be allowed to board the next southbound train."
He continued: "There was another young male, who was seated in close proximity to the group, who was also asked to exit the train. Once off of the train, this male explained he was not with and/or associated with the group. This was confirmed by the larger group as well as an independent passenger. At this point the young male was allowed back on the train and continued about his business."
On Wednesday night around 9 p.m., Mercedes Farguarson said her son, Jelani, called her from the train saying that there was "some confusion," but he didn't want to talk about it right then. When he got home later than his curfew, he told her what happened.
Farguarson said her son was calm after sharing, but that she became angry.
"The kids were telling [the police] that they didn't know him, and it took a white woman to get up and yell and scream and say this kid is innocent for them to leave him alone," she said.
After finding Davenport's Facebook post, Farguarson said she showed Davenport's Facebook picture to Jelani, who confirmed that she was the woman who stood up for him.
Davenport said that the response to her post has been overwhelming, but she wants to reiterate that her point was to share Jelani's story.
"I've been getting a lot of attention for it, but the post doesn't have much to do with me," she said in a phone call. "I was just reporting. … I want to make sure the focus remains on what the post is about, and Black Lives Matter, and not me."
The Transit Police have reached out to Jelani and his mother, according to Sullivan's statement.
"We are continuing to look into this matter and are committed to serving our riding public with the utmost dignity and respect."
Three years after the Black Lives Matter movement began, not everyone understands the movement's mission. And as evidenced during the Republican National Convention, some people like Donald Trump are invested in exploiting those misunderstandings for political points.
But the fire Trump's igniting is fueled by a country that has historically resisted black social justice movements.
According to American National Election Studies, 57 percent of Americans in 1964 said most of black people's actions during the Civil Rights Movement in the most recent year were violent. Sixty-three percent of Americans believed that the Civil Rights Movement was moving "too fast." And a majority of Americans (58 percent) believed that black people's actions for the movement hurt their own cause.
Sound familiar?
And just a reminder: Two of the key actions by civil rights activists in 1963 were the March on Washington, where Dr. Martin Luther King, Jr. gave his famous "I Have a Dream" speech; and "Bloody Sunday," where Alabama state troopers brutally beat peaceful protestors attempting to march from Selma to Montgomery for their right to vote.
But Americans today share similar attitudes toward the Black Lives Matter movement.
According to the Pew Research Center, 43 percent of Americans support the Black Lives Matter movement.
Thirty-six percent of Americans of who have heard about Black Lives Matter don't really understand its goals.
And Americans are split on the effectiveness of the movement in achieving racial equality in the long run: while 8 percent say Black Lives Matter will be very effective, 30 percent say Black Lives Matter will be somewhat effective, compared to 33 percent who doubt the movement's effectiveness. The remaining 29 percent either weren't familiar with the movement or did not provide an opinion.
There are racial and political differences in attitudes. Forty-one percent of African Americans strongly support the movement, while white American's attitudes seem to be split: 26 percent somewhat support the movement and 28 percent expressed opposition to it. Only 14 percent of white Americans strongly support it. But among white Americans, most white Democrats support the movement (64 percent) compared to white Republicans, most of whom oppose the movement (52 percent).
Without a doubt, Trump is propelling himself to victory as 2016's "law and order" candidate and pledging to "Make America Safe Again" by mischaracterizing the Black Lives Matter movement, the most pressing racial justice movement of our time. But it would also be inaccurate to say that Americans haven't done the same with similarly necessary black-led social justice movements of the past. (Emphasis are mine – ks)
The cleaner the election, the better chance the Republicans have.
CLEVELAND, OHIO — As the Republican National Convention unfolded in Cleveland this week with the Republican Party officially calling for measures to make it harder for people to vote, two different courts across the country issued rulings easing those restrictions.
Federal judges this week ruled against voter identification laws in Wisconsin and then Texas, finding that they disproportionately impact minority voters and violate the Voting Rights Act. Those photo ID laws, which have become more prevalent across the country in the years since the U.S. Supreme Court gutted the VRA in 2013, are formally included in the GOP platform.
"We support legislation to require proof of citizenship when registering to vote and secure photo ID when voting," the document reads. "We strongly oppose litigation against states exercising their sovereign authority to enact such laws."
Despite evidence that voter fraud is virtually non-existent and that photo ID laws keep younger, low-income, minority voters from participating in elections, Republican delegates told ThinkProgress the two recent court decisions will hurt democracy and compromise elections.
"Why do we even have any sort of laws? Why do we have speed limits? Why do we have any keys on any doors?" Milwaukee election commissioner and delegate Bob Spindell asked. "We need laws in place because if the election is such, there's no way really to go back afterwards and see what had happened, if somebody was legit or somebody was not."
In the ruling this week, the Wisconsin judge found that the fears of voter fraud are not legitimate enough to warrant the suppressive laws. A Wisconsin study examining the 2004 election found just seven cases of fraud among the 3 million votes cast in the state's 2004 election, and none were the kind of fraud that would be prevented by a voter ID law.
Nonetheless, Rep. Glenn Grothman (R-WI) called the recent court ruling unfortunate and said it will allow Democrats to commit voter fraud.
"I find it interesting that the Democrats don't care that you've got to present a photo ID to get medication, they don't care about that, but they do care about photo ID for voting, which makes me wonder if they're doing something wrong about the voting," he told ThinkProgress from the floor of the RNC.
Also standing among Wisconsin's delegation near the RNC arena stage, Spindell said Tuesday that he has been involved in the past several elections in Milwaukee and has seen "no problem whatsoever" with the state's voter ID law.
"I don't know of even one instance in the city of Milwaukee during the last couple of elections where there was a problem where somebody couldn't have an ID or didn't have an ID and couldn't vote," he said.
As ThinkProgress reported during the Wisconsin primary in April, Milwaukee students were forced to wait in long lines to register and cast ballots on election day, in large part because the state's voter ID law does not accept student IDs. Across the state, non-white voters were more likely to request a free ID card and were more likely to be denied from the polls.
Noting that impact, the Wisconsin federal judge this week shot down the law because it would be "impossible or nearly impossible" for thousands of qualified voters to obtain a free ID card in order to cast a ballot. The ruling will allow Wisconsin citizens to vote without ID this November if they sign an affidavit attesting to their identity.
Spindell said that the acceptance of affidavits, coupled with Wisconsin's allowance of same-day voter registration, will lead to people committing voter fraud. "You can just walk in with all sorts of IDs, whether it be a payroll check or any kind of ID," he said. "What can happen is they can register and go vote, and there's no way of checking on them into well after the election."
In perhaps an even more important decision for civil rights, the United States Court of Appeals for the Fifth Circuit handed down a decision Wednesday finding that Texas' voter ID law violates the VRA. But instead of striking down the law, the appeals court left it up to the district court to decide how to move forward and whether or not the law should be in place during the general election.
If the court strikes the law down before November, Jim Lowder, a Texas delegate who serves as the GOP chairman in Amarillo, Texas, said that we can expect to see Democrats committing voter fraud.
"How many cases of Republican voter fraud have we had in the past several years? Virtually none," he told ThinkProgress. "How many of Democrat voter fraud? There have been some. We're not trying to go after anybody, but we need to do the right thing by everybody."
As the Fifth Circuit noted this week, studies have found that Texas' voter ID disproportionately hurts minorities — mainly Hispanic and black voters. Yet Republican lawmakers and delegates in Texas insist that the laws have no negative effects.
"I've worked in the polls," Lowder said. "We have a real fair system. Anybody that tries to discourage someone else is not allowed to do so. I'm concerned about voter fraud, but I'm concerned that everybody that can legally vote can do so."
A total of 33 states will have laws in place this year requesting or requiring voters to show some form of identification at the polls. As many advocates and reporters have noted, those laws have the ability to swing elections in favor of Republicans.
Some lawmakers, like Grothman, have even admitted that their purpose is to help Republicans win elections. From Cleveland's Quicken Loans Arena on Wednesday, Grothman attempted to explain his admission that photo ID will help Republicans win in Wisconsin.
"I think the cleaner the election, the better chance the Republicans have," he said.
Alice Ollstein contributed reporting.
From a recent press conference…
Russian President Vladimir Putin had kind words for his "stablemate" Donald Trump during an annual end-of-the-year Q&A session in Moscow.
"[Donald Trump is] a really brilliant and talented person, without any doubt," [Vladimir] Putin told reporters, according to a translation by Interfax. "It's not our job to judge his qualities, that's a job for American voters, but he's the absolute leader in the presidential race."
The GOP frontrunner has been blunt about his plans for defrosting U.S. relations with Russia should he be elected president.
"He says he wants to move on to a new, more substantial relationship, a deeper relationship with Russia, how can we not welcome that?" he said. "Of course we welcome that."
Clearly, Putin is ready for a bold leader in the White House that he can team up with to kill the terrorists and keep citizens of both of our nations safe.
By Kosar
There are plenty of politicians of many stripes who are very afraid of the idea of a Donald Trump presidency, and with good reason. One of them seems to be former New York City mayor Michael Bloomberg. Bloomberg was once a Democrat, but switched his party affiliation to Independent circa the year 2000, and ran and won the city's mayorship as a Republican before formally becoming a member of the GOP. However, Bloomberg is definitely not a fall into line party guy.
In 2012, he endorsed President Barack Obama's second bid for the White House, and now, here in 2016, he is endorsing Hillary Clinton for president. Bloomberg is not only endorsing Clinton, but he will speak at the Democratic National Convention in Philadelphia during prime time. That means he will be going on during the same time as Democratic stars such as President Obama and Vice President Joe Biden. One of Bloomberg's top advisers, Howard Wolfson, says of the decision:
"As the nation's leading independent and a pragmatic business leader Mike (Bloomberg) has supported candidates from both sides of the aisle. This week in Philadelphia he will make a strong case that the clear choice in this election is Hillary Clinton."
This isn't necessarily a huge surprise, as Bloomberg has definitely gone after Trump on some of his more alarming policy proposals. This is especially true of Trump's plan to ban Muslims from traveling across the U.S. border, and his ideas regarding building a wall along the southern border and forcing Mexico to pay for it, and the mass deportation plans. Despite the lack of surprise, though, this is an important endorsement. Bloomberg is a billionaire, just like Trump, and he is a high profile GOP politician. This is definitely a signal to the sane Republicans that are left that they need to do the right thing and endorse and vote for Hillary Clinton.
It's not about betraying one's party or one's principles. It's about what is right for the nation and the world.


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Nearing the halfway mark in today's session, here are the individual equity names with the most call and put buying on optionMONSTER's ActionTracker data system.
Eli Lilly (LLY): Some 10,000 January 52.50 calls were purchased for $0.35 and an equal number of January 55 calls were sold for $0.10. The trade cost $0.25 and will earn a maximum profit of 900 if the stock closes at or above $55 on expiration. LLY rose 1.96 percent to $48.40.
U.S. Airways (LCC): More than 9,000 December 15 calls were purchased, mostly for $0.20 as investors look for the airline stock to keep climbing. LCC fell 0.24 percent to $12.58.
Sprint Nextel (S): Activity surged in the February 6 calls and the January 2014 7 calls for $0.20, but volume was far below open interest at each contract. S rose 1.08 percent to $5.61.
Bank of America (BAC): Some 5,000 January 7 puts were bought for $1.08 as investors brace for a potential drop. BAC rose 0.21 percent to $9.41.
Research In Motion (RIMM): More than 6,000 January 9 puts traded, mostly for $1.11 to $1.18, but volume was below open interest at the strike. RIMM is up 1.99 percent to $8.71.
More From optionMONSTER


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Mr. Mohammed Nasim, MP, BCCM Chair and hon'ble Minister, Ministry of Health and Family Welfare speaks in the 82nd BCCM meeting at MOHFW conference room on 02 June, 2015.
82nd BCCM Meeting 3Written by Super User
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In A BIGGER SPLASH, rock legend Marianne Lane (Tilda Swinton) is recuperating on the volcanic island of Pantelleria with her partner Paul (Matthias Schoenaerts) when iconoclast record producer and old flame Harry (Ralph Fiennes) unexpectedly arrives with his daughter Penelope (Dakota Johnson) and interrupts their holiday, bringing with him an A-bomb blast of nostalgia from which there can be no rescue. A BIGGER SPLASH is a sensuous portrait of desire, jealousy and rock and roll, under the Mediterranean sun.
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The New Old Time Chautauqua is one of our favorite returning shows, and this time America's only traveling or circuit Chautauqua, is joining forces with Washington State Parks and Recreation Commission for a 2016 summer tour of seven state parks and nearby communities.
Coming Attractions
90th Anniversary Film Series
As part of the Lincoln Theatre's 90th Anniversary we are screening a series of "Best of the Decade" films, selected by our patrons,
The Met: Live in HD
The Met: Live in HD marks Its Eleventh Season with 10 Live Transmissions, including Five Operas new to the series
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Meet Lisa during downtown Mount Vernon's First Thursday Art Walk on August 4th from 5:00 - 8:00pm.
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I have never used namespaces for my code before. (Other than for using STL functions)
- Other than for avoiding name conflicts, is there any other reason to use namespaces?
- Do I have to enclose both declarations and definitions in namespace scope?
We started with Q&A. Technical documentation is next, and we need your help.
Whether you're a beginner or an experienced developer, you can contribute.
I have never used namespaces for my code before. (Other than for using STL functions)
Here is a good reason (apart from the obvious stated by you).
Since namespace can be discontiguous and spread across translation units, they can also be used to separate interface from implementation details.
Definitions of names in a namespace can be provided either in the same namespace or in any of the enclosing namespaces (with fully qualified names).
One reason that's often overlooked is that simply by changing a single line of code to select one namespaces over another you can select an alternative set of functions/variables/types/constants - such as another version of a protocol, or single-threaded versus multi-threaded support, OS support for platform X or Y - compile and run. The same kind of effect might be achieved by including a header with different declarations, or with
UPDATE: addressing marcv81's comment...
"interface + implementations" is conceptually what choosing a namespace to alias above is doing, but if you mean specifically runtime polymorphism and virtual dispatch:
You can think of namespaces as logical separated units for your application, and logical here means that suppose we have two different classes, putting these two classes each in a file, but when you notice that these classes share something enough to be categorized under one category, that's one strong reason to use namespaces.
It can help you for a better comprehension.
You can also think of it as module in your system.
It can also be usefull for an writing documentation (eg: you can easily document namespace entity in doxygen)


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We will meet in various places accessible by Metro. I will create a discussion of what Metro Stop we will meet. The District is full of opportunities to photograph. Any type of photography is welcome at this meetup.
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|By PR Newswire
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|January 23, 2013 09:31 AM EST
CHICAGO, Jan. 23, 2013 /PRNewswire/ -- InvestorsObserver issues critical PriceWatch Alerts for CBS, HES, KSU, WFT, and BBBY.
(Photo: http://photos.prnewswire.com/prnh/20120712/CG39046)
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The IoT is changing the way enterprises conduct business. In his session at @ThingsExpo, Eric Hoffman, Vice President at EastBanc Technologies, discussed how businesses can gain an edge over competitors by empowering consumers to take control through IoT. He cited examples such as a Washington, D.C.-based sports club that leveraged IoT and the cloud to develop a comprehensive booking system. He also highlighted how IoT can revitalize and restore outdated business models, making them profitable ...
Jul. 29, 2016 10:15 PM EDT Reads: 2,065
SYS-CON Events announced today that Isomorphic Software will exhibit at DevOps Summit at 19th International Cloud Expo, which will take place on November 1–3, 2016, at the Santa Clara Convention Center in Santa Clara, CA. Isomorphic Software provides the SmartClient HTML5/AJAX platform, the most advanced technology for building rich, cutting-edge enterprise web applications for desktop and mobile. SmartClient combines the productivity and performance of traditional desktop software with the simp...
Jul. 29, 2016 10:00 PM EDT Reads: 1,282
"When you think about the data center today, there's constant evolution, The evolution of the data center and the needs of the consumer of technology change, and they change constantly," stated Matt Kalmenson, VP of Sales, Service and Cloud Providers at Veeam Software, in this SYS-CON.tv interview at 18th Cloud Expo, held June 7-9, 2016, at the Javits Center in New York City, NY.
Jul. 29, 2016 09:45 PM EDT Reads: 1,494
Internet of @ThingsExpo, taking place November 1-3, 2016, at the Santa Clara Convention Center in Santa Clara, CA, is co-located with the 19th International Cloud Expo and will feature technical sessions from a rock star conference faculty and the leading industry players in the world and ThingsExpo Silicon Valley Call for Papers is now open.
Jul. 29, 2016 08:00 PM EDT Reads: 2,745
We all know the latest numbers: Gartner, Inc. forecasts that 6.4 billion connected things will be in use worldwide in 2016, up 30 percent from last year, and will reach 20.8 billion by 2020. We're rapidly approaching a data production of 40 zettabytes a day – more than we can every physically store, and exabytes and yottabytes are just around the corner. For many that's a good sign, as data has been proven to equal money – IF it's ingested, integrated, and analyzed fast enough. Without real-ti...
Jul. 29, 2016 07:45 PM EDT Reads: 1,178
Actian Corporation has announced the latest version of the Actian Vector in Hadoop (VectorH) database, generally available at the end of July. VectorH is based on the same query engine that powers Actian Vector, which recently doubled the TPC-H benchmark record for non-clustered systems at the 3000GB scale factor (see tpc.org/3323). The ability to easily ingest information from different data sources and rapidly develop queries to make better business decisions is becoming increasingly importan...
Jul. 29, 2016 06:15 PM EDT Reads: 954
SYS-CON Events announced today that 910Telecom will exhibit at the 19th International Cloud Expo, which will take place on November 1–3, 2016, at the Santa Clara Convention Center in Santa Clara, CA. Housed in the classic Denver Gas & Electric Building, 910 15th St., 910Telecom is a carrier-neutral telecom hotel located in the heart of Denver. Adjacent to CenturyLink, AT&T, and Denver Main, 910Telecom offers connectivity to all major carriers, Internet service providers, Internet backbones and ...
Jul. 29, 2016 06:00 PM EDT Reads: 929
Big Data, cloud, analytics, contextual information, wearable tech, sensors, mobility, and WebRTC: together, these advances have created a perfect storm of technologies that are disrupting and transforming classic communications models and ecosystems. In his session at @ThingsExpo, Erik Perotti, Senior Manager of New Ventures on Plantronics' Innovation team, provided an overview of this technological shift, including associated business and consumer communications impacts, and opportunities it ...
Jul. 29, 2016 05:15 PM EDT Reads: 389
Cloud analytics is dramatically altering business intelligence. Some businesses will capitalize on these promising new technologies and gain key insights that'll help them gain competitive advantage. And others won't. Whether you're a business leader, an IT manager, or an analyst, we want to help you and the people you need to influence with a free copy of "Cloud Analytics for Dummies," the essential guide to this explosive new space for business intelligence.
Jul. 29, 2016 05:15 PM EDT Reads: 986
You think you know what's in your data. But do you? Most organizations are now aware of the business intelligence represented by their data. Data science stands to take this to a level you never thought of – literally. The techniques of data science, when used with the capabilities of Big Data technologies, can make connections you had not yet imagined, helping you discover new insights and ask new questions of your data. In his session at @ThingsExpo, Sarbjit Sarkaria, data science team lead ...
Jul. 29, 2016 04:45 PM EDT Reads: 1,248
WebRTC is bringing significant change to the communications landscape that will bridge the worlds of web and telephony, making the Internet the new standard for communications. Cloud9 took the road less traveled and used WebRTC to create a downloadable enterprise-grade communications platform that is changing the communication dynamic in the financial sector. In his session at @ThingsExpo, Leo Papadopoulos, CTO of Cloud9, discussed the importance of WebRTC and how it enables companies to focus...
Jul. 29, 2016 04:15 PM EDT Reads: 1,085
Qosmos has announced new milestones in the detection of encrypted traffic and in protocol signature coverage. Qosmos latest software can accurately classify traffic encrypted with SSL/TLS (e.g., Google, Facebook, WhatsApp), P2P traffic (e.g., BitTorrent, MuTorrent, Vuze), and Skype, while preserving the privacy of communication content. These new classification techniques mean that traffic optimization, policy enforcement, and user experience are largely unaffected by encryption. In respect wit...
Jul. 29, 2016 04:15 PM EDT Reads: 463
ReadyTalk has expanded the capabilities of the FoxDen collaboration platform announced late last year to include FoxDen Connect, an in-room video collaboration experience that launches with a single touch. With FoxDen Connect, users can now not only engage in HD video conferencing between iOS and Android mobile devices or Chrome browsers, but also set up in-person meeting rooms for video interactions. A host's mobile device automatically recognizes the presence of a meeting room via beacon tech...
Jul. 29, 2016 04:15 PM EDT Reads: 421
Manufacturers are embracing the Industrial Internet the same way consumers are leveraging Fitbits – to improve overall health and wellness. Both can provide consistent measurement, visibility, and suggest performance improvements customized to help reach goals. Fitbit users can view real-time data and make adjustments to increase their activity. In his session at @ThingsExpo, Mark Bernardo Professional Services Leader, Americas, at GE Digital, discussed how leveraging the Industrial Internet a...
Jul. 29, 2016 03:15 PM EDT Reads: 673
On Dice.com, the number of job postings asking for skill in Amazon Web Services increased 76 percent between June 2015 and June 2016. Salesforce.com saw its own skill mentions increase 37 percent, while DevOps and Cloud rose 35 percent and 28 percent, respectively. Even as they expand their presence in the cloud, companies are also looking for tech professionals who can manage projects, crunch data, and figure out how to make systems run more autonomously. Mentions of 'data science' as a skill ...
Jul. 29, 2016 03:00 PM EDT Reads: 496


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Stephen Colbert was in full "Stephen Colbert" mode on Monday night, mock-criticizing Michael Sam for waging a "war on traditional grid-iron values" amidst being drafted by the NFL.
After rolling the clip of Sam receiving the news and then kissing his boyfriend, Colbert threw a flag for "Holding: Unnecessary Tenderness." He then deadpanned, "Folks, this is just wrong. In the NFL, sexuality is supposed to take place off camera, and the fans should only find out about it when the charges are filed."
Of course, there were a few people out there who were actually bothered by Sam's display of basic human emotion, not the least of which was Donald Trump. Watch the clip above to see Colbert take fake issue with the historic moment, and why Trump thought it was a little much.
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