Early discussion of breast density and supplemental breast cancer screening: is it possible?

The purpose of this study is to determine whether it is possible to make breast cancer screening more efficient in those with dense breasts. Over 12 states require that patients with dense breasts receive notification about their breast density in lay letters that are sent after the screening mammogram. Some of these letters advise patients to speak with their primary care providers about the possibility of supplemental breast cancer screening. We sought to determine whether primary care providers can discuss breast density and recommend supplemental breast cancer screening using the density of the previous mammography. This would reduce the burden of additional appointments and might increase the number of patients choosing to have supplemental screening. The mammographic breast density of 250 consecutive patients from May 2011 to September 2011 was compared with the immediate prior mammogram. Patients whose prior mammograms were more than 36 months prior or less than 8 months prior to the current exam were excluded, leaving 217 patients. The proportion of patients with breast density change was analyzed. The concordance of breast density between the two exams was assessed and the effects of patient age and the length of time between mammograms were examined. The breast density of the current and most recent prior mammogram was stable for 86.6% of patients. Neither age nor length of time between mammograms affected concordance. Primary care providers can decrease the need for multiple appointments and decrease patient anxiety by discussing breast density and screening choices prior to the patient's screening mammography. The great majority of patients will receive the correct information about their breast density by using a prior report.

Femoral head shape differences during development may identify hips at risk of degeneration.

Developmental dysplasia of the hip (DDH) is a common cause of elevated contact stress and early onset osteoarthritis (OA). We hypothesized that adaptation to focal loading during postnatal development would result in signature changes to the shape of the femoral head secondary center of ossification (SCO). SCO shape was evaluated in a canine model of DDH at ages 14 and 32 weeks. The evolving 3D morphology of the SCO was captured using serial quantitative computed tomography. A discrete medial representation shape model was fit to each SCO and served as the basis for quantitative thickness and bending measurements. Shape measurements were tested for associations with hip subluxation and degeneration. At 32 weeks, the SCO was thinner (flatter) in the perifoveal region, the site of focal loading; a greater bend to the SCO was present lateral to the site of thinning; SCO thinning and bending were associated with less femoral head coverage and with a higher probability of degeneration. Shape changes were not detected at 14 weeks. Measurement and visualization of SCO shape changes due to altered loading may provide a basis for identifying hips at risk of early onset OA and a tool for surgical planning of hip restructuring.

Femoral head bone mineral density patterns may identify hips at risk of degeneration.

Developmental dysplasia of the hip (DDH) is a common abnormality that causes elevated contact stress and early onset osteoarthritis (OA). We hypothesized that adaptation of femoral head bone mineral density (BMD) patterns to focal loading during postnatal development could be used to identify hips at risk of degeneration. Evolving BMD patterns of the femoral head secondary center of ossification (SCO) were quantified and tested for differences with hip subluxation and degeneration. BMD was measured using quantitative computed tomography of hips in a canine model of DDH from 4 weeks to early skeletal maturity at 32 weeks. During body weight and SCO volumetric growth deceleration, SCO mean BMD increased rapidly and local regions of high BMD formed. Greater subluxation was associated with a lower mean BMD up to 14 weeks. At 32 weeks, greater subluxation was associated with a larger area of high BMD that was more laterally located and had a greater maximum BMD. BMD differences were associated with a higher probability of cartilage degeneration. Measurement and visualization of BMD pattern changes due to altered mechanical loading provide a basis for identifying hips at risk of early onset OA and a tool for surgical planning of contact stress reduction procedures.

Mathematical philology: entropy information in refining classical texts' reconstruction, and early philologists' anticipation of information theory.

Philologists reconstructing ancient texts from variously miscopied manuscripts anticipated information theorists by centuries in conceptualizing information in terms of probability. An example is the editorial principle difficilior lectio potior (DLP): in choosing between otherwise acceptable alternative wordings in different manuscripts, "the more difficult reading [is] preferable." As philologists at least as early as Erasmus observed (and as information theory's version of the second law of thermodynamics would predict), scribal errors tend to replace less frequent and hence entropically more information-rich wordings with more frequent ones. Without measurements, it has been unclear how effectively DLP has been used in the reconstruction of texts, and how effectively it could be used. We analyze a case history of acknowledged editorial excellence that mimics an experiment: the reconstruction of Lucretius's De Rerum Natura, beginning with Lachmann's landmark 1850 edition based on the two oldest manuscripts then known. Treating words as characters in a code, and taking the occurrence frequencies of words from a current, more broadly based edition, we calculate the difference in entropy information between Lachmann's 756 pairs of grammatically acceptable alternatives. His choices average 0.26+/-0.20 bits higher in entropy information (95% confidence interval, P = 0.005), as against the single bit that determines the outcome of a coin toss, and the average 2.16+/-0.10 bits (95%) of (predominantly meaningless) entropy information if the rarer word had always been chosen. As a channel width, 0.26+/-0.20 bits/word corresponds to a 0.790.79(+0.09) (-0.15) likelihood of the rarer word being the one accepted in the reference edition, which is consistent with the observed 547/756 = 0.72+/-0.03 (95%). Statistically informed application of DLP can recover substantial amounts of semantically meaningful entropy information from noise; hence the extension copiosior informatione lectio potior, "the reading richer in information [is] preferable." New applications of information theory promise continued refinement in the reconstruction of culturally fundamental texts.

A portable cell-based impedance sensor for toxicity testing of drinking water.

A major limitation to using mammalian cell-based biosensors for field testing of drinking water samples is the difficulty of maintaining cell viability and sterility without an on-site cell culture facility. This paper describes a portable automated bench-top mammalian cell-based toxicity sensor that incorporates enclosed fluidic biochips containing endothelial cells monitored by Electric Cell-substrate Impedance Sensing (ECIS) technology. Long-term maintenance of cells on the biochips is made possible by using a compact, self-contained disposable media delivery system. The toxicity sensor monitors changes in impedance of cell monolayers on the biochips after the introduction of water samples. The fluidic biochip includes an ECIS electronic layer and a polycarbonate channel layer, which together reduce initial impedance disturbances seen in commercially available open well ECIS chips caused by the mechanics of pipetting while maintaining the ability of the cells to respond to toxicants. A curve discrimination program was developed that compares impedance values over time between the control and treatment channels on the fluidic biochip and determines if they are significantly different. Toxicant responses of bovine pulmonary artery endothelial cells grown on fluidic biochips are similar to cells on commercially-available open well chips, and these cells can be maintained in the toxicity sensor device for at least nine days using an automated media delivery system. Longer-term cell storage is possible; bovine lung microvessel endothelial cells survive for up to four months on the fluidic biochips and remain responsive to a model toxicant. This is the first demonstration of a portable bench top system capable of both supporting cell health over extended periods of time and obtaining impedance measurements from endothelial cell monolayers after toxicant exposure.

Improved cell sensitivity and longevity in a rapid impedance-based toxicity sensor.

A number of toxicity sensors for testing field water using a range of eukaryotic cell types have been proposed, but it has been difficult to identify sensors with both appropriate sensitivity to toxicants and the potential for long-term viability. Assessment of bovine pulmonary artery endothelial cell (BPAEC) monolayer electrical impedance with electric cell-substrate impedance sensing (ECIS) showed promise in a previous systematic evaluation of toxicity sensor technologies. The goal of the study reported here was to improve toxicant responsiveness and field portability of this cell-based toxicity sensor. A variety of human cells, non-human mammalian cells, and non-mammalian vertebrate cells were screened for sensitivity to 12 waterborne industrial chemicals. The results of this assessment show that bovine lung microvessel endothelial cell (BLMVEC) monolayers and iguana heart (IgH-2) cell monolayers could detect nine out of the 12 waterborne industrial chemicals, an improvement over the seven chemicals previously detected using BPAEC monolayers. Both the BLMVEC and IgH-2 cell monolayers were tested for their ability for long-term survival on the ECIS test chips in a laboratory environment. Both cell lines were able to maintain high impedance readings on the ECIS electrodes for 37 days, a key trait in developing a field-portable toxicity sensor for water. Cell line optimization has greatly contributed to the on-going development of a field-portable cell-based biosensor that detects with sensitivity a wide range of waterborne toxicants.

Proof of concept of a method that assesses the spread of microbial infections with spatially explicit and non-spatially explicit data.

BACKGROUND: A method that assesses bacterial spatial dissemination was explored. It measures microbial genotypes (defined by electrophoretic patterns or EP), host, location (farm), interfarm Euclidean distance, and time. Its proof of concept (construct and internal validity) was evaluated using a dataset that included 113 Staphylococcus aureus EPs from 1126 bovine milk isolates collected on 23 farms between 1988 and 2005. RESULTS: Construct validity was assessed by comparing results based on the interfarm Euclidean distance (a spatially explicit measure) and those produced by the (non-spatial) interfarm number of isolates reporting the same EP. The distance associated with EP spread correlated with the interfarm number of isolates/EP (r = .59, P < 0.02). Internal validity was estimated by comparing results obtained with different versions of the same indices. Concordance was observed between: (a) EP distance (estimated microbial dispersal over space) and EP speed (distance/year, r = .72, P < 0.01), and (b) the interfarm number of isolates/EP (when measured on the basis of non-repeated cow testing) and the same measure as expressed by repeated testing of the same animals (r = .87, P < 0.01). Three EPs (2.6% of all EPs) appeared to be super-spreaders: they were found in 26.75% of all isolates. Various indices differentiated local from spatially disseminated infections and, within the local type, infections suspected to be farm-related were distinguished from cow-related ones. CONCLUSION: Findings supported both construct and internal validity. Because 3 EPs explained 12 times more isolates than expected and at least twice as many isolates as other EPs did, false negative results associated with the remaining EPs (those erroneously identified as lacking spatial dispersal when, in fact, they disseminated spatially), if they occurred, seemed to have negligible effects. Spatial analysis of laboratory data may support disease surveillance systems by generating hypotheses on microbial dispersal ability.

Robust hypothesis tests for independence in community assembly.

The extent to which competition affects the distributions of species at large spatial scales is unclear. To evaluate this question, hypothesis tests that do not depend on parametric assumptions are needed. Here, we develop a broadly applicable test that requires only one parametric assumption. Letting i and j denote the ith and jth colonists to arrive at a site, respectively, and [i j] the event that i and j belong to the same "unit" (e.g., functional group, genus), we show how colonists will be partitioned into units if for all i and j, [i j] is independent of whether i and j share unit membership with the other colonists, conditional on other information about shared units. Our distribution of partitions is useful for inferring competitive effects, because these effects predict that for at least one i and j, P ([i j]) will be less when i and j share unit membership than when they do not.

Receiver operating characteristic-based assessment of a serological test used to detect Johne's disease in Israeli dairy herds.

The overall accuracy of an enzyme-linked immunosorbent assay (ELISA) used to detect Johne's disease at herd level was explored in relation to an imperfect test (fecal culture) in 57 Israeli dairy herds. Receiver-operating characteristic (ROC) analysis indicated an area under the curve (AUC) that corresponded to a test accuracy of 82.0% (69.5% to 90.9%; 95% confidence), with optimized herd sensitivity and herd specificity of 70.4% and 83.3%, respectively; and predictive values of 79.2 (+) and 75.8% (-). The optimal ELISA cutoff was 3.16% (> 3.16% seropositive cows in a herd), which was associated with likelihood ratios (LR) of 4.22 (+LR) and 0.36 (-LR), and post-test probabilities of 0.79 (+) and 0.17 (-). For herds with < or = 200 cows (n = 19 herds), the 95% confidence interval (CI) for the AUC was 0.62-0.97 and the optimal cutoff was 3.33% (HSe = 87.5, HSp = 81.8); for herds with > 200 but < or = 270 cows (n = 19 herds), the 95% AUC CI was 0.62-0.97 and the optimal cutoff was 1.13% (HSe = 90.0, HSp = 77.78); and for herds with > 270 cows (n = 19 herds), the 95% AUC CI was 0.69-0.99 and the optimal cutoff was 0.7% (HSe = 100.0, HSp = 70.0). The AUC was not influenced by across-herd prevalence [R2 (adjusted) = 0.0, P > 0.05]. Findings may be applied to facilitate targeted sampling of herds similar to those evaluated. For instance, a test cutoff of 0.76% could be considered for "ruling disease in," while a cutoff of 3.7% could be used for "ruling disease out." Caveats that may influence this analysis are discussed.

Multifactorial relationships between intramammary invasion by Staphylococcus aureus and bovine leukocyte markers.

We explored the hypothesis that the outcome of bacterial invasion (infection or no infection) may depend on immunologic factors when bacterial and environmental factors are kept constant. Leukocyte surface molecules (CD3, CD2, CD4, CD8, CD11b, and CD45r) were assessed before and 3 times after intramammary infusion of Staphylococcus aureus in 5 dairy cows. The somatic cell count (SCC/mL), bacterial count (colony-forming units [CFUs]/mL), ratio of milk phagocytes (mononuclear [Mphi] plus polymorphonuclear [PMN] cells) to lymphocytes (P/L index), and ratio of PMN to Mphi cells (PMN/Mphi index) were determined. Although all cows showed evidence of inflammation resulting from the infusion (the median P/L ratio was 11 times greater 1 d after infusion than before infusion), bacteria were not obtained from the milk of 2 cows. Threshold-like responses, resulting in bacterial counts that approached zero (indicating no infection) and SCCs of less than 500000/mL, were observed when the milk CD2+ lymphocyte proportion exceeded 73% (P < or = 0.007). At 1 d after infusion, 7 immune factors distinguished infected cows from those without infection with more than 95% confidence: compared with infected cows, uninfected cows had higher proportions of CD3+, CD2+, CD4+, and CD8+ T cells, higher densities of CD3 and CD2 molecules per cell, and a higher density of CD11b molecules on milk Mphi cells. At 7 d after infusion, the PMN/Mphi index was lower (94% confidence) in uninfected than in infected cows. At 14 d, the CD2, CD8, and CD45r marker densities were lower than those at 1 d (P < 0.02), findings compatible with memory function. Synergism was suggested by the combined effects of the proportions of CD3+, CD2+, and CD11b+ cells, which explained 75.5% of the bacterial-count variability (P < 0.001); alone, none of these markers predicted CFU variability. These results support further studies aimed at identifying cows capable (or incapable) of early bacterial clearance.

Effect of early postnatal body weight on femoral head ossification onset and hip osteoarthritis in a canine model of developmental dysplasia of the hip.

Developmental dysplasia of the hip (DDH) is a well-known precipitator of hip osteoarthritis. An increase in body weight during the critical early postnatal growth period may alter joint contact, and thus alter hip development and influence joint health in adulthood. The objective of this study was to determine whether early postnatal body weight affected the course of hip development and the onset of osteoarthritis in a canine model of DDH. A longitudinal study, from birth to skeletal maturity, was conducted. Serial body weight, age at femoral head ossification onset, and femoral head coverage at 4 mo were measured. Presence and severity of degeneration at 8 mo were determined using necropsy and cartilage biochemistry. There was a negative association between birth weight and age at femoral head ossification onset; however, the association was likely due to skeletal maturity level rather than body weight per se. Lower birth weight subjects had greater femoral head coverage at 4 mo. Greater birth weight was associated with greater probability of moderate degenerative changes or macroscopic lesions at 8 mo. These results support the hypothesis that increased birth weight is sufficient to alter the course of hip development and result in measurable degenerative changes at adulthood.

Consumption advisories for salmon based on risk of cancer and noncancer health effects.

The levels of dioxins/furans, polychlorinated biphenyls (PCBs), and chlorinated pesticides were determined in farmed salmon for eight regions in Europe, North America, and South America, in salmon fillets purchased in 16 cities in Europe and North America, and in five species of wild Pacific salmon. Upon application of US Environmental Protection Agency (USEPA) methods for developing fish consumption advisories for cancer from mixtures of all of these substance for which USEPA has reported a cancer slope factor, the most stringent recommendation, for farmed salmon from northern Europe, was for consumption of at most one meal every 5 months in order to not exceed an elevated risk of cancer of more than 1 in 100,000. Farmed salmon from North and South America triggered advisories of between 0.4 and one meal per month. Retail market samples, in general, reflected levels found in regionally farmed fish, although much of the US salmon comes from Chile, which had somewhat lower contaminant levels than the North American farmed samples. Upon consideration of all of these organochlorine compounds as a mixture, even wild Pacific salmon triggered advisories of between one and less than five meals per month. The advisories are driven by the non-dioxin-like PCBs and pesticides and not by dioxins/furans and coplanar PCBs. For noncancer effects for contaminants where USEPA has provided a reference dose only endrin and PCBs triggered any significant advisory. For both of these in the worst case, farmed salmon from northern Europe, the advice was not more than three meals per month.

Lipid composition and contaminants in farmed and wild salmon.

Levels of omega-3 (n-3) and omega-6 (n-6) fatty acids and lipid-adjusted concentrations of polychlorinated biphenyls (PCBs), dioxins, toxaphene, and dieldrin were determined in 459 farmed Atlantic salmon, 135 wild Pacific salmon, and 144 supermarket farmed Atlantic salmon fillets purchased in 16 cities in North America and Europe. These were the same fish previously used for measurement of organohalogen contaminants. Farmed salmon had greater levels of total lipid (average 16.6%) than wild salmon (average 6.4%). The n-3 to n-6 ratio was about 10 in wild salmon and 3-4 in farmed salmon. The supermarket samples were similar to the farmed salmon from the same region. Lipid-adjusted contaminant levels were significantly higher in farmed Atlantic salmon than those in wild Pacific salmon (F = 7.27, P = 0.0089 for toxaphene; F = 15.39, P = 0.0002 for dioxin; F > or = 21.31, P < 0.0001 for dieldrin and PCBs, with df = (1.64) for all). Levels of total lipid were in the range of 30-40% in the fish oil/fish meal that is fed to farmed salmon. Salmon, especially farmed salmon, are a good source of healthy n-3 fatty acids, but they also contain high concentrations of organochlorine compounds such as PCBs, dioxins, and chlorinated pesticides. The presence of these contaminants may reduce the net health benefits derived from the consumption of farmed salmon, despite the presence of the high level of n-3 fatty acids in these fish.

Quantitative analysis of the benefits and risks of consuming farmed and wild salmon.

Contaminants in farmed Atlantic and wild Pacific salmon raise important questions about the competing health benefits and risks of fish consumption. A benefit-risk analysis was conducted to compare quantitatively the cancer and noncancer risks of exposure to organic contaminants in salmon with the (n-3) fatty acid-associated health benefits of salmon consumption. Recommended levels of (n-3) fatty acid intake, as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may be achieved by consuming farmed or wild salmon while maintaining an acceptable level of noncarcinogenic risk. However, the recommended level of EPA+DHA intake cannot be achieved solely from farmed or wild salmon while maintaining an acceptable level of carcinogenic risk. Although the benefit-risk ratio for carcinogens and noncarcinogens is significantly greater for wild Pacific salmon than for farmed Atlantic salmon as a group, the ratio for some subgroups of farmed salmon is on par with the ratio for wild salmon. This analysis suggests that risk of exposure to contaminants in farmed and wild salmon is partially offset by the fatty acid-associated health benefits. However, young children, women of child-bearing age, pregnant women, and nursing mothers not at significant risk for sudden cardiac death associated with CHD but concerned with health impairments such as reduction in IQ and other cognitive and behavioral effects, can minimize contaminant exposure by choosing the least contaminated wild salmon or by selecting other sources of (n-3) fatty acids.

Risk-based consumption advice for farmed Atlantic and wild Pacific salmon contaminated with dioxins and dioxin-like compounds.

We reported recently that several organic contaminants occurred at elevated concentrations in farmed Atlantic salmon compared with concentrations of the same contaminants in wild Pacific salmon [Hites et al. Science 303: 226-229 (2004)]. We also found that polychlorinated biphenyls (PCBs), toxaphene, dieldrin, dioxins, and polybrominated diphenyl ethers occurred at higher concentrations in European farm-raised salmon than in farmed salmon from North and South America. Health risks (based on a quantitative cancer risk assessment) associated with consumption of farmed salmon contaminated with PCBs, toxaphene, and dieldrin were higher than risks associated with exposure to the same contaminants in wild salmon. Here we present information on cancer and noncancer health risks of exposure to dioxins in farmed and wild salmon. The analysis is based on a tolerable intake level for dioxin-like compounds established by the World Health Organization and on risk estimates for human exposure to dioxins developed by the U.S. Environmental Protection Agency. Consumption of farmed salmon at relatively low frequencies results in elevated exposure to dioxins and dioxin-like compounds with commensurate elevation in estimates of health risk.

Global assessment of polybrominated diphenyl ethers in farmed and wild salmon.

We have shown recently that levels of persistent, bioaccumulative contaminants (polychlorinated biphenyls, dioxins, and several chlorinated pesticides) are significantly higher in farmed than in wild salmon and that European farm-raised salmon have significantly greater toxic contaminant loads than those raised in North and South America. In this paper, we extend these results to polybrominated diphenyl ethers (PBDEs) and show that farm-raised salmon have higher levels of these compounds than wild salmon. We also show that farm-raised salmon from Europe have higher PBDE levels than those raised in North America and that both European and North American farm-raised salmon have higher PBDE levels than those farm-raised in Chile. Among the species of wild salmon, chinook had significantly elevated PBDE levels relative to the other wild species. These elevated PBDE levels may be related to chinook's feeding behavior and trophic level. Among all of the wild species we studied, chinook tend to feed higher in the food web throughout their adult life and grow to be larger individuals.

A survey of metals in tissues of farmed Atlantic and wild Pacific salmon.

Contamination of fish tissues with organic and inorganic contaminants has been a pervasive environmental and public health problem. The present study reports the concentrations of nine metals in tissues of farmed Atlantic salmon (Salmo salar) and two species of wild-caught salmon (chum [Oncorhynchus keta] and coho [O. kisutch]) analyzed as part of a global survey of contaminants in these fish. Of the nine metals, organic arsenic was significantly higher in farmed than in wild salmon, whereas cobalt, copper, and cadmium were significantly higher in wild salmon. None of the contaminants exceeded federal standards or guidance levels.

Global assessment of organic contaminants in farmed salmon.

The annual global production of farmed salmon has increased by a factor of 40 during the past two decades. Salmon from farms in northern Europe, North America, and Chile are now available widely year-round at relatively low prices. Salmon farms have been criticized for their ecological effects, but the potential human health risks of farmed salmon consumption have not been examined rigorously. Having analyzed over 2 metric tons of farmed and wild salmon from around the world for organochlorine contaminants, we show that concentrations of these contaminants are significantly higher in farmed salmon than in wild. European-raised salmon have significantly greater contaminant loads than those raised in North and South America, indicating the need for further investigation into the sources of contamination. Risk analysis indicates that consumption of farmed Atlantic salmon may pose health risks that detract from the beneficial effects of fish consumption.