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Introduction Syncope is a common clinical problem with a lifetime prevalence of 20%.1 Syncope shares clinical features with other disorders including seizures, metabolic disturbances and sleep disorders.2 The assessment and management of syncope can be challenging. The syncope service at the QEUH is run by geriatricians and cardiologists with an interest in syncope. Although MDTs are recognised key components in contemporary patient care in areas such as heart failure and cancer management, there is no guidance on MDT working in syncope management.3/4 In November 2017, a syncope MDT was introduced at the QEUH involving cardiologists, geriatricians, a neurologist and cardiac physiologists. This in-person MDT occurs monthly with outcomes recorded on electronic medical records in addition to a database. The aim of this review was to understand the potential impact of the MDT on diagnostic yield and time to further investigation or management. Method A retrospective case note analysis was performed for patients reviewed at the Syncope MDT between November 2017 and December 2021. Results 103 patients were discussed with an average age of 64 years. The main reason for referral was cardiology specialist advice (65%), neurology specialist advice (19.4%) and complex case review (13.6%). After MDT discussion, the percentage of patients with unexplained TLoC reduced from 26.2% to 14.6% without requirement for additional investigations. 8.7% of patients were started on anti-epileptic medication prior to outpatient neurology review after a diagnosis of seizure disorder was established and 23.1% of patients were streamlined for pacemaker or ILR insertion. Conclusion Introduction of a syncope MDT reduces unexplained syncope rates in complex patients, streamlines investigations, reduces the need for multi-speciality outpatient reviews and allows earlier introduction of anti-epileptic medication for those with a new seizure disorder. These benefits improve the patient experience by reducing time to diagnosis and treatment.

ObjectiveThe inflammatory signature of human milk is an indicator of mammary gland health and has implications for infant nutrition, growth, and immune system development. We hypothesized that measurement of mammary epithelium permeability would provide important context for the interpretation of the inflammatory signature of human milk.MethodsParticipants were drawn from a previous study of human milk cytokines and growth factors. Analysis included 162 participants (98 Black women, 64 White women) with infants ranging from 1-18 months of age. Levels of twelve inflammatory markers (IL-6, IL8, TNFα, IL-1β, FASL, VEGFD, FLT1, BFGF, PLGF, EGF, leptin, adiponectin) were evaluated previously. Milk sodium (Na) and potassium (K) were measured with ion selective probes. Increased mammary epithelium permeability (IMEP) was indicated by either Na levels or Na/K ratios greater than the 75thpercentile. Multivariate logistic regression models were used to examine associations between maternal-infant characteristics, inflammatory markers, and IMEP.ResultsThresholds of elevated Na and Na/K ratios at the 75thpercentile were found to be 8.0 mmol/L and 0.53 respectively. IMEP was most frequent (42.6%) during early lactation (1-3 months). The strongest predictors of IMEP as defined by Na > 75thpercentile were infant age, Black race, IL6, and BFGF, while maternal age and PLGF were important predictors of IMEP as defined by the Na/K ratio >75thpercentile. IMEP also moderated associations between maternal-infant characteristics and inflammatory markers.DiscussionThis study demonstrates the importance of mammary epithelium permeability measurement for the interpretation of human milk inflammatory profiles during established lactation.

This study examines ten years of financial and production data of 249 farm businesses operating in southwestern Australia. It also identifies the behavioural characteristics of the farm operators through a comprehensive socio-managerial survey of each farm business. The study area has a Mediterranean climate, where three quarters of the rainfall is received during the growing season from April and October. Growers have learned to produce 2 tonnes per hectare of wheat on less than 200 ml of growing season rainfall. Australia is the driest continent in the world and is renowned for its climate variability. In addition, evidence is emerging that its southern parts, like south-western Australia, are experiencing a warming, drying trend in their climate. Average annual rainfall over the last thirty years in the study area has declined and average minimum and maximum temperatures have risen. Moreover, in the last ten years a number of droughts have occurred. This multidisciplinary study examines the business performance of 249 farms from 2002 to 2011 and identifies the strategies farm managers have adopted to adapt to a drying, warming environment. Farms are categorised according to their performance. Their characteristics are compared and contrasted. We find many significant differences between farm performance categories and the adaptation strategies used by the farmers in each category. There are also different socio-managerial and behavioural characteristics between the groups of farmers identified.

Introduction OH is a disabling condition resulting from a sustained reduction in blood pressure (>20 systolic or 10 diastolic) within 3 minutes of standing. It is a common cause of syncope. Patients with concurrent hypertension experiencing syncope present a complex management dilemma where a balance must be established between symptom burden and risk of cardiovascular disease. Current guidance on ABPM use in syncope is limited. European society of cardiology syncope guidelines suggest ABPM in patients with ‘autonomic failure’ to assess nocturnal hypertension or drug-induced hypotension. Could this be improved with further explicit criteria on which patients to assess and how to act on results? The objective of this study is to review the use of 24 hour ABPM in OH within a tertiary referral syncope clinic. Method A retrospective analysis was performed electronically for patients with a final diagnosis of OH seen in a syncope clinic between March 2017 and May 2019. Data was collected on comorbidities, medication history, physical mobility, clinic blood pressure, ABPM Results: (if performed) and medication changes. Comparisons were made between patients who had ABPM and those who did not. Statistics were calculated using Fisher’s Exact Test (2 tailed). Results 119 patients had a final diagnosis of OH in the study period. 45 had ABPM, 74 did not. The ABPM group had a significantly higher proportion of diagnosed hypertension (51.1% vs 23% (p = 0.0025)). A similar proportion of patients in both groups had medication changed however the ABPM group were significantly more likely to have antihypertensive therapy added (19.4% vs 1.8% (p = 0.0053)). Conclusion Using 24 hour ABPM in OH patients can aid clinical decision making in the sub-group with hypertension. This can guide the need for alteration/addition of antihypertensive therapy to balance optimum BP control with symptom burden.

Black women in the United States are disproportionately affected by early-onset, triple-negative breast cancer. DNA methylation has shown differences by race in healthy and tumor breast tissues. We examined associations between genome-wide DNA methylation levels in breast milk and breast cancer risk factors, including race, to explain how this reproductive stage influences a woman's risk for, and potentially contributes to racial disparities in, breast cancer. Breast milk samples and demographic, behavioral, and reproductive data, were obtained from cancer-free, uniparous, and lactating U.S. black (n = 57) and white (n = 82) women, ages 19–44. Genome-wide DNA methylation analysis was performed on extracted breast milk DNA using the Infinium HumanMethylation450 BeadChip. Statistically significant associations between breast cancer risk factors and DNA methylation beta values, adjusting for potential confounders, were determined using linear regression followed by Bonferroni Correction (P < 1.63 × 10−7). Epigenetic analysis in breast milk revealed statistically significant associations with race and lactation duration. Of the 284 CpG sites associated with race, 242 were hypermethylated in black women. All 227 CpG sites associated with lactation duration were hypomethylated in women who lactated longer. Ingenuity Pathway Analysis of differentially methylated promoter region CpGs by race and lactation duration revealed enrichment for networks implicated in carcinogenesis. Associations between DNA methylation and lactation duration may offer insight on its role in lowering breast cancer risk. Epigenetic associations with race may mediate social, behavioral, or other factors related to breast cancer and may provide insight into potential mechanisms underlying racial disparities in breast cancer incidence.

This report describes the demonstration of technologies and procedures developed during April 2002 and May 2004 under the Joint Rapid Airfield Construction (JRAC) Program. The demonstration took place at Sicily Landing Zone (LZ) at Fort Bragg, NC, in July of 2004. The objective of the exercise was to demonstrate the procedures and technologies developed under the JRAC Program by rapidly building two parking aprons capable of supporting C-130 transport aircraft taxiing and parking operations. The exercise was conducted under continuous 24-hr operations to simulate a real-world rapid construction environment. Apron 1 (north apron) was constructed using two technologies, one-half being ACE™ Matting and the other half being a cement-polymer stabilized soil surface. Apron 2 (south apron) was constructed solely of a fiber-cement-stabilized soil system. Both aprons were treated with a polymer emulsion surface application to form a sealed surface against abrasion and water infiltration. The entire construction of both aprons required 76 hr, with Apron 1 finished in 48 hr. The construction of Apron 1 was validated by operation of a C-130 aircraft approximately 31 hr after completion with success and high praises from the aircraft flight crew on the stability and surface of the apron, as well as its dust-abating characteristics.

Introduction: Identifying biomarkers of breast cancer risk among young women would have value in developing effective screening and prevention strategies at early ages. We have proposed that DNA methylation analysis of breast milk may provide breast cancer risk information among young women, and could possibly provide etiologic clues related to the higher rates of early onset cancers among African American as compared with White women in the US. Objective: The purpose of this project was to identify associations between genome-wide DNA methylation levels in breast milk and race adjusted for other breast cancer risk factors. Study Population: Cancer-free, lactating U.S. Black (n=57) and White (n=82) women, ages 19 to 44, provided frozen breast milk samples, as well as demographic, behavioral, and reproductive data, to the Breastmilk Laboratory at University of Massachusetts Amherst. Women were uniparous and did not have a personal history of breast cancer at the time of milk donation. Methods: DNA was extracted from breast milk samples using the phenol-chloroform method. Genome-wide methylation analysis was performed on breast milk samples using the Infinium HumanMethylation450 BeadChip. Probes with 50% or more missing data, cross-reactive probes, as well as probes with minor allelic frequency greater than 0.05 in European- or African-Americans were removed, leaving 379,042 CpG sites for analysis. Multivariate generalized linear regression models were used to examine associations between race and other breast cancer risk factors and methylation beta values, adjusting for potential confounding factors. P-values less than 1E-7 were considered statistically significant. Results: Black women in this study were more likely to be never smokers, to not have used over-the-counter pain medication in the past week, and to breastfeed longer. After adjustment by age, BMI, smoking status, and batch number, race was significantly associated with differential methylation at 1143 CpG sites, including 1024 at which Black women demonstrated increased methylation levels. Additionally, breastfeeding duration was associated with 269 CpG sites, with 268 showing a significant inverse relationship with methylation. Methylation sites significantly associated with Black race and lactation duration were located within tumor suppressor and promoter genes as well as in genes implicated in obesity and diabetes. Conclusion: This preliminarily analysis of DNA methylation in breast milk suggests that Black women have increased methylation and longer breastfeeding is associated with reduced methylation. Further research to understand how etiologic factors related to breast cancer may alter DNA methylation patterns in normal breast may lead to improved understanding of breast cancer risk at a young age and potentially causes of racial disparities in breast cancer incidence between White and Black women. Citation Format: Davis Lynn BC, Bodelon C, Pfeiffer RM, Yang HP, Yang H, Lee M, Laird PW, Campan M, Weisenberger DJ, Murphy J, Sherman ME, Browne EP, Anderton DL, Arcaro KF, Gierach GL. Differences in genome-wide DNA methylation levels in breast milk by race and lactation duration [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-10-07.

BackgroundPrior candidate gene studies have shown tumor suppressor DNA methylation in breast milk related with history of breast biopsy, an established risk factor for breast cancer. To further establish the utility of breast milk as a tissue-specific biospecimen for investigations of breast carcinogenesis we measured genome-wide DNA methylation in breast milk from women with and without a diagnosis of breast cancer in two independent cohorts.MethodsDNA methylation was assessed using Illumina HumanMethylation450k in 87 breast milk samples. After quality control, 368,171 autosomal CpG loci were analyzed. Cell type proportion estimates from RefFreeCellMix were calculated and adjusted for in this Epigenome Wide Association Study using linear mixed effects models adjusted for history of breast biopsy, age, time of delivery, cell type proportion estimates, array chip, and subject as random effect.ResultsEpigenome-wide analyses identified 58 differentially methylated CpG sites associated with a breast cancer diagnosis in the prospectively collected milk samples from the breast that would develop cancer compared with women without a diagnosis of breast cancer (q-value < 0.05). Nearly all CpG sites associated with a breast cancer diagnosis were hypomethylated in cases compared with controls, and were enriched for CpG islands. In addition, inferred repeat element methylation was lower in breast milk DNA from cases compared to controls, and cases exhibited increased estimated epigenetic mitotic tick rate as well as DNA methylation age compared with controls.ConclusionBreast milk has utility as a biospecimen for prospective assessment of disease risk, for understanding the underlying molecular basis of breast cancer risk factors, and improving primary and secondary prevention of breast cancer.

BACKGROUND: Analysis of cytokines and growth factors in human milk offers a noninvasive approach for studying the microenvironment of the postpartum breast, which may better reflect tissue levels than testing blood samples. Given that Black women have a higher incidence of early onset breast cancers than White women, we hypothesized that milk of the former contains higher levels of pro-inflammatory cytokines, adipokines, and growth factors. METHODS: Participants included 130 Black and 162 White women without a history of a breast biopsy who completed a health assessment questionnaire and donated milk for research. Concentrations of 15 analytes in milk were examined using two multiplex and 4 single-analyte electrochemiluminescent sandwich assays to measure pro-inflammatory cytokines, angiogenesis factors, and adipokines. Mixed-effects ordinal logistic regression was used to identify determinants of analyte levels and to compare results by race, with adjustment for confounders. Factor analysis was used to examine covariation among analytes. RESULTS: Thirteen of 15 analytes were detected in ≥25% of the human milk specimens. In multivariable models, elevated BMI was significantly associated with increased concentrations of 5 cytokines: IL-1β, bFGF, FASL, EGF, and leptin (all p-trend < 0.05). Black women had significantly higher levels of leptin and IL-1β, controlling for BMI. Factor analysis of analyte levels identified two factors related to inflammation and growth factor pathways CONCLUSION: This exploratory study demonstrated the feasibility of measuring pro-inflammatory cytokines, adipokines and angiogenesis factors in human milk, and revealed higher levels of some pro-inflammatory factors, as well as increased leptin levels, among Black as compared with White women.

Critical incident stress debriefing (CISD) is a psychoeducational group intervention offered after exposure to potentially traumatizing events. This exploratory inquiry examined how mental health and peer facilitators utilized elements of group work practices during CISD interventions. Narratives from 16 mental health and 14 peer facilitators reported how elements of group planning, performing, and processing appear. Important group-process aspects included attention to establishing ground rules and defining boundaries for confidentiality, managing member disclosure, and pacing the process to prevent harm from over-processing the traumatic event. Implications for practice suggest that following best practice guidelines in group work is protective of the CISD process and the participants.

Epigenetics is a field of study that invites an interdisciplinary interaction of the social and biological sciences. This collaboration has, in fact, led to a blossoming research community over the past two decades, which is using new data, methods, and conceptual frameworks to address a host of old and emergent research questions. A recent (2014) search of PubMed found over a thousand articles on social, behavioral, and cognitive epigenetics. If one includes epidemiological epigenetic studies that incorporate either social causes or consequences in their research, the number expands nearly threefold. Yet, social epigenetics is a still nascent field, marginalized and misunderstood in social science. In this essay, we attempt to review basic epigenetic concepts and the way in which epigenetics has, and can be, of use to social and behavioral scientists in addressing some of the most fundamental sorts of questions their disciplines raise. Keywords: epigenetics; sociobiology; behavioral genetics; inheritance; environmental health; health and social behavior; cognitive neuroscience; methylation; histone modification

This paper examines the mechanical response of precast panel pavement repair joints under static aircraft loadings using the finite-element method. Three-dimensional finite-element models were developed using the Abaqus software code, and their results were compared to and validated against results of full-scale field tests and theoretical calculations. Unlike previous pavement repair modelling efforts for precast panels and dowel retrofitting studies, all parts of the repair joint were modelled, including the dowels, dowel slot material, parent concrete, precast panel and pavement sublayers. Results show that high stress concentrations occur in the dowel slot material and that the current panel design is likely to be improved by modifying the dowel diameter.

This article explores the social interactions of immigration, occupation, and wealth in two urban industrial cities of nineteenth-century New England that were largely built upon, and shaped by, immigration: the very rapidly growing factory town of Holyoke, Massachusetts, and a more mixed-market and steadily growing nearby community of Northampton, Massachusetts. Both communities were emergent, rapidly industrializing, inland cities, providing a quite distinct immigration context than large established cities of the East Coast. Both were destinations for the same general ethnic immigration waves over the late nineteenth century, but with very different, and differently impacted, social spaces into which immigrants arrived. Contrasting and considering both these emergent cities allows us to ascertain the extent to which the occupational distribution and accumulation of wealth by immigrant groups supports the broad pattern of nineteenth-century assimilation, and reveals ways in which other migration processes may have been at odds, or intertwined, with the long-term historical assimilation of immigrants in such communities. Our findings support a traditional assimilationist perspective in emergent urban-industrial centers. However, they also reveal the role of universal immiseration in an industrial city dual-labor market in facilitating or forcing assimilation, the temporal advantages for ethnic groups of arriving early in growing settlements, and the more individualistic nature of economic enclaves in gaining advantages over time that did not manifest across broad immigrant or occupational groups.

TGF-β plays a dual role in breast carcinogenesis, acting at early stages as tumor-suppressors and later as tumor-promoters. TGF-β isoforms are expressed in breast tissues and secreted in milk, suggesting that analysis of levels in milk might be informative for breast cancer risk. Accordingly, we assessed TGF-β2 levels in milk from women who had undergone a breast biopsy and related the concentrations to diagnosis. Milk donated by women who had undergone or were scheduled for a breast biopsy was shipped on ice for processing and testing. Breast cancer risk factors were obtained through a self-administered questionnaire, and biopsy diagnoses were extracted from pathology reports. TGF-β2 levels in milk, assessed as absolute levels and in relation to total protein, were analyzed in bilateral samples donated by 182 women. Linear regression was used to estimate relationships of log-transformed TGF-β2 levels and TGF-β2/ total protein ratios to biopsy category. Milk TGF-β2 levels from biopsied and non-biopsied breasts within women were highly correlated (r 2 = 0.77). Higher mean TGF-β2 milk levels (based on average of bilateral samples) were marginally associated with more severe breast pathological diagnosis, after adjusting for duration of nursing current child (adjusted p trend = 0.07). Our exploratory analysis suggests a borderline significant association between higher mean TGF-β2 levels in breast milk and more severe pathologic diagnoses. Further analysis of TGF-β signaling in milk may increase understanding of postpartum remodeling and advance efforts to analyze milk as a means of assessing risk of breast pathology.

Background Diets rich in fruits and vegetables (F/V) can reduce the inflammatory profile of circulating cytokines and potentially decrease the risk of breast cancer. However, the extent to which a diet rich in F/V alters cytokine levels in breast tissue remains largely unknown. Breast milk provides a means of assessing concentrations of secreted cytokines in the breast microenvironment and is a potential tool for studying the effects of diet on inflammation in breast tissue and breast cancer risk. Objective The aim of this pilot randomized trial was to test the feasibility of increasing F/V intake in breastfeeding women and of measuring changes in markers of inflammation in breast milk. Design and intervention Participants randomized to the intervention (n=5) were provided weekly boxes of F/V, along with dietary counseling, to increase consumption of F/V to 8 to 10 daily servings for 12 consecutive weeks. Controls (n=5) were directed to the US Department of Agriculture’s “ChooseMyPlate” diet for pregnancy and breastfeeding. Participants/setting Ten breastfeeding women consuming fewer than five servings of F/V per day, as estimated by the National Institutes of Health “All-Day” Fruit and Vegetable Screener (F/V Screener), were recruited through flyers and a lactation consultant between February and May 2016 in the Western Massachusetts area. Main outcome measures Baseline demographic and F/V intake data were collected during enrollment. At week 1 and week 13 (final) home visits, participants provided milk samples and anthropometric measurements were recorded. Participants completed F/V screeners at baseline and at study end. Adiponectin, leptin, C-reactive protein, and 11 additional cytokines were measured in breast milk collected at weeks 1 and 13. Statistical analyses F/V consumption at baseline and after the final visit, and between controls and intervention groups, was compared with dependent and independent t tests, respectively. Differences between cytokine levels at weeks 1 and 13 were assessed with a mixed-effects repeated-measures model. Results All women in the intervention increased F/V intake and were consuming more servings than controls by week 13; daily serving of F/V at baseline and final visit: controls=1.6 and 2.0, diet=2.6 and 9.9. Most cytokines were detected in the majority of milk samples: 12 were detected in 90% to 100% of samples, one was detected in 75% of samples, and one was detected in 7.5% of samples; coefficients of variation were below 14% for 11 of the cytokines. Conclusions These preliminary findings indicate that it is feasible to significantly increase F/V intake in breastfeeding women and provide support for conducting a larger diet intervention study in breastfeeding women, in which longer-term benefits of the intervention are assessed.

S-phase kinase-associated protein 2 (SKP2) is an important cell cycle regulator, targeting the cyclin-dependent kinase (CDK) inhibitor p27 for degradation, and is frequently overexpressed in breast cancer. p27 regulates G1 /S transition by abrogating the activity of cyclin/CDK complexes. p27 can undergo phosphorylation at serine 10 (pSer10p27). This phosphorylation event is associated with increased cell proliferation and poor prognosis in patients with glioma. The relationship between SKP2 and pSer10p27 in breast cancer has not been previously investigated. Immunohistochemistry (IHC) of SKP2, p27, pSer10p27, and other genes involved in this pathway, was analyzed in 188 breast tumors and 50 benign reduction mammoplasty samples. IHC showed SKP2 to be more highly expressed in estrogen receptor α (ERα)-negative breast cancers and demonstrated that triple-negative tumors were more likely to have high expression of SKP2 than were non-triple negative, ERα-negative tumors. A significant positive relationship was discovered for SKP2 and pSer10p27. High levels of SKP2 and pSer10p27 were observed significantly more often in ERα-negative and triple-negative than in ERα-positive breast cancers. Use of the triple-negative TMX2-28 breast cancer cell line to address the role of SKP2 in cell cycle progression confirmed that SKP2 contributes to a more rapid cell cycle progression and may regulates pSer10p27 levels. Together, the results indicate that presence of high SKP2 plus high pSer10p27 levels in triple-negative breast cancers is associated with aggressive growth, and highlight the validity of using SKP2 inhibitors as a therapeutic approach for treating this subset of breast cancers.

Matting systems are used for temporary applications on soft soils to reduce ground pressure exerted by aircraft, heavy equipment, vehicles, and construction material. They have been used for military airfields, construction platforms, and similar applications. Previous evaluation studies of matting systems have typically consisted of full-scale testing, with only a limited amount of numerical modeling found in the literature. This paper presents results of full-scale accelerated testing of 21 test sections encompassing five matting systems, five soil-support conditions, and two aircraft loadings. One of the soil-support conditions was instrumented and tested in conjunction with three matting systems and one aircraft loading. Three-dimensional finite-element modeling was performed on the instrumented sections using the measured test data for calibration. Good matches of measured soil stresses were obtained with the model for two of the mats, whereas the model underpredicted stresses in the third mat. Modeling of the type performed in this paper was capable of correctly ranking the performance of the matting systems modeled relative to the full-scale test results.

Roughly two-thirds of all breast cancers are ERα-positive and can be treated with the antiestrogen, Tamoxifen, however resistance occurs in 33% of women who take the drug for more than 5 y. Aberrant DNA methylation, an epigenetic mechanism that alters gene expression in cancer, is thought to play a role in this resistance. To develop an understanding of Tamoxifen-resistance and identify novel pathways and targets of aberrant methylation, DNA from MCF-7 breast cancer cells and Tamoxifen-resistant derivatives, TMX2-11 and TMX2-28, were analyzed using the Illumina HumanMethylation450 BeadChip. Normalizing against MCF-7 values, ERα-positive TMX2-11 had 4000 hypermethylated sites and ERα-negative TMX2-28 had over 33 000. Analysis of CpG sites altered in both TMX2-11 and TMX2-28 revealed that the Tamoxifen-resistant cell lines share 3000 hypermethylated and 200 hypomethylated CpGs. ZNF350 and MAGED1, two genes hypermethylated in both cell lines, were examined in greater detail. Treatment with 5-aza-2ꞌdeoxycitidine caused a significant reduction in promoter methylation of both ZNF350 and MAGED1 and a corresponding increase in expression in TMX2-28. A similar relationship between methylation and expression was not detected in TMX2-11. Our findings are indicative of the variable responses to methylation-targeted breast cancer therapy and highlight the need for biomarkers that accurately predict treatment outcome.

To evaluate how the calculation of a crystal energy landscape can be used in the solid-form screening of pharmaceuticals, a Knowledge Transfer Secondment between GlaxoSmithKline (GSK) and University College London was established to carry out computational crystal structure prediction (CSP) and further guided experimentation on a molecule from GSK’s compound collection. The molecule chosen was 6-[(5-chloro-2-([(4-chloro-2-fluorophenyl)methyl]oxy)phenyl)methyl]-2-pyridinecarboxylic acid (GSK269984B) since the preliminary thermodynamic form screening had only identified one anhydrate, Form I. The calculations confirmed that Form I is the most thermodynamically stable form. The thermodynamically competitive computed structures all had very different conformations of GSK269984B, and further experiments were designed to attempt to generate these conformations in solution and hence the crystalline solid. The experimental screening generated four novel solvates which all eventually transformed to Form I, two of ...

1. IntroductionSocial, economic, and environmental factors all impacted mortality in 19th century Europe and the United States. The type of place (rural or urban, industrial or non-industrial area, stable or growing population) was a powerful predictor of mortality, especially for children, even when socioeconomic status (SES) is taken into account (e.g., Preston and Haines 1991; Vinovskis 1981; Preston and Van de Walle 1978). The effects of structural and social environmental mechanisms (sanitation, overcrowding, occupational structure, population stability) also varied within geographic regions (e.g., Preston and Van de Walle 1978; Melosi 1999). Yet individual-level socioeconomic circumstances influenced mortality across the wider disparities and inequalities of geographic circumstance in 19th century society (e.g., Condran 1995; Garrett et al. 2001; Preston and Haines 1991), and may have even been most salient where other circumstances were most dire (Reid 1997). We sought to expand on our own previous work in 19th century Massachusetts towns, by asking whether individual-level socioeconomic factors influenced mortality from infectious diseases characterized by epidemics in emerging urban, often stressful and harsh, environments.Holyoke, Massachusetts is located on the Connecticut River in the western portion of the state. The township was a planned industrial community and experienced rapid growth from the 1850s through 1910s, fueled primarily by immigration from Ireland, Canada, and Eastern Europe. Structural issues related to sanitation and overcrowding were continual problems in Holyoke during the last half of the 19th century and led to numerous recorded epidemic outbreaks (Green 1939). The industrial structure of the township created a high level of economic and social inequality, with immigrants entering primarily to work in low-paying mill jobs. The constant influx of new workers further impacted the township's demography by maintaining a relatively young population (Leonard, Beemer, and Anderton 2012). Immigrants of Irish and Canadian origin then experienced an accumulation in both personal and real estate wealth at a fast rate, eventually bringing their level of wealth close to that of the native-born. We argue that this accumulation of wealth over time represents a maturation effect, whereby later immigrants from a specific country of origin benefit from established social connections and resources of prior co-nationals. Overall mortality was high during periods of rapid growth, and only recent immigration significantly lowered the likelihood of death.2. Data and methodsWe utilized two datasets for this analysis. The first dataset includes records of all deaths in Holyoke between 1850 and 1912. The second dataset is an urban-based geographic sample of Federal census records, linked to property tax information and death records in the year following the census, allowing us to analyze personal and family characteristics not available from the death records. Gutman (1956) demonstrates the extraordinary completeness of Massachusetts death reporting and previous research (e.g., Leonard, Beemer, and Anderton 2012) demonstrates representation of the impoverished within the tax-linked dataset. We looked at trends in mortality rates for the entire population using the first dataset, and modeled mortality rates for the sampled census population using Poisson rate regression. Cause-specific counts of deaths are the numerators of the rates, with interpolated census population counts as the denominators. The model presented here was developed in prior research and applied to overall adult and child mortality (Leonard, Beemer, and Anderton 2012). In this note we replicate the same model, limited to mortality from the important infectious diseases of the time in this place.We focused on infectious diseases that caused significant epidemics in the 19th century United States (Condran and Murphy 2008) and were continually present in Holyoke between 1850 and 1912. …

Background: Breast cancer risk increases during pregnancy and remains elevated for a number of years thereafter. Cancer-associated proteins that are secreted into breast milk may provide a means to detect cancer in the lactating breast or to assess future breast cancer risk. Objective: To determine whether proteins linked to breast cancer would be differentially expressed in matched (both breasts from each participant) human milk samples collected from women with unilateral breast cancer. Methods: Five cancer-associated proteins (basic fibroblast growth factor [bFGF], YKL-40, neutrophil gelatinase-associated lipocalin, and transforming growth factor β1 and β2) were analyzed in milk provided by 5 lactating women, 4 of whom were known to have cancer in 1 breast (and the opposite breast clinically disease free) at the time of milk collection and 1 who developed breast cancer 2 years after milk collection. Results: Expression was significantly higher for TGFβ2 ( P = .03) and bFGF ( P =.03) in the breasts with cancer. Conclusion: These proteins may play a role in assessing a woman’s risk of pregnancy-associated breast cancer. Because of variable protein concentration among patients and the limited sample size, the results are considered preliminary.

Accurately identifying women at increased risk of developing breast cancer will provide greater opportunity for early detection and prevention. DNA promoter methylation is a promising biomarker for assessing breast cancer risk. Breast milk contains large numbers of exfoliated epithelial cells that are ideal for methylation analyses. Exfoliated epithelial cells were isolated from the milk obtained from each breast of 134 women with a history of a non-proliferative benign breast biopsy (Biopsy Group). Promoter methylation of three tumor suppressor genes, RASSF1, SFRP1 and GSTP1, was assessed by pyrosequencing of bisulfite-modified DNA. Methylation scores from the milk of the 134 women in the Biopsy Group were compared to scores from 102 women for whom a breast biopsy was not a recruitment requirement (Reference Group). Mean methylation scores for RASSF1 and GSTP1 were significantly higher in the Biopsy than in the Reference Group. For all three genes the percentage of outlier scores was greater in the Biopsy than in the Reference Group but reached statistical significance only for GSTP1. A comparison between the biopsied and non-biopsied breasts of the Biopsy Group revealed higher mean methylation and a greater number of outlier scores in the biopsied breast for both SFRP1 and RASSF1, but not for GSTP1. This is the first evidence of CpG island methylation in tumor suppressor genes of women who may be at increased risk of developing breast cancer based on having had a prior breast biopsy.

Over the past 20 years, numerous research studies have been published indicating that lesbian, gay, and bisexual (LGB) individuals, LGB couples, and family members of LGB individuals are experiencing religious identity/sexual orientation identity conflict. In addition, many of these same studies have included in the findings resolution strategies utilized by participants to negotiate this type of conflict. This article presents a review of the religious identity/sexual orientation identity conflict research and links it to cognitive dissonance theory. Subsequently, implications for counselors and future research are offered in light of this literature review.

Manipulation of ploidy in switchgrass has potential to accelerate inbred production and to provide insight about genome structure through either sequencing or cytogenetic approaches. We have identified two dihaploid individuals isolated from among the progeny of a controlled cross between two individuals of the cultivars Alamo and Kanlow. The dihaploid lines were initially distinguished from the parental lines by their reduced heterozygosity and were subsequently confirmed through estimation of C values by flow cytometry and chromosome counts of metaphase root tip squash preparations. These plants are functionally sterile, with floral bracts that remain closed and inviable pollen. They can be easily distinguished from tetraploid individuals by their reduced stature, smaller epidermal cell size, and lower number of chloroplasts per guard cell. Aberrant meiosis in these individuals is evidenced by a lack of regular pairing at diakinesis and metaphase I and suggests that the non-homologous genomes are distinct from one another. The reduced genome size of these dihaploids will facilitate basic genome studies and genetic analyses that are impossible or problematic in polyploid accessions.

The focus of this work was to evaluate the use of commercially available matting systems to sustain C-130 and C-17 transport aircraft loads over soil bases having different California bearing ratio (CBR) ranges. Test sections were constructed using three range of CBR: high (CBR=40–50), medium (CBR=8–10), and low (CBR=5–6). Testing began with the C-130 load cart and six different matting systems. The C-130 was the lesser of the two aircraft loads examined and this initial testing was used as an "elimination round" for the various matting systems chosen. Matting systems deemed suitable for the C-130 were further tested under the C-17 load cart. Systems were evaluated based on logistical and assembly requirements, mat damage sustained during traffic, and accumulated deformation of the mats and soil during traffic. The latter are shown in line plots of passes versus plastic rut formation. Summary information on each matting system tested and the test sections themselves is presented. Conclusions on the matting systems tested and their application are discussed.

Purpose Poor living conditions are posited as an underlying cause of American Indian (AI) infant mortality, which is unusually high in the postneonatal period. We explore whether the effects of neighborhood poverty on AI infant death are identifiable by using observational data. Methods Vital records for infants born between 1990 and 1999 to AI women in a metropolitan area (n = 4751) are linked with tract-level poverty data. A counterfactual framework, an explicit causal contrast study design, and propensity score matching methods were used. For each comparison, we created exchangeable groups by matching infants with the same probability of exposure to poverty when one was exposed and the other was not. Results Our results suggest that neighborhood poverty has little effect on AI infant death outcomes. Importantly, the study design makes transparent the challenge of identifying appropriate analytic comparison groups in studies of neighborhood poverty and health. Conclusions Collecting additional data will likely not overcome the fact that AIs with a high probability of living in poverty rarely reside in low-poverty neighborhoods. Yet, some of them must if a meaningful counterfactual comparison is to be made and the effects of neighborhood poverty on AI infant death are to be identified.

In this study, we investigate the extent to which women and men differ in patterns of medication use, based on quantitative and qualitative data from a household survey in Western Massachusetts. Using a broad definition of medications, 96% of the sample reported taking one or more medications in the month preceding the survey (86% if vitamins, supplements, and alternative medications are excluded). Twenty-one percent of respondents reported taking five or more medications, and women were significantly more likely to report taking five or more medications in the month preceding the survey. For both sexes, analgesics and vitamins were the most commonly used medications, but women were more likely to report having taken hormones, supplements, and antihistamines. The likelihood of medicating reported health conditions did not differ by sex, but the frequency of reporting health conditions was higher among women, and the difference was significant for body aches and psychosomatic conditions. Analyses of qualitative data indicate that female networks of relatives and friends are an important source of advice on medications for both men and women. Responses to open-ended questions suggest that women's discourse about the effect of medications differs from men's in terms of the range and detail of descriptions of symptoms and side effects.

Kentucky bluegrass (Poa pratensis L.), one of the most commonly grown turfgrasses in temperate regions, is being developed for possible commercial release with transgenic traits. The use of this technology raises risk assessment questions because P. pratensis is perennial, often apomictic, competitive in many habitats, and hybridizes with other Poa. To further understand the potential environmental impact of a transgenic P. pratensis, we measured intra- and interspecific pollen-mediated gene flow in field conditions from P. pratensis to other Poa. We used a wagon-wheel design with a glyphosate (N-phosphono methyl-glycine) resistant P. pratensis as a pollen donor and a pollen receptor plot at 0 m and plots at 13 and 53 m along six equally spaced vectors. Each receptor plot included accessions from 25 Poa species. Seedlings from the receptor plants were screened for resistance to glyphosate and potential hybrids verified by PCR and genomic fingerprinting. Hybrids were found with P. arachnifera Torrey, P. interior Rydb., P. pratensis x P. secunda J. Presl, and three other P. pratensis entries, but did not occur with P. annua L., P. palustris L., P. trivialis L., or P. compressa L., among other species. Overall hybrid frequency was 0.048% and hybrid frequency at the 0-m distance was 0.53%. While apomixis in receptor plants and pollen competition likely reduced the number of hybrids, gene flow did occur but at low frequency and over short distances.

Historical mortality analysis is often confounded by changing disease environments, diagnostic criteria, and terminology. Recorded causes of death are shaped by these local and historical contexts. We analyze changing literal causes of death during the shift from miasmatic to germ theories of disease using death records from two Massachusetts towns for selected years spanning 1850 to 1912. This analysis demonstrates that (1) International Classification of Diseases (ICD) classifications are more stable, yet potentially less informative, than the literal causes recorded in death accounts, (2) recorded causes of death often include additional qualifications and elaborations beyond basic literal causes of death, and the use of such qualifiers rose dramatically during the late nineteenth century, (3) social biases are clearly evident in the extent to which causes of death were further described or qualified, and (4) the additional descriptive qualification of deaths during this period of often ambiguous historical causes of death can potentially aid in efforts to classify causes of death and derive robust estimates of cause-specific mortality trends.

A method has been developed that enables resonance Raman spectra of photolabile species in solution to be recorded under conditions where the level of photoalteration is controlled: a low level enables reactant spectra to be recorded, whereas a high level enables the spectra of short-lived transient species to be recorded in real time using continuous-wave (CW) lasers and standard Raman detection equipment. The design includes a sealed flow system, enabling air-sensitive species to be studied under an inert atmosphere. A simple theoretical model has been developed to aid the interpretation of experimental results, and its applicability is demonstrated. Controlled photoalteration and its theory are demonstrated with 413.1-nm excitation of carbonmonoxymyoglobin (MbCO), which generates deoxymyoglobin (deoxy-Mb) on photolysis, and for which the spectra of both species are well established. The methods have also been applied to two air-sensitive, photolabile transition metal carbonyls using 514.5-nm wavelength excitation: for Cp2Mo2(CO)6 (Cp = η5–C5H5), increasing levels of photoalteration result only in a decrease in the parent band intensities, relative to the solvent bands; for Cp2Fe2(CO)4, increasing levels of photoalteration result in the appearance of additional bands that are assigned to the transient species CpFe(μ–CO)3FeCp, formed following the loss of a CO ligand.

The present paper focuses on the economic evaluation of the observed differences in maternal productivity of different genetic lines in Angus cattle that were managed under contrasting nutritional regimes typical of southern Australia. Five hundred Angus cows were managed concurrently at two locations in southern Australia. On each site, the cows were managed under the following two different nutritional treatments: High and Low, to simulate different stocking rates. Cows selected for a divergence in either carcass rib-fat depth or residual feed intake based on mid-parent estimated breeding values for those traits, were allocated in replicate groups to either High- or Low-nutrition treatments. By design, the supplementary feeding regime was the same for the High and Low genetic lines to ensure genetic differences were not confounded with management differences. Animal productivity results from the experiment were used as input data to evaluate the economic performance of the four genetic lines under the two nutritional treatments. Two methods were used; the first was a gross-margin calculation of income minus variable costs as AU$ per breeding cow for a 1000-cow herd; the second was a whole-farm linear programming model maximising the gross margin. Stocking rates were optimised by matching the energy requirements for the whole herd with the energy available from pasture and supplementary feed on a representative 700-ha farm. Using the two methods of calculating gross margin (per cow and optimised per hectare), including examination of sensitivity to changes in prices of cattle and supplementary feed, the present study demonstrated that genetically leaner cows due to selection of low fat or low residual feed intake, had gross margins superior to those of genetically fatter cows. They generated more income by selling more liveweight due to heavier weights and higher stocking rates. The results are affected by the management system utilised and some confounding with growth (leaner genetic lines had higher growth estimated breeding values), but will assist producers to make more informed decisions about how to manage animal breeding and nutritional interactions.

Prior candidate gene studies have shown that methylation-induced silencing of tumor suppressor genes in breast milk is related with history of breast biopsy, an established risk factor for breast cancer. To further establish the utility of breast milk as a tissue-specific biospecimen for investigations of breast carcinogenesis we measured genome-wide DNA methylation in breast milk from women with and without a diagnosis of breast cancer. Breast milk provides a source of cells without invasive procedure that is available during a window of increased breast cancer risk. Actively lactating women were enrolled and consented through the University of Massachusetts Amherst breast milk study targeting high risk subjects. Participants completed a questionnaire to provide demographic and breast cancer risk factor data. Genome-wide DNA methylation levels were quantified using the Illumina 450K HumanMethylation array. Data was processed in R using RnBeads. Beta-values were normalized (FUNnorm), low quality probes were filtered and transformed to M-values. Linear mixed effects models were fit including a random effect for subject and adjusted for history of breast biopsy, age, body mass index, age of the baby, and estimated cell type proportions, an interaction term for time of diagnosis was included. DNA methylation in women with breast cancer (n=9), was compared with women without a history of breast cancer (n=22). Among women with a diagnosis of breast cancer there were two groups: those diagnosed within one year of donating breast milk, and those diagnosed more than one year before sample collection. Four women in the control and five women in the cancer group provided bilateral breast milk samples at recruitment and both samples were included in the analyses. CpGs with significant differential methylation were tested for enrichment in gene pathways using the KEGG database. We identified 215 differentially methylated CpG sites in women diagnosed within one year of sample donation compared with women without a diagnosis of breast cancer (Q Citation Format: Lucas A. Salas, Sara N. Lundgren, Eva P. Browne, Elizabeth C. Punska, Douglas L. Anderton, Kathleen F. Arcaro, Brock C. Christensen. Altered DNA methylation in breast milk from women with breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4355. doi:10.1158/1538-7445.AM2017-4355

Recent research has considerably increased our understanding of the factors associated with the American epidemiological transition in the late nineteenth century. However, uncertainty remains regarding the impact on mortality of specific changes ancillary to urbanization and industrialization in American cities and towns. The broad objective of the Connecticut Valley Historical Demography Project is to examine changing relationships between socioeconomic status, the rise of new urban-industrial communities, and cause-specific mortality trends during the rapid development of New England manufacturing. To address these issues, the present analysis examines two emergent urban centers in Massachusetts, adopting a micro-demographic approach to explore late-nineteenth-century and turn-of-the-century determinants of mortality.

Background: Breast cancer is the most frequently diagnosed cancer among Turkish women and both the incidence and associated mortality appear to be increasing. Of particular concern is the percentage of young women diagnosed with breast cancer; roughly 20% of all breast cancer diagnoses in Turkey are in women younger than 40 years. Increased DNA methylation in the promoter region of tumor suppressor genes is a promising molecular biomarker, and human milk provides exfoliated breast epithelial cells appropriate for DNA methylation analyses. Comparisons between DNA methylation patterns in epithelial (epithelial-enriched) and nonepithelial (epithelial-depleted) cell fractions from breast milk have not been reported previously. Objective: In the present study, we examined promoter methylation of 3 tumor suppressor genes in epithelial-enriched and epithelial-depleted cell fractions isolated from breast milk of 43 Turkish women. Methods: Percentage methylation in the promoter region of Rass association domain family 1 (RASSF1), secreted frizzle related protein 1 (SFRP1), and glutathione- S-transferase class pi 1 was determined by pyrosequencing of the epithelial-enriched and epithelial-depleted cell fractions. Results: Pyrosequencing identified a few subjects with significantly increased methylation in 1 or more genes. There was little correlation between the 2 cell fractions within individuals; only 1 woman had increased methylation for 1 gene (SFRP1) in both her enriched and depleted cell fractions. Methylation was positively associated with age for SFRP1 (epithelial-depleted fraction) and with body mass index for RASSF1 (epithelial-enriched cell fraction), respectively. Conclusion: Overall, results show that the methylation signals vary between different cell types in breast milk and suggest that breast milk can be used to assess DNA methylation patterns associated with increased breast cancer risk.

A finite-element analysis was conducted of flexible pavement test sections subjected to a moving aircraft tire. The test sections failed primarily as a result of shear in the base course. Excavation of the test sections at the end of the tests revealed that there was transverse shear flow of the base as a result of repetitive loading. Deflections at various depths were recorded with multidepth deflectometers. These deflections were used to calibrate the finite-element model. Subsequently, excellent agreement was obtained between measured and predicted time histories of deflections at the various depths. Also, excellent agreement was obtained between predicted and accumulated rutting. The analysis predicted that the shear stress in the base would equal the shear strength, which confirms the mode of failure observed in the test sections.

S-phase kinase-associated protein 2 (SKP2) is an important cell cycle regulator, targeting the cyclin-dependent kinase (CDK) inhibitor p27 for degradation, and is frequently overexpressed in breast cancer. p27 regulates G1 /S transition by abrogating the activity of cyclin/CDK complexes. p27 can undergo phosphorylation at serine 10 (pSer10p27). This phosphorylation event is associated with increased cell proliferation and poor prognosis in patients with glioma. The relationship between SKP2 and pSer10p27 in breast cancer has not been previously investigated. Immunohistochemistry (IHC) of SKP2, p27, pSer10p27, and other genes involved in this pathway, was analyzed in 188 breast tumors and 50 benign reduction mammoplasty samples. IHC showed SKP2 to be more highly expressed in estrogen receptor α (ERα)-negative breast cancers and demonstrated that triple-negative tumors were more likely to have high expression of SKP2 than were non-triple negative, ERα-negative tumors. A significant positive relationship was discovered for SKP2 and pSer10p27. High levels of SKP2 and pSer10p27 were observed significantly more often in ERα-negative and triple-negative than in ERα-positive breast cancers. Use of the triple-negative TMX2-28 breast cancer cell line to address the role of SKP2 in cell cycle progression confirmed that SKP2 contributes to a more rapid cell cycle progression and may regulates pSer10p27 levels. Together, the results indicate that presence of high SKP2 plus high pSer10p27 levels in triple-negative breast cancers is associated with aggressive growth, and highlight the validity of using SKP2 inhibitors as a therapeutic approach for treating this subset of breast cancers.

Bisphenol A (BPA) is a synthetic, endocrine-disrupting compound. Free BPA has been detected in human samples indicating that humans are internally exposed to estrogenically active BPA. The purpose of this study was to develop a sensitive method to detect free BPA in human breast milk. BPA was isolated from the milk of 21 nursing mothers in the U.S. by solid-phase extraction. It was then derivatized to improve sensitivity and subsequently analyzed by ultra high performance liquid chromatography-tandem mass spectrometry. Free BPA was detected in 62% of the milk samples (≤ 0.22-10.8 ng mL(-1), median 0.68 ng mL(-1), mean 3.13 ng mL(-1)). No statistical difference in BPA concentrations was observed between women with a low or high Body Mass Index (BMI) (30 (n=11) and30 (n=10), respectively). However, there was a significant association between BPA concentration and race. Caucasian women had significantly higher levels of free BPA in their breast milk than non-Caucasian women (mean=4.44 (n=14) and 0.52 (n=7), respectively; p0.05). The difference between races could be attributed to variations in exposure, lifestyle or metabolism and suggests that certain populations should take extra precautions to limit BPA exposure, particularly during pregnancy and lactation.

The mortality transition in Western Europe and the United States encompassed a much more complex set of conditions and experiences than earlier thought. Our research addresses the complex set of relationships among growing urban communities, family wealth, immigration and mortality in New England by examining individual-level, sociodemographic mortality correlates during the nineteenth-century mortality plateau and its early twentieth-century decline. In contrast to earlier theories that proposed a more uniform mortality transition, we offer an alternative hypothesis that focuses on the impact of family wealth and immigration on individual-level mortality during the early stages of the mortality transition in Northampton and Holyoke, Massachusetts.