Search

To examine the impact of the German Occupation of Guernsey (1940-1945) on breast cancer risk factors and incidence. Under study were 1019 women who stayed, or whose mothers had stayed, in Guernsey, and 1358 women evacuated or born to evacuated mothers. Amongst those born 1926-1934 who remained in Guernsey, the secular trend of earlier menarche disappeared: menarche was delayed by 12 months for those born in 1930. By March 2006, 97 breast cancers had been diagnosed, 37 in the occupied group. Unusually, higher age at menarche appeared to be associated with increased risk of breast cancer (>/=14 years vs.

Using various indicators of financial development, this paper investigates the role of financial intermediation in stimulating economic growth in Southern Africa. The results lend some support to the hypothesis that financial development is positively correlated with the growth rate of real per capita GDP. This relationship is more evident in regressions that use pooled data (5-year cross-sections) than those using annual data. This finding suggests that the finance-growth nexus is a long-run phenomenon. The data indicate that while Botswana and Mauritius are catching up with South Africa towards a high-income steady state, the rest of the countries are stagnating to low income levels and low growth rates. [ABSTRACT FROM AUTHOR]

Training needs of Special Operations Forces (SOF) medics were surveyed and new training initiatives have been created to meet their needs. SOF medics perform an array of medical procedures in austere environments with minimal supervision. Medical skills decay over time after initial training and the perceived training needs of active SOF medics were unclear. To fill this gap, active SOF medics (n=57) completed a survey that included confidence ratings and indications of whether additional training would make them more proficient in 70 medical knowledge and procedural skills, assembled into categories by a panel of experts (airway, trauma, neuro, differential diagnosis, administrative, infection, critical care, environmental, other). Data were analyzed with analysis of variance (ANOVA) and nonparametric statistics at P<.05. Confidence was highest in the trauma, administrative, and airway categories, and lowest in the infection, differential diagnosis, and neuro categories (P<.05 or less). Categories indicating the greatest need for additional training were environmental and critical care, while those indicating lowest need were the airway and trauma categories (P=.05). Additional training was endorsed by >75% of participants in each category. SOF medics also wanted additional training in all areas, preferably hands-on with live patients in realistic scenarios, taught by experienced medics. Findings highlight the training needs of SOF medics and demonstrate the value of bottom-up feedback toward optimizing sustainment training. Based on present findings, two TACMED (Tactical Medicine) Divisions at the SOF Echelon III level were created to meet the sustainment training needs of SOF medics., Competing Interests: The authors have no financial relationships relevant to this article to disclose., (2024.)

Current regulations require that toxicity assessments be performed using standardized toxicity testing methods, often using fish. Recent legislation in both the European Union and United States has mandated that toxicity testing alternatives implement the 3Rs of animal research (replacement, reduction, and refinement) whenever possible. There have been advances in the development of alternatives for freshwater assessments, but there is a lack of analogous developments for marine assessments. One potential alternative testing method is the fish embryo toxicity (FET) test, which uses fish embryos rather than older fish. In the present study, FET methods were applied to two marine model organisms, the sheepshead minnow and the inland silverside. Another potential alternative is the mysid shrimp survival and growth test, which uses an invertebrate model. The primary objective of the present study was to compare the sensitivity of these three potential alternative testing methods to two standardized fish-based tests using 3,4-dichloroaniline (DCA), a common reference toxicant. A secondary objective was to characterize the ontogeny of sheepshead minnows and inland silversides. This provided a temporal and visual guide that can be used to identify appropriately staged embryos for inclusion in FET tests and delineate key developmental events (e.g., somite development, eyespot formation, etc.). Comparison of the testing strategies for assessing DCA indicated that: (1) the standardized fish tests possessed comparable sensitivity to each other; (2) the mysid shrimp tests possessed comparable sensitivity to the standardized fish tests; (3) the sheepshead minnow and inland silverside FET tests were the least sensitive testing strategies employed; and (4) inclusion of sublethal endpoints (i.e., hatchability and pericardial edema) in the marine FETs increased their sensitivity. Environ Toxicol Chem 2024;43:1285-1299. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC., (© 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.)

Human immunodeficiency virus type 1 (HIV-1) stimulates innate immune responses upon infection, including cyclic GMP-AMP synthase (cGAS) signaling that results in type I interferon production. HIV-1-induced activation of cGAS requires the host cell factor polyglutamine binding protein 1 (PQBP1), an intrinsically disordered protein that bridges capsid recognition and cGAS recruitment. However, the molecular details of PQBP1 interactions with the HIV-1 capsid and their functional implications remain poorly understood. Here, we show that PQBP1 binds to HIV-1 capsids through charge complementing contacts between acidic residues in the N-terminal region of PQBP1 and an arginine ring in the central channel of the HIV-1 CA hexamer that makes up the viral capsid. These studies reveal the molecular details of PQBP1's primary interaction with the HIV-1 capsid and suggest that additional elements are likely to contribute to stable capsid binding., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Due to the decline of the Aral Sea fishery and recent efforts to expand the fisheries sector in Kazakhstan for both local consumption and global export, there is a need to sustain other fisheries in the area, including the Shardara Reservoir, which lies in the Syr Darya basin. Metals are present in the Syr Darya; yet, their impacts on fishery and consumer health remain unclear. Thus, the objectives of this study were to evaluate: 1) the potential impacts of metals on Syr Darya basin fish and 2) the human health risks posed by consumption of Shardara Reservoir fish. The health of the fishery was assessed by comparing surface water metal concentrations to maximum permissible concentrations (MPCs), calculating water quality index (WQI) and degree of contamination (C d ) values, and evaluating gene expression biomarker responses in wild-caught roach (Rutilus rutilus). To assess the risk to consumers, metal concentrations in roach were used to calculate hazard quotients (HQs) and hazard indices (HIs). Water concentrations of Cu, Fe, Mn, Se, Sr and V exceeded MPCs and all sites were classified as highly polluted based upon WQI and C d values. This, along with site-specific differences in the expression of genes associated with xenobiotic metabolism and oxidative stress in roach, indicates potential risks to the fishery. Though all HQs and HIs were below 1 indicating a lack of significant risk to consumers, Pb levels in roach exceeded MPCs for safe consumption indicating a potential risk. Given the potential risks to the fishery and consumers, the development of pollution monitoring and management programs are warranted. The work presented here provides initial monitoring data that can be used to aid such efforts and also underscores the need to identify environmental stressors that may thwart the anticipated growth of fisheries in this region., Competing Interests: Declaration of competing interest Dan Snow, Alan Kolok, Shannon Bartelt-Hunt, and Marlo Jeffries report financial support was provided by National Science Foundation. Bolat Uralbekov reports financial support was provided by Committee of Science of the Ministry of Education and Science of the Republic of Kazakhstan., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Ancestry is often viewed as a more objective and less objectionable population descriptor than race or ethnicity. Perhaps reflecting this, usage of the term "ancestry" is rapidly growing in genetics research, with ancestry groups referenced in many situations. The appropriate usage of population descriptors in genetics research is an ongoing source of debate. Sound normative guidance should rest on an empirical understanding of current usage; in the case of ancestry, questions about how researchers use the concept, and what they mean by it, remain unanswered. Methods: Systematic literature analysis of 205 articles at least tangentially related to human health from diverse disciplines that use the concept of ancestry, and semi-structured interviews with 44 lead authors of some of those articles. Results: Ancestry is relied on to structure research questions and key methodological approaches. Yet researchers struggle to define it, and/or offer diverse definitions. For some ancestry is a genetic concept, but for many-including geneticists-ancestry is only tangentially related to genetics. For some interviewees, ancestry is explicitly equated to ethnicity; for others it is explicitly distanced from it. Ancestry is operationalized using multiple data types (including genetic variation and self-reported identities), though for a large fraction of articles (26%) it is impossible to tell which data types were used. Across the literature and interviews there is no consistent understanding of how ancestry relates to genetic concepts (including genetic ancestry and population structure), nor how these genetic concepts relate to each other. Beyond this conceptual confusion, practices related to summarizing patterns of genetic variation often rest on uninterrogated conventions. Continental labels are by far the most common type of label applied to ancestry groups. We observed many instances of slippage between reference to ancestry groups and racial groups. Conclusion: Ancestry is in practice a highly ambiguous concept, and far from an objective counterpart to race or ethnicity. It is not uniquely a "biological" construct, and it does not represent a "safe haven" for researchers seeking to avoid evoking race or ethnicity in their work. Distinguishing genetic ancestry from ancestry more broadly will be a necessary part of providing conceptual clarity., Competing Interests: AL owns stock in Fabric Genomics; BN is a member of the scientific advisory board at Deep Genomics and RBNC Therapeutics, Member of the scientific advisory committee at Milken and a consultant for Camp4 Therapeutics and Merck. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dauda, Molina, Allen, Fuentes, Ghosh, Mauro, Neale, Panofsky, Sohail, Zhang and Lewis.)

A wide range of research uses patterns of genetic variation to infer genetic similarity between individuals, typically referred to as genetic ancestry. This research includes inference of human demographic history, understanding the genetic architecture of traits, and predicting disease risk. Researchers are not just structuring an intellectual inquiry when using genetic ancestry, they are also creating analytical frameworks with broader societal ramifications. This essay presents an ethics framework in the spirit of virtue ethics for these researchers: rather than focus on rule following, the framework is designed to build researchers' capacities to react to the ethical dimensions of their work. The authors identify one overarching principle of intellectual freedom and responsibility, noting that freedom in all its guises comes with responsibility, and they identify and define four principles that collectively uphold researchers' intellectual responsibility: truthfulness, justice and fairness, anti-racism, and public beneficence. Researchers should bring their practices into alignment with these principles, and to aid this, the authors name three common ways research practices infringe these principles, suggest a step-by-step process for aligning research choices with the principles, provide rules of thumb for achieving alignment, and give a worked case. The essay concludes by identifying support needed by researchers to act in accord with the proposed framework.

The use of population descriptors such as race, ethnicity, and ancestry in science, medicine, and public health has a long, complicated, and at times dark history, particularly for genetics, given the field's perceived importance for understanding between-group differences. The historical and potential harms that come with irresponsible use of these categories suggests a clear need for definitive guidance about when and how they can be used appropriately. However, while many prior authors have provided such guidance, no established consensus exists, and the extant literature has not been examined for implied consensus and sources of disagreement. Here, we present the results of a scoping review of published normative recommendations regarding the use of population categories, particularly in genetics research. Following PRISMA guidelines, we extracted recommendations from n = 121 articles matching inclusion criteria. Articles were published consistently throughout the time period examined and in a broad range of journals, demonstrating an ongoing and interdisciplinary perceived need for guidance. Examined recommendations fall under one of eight themes identified during analysis. Seven are characterized by broad agreement across articles; one, "appropriate definitions of population categories and contexts for use," revealed substantial fundamental disagreement among articles. Additionally, while many articles focus on the inappropriate use of race, none fundamentally problematize ancestry. This work can be a resource to researchers looking for normative guidance on the use of population descriptors and can orient authors of future guidelines to this complex field, thereby contributing to the development of more effective future guidelines for genetics research., Competing Interests: Declaration of interests B.M.N. is a member of the scientific advisory board at Deep Genomics and RBNC Therapeutics, a member of the scientific advisory committee at Milken, and a consultant for Camp4 Therapeutics and Merck. A.C.F.L. owns stock in Fabric Genomics., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

We must embrace a multidimensional, continuous view of ancestry and move away from continental ancestry categories.

Despite increasing complexity of contemporary procedures at tertiary care hospitals, the relationship between interventional cardiology fellows-in-training (ICFITs) and complications of percutaneous coronary intervention (PCI) has not been reported. We compiled logbooks of 6 ICFITs at an academic hospital and evaluated patient and procedural characteristics of PCIs performed with and without presence of an ICFIT. The primary end point was the composite of all in-hospital PCI complications defined by the American College of Cardiology's National Cardiovascular Data Registry: (1) catheterization laboratory events such as no-reflow and dissection/perforation, (2) general clinical events such as stroke or cardiogenic shock, (3) vascular and bleeding complications, and (4) miscellaneous complications such as peak troponin or creatinine levels. Logistic regression adjusted for differences in measured confounders between patients treated with and without presence of an ICFIT. All analyses were repeated after excluding PCI for ST-elevation myocardial infarction. Of 2,605 PCI procedures at the academic hospital between July 2007 and April 2010, an ICFIT was present for 1,638 procedures (63%). Despite having worse clinical and procedural characteristics, patients in the ICFIT group experienced similar rates of the composite end point (12.9% vs 14.5% without ICFIT, p = 0.27). Longer mean fluoroscopy times and greater number of stents were noted in the ICFIT group; however, hospital length of stay was shorter and no individual adverse events were increased in the ICFIT procedures. Presence of an ICFIT remained unrelated to the composite end point after multivariable adjustment (odds ratio 0.92, 95% confidence interval 0.71 to 1.20; p = 0.53), and findings were similar after excluding PCI for ST-elevation myocardial infarction. In conclusion, in contemporary practice at a large academic medical center, PCI complication rates were not adversely affected by the presence of an ICFIT., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: In breast cancer patients (≥70 years), tumour resection plus tamoxifen (T + T) has a higher loco-regional relapse (LR) rate than mastectomy. This study examines factors influencing local recurrence in these cases., Methods: Clinical records of 71 patients aged ≥70 years, randomised to the T + T arm of 2 randomised trials were reviewed. Cox Proportional Hazards model was used to determine the most significant variables., Results: After 15-years follow-up, LR relapse occurred in 29/71, of whom 5 had synchronous metastatic disease. Most tumours recurred in the index quadrant. Subsequently 21/24 patients with loco-regional recurrence only had salvage mastectomy. Three variables significantly predicted LR: lympho-vascular invasion (LVI) (HR [95% CI]: 11.18 [4.47, 27.95], p < 0.01), ER negative status (HR [95% CI]: 0.27 [0.10, 0.72] p = 0.01), and tumour necrosis (HR [95% CI]: 2.65 [1.10, 6.37], p = 0.03). Final margin status was not associated with LR., Conclusions: Tumour resection + Tamoxifen in older patients results in long-term local control in the majority with most loco-regional failures being salvageable. Risk factors for LR are lympho-vascular invasion, ER status and tumour necrosis. Negative tumour excision margins did not significantly change local outcome in the absence of radiotherapy. In these older patients LVI significantly reduced survival time., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Arterial closure devices (ACDs) provide immediate hemostasis, improve comfort, and allow early ambulation after percutaneous coronary intervention (PCI). The aim of this study was to evaluate ACD utilization and post-PCI major bleeding in an unselected cohort. Patients receiving ACDs were propensity matched to those with manual compression to evaluate a primary end point of National Cardiovascular Data Registry (NCDR) major bleeding and a secondary end point of major bleeding stratified by previously developed NCDR bleeding risk categories. Bleeding events that required transfusion, prolonged hospital stays, and/or decreases in hemoglobin ≥3.0 g/dl were included. Length of stay, defined as days after PCI until discharge, was also evaluated. Secondary analysis of bleeding and complication rates between ACD types (suture vs collagen plug) was performed. Five thousand four hundred twenty-one patients underwent PCI, and 2,324 patients (43%) were included in the final propensity matching: 1,162 with ACDs and 1,162 manual compression patients. Major bleeding was reduced in ACD patients compared to those with manual compression (2.4% vs 5.2%, p <0.001), and NCDR high-risk patients receiving ACDs had the greatest reduction in major bleeds (3.1% vs 10.3%, p <0.001). Length of stay (1.9 ± 1.9 vs 2.3 ± 5.3 days, p = 0.007) and pseudoaneurysms (0.3% vs 1.1%, p = 0.028) were decreased in ACD patients. Suture-based devices revealed a lower composite event rate than collagen-plug ACDs (1.4% vs 3.4%, p = 0.048). In conclusion, ACD use is associated with reductions in NCDR major bleeding, length of stay, and pseudoaneurysms in PCI patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: It has been reported that there is an increased risk of cancer in individuals with elevated levels of serum gamma-glutamyl transferase (GGT)., Methods: In the Guernsey Breast Cancer Cohort Study, GGT was measured in sera from 1803 normal women. Among these women, 251 subsequently developed cancer, of whom 96 developed breast cancer., Results: After adjustment for age at entry, height, weight, age at menarche and first birth with nulliparity, there was a highly significant relationship between elevated GGT and breast cancer risk. In the highest quartile, the hazard ratio (HR) was 2.17 (95% confidence interval (CI): 1.19, 3.93). When subdivided by menopausal status, there was a reduced non-significant effect in postmenopausal women, whereas for premenopausal women in the highest quartile, HR was 3.81 (95% CI: 1.37, 10.59). Premenopausal women with serum GGT levels above the normal range had a significantly elevated HR of 4.90 (95% CI: 1.86, 12.94)., Conclusions: These results suggest that premenopausal women with high normal (above median) serum GGT or elevated levels (< or =40 IU l(-1)) are at increased risk of breast cancer and might benefit from close surveillance, possibly with breast magnetic resonance imaging scans. Serum GGT may mark previous exposure to carcinogens and lead to the identification of DNA adducts involved in mammary carcinogenesis.

Gonadotropins have been indicted in ovarian carcinogenesis but direct evidence has been limited and inconsistent. The aim of this study was to determine the association between prediagnostic levels of follicle stimulating hormone (FSH) and subsequent development of invasive epithelial ovarian cancer. A nested case-control study was conducted using cases and controls drawn from three cohorts: CLUE I and CLUE II of Washington County, MD, and the Island of Guernsey Study, United Kingdom. In total, 67 incident invasive epithelial ovarian cancer cases were each matched to 1 to 2 controls on age, menopausal status, time since last menstrual period, current hormone use and other relevant factors. FSH concentrations were classified into ranked thirds of low, medium or high based on the distribution among controls. Conditional logistic regression was used to estimate the odds ratio (OR) across increasing thirds of FSH concentrations. Results of the analysis showed that ovarian cancer risk decreased with higher FSH concentrations (p-trend = 0.005). Compared with the lowest third of FSH concentrations, the OR among those in the middle and highest thirds were 0.45 [95% Confidence Interval (CI): 0.20-1.00] and 0.26 (95% CI: 0.10-0.70), respectively. Associations persisted after excluding cases diagnosed within 5 years of follow-up. In conclusion, a reduction in subsequent risk of invasive epithelial ovarian cancer was observed among women with higher circulating FSH concentrations. These findings contradict the hypothesized role of FSH as a risk factor in ovarian carcinogenesis.

Background: The prognosis of patients with synchronous bilateral breast cancer (SBBC) is usually based on the tumour with the worst pathological features. There is little evidence in the literature for this assumption, potentially impairing reasoned decisions on optimal adjuvant therapy., Methods: This was a case-control study in which 68 women with SBBC were matched with 128 women with unilateral breast cancer. Both the GuysRisk prognostic model and the Nottingham Prognostic Index were used to determine the bilateral tumour with the poorer prognosis. Controls were matched for age, menopausal status, date of diagnosis, histological type and grade, and oestrogen receptor and axillary node status., Results: Both prognostic models indicated the same side tumour with the worst prognosis. Kaplan-Meier survival curves for both disease-free and overall survival showed no significant difference in outcome between the two groups., Conclusion: Prognosis was determined by the tumour with the worst prognosis, with no additional worsening of outcome incurred from the second tumour., ((c) 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Objectives: To develop an algorithm to standardize capillary blood glucose (CBG) testing in nursing home and rehabilitation patients., Design: Descriptive study in which an interdisciplinary team from a nursing home, a rehabilitation center, and a diabetes mellitus care program developed and tested a protocol to standardize diabetes management parameters and CBG testing frequency., Setting: Department of Veterans Affairs nursing home and rehabilitation unit., Participants: One hundred one patients admitted to the units during the 6-month study period who had orders for CBG testing., Intervention: Use of a standardized CBG testing protocol., Measurements: Use of management goal, use of CBG testing protocol, total CBG tests/month., Results: One hundred one subjects received orders for CBG testing; 72 (72%) received orders for a management goal, and 69 (69%) received orders to use the CBG protocol. Of these 69 patients, 22 met their CBG goals and were advanced to less-frequent CBG testing using the protocol, and 15 did not meet their CBG goals and were not advanced. An additional 15 patients were advanced to less-frequent CBG testing but not using the protocol. In all, 54 of 69 patients (78%) were advanced or could have been advanced by protocol to less-frequent CBG testing. Total CBG testing per month did not change before, during, or after the study period., Conclusion: This protocol would be useful in long-term care facilities and in other congregate living settings where patients with diabetes mellitus have staff assisting with their diabetes management. Barriers to successful implementation are discussed.

The aim of this study was to determine whether endogenous estradiol levels in postmenopausal women helped determine the estrogen receptor status of subsequent breast cancers. Within the Guernsey Cohort study of 6127 women, 140 have been diagnosed with breast cancer of whom 59 had estradiol assays performed and ER status available. Estradiol levels in serum and urine were measured by radioimmunoassay and ER status of tumours by immunohistochemistry. Of the individuals in the highest tertile of serum estradiol 35% had ER+ve tumours compared with 27% in the lowest tertile. In terms of 16hydroxyestrone excretion the proportions ER+ve tumours were 22% in the lowest tertile and 38% in the highest tertile. This suggests that endogenous estrogen levels do impact on the phenotype of subsequent breast cancer.

High levels of circulating insulin-like growth factor-I (IGF-I) and its major binding protein (IGFBP-3) at premenopausal ages have been associated with an increased breast cancer risk. We conducted a cross-sectional study (215 premenopausal women and 241 after natural menopause) nested within the Guernsey prospective studies to examine the relationship between the IGF system and mammographic features of the breast. The mammographically dense area in the breast increased with increasing serum levels of IGF-I (P for linear trend, P(t) = 0.05), IGF-II (P(t) = 0.08), and IGFBP-3 (P(t) = 0.01) only in premenopausal women. IGF-II and IGFBP-3 serum levels were associated with increases in the mammographically lucent area in both premenopausal (P(t) = 0.01 and 0.04, respectively) and postmenopausal women (P(t) < 0.001 for both), but these associations were no longer statistically significant after adjustment for body mass index and waist circumference. Neither the IGF-I/IGFBP-3 nor the IGF-II/IGFBP-3 molar ratio was associated with any of these mammographic features. The number of A alleles at a polymorphic locus in the promoter region of the IGFBP-3 gene was associated with increasing mean IGFBP-3 levels in both premenopausal (P(t) = 0.01) and postmenopausal (P(t) <0.001) women but not with mammographically dense area. These results support the hypothesis that the IGF system may affect the amount of mammographically dense tissue in premenopausal women, possibly by promoting cell proliferation and inhibiting apoptosis in the fibroglandular tissue. The findings also show strong relations between IGF-II and IGFBP-3 levels and the amount of mammographically lucent tissue, reflecting the associations between body adiposity and amount of fat tissue in the breast and between body adiposity and circulating levels of these growth factors.

The hypothesis was that smokers might have more aggressive types of breast cancer because of either delayed diagnosis or higher grade and hence have a worse prognosis. A cohort of breast cancer patients completed a lifestyle questionnaire at the time of diagnosis, including whether they were current smokers, ex-smokers or lifelong non-smokers. Ex-smokers were asked when they had stopped. The participants were 166 women with stage I/II invasive breast cancer diagnosed between October 1984 and March 1987. Participants were divided into three groups: current smokers, ex-smokers and non-smokers. Survival curves were produced by using Cox proportional hazards analysis, with outcome variables for overall and breast cancer-specific survival together with distant relapse-free survival. Smoking was the third most important predictor of distant relapse-free, breast cancer-specific and overall survival after stage and age at diagnosis. These results suggest that smokers are not only more likely to die of other diseases, but also have a higher mortality from breast cancer, compared with those with the disease who have never smoked. The best prognosis, however, was found in those who had given up smoking.

Mammographic features are known to be associated with breast cancer but the magnitude of the effect differs markedly from study to study. Methods to assess mammographic features range from subjective qualitative classifications to computer-automated quantitative measures. We used data from the UK Guernsey prospective studies to examine the relative value of these methods in predicting breast cancer risk. In all, 3,211 women ages > or =35 years who had a mammogram taken in 1986 to 1989 were followed-up to the end of October 2003, with 111 developing breast cancer during this period. Mammograms were classified using the subjective qualitative Wolfe classification and several quantitative mammographic features measured using computer-based techniques. Breast cancer risk was positively associated with high-grade Wolfe classification, percent breast density and area of dense tissue, and negatively associated with area of lucent tissue, fractal dimension, and lacunarity. Inclusion of the quantitative measures in the same model identified area of dense tissue and lacunarity as the best predictors of breast cancer, with risk increasing by 59% [95% confidence interval (95% CI), 29-94%] per SD increase in total area of dense tissue but declining by 39% (95% CI, 53-22%) per SD increase in lacunarity, after adjusting for each other and for other confounders. Comparison of models that included both the qualitative Wolfe classification and these two quantitative measures to models that included either the qualitative or the two quantitative variables showed that they all made significant contributions to prediction of breast cancer risk. These findings indicate that breast cancer risk is affected not only by the amount of mammographic density but also by the degree of heterogeneity of the parenchymal pattern and, presumably, by other features captured by the Wolfe classification.

The associations between serum concentrations of insulin-like growth factor-I (IGF-I), IGF-II and IGF-binding proteins (IGFBP)-3 and risk of breast cancer were investigated in a nested case-control study involving 117 cases (70 premenopausal and 47 postmenopausal at blood collection) and 350 matched controls within a cohort of women from the island of Guernsey, UK. Women using exogenous hormones at the time of blood collection were excluded. Premenopausal women in the top vs bottom third of serum IGF-I concentration had a nonsignificantly increased risk for breast cancer after adjustment for IGFBP-3 (odds ratio (OR) 1.71; 95% confidence interval (CI): 0.74-3.95; test for linear trend, P=0.21). Serum IGFBP-3 was associated with a reduction in risk in premenopausal women after adjustment for IGF-I (top third vs the bottom third: OR 0.49; 95% CI: 0.21-1.12, P for trend=0.07). Neither IGF-I nor IGFBP-3 was associated with risk in postmenopausal women and serum IGF-II concentration was not associated with risk in pre- or postmenopausal women. These data are compatible with the hypothesis that premenopausal women with a relatively high circulating concentration of IGF-I and low IGFBP-3 are at an increased risk of developing breast cancer.

Background: Experimental data from animals suggest a protective role for the pineal hormone melatonin in the etiology of breast cancer, but results from the few retrospective case-control studies that examined the association in humans have been inconsistent. To determine whether low levels of endogenous melatonin are associated with an increased risk for developing breast cancer, we conducted a prospective nested case-control study among British women., Methods: Concentrations of 6-sulfatoxymelatonin, the main metabolite of melatonin in urine and a validated marker of circulating melatonin levels, were measured by radioimmunoassay in 24-hour urine samples collected from women shortly after enrollment in the prospective Guernsey III Study. Levels of 6-sulfatoxymelatonin were compared among 127 patients diagnosed with breast cancer during follow-up and among 353 control subjects, matched for age, recruitment date, menopausal status, and day of menstrual cycle for premenopausal women or number of years postmenopausal for postmenopausal women. Associations were examined by analyses of covariance and conditional logistic regression. All tests of statistical significance were two-sided., Results: No statistically significant differences in urinary 6-sulfatoxymelatonin concentrations were observed between women who developed breast cancer and control subjects among premenopausal or postmenopausal women (P=.8 and P=.9, respectively). When data from premenopausal and postmenopausal women were combined in a multivariable analysis adjusted for potential confounders and grouped into three categories defined by 6-sulfatoxymelatonin tertiles of control subjects, the level of 6-sulfatoxymelatonin excreted was not statistically significantly associated with the risk of breast cancer (odds ratio [OR] for breast cancer = 0.95, 95% confidence interval [CI] = 0.55 to 1.65, comparing the middle category with the lowest category of 6-sulfatoxymelatonin concentration, and OR = 0.99, 95% CI = 0.58 to 1.70, comparing the highest category with the lowest category)., Conclusion: We found no evidence that the level of melatonin is strongly associated with the risk for breast cancer.

Background: Obesity is associated with increased breast cancer risk among postmenopausal women. We examined whether this association could be explained by the relationship of body mass index (BMI) with serum sex hormone concentrations., Methods: We analyzed individual data from eight prospective studies of postmenopausal women. Data on BMI and prediagnostic estradiol levels were available for 624 case subjects and 1669 control subjects; data on the other sex hormones were available for fewer subjects. The relative risks (RRs) with 95% confidence intervals (CIs) of breast cancer associated with increasing BMI were estimated by conditional logistic regression on case-control sets, matched within each study for age and recruitment date, and adjusted for parity. All statistical tests were two-sided., Results: Breast cancer risk increased with increasing BMI (P(trend) =.002), and this increase in RR was substantially reduced by adjustment for serum estrogen concentrations. Adjusting for free estradiol reduced the RR for breast cancer associated with a 5 kg/m2 increase in BMI from 1.19 (95% CI = 1.05 to 1.34) to 1.02 (95% CI = 0.89 to 1.17). The increased risk was also substantially reduced after adjusting for other estrogens (total estradiol, non-sex hormone-binding globulin-bound estradiol, estrone, and estrone sulfate), and moderately reduced after adjusting for sex hormone-binding globulin, whereas adjustment for the androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone) had little effect on the excess risk., Conclusion: The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.

Secondary bile acids produced by the action of the colonic microflora may increase risk of colorectal cancer. Serum bile acid concentrations reflect the faecal bile acid profile and may be of value as biomarkers of risk of colorectal cancer. In a pilot investigation we examined: (i) the reproducibility of measurements of serum bile acids in two blood samples collected several years apart; and (ii) the hypothesis that relatively high levels of secondary bile acids, particularly deoxycholic acid, would be positively associated with an increased risk of colorectal cancer in a prospective study of 3680 women in Guernsey. There was poor reproducibility between repeat measurements of absolute serum concentrations of bile acids, but there was moderately good reproducibility for the ratios of serum concentrations of deoxycholic/cholic acid, lithocholic/chenodeoxycholic and secondary/primary bile acid concentrations (duplicate blood samples were available for 30 women). There were no significant differences in ratios of serum secondary to primary bile acids or in absolute concentrations of bile acids between the 46 women who developed colorectal cancer and their matched controls, although there was a suggestion that an increased risk was associated with a high ratio of deoxycholic/cholic acid (relative risk in top third compared to lower third=3.92 (95% CI 0.91-17.0, P for trend=0.096). These findings suggest that the ratios of serum bile acid concentrations are sufficiently reproducible for epidemiological studies, but that a larger study than our own is needed to adequately test the hypothesis of their relation to cancer risk., (Copyright 2002 Cancer Research UK)

Associations have been found between birth weight and many diseases in adult life. In most countries, few birth records exist for older adults; therefore, birth weight is usually obtained by maternal recall or self-report. This study examined determinants of the availability and accuracy of self-report in middle-aged and elderly women. Birth weights, recorded at the time of birth, were found in 1999 for a subset of 363 women participating in a long-running cancer research study in the United Kingdom. Questionnaires were sent to the surviving 286 women requesting information on their birth weight and other factors related to their birth family. Twenty-five percent of the 244 respondents were able to report their birth weight to within 4 ounces (113.4 g) of that listed in birth records, 28% reported it inaccurately, and 47% did not know their birth weight. The most important factors determining the availability of self-reported birth weight were having a living mother and a low birth weight (< or = 6 pounds (2,722 g)). The most important determinants of accuracy, for those who provided a report, were being younger and the eldest child. Research studies relying on self-reported birth weight should take these factors into account.

Between 1961 and 1967 a cohort of over 5000 women volunteered for a prospective study to determine the relationship between the urinary androgen metabolites, androsterone (A) and aetiocholanolone (E), and risk of breast cancer. During the first 10 years of the study the concentration of urinary A and E was determined in 1887 of the urine specimens. In 1971 we reported that subnormal amounts of urinary A and E were associated with a significantly increased risk of breast cancer. The cohort has been followed regularly during the 37 years since inception of the study and, by May 1998, 248 women had been diagnosed with breast cancer. Urinary androgen metabolites had been measured in 116 of these cases. Analysis of these data confirmed that women diagnosed in the first decade of the study were more likely to have low levels of urinary androgen metabolites. In the following decades, however, those who developed breast cancer were more likely to have manifested an increased A and E excretion. The reversal in the relationship between androgen metabolite excretion and risk suggests that age, or probably more importantly, menopausal status at diagnosis is an important modifying factor. Dichotomizing at age 50 it was found that in the younger age group (predominantly premenopausal) the rate ratios in the lowest tertile of A or E excretion were two- to threefold greater than for those in the highest tertile (chi2(1) = 3.57; P = 0.06: chi2(1) = 4.70; P = 0.03 for A and E respectively). In contrast, in the older age group comprising predominantly post-menopausal women, the rate ratios associated with the lowest tertile of A or E were half that of those in the highest tertile (chi2(1) = 4.10; P = 0.04; chi2(1) = 8.72; P = 0.003 for A and E respectively). This suggests that there may be different endocrine promotional factors for pre-and post-menopausal breast cancer. Hormonal risk factors may vary during the lifetime of an individual woman and this may have profound consequences for prevention strategies.

This study examined the hormonal differences between premenopausal mothers of twins and other premenopausal parous women during and after pregnancy. Serum concentrations of oestradiol and testosterone between 6 and 20 weeks of gestation were measured for 11 mothers of twins and 115 mothers of singletons selected from the controls in a case-control study of cryptorchidism. Serum concentrations of oestradiol, progesterone, testosterone, follicle stimulating hormone and sex hormone-binding globulin during the menstrual cycle were measured for 25 mothers of twins and 38 mothers of singletons recruited as a part of a prospective study of breast cancer risk. During pregnancy, women carrying twins had a 58% higher geometric mean oestradiol concentration (p = 0.02) and a 50% higher testosterone concentration (p = 0.03) than women carrying singletons. Women who had previously had twins demonstrated a 49% higher mean concentration of follicle stimulating hormone (p = 0.02) and a 42% higher concentration of sex hormone-binding globulin (p = 0.03) than women who had singletons only, but no significant differences in oestradiol, progesterone and testosterone concentrations. The increased concentrations of follicle stimulating hormone during the menstrual cycle of mothers of twins, which has also been reported in two previous studies suggests that follicle stimulating hormone level may be an important determinant of dizygotic twinning.

A study of 13 male opiate addicts was undertaken to investigate the feasibility of transferring abruptly from methadone maintenance treatment to buprenorphine in an outpatient setting. The mean age of subjects was 30 years (range 18-45) and all fulfilled DSM-III-R criteria for opioid dependence. All were maintained on a methadone dose of 20-30 mg mixture daily and were transferred for 3 days to 4 mg buprenorphine sublingually 24-26 hours after their last dose of methadone. On day 1 repeated measures of drug effects were performed, including agonist and withdrawal effects, and this was complemented by saccadic eye movements, a potential new measure of central opioid effects. These recordings were repeated once on days 2 and 3 and the subjects returned to their previous dose of methadone on day 4. Buprenorphine caused no detectable agonist effects or drug "high", but had "good" effects, was "liked" and well tolerated, suggesting that subjects would comply with buprenorphine treatment despite the lack of reinforcing effects. A mild increase in subjective withdrawal symptoms, which was not clinically significant, was seen in association with an increase in saccadic peak velocity on day 2 of the study but no withdrawal occurred on the other days, indicating that the abrupt transfer technique was acceptable.

Inter- and intra-national epidemiological studies point to an association between socio-economic status and breast cancer risk. Although there is no direct evidence, the most favoured reason for this relationship is nutritional. An enhanced dietary status, especially during childhood, would be reflected in adult body build. It is, therefore, surprising that there is uncertainty in the literature concerning the association between height and breast cancer risk. In reviewing the publications on this topic it became apparent that case-control studies which found no association between height and risk tended to use self-reported height. In contrast reports claiming a significant, and positive, correlation tended to use heights which were measured by the investigators. In a prospective study we found in a cohort of 2731 ostensibly normal women that, although there was a highly significant linear correlation between self-reported and measured height, the shortest women over-estimated their height whilst the tallest volunteers under-estimated theirs. The significance of crude relative risk and height in this cohort was markedly attenuated when self-reported height was used compared to measured height. Such a systematic error could have a profound effect on the conclusions of studies in this field which relied on self-reporting and could explain the conflicting reports in the literature.

The prognostic value of serum prolactin levels was assessed in a sequential series of 739 patients who were initially treated at Guy's Hospital, London, between 1975 and 1980. Prolactin was measured in 472 patients 1 day before (Hpr1) and in 457 patients 10 days after (Hpr2) mastectomy. Follow-up of the patients was up to August 1992 giving 6139 women-years with a median follow-up time of 11.5 years (13.7 for patients still living and 5.1 for those dead). The association between the three prolactin variables and reproductive and clinical factors was examined before assessing the prognostic value of prolactin levels in terms of overall, disease-specific and disease-free survival. Multivariate survival models were used in order to adjust for the effect of other prognostic variables. These were found to be: tumour size, degree of nodal involvement, tumour grade and age at diagnosis. The results showed that high Hpr2 or high postoperative increase in prolactin (i.e. Hpr2-Hpr1) were significantly related to shorter disease-specific survival (p = 0.04 and 0.01, respectively) in postmenopausal women. In addition there was some indication, which did not attain formal significance, for this association to occur for disease-free survival. Thus the rise in blood prolactin levels after surgery may be a weak indicator of poor prognosis of breast cancer in postmenopausal women.

To evaluate the relationship between duration of hormone replacement therapy (HRT) and forearm bone density, a population-based study has been conducted of 4638 women comparing bone density of 1079 women who had taken HRT for varying times with those who had never taken it. Forearm bone mineral content (BMC) was measured by single photon absorptiometry. Additionally, free oestradiol and sex hormone binding globulin levels were measured in women with high and low bone mineral content. There were no detectable differences in BMC in those who took HRT for up to 24 months compared with those who did not. Thereafter there were significant positive regression coefficients for duration periods of 2 to 5 yr (beta = 0.77, P = 0.04 and beta = 1.76, P = 0.03) and more than 5 yr (beta = 1.66, P < 0.0005 and beta = 1.87, P = 0.009) in post-menopausal and oophorectomized women. The major determinants of BMC were height, and in post-menopausal or oophorectomized women, age. Weight and parity also had additional explanatory power for pre- and post-menopausal women. Those who were in the highest quintile of BMC but had never taken HRT showed significantly elevated percentage free oestradiol compared with those in the lowest quintile. Thus HRT is osteoprotective if taken after the menopause for more than 24 months.

The association with breast cancer of menstrual and reproductive events, family history of breast cancer, and body size have been studied on two cohorts of 6,706 volunteers on the island of Guernsey (United Kingdom), 168 of whom had breast cancer detected during follow-up. The median follow-up time of the non-cases was 21 years in the first study and 10 years in the second. A time-dependent Cox regression model was fitted to the data with age as the time-dependent variable in order to represent the effect of changing menopausal status. Other variables examined in the model were age at menarche, parity, age at first birth, family history of breast cancer, height, weight (both directly measured), relative weight (weight [kg]/height[m]), and Quetelet's body mass index (weight[kg]/height[m]2). Interactions between age and all other covariates also were examined. Family history was found to be the most important risk factor for women aged less than 51 years (relative risk [RR] = 3.5, 95 percent confidence interval [CI] = 2.0-6.0), and intervals between menarche and first birth longer than 14 years were found to increase significantly the risk of breast cancer in women older than 61 years (RR = 2.4, CI = 1.3-4.4). Height was the only indicator of body size which was associated significantly with risk of breast cancer, the estimated regression coefficient indicating an increase in risk of about 70 percent for women on the 90th centile of height relative to those on the 10th centile. A survey of the literature showed that the association between risk of breast cancer and height was found in those studies which used direct measurements of height but not in others which used self-reported values.

In 1968-1975, a cohort of 5,100 ostensibly healthy women was established on the island of Guernsey, England, for investigation of the influence of hormonal factors on breast cancer. At the women's entry into the study, blood samples were drawn from each participant, and each woman completed a questionnaire that provided information on established risk indicators in human mammary carcinogenesis. Plasma copper levels were measured in 46 breast cancer cases diagnosed an average of 11 years (standard deviation (SD), 4) after entry into the study cohort and in an age-stratified random sample of 138 women drawn from the total initial cohort at risk. Plasma copper levels were 1.31 mg/liter (SD, 0.37) in the cases and 1.26 mg/liter (SD, 0.36) in the controls; the 95% confidence interval for the overall difference was -0.07 to 0.17. A U-shaped relation between premorbid plasma copper levels and the risk of developing breast cancer was seen. Adjusted odds ratios for breast cancer were 1.8, 1.0, 1.6, and 3.2, respectively, in the four quartiles of the copper distribution. No major changes in the risk estimates were observed when statistical evaluation was restricted to cases diagnosed more than 10 years after collection of blood samples.