Evolution of diapause in the African turquoise killifish by remodeling the ancient gene regulatory landscape.

Suspended animation states allow organisms to survive extreme environments. The African turquoise killifish has evolved diapause as a form of suspended development to survive a complete drought. However, the mechanisms underlying the evolution of extreme survival states are unknown. To understand diapause evolution, we performed integrative multi-omics (gene expression, chromatin accessibility, and lipidomics) in the embryos of multiple killifish species. We find that diapause evolved by a recent remodeling of regulatory elements at very ancient gene duplicates (paralogs) present in all vertebrates. CRISPR-Cas9-based perturbations identify the transcription factors REST/NRSF and FOXOs as critical for the diapause gene expression program, including genes involved in lipid metabolism. Indeed, diapause shows a distinct lipid profile, with an increase in triglycerides with very-long-chain fatty acids. Our work suggests a mechanism for the evolution of complex adaptations and offers strategies to promote long-term survival by activating suspended animation programs in other species.

Ethnicity and the surgical management of early invasive breast cancer in over 164 000 women.

BACKGROUND: Limited information is available about patterns of surgical management of early breast cancer by ethnicity of women in England, and any potential inequalities in the treatment received for breast cancer. METHODS: National Cancer Registration and Analysis Service data for women diagnosed with early invasive breast cancer (ICD-10 C50) during 2012-2017 were analysed. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95 per cent confidence intervals for the risk of mastectomy versus breast-conserving surgery by ethnicity (black African, black Caribbean, Indian, Pakistani and white), adjusting for age, region, deprivation, year of diagnosis, co-morbidity and stage at diagnosis. RESULTS: Data from 164 143 women were included in the analysis. The proportion of women undergoing mastectomy fell by approximately 5 per cent between 2012 and 2017 across all the ethnic groups examined. In unadjusted analyses, each ethnic minority group had a significantly higher odds of mastectomy than white women; however, in the fully adjusted model, there were no significantly increased odds of having mastectomy for women of any ethnic minority group examined. For example, compared with white women, the unadjusted and fully adjusted ORs for mastectomy were 1·14 (95 per cent c.i. 1·05 to 1·20) and 1·04 (0·96 to 1·14) respectively for Indian women, and 1·45 (1·30 to 1·62) and 1·00 (0·89 to 1·13) for black African women. This attenuation in OR by ethnicity was largely due to adjustment for age and stage. CONCLUSION: Allowing for different patterns of age and stage at presentation, the surgical management of early breast cancer is similar in all women, regardless of ethnicity.

Oxygen torus and its coincidence with EMIC wave in the deep inner magnetosphere: Van Allen Probe B and Arase observations.

We investigate the longitudinal structure of the oxygen torus in the inner magnetosphere for a specific event found on 12 September 2017, using simultaneous observations from the Van Allen Probe B and Arase satellites. It is found that Probe B observed a clear enhancement in the average plasma mass (M) up to 3-4 amu at L = 3.3-3.6 and magnetic local time (MLT) = 9.0 h. In the afternoon sector at MLT ~ 16.0 h, both Probe B and Arase found no clear enhancements in M. This result suggests that the oxygen torus does not extend over all MLT but is skewed toward the dawn. Since a similar result has been reported for another event of the oxygen torus in a previous study, a crescent-shaped torus or a pinched torus centered around dawn may be a general feature of the O+ density enhancement in the inner magnetosphere. We newly find that an electromagnetic ion cyclotron (EMIC) wave in the H+ band appeared coincidently with the oxygen torus. From the lower cutoff frequency of the EMIC wave, the ion composition of the oxygen torus is estimated to be 80.6% H+, 3.4% He+, and 16.0% O+. According to the linearized dispersion relation for EMIC waves, both He+ and O+ ions inhibit EMIC wave growth and the stabilizing effect is stronger for He+ than O+. Therefore, when the H+ fraction or M is constant, the denser O+ ions are naturally accompanied by the more tenuous He+ ions, resulting in a weaker stabilizing effect (i.e., larger growth rate). From the Probe B observations, we find that the growth rate becomes larger in the oxygen torus than in the adjacent regions in the plasma trough and the plasmasphere.

Rapid local acceleration of relativistic radiation-belt electrons by magnetospheric chorus.

Recent analysis of satellite data obtained during the 9 October 2012 geomagnetic storm identified the development of peaks in electron phase space density, which are compelling evidence for local electron acceleration in the heart of the outer radiation belt, but are inconsistent with acceleration by inward radial diffusive transport. However, the precise physical mechanism responsible for the acceleration on 9 October was not identified. Previous modelling has indicated that a magnetospheric electromagnetic emission known as chorus could be a potential candidate for local electron acceleration, but a definitive resolution of the importance of chorus for radiation-belt acceleration was not possible because of limitations in the energy range and resolution of previous electron observations and the lack of a dynamic global wave model. Here we report high-resolution electron observations obtained during the 9 October storm and demonstrate, using a two-dimensional simulation performed with a recently developed time-varying data-driven model, that chorus scattering explains the temporal evolution of both the energy and angular distribution of the observed relativistic electron flux increase. Our detailed modelling demonstrates the remarkable efficiency of wave acceleration in the Earth's outer radiation belt, and the results presented have potential application to Jupiter, Saturn and other magnetized astrophysical objects.

Disability and participation in breast and bowel cancer screening in England: a large prospective study.

BACKGROUND: There is limited information about participation in organised population-wide screening programmes by people with disabilities. METHODS: Data from the National Health Service routine screening programmes in England were linked to information on disability reported by the Million Women Study cohort participants. RESULTS: Of the 473 185 women offered routine breast or bowel cancer screening, 23% reported some disability. Women with disabilities were less likely than other women to participate in breast cancer screening (RR=0.64, 95% CI: 0.62-0.65) and in bowel cancer screening (RR=0.75, 0.73-0.76). Difficulties with self-care or vision were associated with the greatest reduction in screening participation. CONCLUSION: Participation in routine cancer screening programmes in England is reduced in people with disabilities and participation varies by type of disability.

Cancer risk among 21st century blood transfusion recipients.

Background: Some carcinogenic viruses are known to be transmissible by blood transfusion. Intensive viral screening of transfused blood now exists in most countries. In the UK, high-sensitivity nucleic acid amplification tests for hepatitis C virus were introduced in 1999 and it was thought that this would reduce, and possibly eliminate, transfusion-related liver cancer. We aimed to investigate cancer risk in recipients of blood transfusion in 2000 or after. Methods: A total of 1.3 million UK women recruited in 1998 on average were followed for hospital records of blood transfusion and for cancer registrations. After excluding women with cancer or precancerous conditions before or at the time of transfusion, Cox regression yielded adjusted relative risks of 11 site-specific cancers for women with compared to without prior blood transfusion. Results: During follow up, 11 274 (0.9%) women had a first recorded transfusion in 2000 or after, and 1648 (14.6%) of them were subsequently diagnosed with cancer, a mean 6.8 years after the transfusion. In the first 5 years after transfusion there were significant excesses for most site-specific cancers examined, presumably because some had preclinical cancer. However, 5 or more years (mean 8 years) after blood transfusion, there were significant excess risks only for liver cancer (adjusted relative risk = 2.63, 95%CI 1.45-4.78) and for non-Hodgkin lymphoma (adjusted relative risk = 1.74, 1.21-2.51). When analyses were restricted to those undergoing hip or knee replacement surgery, the commonest procedure associated with transfusion, these relative risks were not materially altered. Conclusions: In a large cohort of UK women, transfusions in the 21st century were associated with long-term increased risks of liver cancer and non-Hodgkin lymphoma. Some of these malignancies may have been caused by carcinogenic agents that are not currently screened for in transfused blood.

Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies.

BACKGROUND: Half the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk. METHODS: Individual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use. FINDINGS: During prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with <5 years of use (RR 1·43, 95% CI 1·31-1·56; p<0·0001). Combining current-or-recent use (any duration, but stopped <5 years before diagnosis) resulted in an RR of 1·37 (95% CI 1·29-1·46; p<0·0001); this risk was similar in European and American prospective studies and for oestrogen-only and oestrogen-progestagen preparations, but differed across the four main tumour types (heterogeneity p<0·0001), being definitely increased only for the two most common types, serous (RR 1·53, 95% CI 1·40-1·66; p<0·0001) and endometrioid (1·42, 1·20-1·67; p<0·0001). Risk declined the longer ago use had ceased, although about 10 years after stopping long-duration hormone therapy use there was still an excess of serous or endometrioid tumours (RR 1·25, 95% CI 1·07-1·46, p=0·005). INTERPRETATION: The increased risk may well be largely or wholly causal; if it is, women who use hormone therapy for 5 years from around age 50 years have about one extra ovarian cancer per 1000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1700 users. FUNDING: Medical Research Council, Cancer Research UK.

Genetic analysis of variation in lifespan using a multiparental advanced intercross Drosophila mapping population.

BACKGROUND: Considerable natural variation for lifespan exists within human and animal populations. Genetically dissecting this variation can elucidate the pathways and genes involved in aging, and help uncover the genetic mechanisms underlying risk for age-related diseases. Studying aging in model systems is attractive due to their relatively short lifespan, and the ability to carry out programmed crosses under environmentally-controlled conditions. Here we investigate the genetic architecture of lifespan using the Drosophila Synthetic Population Resource (DSPR), a multiparental advanced intercross mapping population. RESULTS: We measured lifespan in females from 805 DSPR lines, mapping five QTL (Quantitative Trait Loci) that each contribute 4-5 % to among-line lifespan variation in the DSPR. Each of these QTL co-localizes with the position of at least one QTL mapped in 13 previous studies of lifespan variation in flies. However, given that these studies implicate >90 % of the genome in the control of lifespan, this level of overlap is unsurprising. DSPR QTL intervals harbor 11-155 protein-coding genes, and we used RNAseq on samples of young and old flies to help resolve pathways affecting lifespan, and identify potentially causative loci present within mapped QTL intervals. Broad age-related patterns of expression revealed by these data recapitulate results from previous work. For example, we see an increase in antimicrobial defense gene expression with age, and a decrease in expression of genes involved in the electron transport chain. Several genes within QTL intervals are highlighted by our RNAseq data, such as Relish, a critical immune response gene, that shows increased expression with age, and UQCR-14, a gene involved in mitochondrial electron transport, that has reduced expression in older flies. CONCLUSIONS: The five QTL we isolate collectively explain a considerable fraction of the genetic variation for female lifespan in the DSPR, and implicate modest numbers of genes. In several cases the candidate loci we highlight reside in biological pathways already implicated in the control of lifespan variation. Thus, our results provide further evidence that functional genetics tests targeting these genes will be fruitful, lead to the identification of natural sequence variants contributing to lifespan variation, and help uncover the mechanisms of aging.

Lifestyle and reproductive risk factors associated with anal cancer in women aged over 50 years.

BACKGROUND: Anal cancer incidence increases with age and is higher in women than men. Risk factors in this group other than high-risk human papillomavirus infection are unclear. METHODS: In all, 1.3 million women were recruited in 1996-2001 and followed for incident anal cancer. Cox regression models were used to calculate relative risks (RRs) for anal cancer by various potential risk factors. RESULTS: Five hundred and seventeen incident anal cancers were registered over 13 years of follow-up. The largest RR was associated with a history of cervical intraepithelial neoplasia grade 3 (CIN 3; RR=4.03, 95% CI 2.59-6.28). Other factors associated with significantly increased risks in multivariate analyses were: ever smoking (RR=1.49, 1.24-1.80); previous use of oral contraceptives (RR=1.51, 1.24-1.83); nulliparity (RR=1.61, 1.24-2.07); tubal ligation (RR=1.39, 1.13-1.70) and not living with a partner (RR=1.82, 1.40-2.38). The association with smoking was significantly greater for squamous cell carcinoma than adenocarcinoma of the anus (RR 1.66 vs 0.89, P for heterogeneity=0.04). CONCLUSIONS: History of CIN 3, smoking, past oral contraceptive use, nulliparity, tubal ligation and not living with a partner are risk factors for anal cancer in women. There was a significant increase in risk associated with smoking for squamous cell anal cancers but not adenocarcinomas.

Nationwide bowel cancer screening programme in England: cohort study of lifestyle factors affecting participation and outcomes in women.

BACKGROUND: In 2006, the National Health Service Bowel Cancer Screening Programme in England (NHSBCSP) began offering routine population-based biennial faecal occult blood testing (FOBt) at ages 60-69. There is, however, limited information on how characteristics of individuals affect participation and outcomes of screening, and we studied this association by linking NHSBCSP data to a large prospective cohort of women. METHODS: Electronic linkage of the NHSBCSP and Million Women Study records identified 899 166 women in the study cohort with at least one invitation for screening. NHSBCSP provided information on screening acceptance, FOBt results, screen-detected colorectal cancer and other outcomes. The Million Women Study provided prospectively collected information on personal and lifestyle factors. Multiple regression was used to estimate relative risks (RRs) of factors associated with acceptance and outcomes of screening. RESULTS: Overall, 70% of women (628 976/899 166) accepted their first invitation for bowel cancer screening, of whom 9133 (1.5%) were FOBt-positive, 743 (0.1%) had screen-detected colorectal cancer and 3056 (0.5%) had screen-detected colorectal adenoma. Acceptance was lower in women from the most than the least deprived tertile, in South Asians and in Blacks than in Whites, in current than in never smokers and in obese than in normal weight women: adjusted RRs (95% confidence interval) for acceptance vs not, 0.90 (0.90-0.90); 0.77 (0.75-79); 0.94 (0.92-0.96); 0.78 (0.77-0.78); and 0.88 (0.88-0.89), respectively: P<0.001 for each. These factors were also associated with an increased risk of being FOBt-positive and of having screen-detected adenoma, but were not strongly associated with the risk of screen-detected colorectal cancer. Relative risks for screen-detected adenoma were 1.22 (1.12-1.34), 2.46 (1.75-3.45), 1.61 (1.05-2.48), 1.53 (1.38-1.68) and 1.77 (1.60-1.95), respectively (P<0.001 for all, except for Blacks vs Whites P=0.03). Use of hormone therapy for menopause was associated with reduced risk of screen-detected adenoma, RR ever vs never use, 0.87 (0.81-0.93), P<0.001 and colorectal cancer, 0.78 (0.68-0.91), P=0.001. INTERPRETATION: Among women in England, socioeconomic and lifestyle factors strongly affect participation in routine bowel cancer screening, risk of being FOBt-positive and risk of having screen-detected colorectal adenoma. However, screen-detected colorectal cancer risk is not strongly related to these factors.

Acceleration and loss of relativistic electrons during small geomagnetic storms.

Past studies of radiation belt relativistic electrons have favored active storm time periods, while the effects of small geomagnetic storms (Dst > -50 nT) have not been statistically characterized. In this timely study, given the current weak solar cycle, we identify 342 small storms from 1989 through 2000 and quantify the corresponding change in relativistic electron flux at geosynchronous orbit. Surprisingly, small storms can be equally as effective as large storms at enhancing and depleting fluxes. Slight differences exist, as small storms are 10% less likely to result in flux enhancement and 10% more likely to result in flux depletion than large storms. Nevertheless, it is clear that neither acceleration nor loss mechanisms scale with storm drivers as would be expected. Small geomagnetic storms play a significant role in radiation belt relativistic electron dynamics and provide opportunities to gain new insights into the complex balance of acceleration and loss processes.

Ethnic differences in breast cancer incidence in England are due to differences in known risk factors for the disease: prospective study.

BACKGROUND: In the United Kingdom, breast cancer incidence is lower in South Asian and Black women than in White women, but the extent to which this is due to known risk factors is unknown. In a large prospective study, we describe breast cancer incidence by ethnicity, before and after adjustment for known risk factors for the disease. METHODS: Women were recruited into the Million Women Study in 1996-2001, when information on reproductive and lifestyle factors known to influence the risk of breast cancer was obtained. Ethnicity was determined from study questionnaires and hospital admission data. Cox regression models were used to calculate adjusted relative risks (RR) for incident breast cancer in South Asians and Blacks compared with Whites. RESULTS: Analyses included 5877 South Asian, 4919 Black, and 1,038,144 White women in England. The prevalence of 8 out of the 9 risk factors for breast cancer examined, differed substantially by ethnicity (P<0.001 for each), such that South Asian and Black women were at a lower risk of the disease than White women. During 12.2 years of follow-up incident breast cancer occurred in 217 South Asians, 180 Blacks, and 45,191 Whites. As expected, breast cancer incidence was lower in South Asians (RR=0.82, 95% CI 0.72-0.94) and Blacks (RR=0.85, 0.73-0.98) than in Whites when the analyses were adjusted only for age and region of residence. However, after additional adjustment for the known risk factors for the disease, breast cancer incidence was similar to that of Whites, both in South Asians (0.95, 0.83-1.09) and in Blacks (0.91, 0.78-1.05). CONCLUSION: South Asian and Black women in England have lower incidence rates of breast cancer than White women, but this is largely, if not wholly, because of differences in known risk factors for the disease.

Organic food consumption and the incidence of cancer in a large prospective study of women in the United Kingdom.

BACKGROUND: Organically produced foods are less likely than conventionally produced foods to contain pesticide residues. METHODS: We examined the hypothesis that eating organic food may reduce the risk of soft tissue sarcoma, breast cancer, non-Hodgkin lymphoma and other common cancers in a large prospective study of 623 080 middle-aged UK women. Women reported their consumption of organic food and were followed for cancer incidence over the next 9.3 years. Cox regression models were used to estimate adjusted relative risks for cancer incidence by the reported frequency of consumption of organic foods. RESULTS: At baseline, 30%, 63% and 7% of women reported never, sometimes, or usually/always eating organic food, respectively. Consumption of organic food was not associated with a reduction in the incidence of all cancer (n=53 769 cases in total) (RR for usually/always vs never=1.03, 95% confidence interval (CI): 0.99-1.07), soft tissue sarcoma (RR=1.37, 95% CI: 0.82-2.27), or breast cancer (RR=1.09, 95% CI: 1.02-1.15), but was associated for non-Hodgkin lymphoma (RR=0.79, 95% CI: 0.65-0.96). CONCLUSIONS: In this large prospective study there was little or no decrease in the incidence of cancer associated with consumption of organic food, except possibly for non-Hodgkin lymphoma.

Birth weight and adult cancer incidence: large prospective study and meta-analysis.

BACKGROUND: Most evidence about associations between birth weight and adult cancer risk comes from studies linking birth records to cancer registration data, where information on known risk factors for cancer is generally lacking. Here, we report on associations between birth weight and cause-specific cancer risk in a large cohort of UK women, and investigate how observed associations are affected by other factors. METHODS: A total of 453 023 women, born in the 1930s and 1940s, reported their birth weight, maternal smoking, parental heights, age at menarche, adult height, adult smoking, and many other personal characteristics. They were followed for incident cancer. Using Cox regression, relative risks by birth weight were estimated for cancers with more than 1500 incident cases, adjusting for 17 potential confounding factors, individually and simultaneously. RESULTS: Birth weight reported in adulthood was strongly correlated with that recorded at birth (correlation coefficient = 0.78, P < 0.0001). Reported birth weight was associated with most of the potential confounding factors examined, the strongest association being with adult height. After 9.2 years follow-up per woman, 39 060 incident cancers were registered (4414 colorectal, 3175 lung, 1795 malignant melanoma, 14 542 breast, 2623 endometrial, 2009 ovarian, 1565 non-Hodgkin lymphoma, and 8937 other cancers). Associations with birth weight were null or weak and reduced after adjustment by adult height (P[trend] > 0.01 for every cancer, after adjustment). In contrast, adult height was strongly related to the risk of every cancer except lung cancer, after adjusting for birth weight and other factors (P[trend] < 0.0001 for most cancers). For lung cancer, adjusting for smoking reduced the association with birth weight. Meta-analyses were dominated by our findings. CONCLUSION: Birth weight and adult height are correlated and likely to be markers of some aspect of growth that affects cancer risk in adulthood. However, birth weight adds little, if any, additional information to adult height as a predictor of cancer incidence in women.

Direct observation of radiation-belt electron acceleration from electron-volt energies to megavolts by nonlinear whistlers.

The mechanisms for accelerating electrons from thermal to relativistic energies in the terrestrial magnetosphere, on the sun, and in many astrophysical environments have never been verified. We present the first direct observation of two processes that, in a chain, cause this acceleration in Earth's outer radiation belt. The two processes are parallel acceleration from electron-volt to kilovolt energies by parallel electric fields in time-domain structures (TDS), after which the parallel electron velocity becomes sufficiently large for Doppler-shifted upper band whistler frequencies to be in resonance with the electron gyration frequency, even though the electron energies are kilovolts and not hundreds of kilovolts. The electrons are then accelerated by the whistler perpendicular electric field to relativistic energies in several resonant interactions. TDS are packets of electric field spikes, each spike having duration of a few hundred microseconds and containing a local parallel electric field. The TDS of interest resulted from nonlinearity of the parallel electric field component in oblique whistlers and consisted of ∼ 0.1 msec pulses superposed on the whistler waveform with each such spike containing a net parallel potential the order of 50 V. Local magnetic field compression from remote activity provided the free energy to drive the two processes. The expected temporal correlations between the compressed magnetic field, the nonlinear whistlers with their parallel electric field spikes, the electron flux and the electron pitch angle distributions were all observed.

Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies.

BACKGROUND: Associations between circulating concentrations of oestrogens, progesterone, and androgens with breast cancer and related risk factors in premenopausal women are not well understood. We aimed to characterise these associations with a pooled analysis of data from seven studies. METHODS: Individual participant data for prediagnostic sex hormone and sex hormone-binding globulin (SHBG) concentrations were contributed from seven prospective studies. We restricted analyses to women who were premenopausal and younger than 50 years at blood collection, and to women with breast cancer diagnosed before age 50 years. We estimated odds ratios (ORs) with 95% CIs for breast cancer associated with hormone concentrations by conditional logistic regression in cases and controls matched for age, date of blood collection, and day of cycle, with stratification by study and further adjustment for cycle phase. We examined associations of hormones with risk factors for breast cancer in control women by comparing geometric mean hormone concentrations in categories of these risk factors, adjusted for study, age, phase of menstrual cycle, and body-mass index (BMI). All statistical tests were two-sided. FINDINGS: We included data for up to 767 women with breast cancer and 1699 controls in the risk analyses. Breast cancer risk was associated with a doubling in concentrations of oestradiol (OR 1·19, 95% CI 1·06-1·35), calculated free oestradiol (1·17, 1·03-1·33), oestrone (1·27, 1·05-1·54), androstenedione (1·30, 1·10-1·55), dehydroepiandrosterone sulphate (1·17, 1·04-1·32), testosterone (1·18, 1·03-1·35), and calculated free testosterone (1·08, 0·97-1·21). Breast cancer risk was not associated with luteal phase progesterone (doubling in concentration OR 1·00, 95% CI 0·92-1·09), and adjustment for other factors had little effect on any of these ORs. Cross-sectional analyses in control women showed several associations of sex hormones with breast cancer risk factors. INTERPRETATION: Circulating oestrogens and androgens are positively associated with the risk for breast cancer in premenopausal women.

Chromatin Accessibility Profiling and Data Analysis Using ATAC-seq in Nothobranchius furzeri.

The state of genome-wide chromatin accessibility in cells, tissues, or organisms can be investigated with a technique called assay for transposase-accessible chromatin using sequencing (ATAC-seq). ATAC-seq is a powerful approach for profiling the epigenomic landscape of cells using very low input materials. Analysis of chromatin accessibility data allows for prediction of gene expression and identification of regulatory elements such as potential enhancers and specific transcription-factor binding sites. Here, we describe an optimized ATAC-seq protocol for the preparation of isolated nuclei and subsequent next-generation sequencing from whole embryos and tissues of the African turquoise killifish (Nothobranchius furzeri). Importantly, we provide an overview of a pipeline for processing and analyzing ATAC-seq data from killifish.

Attenuated psychosis symptoms are related to working alliance between therapist and service user.

AIM: Many trials have demonstrated the efficacy of specific therapy modalities for individuals with attenuated psychosis symptoms (APS). Less is known regarding mechanisms behind positive outcomes, including the role of nonspecific therapeutic factors. This study explored working alliance (WA) in a clinic serving individuals with APS to see how WA changed across the course of treatment and its relation to APS. METHODS: Session level APS and WA data was available for 12 individuals of diverse racial and gender identity, (M = 48 sessions each). Multilevel models with random intercepts tested change in WA and APS over time, and cross-sectional and prospective relations. RESULTS: WA increased and APS decreased over time. Cross sectionally, WA and APS were inversely related. Prospective relations were non-significant. CONCLUSION: When symptoms increase, therapists for individuals with APS should be attentive to potential disruptions in WA, though strong WA may be a cross-sectional protective factor.

Body size in relation to incidence of subtypes of haematological malignancy in the prospective Million Women Study.

BACKGROUND: Greater adiposity and height have been associated with increased risk of haematological malignancies. Associations for disease subtypes are uncertain. METHODS: A cohort of 1.3 million middle-aged U.K. women was recruited in 1996-2001 and followed for 10 years on average. Potential risk factors were assessed by questionnaire. Death, emigration, and incident cancer were ascertained by linkage to national registers. Adjusted relative risks were estimated by Cox regression. RESULTS: During follow-up, 9162 participants were diagnosed with lymphatic or haematopoietic cancers. Each 10 kg m(-2) increase in body mass index was associated with relative risk of 1.20 (95% confidence interval: 1.13-1.28) for lymphoid and 1.37 (1.22-1.53) for myeloid malignancy (P=0.06 for heterogeneity); similarly, Hodgkin lymphoma 1.64 (1.21-2.21), diffuse large B-cell lymphoma 1.36 (1.17-1.58), plasma cell neoplasms 1.21 (1.06-1.39), acute myeloid leukaemia 1.47 (1.19-1.81), and myeloproliferative/myelodysplastic syndromes 1.32 (1.15-1.52). Each 10 cm increase in height was associated with relative risk of 1.21 (1.16-1.27) for lymphoid and 1.11 (1.02-1.21) for myeloid malignancy (P=0.07 for heterogeneity); similarly, mature T-cell malignancies 1.36 (1.03-1.79), diffuse large B-cell lymphoma 1.28 (1.14-1.43), follicular lymphoma 1.28 (1.13-1.44), plasma cell neoplasms 1.12 (1.01-1.24), chronic lymphocytic leukaemia/small lymphocytic lymphoma 1.23 (1.08-1.40), and acute myeloid leukaemia 1.22 (1.04-1.42). There was no significant heterogeneity between subtypes. CONCLUSION: In middle-aged women, greater body mass index and height were associated with modestly increased risks of many subtypes of haematological malignancy.

Persistent effects of women's parity and breastfeeding patterns on their body mass index: results from the Million Women Study.

OBJECTIVE: To explore the long-term effects of women's childbearing patterns on their body mass index. DESIGN: Cross-sectional analysis. SETTING: Population-based study of UK women. PARTICIPANTS: 740 628 postmenopausal participants in the Million Women Study who reported their height, weight, reproductive histories and other relevant factors. MAIN OUTCOME MEASURES: Standardized mean BMI (kg m(-2)) in groups defined by their parity and breastfeeding history. RESULTS: Women were aged 57.5 (s.d. 4) years on average, and had a mean BMI of 26.2 kg m(-2) (s.d. 5); 88% were parous, with 2.1 (s.d. 1.2) children on average. The standardised mean BMI increased progressively with the number of births from 25.6 kg m(-2) (95% confidence interval (CI): 25.5-25.6) in nulliparous women up to 27.2 kg m(-2) (CI: 27.2-27.3) for women with four or more births, a difference of 1.7 kg m(-2) (CI: 1.6-1.7). Among the parous women 70% had ever breastfed and their average total duration of breastfeeding was 7.7 (s.d. 8.8) months. At every parity level the standardised mean BMI was significantly lower among women who had breastfed than those who had not, decreasing by 0.22 kg m(-2) (CI: 0.21-0.22) for every 6 months of breastfeeding, that is, women's mean BMI was 1% lower for every 6 months that they had breastfed. These associations were highly statistically significant (P<0.0001) and independent of the effects of socioeconomic group, region of residence, smoking and physical activity. CONCLUSIONS: Childbearing patterns have a persistent effect on adiposity in this population. The reduction in BMI associated with just 6 months breastfeeding in UK women could importantly reduce their risk of obesity-related disease as they age.