Endometriosis Typology and Ovarian Cancer Risk.

Importance: Endometriosis has been associated with an increased risk of ovarian cancer; however, the associations between endometriosis subtypes and ovarian cancer histotypes have not been well-described. Objective: To evaluate the associations of endometriosis subtypes with incidence of ovarian cancer, both overall and by histotype. Design, Setting, and Participants: Population-based cohort study using data from the Utah Population Database. The cohort was assembled by matching 78 893 women with endometriosis in a 1:5 ratio to women without endometriosis. Exposures: Endometriosis cases were identified via electronic health records and categorized as superficial endometriosis, ovarian endometriomas, deep infiltrating endometriosis, or other. Main Outcomes and Measures: Estimated adjusted hazard ratios (aHRs), adjusted risk differences (aRDs) per 10 000 women, and 95% CIs for overall ovarian cancer, type I ovarian cancer, and type II ovarian cancer comparing women with each type of endometriosis with women without endometriosis. Models accounted for sociodemographic factors, reproductive history, and past gynecologic operations. Results: In this Utah-based cohort, the mean (SD) age at first endometriosis diagnosis was 36 (10) years. There were 597 women with ovarian cancer. Ovarian cancer risk was higher among women with endometriosis compared with women without endometriosis (aHR, 4.20 [95% CI, 3.59-4.91]; aRD, 9.90 [95% CI, 7.22-12.57]), and risk of type I ovarian cancer was especially high (aHR, 7.48 [95% CI, 5.80-9.65]; aRD, 7.53 [95% CI, 5.46-9.61]). Ovarian cancer risk was highest in women with deep infiltrating endometriosis and/or ovarian endometriomas for all ovarian cancers (aHR, 9.66 [95% CI, 7.77-12.00]; aRD, 26.71 [95% CI, 20.01-33.41]), type I ovarian cancer (aHR, 18.96 [95% CI, 13.78-26.08]; aRD, 19.57 [95% CI, 13.80-25.35]), and type II ovarian cancer (aHR, 3.72 [95% CI, 2.31-5.98]; aRD, 2.42 [95% CI, -0.01 to 4.85]). Conclusions and Relevance: Ovarian cancer risk was markedly increased among women with ovarian endometriomas and/or deep infiltrating endometriosis. This population may benefit from counseling regarding ovarian cancer risk and prevention and could be an important population for targeted screening and prevention studies.

Endometriosis diagnosis, staging and typology and adverse pregnancy outcome history.

BACKGROUND: Women with endometriosis may have an increased risk of adverse pregnancy outcomes. Research has focused on infertility clinic populations limiting generalisability. Few studies report differences by endometriosis severity. OBJECTIVES: We investigated the relationships between endometriosis diagnosis, staging and typology and pregnancy outcomes among an operative and population-based sample of women. METHODS: Menstruating women ages 18-44 years enrolled in the ENDO Study (2007-2009), including the operative cohort: 316 gravid women undergoing laparoscopy/laparotomy at surgical centres in Utah and California; and the population cohort: 76 gravid women from the surgical centres' geographic catchment areas. Pregnancy outcomes were ascertained by questionnaire and included all pregnancies prior to study enrolment. Endometriosis was diagnosed via surgical visualisation in the operative cohort and pelvic magnetic resonance imaging in the population cohort. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) were estimated using generalised linear mixed models for pregnancy outcomes, adjusting for women's age at study enrolment and at pregnancy, surgical site, body mass index and lifestyle factors. RESULTS: Women in the operative cohort with visualised endometriosis (n = 109, 34%) had a lower prevalence of live births, aPR 0.94 (95% CI 0.85, 1.03) and a higher prevalence of miscarriages, aPR 1.48 (95% CI 1.23, 1.77) compared with women without endometriosis. The direction and magnitude of estimates were similar in the population cohort. Women with deep endometriosis were 2.98-fold more likely (95% CI 1.12, 7.95) to report a miscarriage compared with women without endometriosis after adjusting for women's age at study enrolment and at pregnancy, surgical site and body mass index. No differences were seen between endometriosis staging and pregnancy outcomes. CONCLUSIONS: While there was no difference in number of pregnancies among women with and without endometriosis in a population-based sample, pregnancy loss was more common among women with endometriosis, notably among those with deep endometriosis.

Induction of the integrated stress response in the rat cornea.

Keratoconus (KC), a progressive, degenerative corneal disease, represents the second leading indication for corneal transplantation globally. We have previously demonstrated that components of the Integrated Stress Response (ISR) are upregulated in human keratoconic donor tissue, and treatment of normal tissue with ISR agonists attenuates collagen production. With no consistently accepted animal models available for translational KC research, we sought to establish an in vivo model based on ISR activation to elucidate its role in the development of the KC phenotype. Four-week-old female SD rats were treated with topical SAL003 formulated as a nanosuspension or vehicle every 48 h for four doses. Animals were subject to monitoring for ocular inflammation and discomfort before being euthanized at 1, 14, or 28 days after treatment was withdrawn. Schirmer's tear test, intraocular pressure, and body weight measurements were obtained at baseline and prior to euthanasia. Globes were subject to routine histopathology, immunohistochemistry for ATF4, and qPCR for Col1a1 expression. ANOVAs and Student's t tests were used to assess statistical significance (α = 0.05). SAL003 treatment did not produce any adverse ocular or systemic phenotype but did result in decreased keratocyte density. Col1a1 transcripts were reduced, corresponding to nuclear ATF4 expression within the axial cornea. In vivo topical treatment with a gel-formulated ISR agonist recapitulates key features of the activated ISR including nuclear ATF4 expression and decreased extracellular matrix (ECM) production. Exogenous ISR agonists may present one approach to establishing a rodent model for keratoconus, a charge essential for future evaluations of pathogenesis and therapeutic interventions.

A Randomized Trial to Evaluate the Effects of Folic Acid and Zinc Supplementation on Male Fertility and Livebirth: Design and Baseline Characteristics.

The Folic Acid and Zinc Supplementation Trial (FAZST) was a multicenter, double-blind, block-randomized, placebo-controlled trial to determine whether folic acid and zinc supplementation in men improves semen quality and increases livebirth rate among couples seeking infertility treatment (2013-2017). Eligible men were aged 18 years or older with female partners aged 18-45 years, seeking infertility treatment. Men were randomized (1:1) to 5 mg folic acid and 30 mg elemental zinc daily or matching placebo for 6 months. Randomization was stratified by site and intended infertility treatment (in vitro fertilization (IVF), non-IVF/study site, and non-IVF/outside clinic). Follow-up of men continued for 6 months, and female partners were passively followed for a minimum of 9 months. Women who conceived were followed throughout pregnancy. Overall, 2,370 men were randomized during 2013-2017 (1,185 folic acid and zinc, 1,185 placebo); they had a mean age of 33 years and body mass index (weight (kg)/height (m)2) of 29.8. Most participants were white (82%), well educated (83% with some college), and employed (72%). Participant characteristics were balanced across intervention arms. Study visits were completed by 89%, 77%, and 75% of men at months 2, 4, and 6, respectively. Here we describe the study design, recruitment, data collection, lessons learned, and baseline participant characteristics.

Hippocampal subfield pathologic burden in Lewy body diseases vs. Alzheimer's disease.

AIMS: Lewy body diseases (LBD) are characterized by alpha-synuclein (SYN) pathology, but comorbid Alzheimer's disease (AD) pathology is common and the relationship between these pathologies in microanatomic hippocampal subfields is understudied. Here we use digital histological methods to test the association between hippocampal SYN pathology and the distribution of tau and amyloid-beta (Aß) pathology in LBD and contrast with AD subjects. We also correlate pathologic burden with antemortem episodic memory testing. METHODS: Hippocampal sections from 49 autopsy-confirmed LBD cases, 30 with no/low AD copathology (LBD - AD) and 19 with moderate/severe AD copathology (LBD + AD), and 30 AD patients were stained for SYN, tau, and Aß. Sections underwent digital histological analysis of subfield pathological burden which was correlated with antemortem memory testing. RESULTS: LBD - AD and LBD + AD had similar severity and distribution of SYN pathology (P > 0.05), CA2/3 being the most affected subfield (P < 0.02). In LBD, SYN correlated with tau across subfields (R = 0.49, P < 0.001). Tau burden was higher in AD than LBD + AD (P < 0.001), CA1/subiculum and entorhinal cortex (ERC) being most affected regions (P = 0.04 to <0.01). However, tau pathology in LBD - AD was greatest in CA2/3, which was equivalent to LBD + AD. Aß severity and distribution was similar between LBD + AD and AD. Total hippocampal tau and CA2/3 tau was inversely correlated with memory performance in LBD (R = -0.52, -0.69, P = 0.04, 0.009). CONCLUSIONS: Our findings suggest that tau burden in hippocampal subfields may map closely with the distribution of SYN pathology in subfield CA2/3 in LBD diverging from traditional AD and contribute to episodic memory dysfunction in LBD.

Adiposity and Endometriosis Severity and Typology.

STUDY OBJECTIVE: Prior research has collectively shown that endometriosis is inversely related to women's adiposity. The aim of this study was to assess whether this inverse relationship holds true by disease severity and typology. DESIGN: Cross-sectional study among women with no prior diagnosis of endometriosis. SETTING: Fourteen clinical centers in Salt Lake City, UT, and San Francisco, CA. PATIENTS: A total of 495 women (of which 473 were analyzed), aged 18-44 years, were enrolled in the operative cohort of the Endometriosis, Natural History, Diagnosis, and Outcomes (ENDO) Study. INTERVENTIONS: Gynecologic laparoscopy/laparotomy regardless of clinical indication. MEASUREMENTS AND MAIN RESULTS: Participants underwent anthropometric assessments, body composition measurements, and evaluations of body fat distribution ratios before surgery. Surgeons completed a standardized operative report immediately after surgery to capture revised American Society for Reproductive Medicine staging (I-IV) and typology of disease (superficial endometriosis [SE], ovarian endometrioma [OE], and deep infiltrating endometriosis [DIE]). Linear mixed models, taking into account within-clinical-center correlation, were used to generate least square means (95% confidence intervals) to assess differences in adiposity measures by endometriosis stage (no endometriosis, I-IV) and typology (no endometriosis, SE, DIE, OE, OE + DIE) adjusting for age, race/ethnicity, and parity. Although most confidence intervals were wide and overlapping, 3 general impressions emerged: (1) women with incident endometriosis had the lowest anthropometric/body composition indicators compared with those without incident endometriosis, (2) women with stage I or IV endometriosis had lower indicators compared with women with stage II or III, and (3) women with OE and/or DIE tended to have the lowest indicators, whereas women with SE had the highest indicators. CONCLUSION: Our research highlights that the relationship between women's adiposity and endometriosis severity and typology may be more complicated than prior research indicates.

Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment: A Randomized Clinical Trial.

Importance: Dietary supplements marketed for male fertility commonly contain folic acid and zinc based on limited prior evidence for improving semen quality. However, no large-scale trial has examined the efficacy of this therapy for improving semen quality or live birth. Objective: To determine the effect of daily folic acid and zinc supplementation on semen quality and live birth. Design, Setting, and Participants: The Folic Acid and Zinc Supplementation Trial was a multicenter randomized clinical trial. Couples (n = 2370; men aged ≥18 years and women aged 18-45 years) planning infertility treatment were enrolled at 4 US reproductive endocrinology and infertility care study centers between June 2013 and December 2017. The last 6-month study visit for semen collection occurred during August 2018, with chart abstraction of live birth and pregnancy information completed during April 2019. Interventions: Men were block randomized by study center and planned infertility treatment (in vitro fertilization, other treatment at a study site, and other treatment at an outside clinic) to receive either 5 mg of folic acid and 30 mg of elemental zinc (n = 1185) or placebo (n = 1185) daily for 6 months. Main Outcomes and Measures: The co-primary outcomes were live birth (resulting from pregnancies occurring within 9 months of randomization) and semen quality parameters (sperm concentration, motility, morphology, volume, DNA fragmentation, and total motile sperm count) at 6 months after randomization. Results: Among 2370 men who were randomized (mean age, 33 years), 1773 (75%) attended the final 6-month study visit. Live birth outcomes were available for all couples, and 1629 men (69%) had semen available for analysis at 6 months after randomization. Live birth was not significantly different between treatment groups (404 [34%] in the folic acid and zinc group and 416 [35%] in the placebo group; risk difference, -0.9% [95% CI, -4.7% to 2.8%]). Most of the semen quality parameters (sperm concentration, motility, morphology, volume, and total motile sperm count) were not significantly different between treatment groups at 6 months after randomization. A statistically significant increase in DNA fragmentation was observed with folic acid and zinc supplementation (mean of 29.7% for percentage of DNA fragmentation in the folic acid and zinc group and 27.2% in the placebo group; mean difference, 2.4% [95% CI, 0.5% to 4.4%]). Gastrointestinal symptoms were more common with folic acid and zinc supplementation compared with placebo (abdominal discomfort or pain: 66 [6%] vs 40 [3%], respectively; nausea: 50 [4%] vs 24 [2%]; and vomiting: 32 [3%] vs 17 [1%]). Conclusions and Relevance: Among a general population of couples seeking infertility treatment, the use of folic acid and zinc supplementation by male partners, compared with placebo, did not significantly improve semen quality or couples' live birth rates. These findings do not support the use of folic acid and zinc supplementation by male partners in the treatment of infertility. Trial Registration: ClinicalTrials.gov Identifier: NCT01857310.

Alterations in quadriceps muscle cellular and molecular properties in adults with moderate knee osteoarthritis.

OBJECTIVE: Quadriceps muscle weakness is common in knee osteoarthritis (OA). While pain, disuse, and atrophy are commonly cited causes for muscle weakness in OA, emerging evidence suggests changes in muscle quality also occur. Alterations in muscle quality are not well understood, but likely include both cellular and morphologic adaptions. The purpose of this study was to conduct the first cellular-level analysis of the vastus lateralis in adults with moderate knee OA. METHODS: Vastus lateralis biopsies were obtained from 24 subjects with moderate knee OA and 15 healthy controls. Quadriceps strength, muscle fiber cross sectional area (CSA), fiber type distribution, extracellular matrix (ECM) content, satellite cell abundance, and profibrotic gene expression were assessed. RESULTS: Relative to controls, quadriceps strength was significantly lower in OA subjects (OA 62.23, 50.67-73.8 Nm vs 91.46, 75.91-107.0 Nm, P = 0.003) despite no difference in fiber CSA. OA subjects had significantly fewer Type I fibers (OA 41.51, 35.56-47.47% vs 53.07, 44.86-61.29%, P = 0.022) and more hybrid IIa/x fibers (OA 24.61, 20.61-28.61% vs 16.4, 11.60-21.20%, P = 0.009). Significantly greater ECM content, lower satellite cell density, and higher profibrotic gene expression was observed with OA, and muscle collagen content was inversely correlated to strength and satellite cell (SC) density. CONCLUSION: Lower quadriceps function with moderate OA may not result from fiber size impairments, but is associated with ECM expansion. Impaired satellite cell density, high profibrotic gene expression, and a slow-to-fast fiber type transition may contribute to reduced muscle quality in OA. These findings can help guide therapeutic interventions to enhance muscle function with OA.

Endometrial Cancers Harboring Mutated Fibroblast Growth Factor Receptor 2 Protein Are Successfully Treated With a New Small Tyrosine Kinase Inhibitor in an Orthotopic Mouse Model.

OBJECTIVES: AL3818 (anlotinib) is a receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors (VEGFR1, VEGFR2/KDR, and VEGFR3), stem cell factor receptor (C-kit), platelet-derived growth factor (PDGFß), and fibroblast growth factor receptors (FGFR1, FGFR2, and FGFR3). This study evaluates the efficacy of AL3818 studying tumor regression in an orthotopic murine endometrial cancer model. METHODS: We tested the cytotoxicity of AL3818 on a panel of 7 human endometrial cancer cell lines expressing either wild-type or mutant FGFR2 and also assessed the in vivo antitumor efficacy in a murine, orthotopic AN3CA endometrial cancer model. AL3818 was administered daily per os either alone or in combination with carboplatin and paclitaxel, which represent the current standard of adjuvant care for endometrial cancer. RESULTS: AL3818 significantly reduces AN3CA cell number in vitro, characterized by high expression of a mutated FGFR2 protein. Daily oral administration of AL3818 (5 mg/kg) resulted in a complete response in 55% of animals treated and in a reduced tumor volume, as well as decreased tumor weights of AN3CA tumors by 94% and 96%, respectively, following a 29-day treatment cycle. Whereas carboplatin and paclitaxel failed to alter tumor growth, the combination with AL3818 did not seem to exhibit a superior effect when compared with AL3818 treatment alone. CONCLUSIONS: AL3818 shows superior efficacy for the treatment of endometrial cancer irresponsive to conventional carboplatin and paclitaxel combination and warrants further investigation.

Eight weeks of overfeeding alters substrate partitioning without affecting metabolic flexibility in men.

BACKGROUND/OBJECTIVE: Impairments in metabolic flexibility (MF) and substrate handling are associated with metabolic syndrome. However, it is unknown whether metabolic inflexibility causes insulin resistance. We therefore measured MF and substrate handling before and after 8 weeks of overfeeding in initially healthy adults as a model of the early stages of insulin resistance. SUBJECTS/METHODS: Twenty-nine healthy men (27±5 years old; body mass index 25.5±2.3 kg m-2) were overfed by 40% above baseline energy requirements for 8 weeks and gained 7.6±2.1 kg of weight. Before and after overfeeding, energy expenditure, substrate oxidation and MF were measured in two ways: (a) during 1 day of eucaloric feeding in a whole-room indirect calorimeter and (b) during a two-step hyperinsulinemic-euglycemic clamp. RESULTS: Eight weeks of overfeeding decreased insulin sensitivity at low and high doses of insulin (P=0.001 and P=0.06, respectively). This was accompanied by decreases in the respiratory quotient (RQ) while sleeping (from 0.877±0.020 to 0.864±0.026; P=0.05) and at low insulin levels during the clamp (from 0.927±0.047 to 0.907±0.032; P=0.01). Overfeeding did not affect MF as measured during a clamp (P⩾0.17), but it tended to increase 24-h MF (awake RQ-sleep RQ) as measured by chamber by 0.010±0.028 (P=0.08). In terms of substrate oxidation, overfeeding increased protein oxidation by 13±23 g day-1 (P=0.003) and tended to increase fat oxidation by 6±16 g day-1 (P=0.07) but did not affect carbohydrate oxidation (P=0.64). Individuals with greater metabolic adaptation to overfeeding had higher carbohydrate oxidation rates (r=0.66, P=8 × 10-5) but not fat oxidation rates (P=0.09). CONCLUSIONS: The early stages of insulin resistance are accompanied by modest declines in the RQs during sleep and during a clamp, with no changes in fasting RQ or signs of metabolic inflexibility. Our data therefore suggest that metabolic inflexibility does not cause insulin resistance.

TreeQTL: hierarchical error control for eQTL findings.

UNLABELLED: : Commonly used multiplicity adjustments fail to control the error rate for reported findings in many expression quantitative trait loci (eQTL) studies. TreeQTL implements a hierarchical multiple testing procedure which allows control of appropriate error rates defined relative to a grouping of the eQTL hypotheses. AVAILABILITY AND IMPLEMENTATION: The R package TreeQTL is available for download at http://bioinformatics.org/treeqtl CONTACT: sabatti@stanford.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Endometriosis diagnosis and staging by operating surgeon and expert review using multiple diagnostic tools: an inter-rater agreement study.

OBJECTIVE: To determine agreement on endometriosis diagnosis between real-time laparoscopy and subsequent expert review of digital images, operative reports, magnetic resonance imaging (MRI), and histopathology, viewed sequentially. DESIGN: Inter-rater agreement study. SETTING: Five urban surgical centres. POPULATION: Women, aged 18-44 years, who underwent a laparoscopy regardless of clinical indication. A random sample of 105 women with and 43 women without a postoperative endometriosis diagnosis was obtained from the ENDO study. METHODS: Laparoscopies were diagnosed, digitally recorded, and reassessed. MAIN OUTCOME MEASURES: Inter-observer agreement of endometriosis diagnosis and staging according to the revised American Society for Reproductive Medicine criteria. Prevalence and bias-adjusted kappa values (κ) were calculated for diagnosis, and weighted κ values were calculated for staging. RESULTS: Surgeons and expert reviewers had substantial agreement on diagnosis and staging after viewing digital images (n = 148; mean κ = 0.67, range 0.61-0.69; mean κ = 0.64, range 0.53-0.78, respectively) and after additionally viewing operative reports (n = 148; mean κ = 0.88, range 0.85-0.89; mean κ = 0.85, range 0.84-0.86, respectively). Although additionally viewing MRI findings (n = 36) did not greatly impact agreement, agreement substantially decreased after viewing histological findings (n = 67), with expert reviewers changing their assessment from a positive to a negative diagnosis in up to 20% of cases. CONCLUSION: Although these findings suggest that misclassification bias in the diagnosis or staging of endometriosis via visualised disease is minimal, they should alert gynaecologists who review operative images in order to make decisions on endometriosis treatment that operative reports/drawings and histopathology, but not necessarily MRI, will improve their ability to make sound judgments. TWEETABLE ABSTRACT: Endometriosis diagnosis and staging agreement between expert reviewers and operating surgeons was substantial.

Female infertility, infertility-associated diagnoses, and comorbidities: a review.

PURPOSE: The purpose of the study is to evaluate existing literature for possible associations between female infertility, infertility-associated diagnoses, and the following areas of disease: psychiatric disorders, breast cancer, ovarian cancer, endometrial cancer, cardiovascular disease, and metabolic dysfunction. METHODS: The design of the study is a literature review. The patients were women included in 26 selected studies due to a diagnosis of infertility or a reproductive disorder associated with infertility. This study has no interventions, and the main outcome measure is the association between female infertility or a related diagnosis and psychiatric disorders, breast cancer, ovarian cancer, endometrial cancer, cardiovascular disease, and metabolic dysfunction. RESULTS: Female infertility and related reproductive disorders may have ramifications for women beyond reproductive health. An analysis of publications shows that women with infertility had higher rates of psychiatric disorders and endometrial cancer than the general population [1-10]. Data is conflicting about whether infertile women are at increased risk for breast cancer and ovarian cancer [7, 8, 10-20]. A generalized diagnosis of infertility was not clearly associated with an increased risk of cardiovascular disease or metabolic dysfunction, but women with infertility related to polycystic ovarian syndrome (PCOS) do appear more likely to develop cardiovascular disease and metabolic disorders such as diabetes than the general population [16, 21-26]. CONCLUSIONS: Female infertility and associated diagnoses have overall health implications. Beyond treatment of patients' immediate reproductive needs, healthcare professionals must be aware of the broader health impact of specific causes of infertility in order to provide accurate counseling regarding long-term risk.

Sexual and physical abuse and gynecologic disorders.

STUDY QUESTION: Is sexual and/or physical abuse history associated with incident endometriosis diagnosis or other gynecologic disorders among premenopausal women undergoing diagnostic and/or therapeutic laparoscopy or laparotomy regardless of clinical indication? SUMMARY ANSWER: No association was observed between either a history of sexual or physical abuse and risk of endometriosis, ovarian cysts or fibroids; however, a history of physical abuse was associated with a higher likelihood of adhesions after taking into account important confounding and mediating factors. WHAT IS KNOWN ALREADY: Sexual and physical abuse may alter neuroendocrine-immune processes leading to a higher risk for endometriosis and other noninfectious gynecologic disorders, but few studies have assessed abuse history prior to diagnosis. STUDY DESIGN, SIZE, DURATION: The study population for these analyses includes the ENDO Study (2007-2009) operative cohort: 473 women, ages 18-44 years, who underwent a diagnostic and/or therapeutic laparoscopy or laparotomy at 1 of the 14 surgical centers located in Salt Lake City, UT, USA or San Francisco, CA, USA. Women with a history of surgically confirmed endometriosis were excluded. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Prior to surgery, women completed standardized abuse questionnaires. Relative risk (RR) of incident endometriosis, uterine fibroids, adhesions or ovarian cysts by abuse history were estimated, adjusting for age, race/ethnicity, education, marital status, smoking, gravidity and recruitment site. We assessed whether a history of chronic pelvic pain, depression, or STIs explained any relationships via mediation analyses. MAIN RESULTS AND ROLE OF CHANCE: 43 and 39% of women reported experiencing sexual and physical abuse. No association was observed between either a history of sexual or physical abuse, versus no history, and risk of endometriosis (aRR: 1.00 [95% confidence interval (CI): 0.80-1.25]); aRR: 0.83 [95% CI: 0.65-1.06]), ovarian cysts (aRR: 0.67 [95% CI: 0.39-1.15]); aRR: 0.60 [95% CI: 0.34-1.09]) or fibroids (aRR: 1.25 [95% CI: 0.85-1.83]); aRR: 1.36 [95% CI: 0.92-2.01]). Conversely, a history of physical abuse, versus no history, was associated with higher risk of adhesions (aRR: 2.39 [95% CI: 1.18-4.85]). We found no indication that the effect of abuse on women's adhesion risk could be explained by a history of chronic pelvic pain, depression or STIs. LIMITATIONS, REASONS FOR CAUTION: Limitations to our study include inquiries on childhood physical but not sexual abuse. Additionally, we did not inquire about childhood or adulthood emotional support systems, found to buffer the negative impact of stress on gynecologic health. WIDER IMPLICATIONS OF THE FINDINGS: Abuse may be associated with some but not all gynecologic disorders with neuroendocrine-inflammatory origin. High prevalence of abuse reporting supports the need for care providers to screen for abuse and initiate appropriate follow-up. STUDY FUNDING/COMPETING INTERESTS: Supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts NO1-DK-6-3428, NO1-DK-6-3427, and 10001406-02). The authors have no potential competing interests.

Imiquimod Induces Apoptosis in Human Endometrial Cancer Cells In vitro and Prevents Tumor Progression In vivo.

PURPOSE: The increasing incidence of endometrial cancer (EC), in younger age at diagnosis, calls for new tissue-sparing treatment options. This work aims to evaluate the potential of imiquimod (IQ) in the treatment of low-grade EC. METHODS: Effects of IQ on the viabilities of Ishikawa and HEC-1A cells were evaluated using MTT assay. The ability of IQ to induce apoptosis was evaluated by testing changes in caspase 3/7 levels and expression of cleaved caspase-3, using luminescence assay and western blot. Apoptosis was confirmed by flow cytometry and the expression of cleaved PARP. Western blot was used to evaluate the effect of IQ on expression levels of Bcl-2, Bcl-xL, and BAX. Finally, the in vivo efficacy of IQ was tested in an EC mouse model. RESULTS: There was a decrease in EC cell viability following IQ treatment as well as increased caspase 3/7 activities, cleaved caspase-3 expression, and Annexin-V/ 7AAD positive cell population. Western blot results showed the ability of IQ in cleaving PARP, decreasing Bcl-2 and Bcl-xL expressions, but not affecting BAX expression. In vivo study demonstrated IQ's ability to inhibit EC tumor growth and progression without significant toxicity. CONCLUSIONS: IQ induces apoptosis in low-grade EC cells in vitro, probably through its direct effect on Bcl-2 family protein expression. In, vivo, IQ attenuates EC tumor growth and progression, without an obvious toxicity. Our study provides the first building block for the potential role of IQ in the non-surgical management of low-grades EC and encouraging further investigations.

Immune homeostasis, dysbiosis and therapeutic modulation of the gut microbiota.

The distal gut harbours ∼10(13) bacteria, representing the most densely populated ecosystem known. The functional diversity expressed by these communities is enormous and relatively unexplored. The past decade of research has unveiled the profound influence that the resident microbial populations bestow to host immunity and metabolism. The evolution of these communities from birth generates a highly adapted and highly personalized microbiota that is stable in healthy individuals. Immune homeostasis is achieved and maintained due in part to the extensive interplay between the gut microbiota and host mucosal immune system. Imbalances of gut microbiota may lead to a number of pathologies such as obesity, type I and type II diabetes, inflammatory bowel disease (IBD), colorectal cancer (CRC) and inflammaging/immunosenscence in the elderly. In-depth understanding of the underlying mechanisms that control homeostasis and dysbiosis of the gut microbiota represents an important step in our ability to reliably modulate the gut microbiota with positive clinical outcomes. The potential of microbiome-based therapeutics to treat epidemic human disease is of great interest. New therapeutic paradigms, including second-generation personalized probiotics, prebiotics, narrow spectrum antibiotic treatment and faecal microbiome transplantation, may provide safer and natural alternatives to traditional clinical interventions for chronic diseases. This review discusses host-microbiota homeostasis, consequences of its perturbation and the associated challenges in therapeutic developments that lie ahead.

Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia.

The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. We hypothesized that variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL). We studied 522 Danish children with ALL, 93% of all those eligible. Risk of relapse was increased 2.9-fold for patients with the 1199GA variant versus 1199GG (P=0.001), and reduced 61% and 40%, respectively, for patients with the 3435CT or 3435TT variants versus 3435CC (overall P=0.02). The degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was more prominent in patients with 3435TT variant versus 3435CT/3435CC (P=0.01/P<0.0001). We observed more liver toxicity after high-dose methotrexate in patients with 3435CC variant versus 3435CT/TT (P=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL, and ABCB1 1199G>A may be a new possible predictive marker for outcome in childhood ALL.

Pain typology and incident endometriosis.

STUDY QUESTION: What are the pain characteristics among women, with no prior endometriosis diagnosis, undergoing laparoscopy or laparotomy regardless of clinical indication? SUMMARY ANSWER: Women with surgically visualized endometriosis reported the highest chronic/cyclic pain and significantly greater dyspareunia, dysmenorrhea, and dyschezia compared with women with other gynecologic pathology (including uterine fibroids, pelvic adhesions, benign ovarian cysts, neoplasms and congenital Müllerian anomalies) or a normal pelvis. WHAT IS KNOWN ALREADY: Prior research has shown that various treatments for pain associated with endometriosis can be effective, making identification of specific pain characteristics in relation to endometriosis necessary for informing disease diagnosis and management. STUDY DESIGN, SIZE, DURATION: The study population for these analyses includes the ENDO Study (2007-2009) operative cohort: 473 women, ages 18-44 years, who underwent a diagnostic and/or therapeutic laparoscopy or laparotomy at one of 14 surgical centers located in Salt Lake City, UT or San Francisco, CA. Women with a history of surgically confirmed endometriosis were excluded. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Endometriosis was defined as surgically visualized disease; staging was based on revised American Society for Reproductive Medicine (rASRM) criteria. All women completed a computer-assisted personal interview at baseline specifying 17 types of pain (rating severity via 11-point visual analog scale) and identifying any of 35 perineal and 60 full-body front and 60 full-body back sites for which they experienced pain in the last 6 months. MAIN RESULTS AND THE ROLE OF CHANCE: There was a high prevalence (≥30%) of chronic and cyclic pelvic pain reported by the entire study cohort regardless of post-operative diagnosis. However, women with a post-operative endometriosis diagnosis, compared with women diagnosed with other gynecologic disorders or a normal pelvis, reported more cyclic pelvic pain (49.5% versus 31.0% and 33.1%, P < 0.001). Additionally, women with endometriosis compared with women with a normal pelvis experienced more chronic pain (44.2 versus 30.2%, P = 0.04). Deep pain with intercourse, cramping with periods, and pain with bowel elimination were much more likely reported in women with versus without endometriosis (all P < 0.002). A higher percentage of women diagnosed with endometriosis compared with women with a normal pelvis reported vaginal (22.6 versus 10.3%, P < 0.01), right labial (18.4 versus 8.1%, P < 0.05) and left labial pain (15.3 versus 3.7%, P < 0.01) along with pain in the right/left hypogastric and umbilical abdominopelvic regions (P < 0.05 for all). Among women with endometriosis, no clear and consistent patterns emerged regarding pain characteristics and endometriosis staging or anatomic location. LIMITATIONS, REASONS FOR CAUTION: Interpretation of our findings requires caution given that we were limited in our assessment of pain characteristics by endometriosis staging and anatomic location due to the majority of women having minimal (stage I) disease (56%) and lesions in peritoneum-only location (51%). Significance tests for pain topology related to gynecologic pathology were not corrected for multiple comparisons. WIDER IMPLICATIONS OF THE FINDINGS: Results of our research suggest that while women with endometriosis appear to have higher pelvic pain, particularly dyspareunia, dysmenorrhea, dyschezia and pain in the vaginal and abdominopelvic area than women with other gynecologic disorders or a normal pelvis, pelvic pain is commonly reported among women undergoing laparoscopy, even among women with no identified gynecologic pathology. Future research should explore causes of pelvic pain among women who seek out gynecologic care but with no apparent gynecologic pathology. Given our and other's research showing little correlation between pelvic pain and rASRM staging among women with endometriosis, further development and use of a classification system that can better predict outcomes for endometriosis patients with pelvic pain for both surgical and nonsurgical treatment is needed. STUDY FUNDING/COMPETING INTERESTS: Supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts NO1-DK-6-3428, NO1-DK-6-3427, and 10001406-02). The authors have no potential competing interests.

Identification of Cephalosporium stripe resistance quantitative trait loci in two recombinant inbred line populations of winter wheat.

KEY MESSAGE: Identification of genome regions linked to Cephalosporium stripe resistance across two populations on chromosome 3BS, 4BS, 5AL, C5BL. Results were compared to a similar previous study. Cephalosporium stripe is a vascular wilt disease of winter wheat (Triticum aestivum L.) caused by the soil-borne fungus Cephalosporium gramineum Nisikado & Ikata. In the USA it is known to be a recurring disease when susceptible cultivars are grown in the wheat-growing region of Midwest and Pacific Northwest. There is no complete resistance in commercial wheat cultivars, although the use of moderately resistant cultivars reduces the disease severity and the amount of inoculum in subsequent seasons. The goal of this study was to detect and to compare chromosomal regions for resistance to Cephalosporium stripe in two winter wheat populations. Field inoculation was performed and Cephalosporium stripe severity was visually scored as percent of prematurely ripening heads (whiteheads) per plot. 'Tubbs'/'NSA-98-0995' and 'Einstein'/'Tubbs', each comprising a cross of a resistant and a susceptible cultivar, with population sizes of 271 and 259 F (5:6) recombinant inbred lines, respectively, were genotyped and phenotyped across four environments. In the quantitative trait loci (QTL) analysis, six and nine QTL were found, explaining in total, around 30 and 50 % of the phenotypic variation in 'Tubbs'/'NSA-98-0995' and 'Einstein'/'Tubbs', respectively. The QTL with the largest effect from both 'NSA-98-0995' and 'Einstein' was on chromosome 5AL.1 and linked to marker gwm291. Several QTL with smaller effects were identified in both populations on chromosomes 5AL, 6BS, and 3BS, along with other QTL identified in just one population. These results indicate that resistance to Cephalosporium stripe in both mapping populations was of a quantitative nature.

Multi-location wheat stripe rust QTL analysis: genetic background and epistatic interactions.

KEY MESSAGE: Epistasis and genetic background were important influences on expression of stripe rust resistance in two wheat RIL populations, one with resistance conditioned by two major genes and the other conditioned by several minor QTL. Stripe rust is a foliar disease of wheat (Triticum aestivum L.) caused by the air-borne fungus Puccinia striiformis f. sp. tritici and is present in most regions around the world where commercial wheat is grown. Breeding for durable resistance to stripe rust continues to be a priority, but also is a challenge due to the complexity of interactions among resistance genes and to the wide diversity and continuous evolution of the pathogen races. The goal of this study was to detect chromosomal regions for resistance to stripe rust in two winter wheat populations, 'Tubbs'/'NSA-98-0995' (T/N) and 'Einstein'/'Tubbs' (E/T), evaluated across seven environments and mapped with diversity array technology and simple sequence repeat markers covering polymorphic regions of ≈1480 and 1117 cM, respectively. Analysis of variance for phenotypic data revealed significant (P < 0.01) genotypic differentiation for stripe rust among the recombinant inbred lines. Results for quantitative trait loci/locus (QTL) analysis in the E/T population indicated that two major QTL located in chromosomes 2AS and 6AL, with epistatic interaction between them, were responsible for the main phenotypic response. For the T/N population, eight QTL were identified, with those in chromosomes 2AL and 2BL accounting for the largest percentage of the phenotypic variance.