The endoplasmic reticulum and its signaling pathways - a novel target for multiple myeloma treatment.

BACKGROUND: The endoplasmic reticulum (ER), an organelle composed of a system of cisternae and tubules, is essential for many cellular processes, including protein synthesis and transport. When misfolded proteins accumulate in the ER lumen, ER stress is induced, and the subsequent response to the disruption of homeostasis is the activation of the unfolded protein response (UPR). The purpose of this process is to restore homeostasis by increasing the capacity of the ER and its ability to fold proteins. Activation of the homeostatic UPR occurs via one of three transmembrane proteins, inositol-requiring enzyme 1a (IRE1a), protein kinase R-like ER kinase (PERK) and activating transcription factor 6 (ATF6). Failure of the attempt to restore homeostasis, on the other hand, leads to the development of terminal UPR and apoptosis via hyperactivation of the same proteins. Activation of UPR has been described in many malignancies, including multiple myeloma (MM), which is characterized by malignant transformation of plasma cells and increased monoclonal immunoglobulin synthesis, where the role of the ER is of particular importance. Despite advances in the treatment of MM, the disease remains difficult to treat and targeting signaling pathways associated with the UPR could, for example, enhance the effect of proteasome inhibitors. PURPOSE: This review intends to present the molecular response to ER stress under physiological circumstances and in the context of cancer, particularly with regard to potential therapeutic targets in MM.

Informing a PCOS Lifestyle Program: Mapping Behavior Change Techniques to Barriers and Enablers to Behavior Change Using the Theoretical Domains Framework.

This article aimed to identify the behavior change techniques (BCTs) based on facilitators and barriers to lifestyle management in women with polycystic ovary syndrome (PCOS) according to the behavior change wheel (BCW). This qualitative study design using inductive thematic analysis following semistructured interviews (n = 20) identified barriers and enablers to lifestyle management. These were then mapped to Capability, Opportunity, Motivation-Behavioral Model (COM-B) constructs and the corresponding Theoretical Domains Framework (TDF) domains. This study included women with PCOS residing in Australia. Main outcome measures include intervention functions, policy categories, and BCTs described in the BCW. Twenty-three BCTs were recognized to influence behavior change in women with PCOS. Factors were categorized into the subcomponents of the COM-B: psychological capability (e.g., lack of credible information), physical capability (e.g., managing multiple health conditions), physical opportunity (e.g., limited access to resources), social opportunity (e.g., adequate social support), reflective motivation (e.g., positive health expectancies following behavior change), and automatic motivation (e.g., emotional eating). Future research should use this work to guide PCOS lifestyle intervention development and then test intervention effectiveness through an experimental phase to provide empirical evidence for wider use and implementation of tailored, theory-informed PCOS lifestyle programs as part of evidence-based PCOS management.

Rationale, design and methodology of TESEO study: a registry of thrombosis and neoplasia of SEOM (Spanish Society of Medical Oncology).

BACKGROUND AND RATIONALE: Thromboembolic complications are a serious, preventable and common event in cancer patients that contributes to increasing morbidity and mortality. Despite increasing knowledge on cancer-associated thrombosis (CAT), there are still several aspects of diagnosis, clinical management, treatment and prognosis with uncertainties that are under-represented in randomized clinical trials. For this reason, the Spanish Society of Medical Oncology (SEOM) launched in June 2018 a registry of CAT. METHODS/DESIGN: TESEO is an ongoing prospective, non-interventional, multicentric study in consecutive cancer patients with newly diagnosed of thromboembolic event (TEE). Eligibility criteria include being > 18 years with a histologically confirmed diagnosis of cancer and a symptomatic or incidental TEE confirmed with an imaging technique in the previous month or any time after the cancer diagnosis and signing of informed consent. The study consists of two types of integrated but independent prospective registries. Regular CAT sub-registry includes information on patient's cancer´s characteristics, anticoagulant treatment provided and outcome data. Special CAT sub-registry includes variables related to special situations of CAT that comprise patients with severe kidney failure, thrombocytopenia, high risk of bleeding related to the cancer or with coexistence of bleeding and patients who receive new treatments such a targeted therapy, antiangiogenics agents and immunotherapy. The registry considers the status of the cancer and the time to assess how the prognosis is changed based on when the thrombus occurs. Some outcomes such as rethrombosis, major bleeding, tumor progression and survival will be valued in various time intervals including 1, 3, 6 and 12 months after the even in the first year; and then every 6 months until the patient's death. RESULTS: After 18 months and with 35 centers and researchers, the registry has 1128 patients. CONCLUSION: TESEO registry will provide clinical real-world evidence for prevention, treatment and complications of CAT in different scenarios that are under-represented in randomized clinical trials.

Incidence of venous thromboembolism in patients with colorectal cancer according to oncogenic status.

BACKGROUND: There are conflicting data regarding the role of KRAS mutation on the risk of venous thromboembolism (VTE) in colorectal cancer (CRC) patients. Moreover, the role of other biomarkers such as NRAS or BRAF has not been studied. PURPOSE: To analyze the incidence of VTE in a cohort of patients with CRC based on KRAS, NRAS, and BRAF status. METHODS: We performed a retrospective review of patients with unresectable locally advanced and metastatic CRC (mCRC) and known KRAS/NRAS/BRAF status, attended in the Medical Oncology Department of the Hospital General Universitario Gregorio Marañón (Madrid, Spain). The primary outcome was VTE defined as any venous thromboembolic event that occurred either 6 months before or at any time after the diagnosis of CRC. The biomarker status (KRAS, NRAS, and BRAF) and other predictors of thrombosis were collected. RESULTS: One hundred and ninety-four patients were identified and included in the analysis. Forty-one patients (21.1%) experienced VTE. The incidence was 19.1% in RAS-mutated patients, 28.6% in BRAF-mutated patients and 21% in triple wild-type patients (p = NS). In multivariate analysis, ECOG ≥ 2 was the only independent predictor of VTE (OR 8.73; CI 95% 1.32-57.82; p = 0.025). CONCLUSIONS: In our study, biomarkers have not been associated with an increased risk of VTE in CRC patients. A high incidence of VTE in BRAF-mutated patients has been observed and should be explored in further studies.

Monitoring anti-Xa levels in patients with cancer-associated venous thromboembolism treated with bemiparin.

OBJECTIVE: To analyze the relationship between therapeutic (weight-adjusted) dose of bemiparin and anti-Xa activity in patients with venous thromboembolism (VTE) and cancer in comparison with a cohort of patients with VTE without cancer, and its relationship with outcomes. MATERIALS AND METHODS: This is a prospective cohort study that comprised a cohort of patients with cancer-associated VTE and a cohort of non-cancer patients with VTE, all of them treated with bemiparin. The ethics committee approved the study and informed consent was obtained from the patients. RESULTS: One hundred patients were included (52 with cancer and 48 without cancer), with a median follow-up of 9.8 months. Mean anti-Xa activity was 0.89 (± 0.33) UI/mL in oncological patients and 0.83 (± 0.30) UI/mL in non-cancer patients (mean difference - 0.05 95% CI - 0.18; 0.06). A multiple linear regression model showed that anti-Xa peak was associated with the dose/kg independently of possible confounding variables (presence of cancer, age, sex and eGFR-estimated Glomerular Filtration Rate), in a way that for every 1 UI of dose/kg increase, the anti-Xa peak activity increased 0.006 UI/mL (95% CI 0.003; 0.009) (p < 0.001). The predictive capacity of anti-Xa peak in the oncology cohort showed an area under the ROC curve of 0.46 (95% CI 0.24-0.68), 0.70 (95% CI 0.49-0.91) and 0.74 (95% CI 0.44-0.94) for death, first bleeding and recurrence of VTE, respectively, and none was statistically significant. CONCLUSION: In patients with venous thromboembolism treated with bemiparin, anti-Xa levels were not influenced by the presence of cancer.

Cardiometabolic risks in PCOS: a review of the current state of knowledge.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting up to 18% women of reproductive age. It is associated with a range of metabolic, reproductive, and psychological features. Current evidence indicates a role of PCOS in the development of metabolic and increased cardiovascular risk factors (CVRF) with implications for compromised cardiovascular endpoint disease, which may have a considerable impact on health and health care costs. AREAS COVERED: Existing studies examining long-term cardiometabolic health in PCOS are heterogeneous with inconsistent findings. In the current review, we aim to explore and critically review retrospective, prospective, meta-analysis and review articles relating to PCOS on cardiometabolic risk factors and clinical consequences to summarize the evidence, note evidence gaps, and suggest implications for future research. EXPERT COMMENTARY: Although there is an established association between PCOS and metabolic health, implications on cardiac health are more uncertain with associations observed for CVRF and subclinical disease, yet limited and conflicting data on actual cardiovascular endpoints. There is a lack of population-based long-term studies examining cardiometabolic morbidity and mortality in PCOS with a need for further research to progress toward a better understanding of the long-term cardiometabolic impacts in women with PCOS.

Metabolic syndrome in polycystic ovary syndrome: a systematic review, meta-analysis and meta-regression.

INTRODUCTION: Women with polycystic ovary syndrome (PCOS) have increased risk of metabolic syndrome. The relative contribution of clinical, demographic or biochemical factors to metabolic syndrome in PCOS is not known. A literature search was conducted in MEDLINE, CINAHL, EMBASE and clinical trial registries. Of 4530 studies reviewed, 59 were included in the systematic review and 27 in the meta-analysis and meta-regression. In good and fair quality studies, women with PCOS had an overall increased prevalence of metabolic syndrome (odds ratio, OR 3.35, 95% confidence interval, CI 2.44, 4.59). Increased prevalence of metabolic syndrome occurred in overweight or obese women with PCOS (OR 1.88, 95% 1.16, 3.04) but not in lean women (OR 1.45, 95% CI 0.35, 6.12). In meta-regression analyses, the markers of metabolic syndrome diagnostic criteria (waist circumference, high-density lipoprotein cholesterol, triglyceride, blood pressure), BMI, glucose tolerance (2-hr oral glucose tolerance test) and surrogate markers of insulin resistance (HOMA-IR) but not markers of reproductive dysfunction (sex hormone binding globulin, testosterone, PCOS phenotypes) contributed significantly to the heterogeneity in the prevalence of metabolic syndrome. Women with PCOS have increased risk of metabolic syndrome which was associated with obesity and metabolic features but not with indices of hyperandrogenism.

Ethnicity, obesity and the prevalence of impaired glucose tolerance and type 2 diabetes in PCOS: a systematic review and meta-regression.

BACKGROUND: Our prior meta-analyses demonstrated an increased prevalence of impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) with polycystic ovary syndrome (PCOS), but with substantial clinical heterogeneity. OBJECTIVE AND RATIONALE: We aimed to update our previous review to quantify the prevalence of IGT and T2DM in PCOS with only quality studies (good and fair quality). We also aimed to examine the contribution of parameters including ethnicity, obesity and method of diagnosing T2DM in explaining the observed heterogeneity in IGT and T2DM prevalence in PCOS. SEARCH METHODS: We conducted a literature search (MEDLINE, CINAHL, EMBASE, clinical trial registries and hand-searching) up to June 2016 to identify studies reporting the prevalence of dysglycemia (IGT and T2DM) in women with and without PCOS. We included studies where women with PCOS (defined according to original National Institute of Health) were compared to women without PCOS for the end-points of the prevalence of IGT or T2DM. We excluded case reports, case series, editorials, and narrative reviews. Studies where PCOS was diagnosed by self-report, or where IGT or T2DM were measured by fasting glucose, only were excluded. We assessed the methodological quality of the included studies using a priori criteria based on the Newcastle-Ottawa Scaling (NOS) for non-randomized studies. Data are presented as odds ratio (OR) (95% CI) with random-effects meta-analysis by Mantel-Haenszel methods. We assessed the contribution of demographic and clinical factors to heterogeneity using subgroup and meta-regression analysis. OUTCOMES: We reviewed 4530 studies and included 40 eligible studies in the final analysis. On meta-analysis of quality studies, women with PCOS had an increased prevalence of IGT (OR = 3.26, 95% CI: 2.17-4.90) and T2DM (OR = 2.87, 95% CI: 1.44-5.72), which differed by ethnicity (for IGT, Asia: 5-fold, the Americas: 4-fold and Europe: 3-fold), was higher with obesity, and doubled among studies using self-report or administrative data for diagnosing diabetes. The ethnicity-related difference retained its significance for Asia and Europe in BMI-matched subgroups. Clear contributors to heterogeneity did not emerge in meta-regression. WIDER IMPLICATIONS: Our findings underscore the importance of PCOS as a cause of dysglycemia with a higher prevalence of IGT and T2DM. They support the relevance of ethnicity and obesity and emphasize the need for accurate diagnostic methods for diabetes. PROSPERO REGISTRATION NUMBER: CRD42017056524.

Systematic review and meta-analysis of the impact of preconception lifestyle interventions on fertility, obstetric, fetal, anthropometric and metabolic outcomes in men and women.

STUDY QUESTION: What is the impact of preconception lifestyle interventions on live birth, birth weight and pregnancy rate? SUMMARY ANSWER: Lifestyle interventions showed benefits for weight loss and increased natural pregnancy rate, but not for live birth or birth weight. WHAT IS KNOWN ALREADY: Evidence on the practice and content of preconception counseling and interventions is variable and limited. STUDY DESIGN, SIZE, DURATION: Systematic review and meta-analysis (MA). Main search terms were those related to preconception lifestyle. Database searched were Ovid MEDLINE(R), EBM Reviews, PsycINFO, EMBASE and CINAHL Plus. No language restriction was placed on the published articles. The final search was performed on 10 January 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were non-pregnant women of childbearing age intent on conceiving or their male partners. Exclusion criteria include participants with BMI < 18 kg/m2, animal trials, hereditary disorder in one or both partners and trials focusing solely on alcohol or smoking cessation/reduction, micronutrient supplementation, or diabetes control. Anthropometric, fertility, obstetric and fetal outcomes were assessed. Bias and quality assessments were performed. MAIN RESULTS AND THE ROLE OF CHANCE: The search returned 1802 articles and eight studies were included for analysis. Populations targeted were primarily overweight or obese subfertile women seeking reproductive assistance, with few community-based studies and none including men. MA showed greater reduction in weight (n = 3, P < 0.00001, mean difference: -3.48 kg, 95% CI: -4.29, -2.67, I2 = 0%) and BMI (n = 2, P < 0.00001, mean difference: -1.40 kg/m2, 95% CI: -1.95, -0.84, I2 = 24%) with intervention. The only significant fertility outcome was an increased natural pregnancy rate (n = 2, P = 0.003, odds ratio: 1.87, CI: 1.24, 2.81, I2 = 0%). No differences were observed for ART adverse events, clinical pregnancy, pregnancy complications, delivery complications, live birth, premature birth, birth weight, neonatal mortality or anxiety. Risk of bias were high for three studies, moderate for three studies and low for two studies, Attrition bias was moderate or high in majority of studies. LIMITATIONS, REASONS FOR CAUTION: Results were limited to subfertile or infertile women who were overweight or obese undergoing ART with no studies in men. The heterogeneous nature of the interventions in terms of duration and regimen means no conclusions could be made regarding the method or components of optimal lifestyle intervention. Attrition bias itself is an important factor that could affect efficacy of interventions. WIDER IMPLICATIONS OF THE FINDINGS: Existing preconception lifestyle interventions primarily targeted overweight and obese subfertile women undergoing ART with a focus on weight loss. It is important to note that natural conception increased with lifestyle intervention. This emphasizes the need for further research exploring optimal components of preconception lifestyle interventions in the broader population and on the optimal nature, intensity and timing of interventions. STUDY FUNDING/COMPETING INTEREST(S): No conflict of interest declared. C.L.H. is a National Heart Foundation Postdoctoral Research Fellow. B.H. is funded by an Alfred Deakin Postdoctoral Research Fellowship. H.J.T. and B.W.M. hold NHMRC Practitioner fellowships. L.J.M. is supported by a SACVRDP Fellowship; a program collaboratively funded by the NHF, the South Australian Department of Health and the South Australian Health and Medical Research Institute. PROSPERO REGISTRATION NUMBER: CRD42015023952.

The association of the lipidomic profile with features of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) affects up to 18% of reproductive-aged women with reproductive and metabolic complications. While lipidomics can identify associations between lipid species and metabolic diseases, no research has examined the association of lipid species with the pathophysiological features of PCOS. The aim of this study was to examine the lipidomic profile in women with and without PCOS. This study was a cross-sectional study in 156 age-matched pre-menopausal women (18-45 years, BMI >20 kg/m2; n = 92 with PCOS, n = 64 without PCOS). Outcomes included the association between the plasma lipidomic profile (325 lipid species (24 classes) using liquid chromatography mass spectrometry) and PCOS, adiposity, homeostasis assessment of insulin resistance (HOMA), sex hormone-binding globulin (SHBG) and free androgen index (FAI). There were no associations of the lipidomic profile with PCOS or testosterone. HOMA was positively associated with 2 classes (dihydroceramide and triacylglycerol), SHBG was inversely associated with 2 classes (diacylglycerol and triacylglycerol), FAI was positively associated with 8 classes (ceramide, phosphatidylcholine, lysophosphatidylcholine, phosphatidylethanolamine, lysophosphatidylethanolamine, phosphatidylinositol, diacylglycerol and triacylglycerol) and waist circumference was associated with 8 classes (4 positively (dihydroceramide, phosphatidylglycerol, diacylglycerol and triacylglycerol) and 4 inversely (trihexosylceramide, GM3 ganglioside, alkenylphosphatidylcholine and alkylphosphatidylethanolamine)). The lipidomic profile was primarily related to central adiposity and FAI in women with or without PCOS. This supports prior findings that adiposity is a key driver of dyslipidaemia in PCOS and highlights the need for weight management through lifestyle interventions.

Weight management practices associated with PCOS and their relationships with diet and physical activity.

STUDY QUESTION: Do weight management practices differ in women with and without PCOS? SUMMARY ANSWER: Women in the general population with self-reported PCOS are more likely to be using healthy weight management practices and alternative non-lifestyle measures for weight management than women without PCOS. WHAT IS KNOWN ALREADY: Lifestyle management is the first-line treatment in PCOS. However, the specific weight management practices used by women with PCOS and their effect on diet and physical activity are unclear. STUDY DESIGN, SIZE, DURATION: The study was a population-based observational cross-sectional study involving women in the 1973-1978 cohort (n = 7767 total; n = 556 with PCOS, n = 7211 without PCOS). PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with and without self-reported PCOS were included. Self-reported outcome measures included healthy lifestyle-related or alternative non-lifestyle-related (e.g. laxatives or smoking) weight management practices, dietary intake and physical activity. MAIN RESULTS AND THE ROLE OF CHANCE: Women with PCOS were more likely to be following both healthy [reducing meal or snack size (odds ratio (OR) 1.50, 95% CI 1.14, 1.96, P = 0.004) and reducing fat or sugar intake (OR 1.32, 95% CI 1.03, 1.69, P = 0.027) or following a low glycaemic index diet (OR 2.88, 95% CI 2.30, 3.59, P < 0.001)] and alternative [smoking (OR 1.60, 95% CI 1.02, 2.52, P = 0.043) or use of laxative, diet pills, fasting or diuretics (OR 1.45, 95% CI 1.07, 1.97, P = 0.017)] weight management practices than women without PCOS. In PCOS, the use of a range of healthy weight management practices was associated with increases in physical activity (P < 0.001), diet quality (P < 0.001), percentage protein intake (P < 0.001) and decreases in glycaemic index (P < 0.001), and percentages of fat (P = 0.001), saturated fat (P < 0.001) or fibre (P = 0.003). Use of alternative weight management practices was associated with decreases in diet quality. LIMITATIONS, REASONS FOR CAUTION: Limitations include the use of self-reported data for PCOS, height, weight, diet, physical activity and weight management behaviours. WIDER IMPLICATIONS OF THE FINDINGS: In PCOS, we should focus on improving healthy weight practices across both diet quality and quantity, and on assessing alternative weight practices and their potential adverse effect on dietary intake. STUDY FUNDING/COMPETING INTEREST(S): L.M. is supported by a South Australian Cardiovascular Research Development Program Fellowship (ID AC11S374); a program collaboratively funded by the National Heart Foundation, the South Australian Department of Health and the South Australian Health and Medical Research Institute. H.T. is supported by the NHMRC. S.A.M. is supported by an NHMRC Career Development Fellowship Level 2, ID1104636 and was previously supported by an ARC Future Fellowship (2011-2015, FT100100581). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable.

Performance of mass spectrometry steroid profiling for diagnosis of polycystic ovary syndrome.

STUDY QUESTION: How well does multi-analyte steroid mass spectrometry (MS) profiling classify women with and without polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Our liquid chromatography MS (LC-MS) steroid profiling only minimally improves discrimination of women with and without PCOS compared with a direct testosterone immunoassay (T_IA) and the free androgen index (FAI). WHAT IS KNOWN ALREADY: Blood testosterone measured by direct (non-extraction) immunoassay overlaps between women with and without PCOS. Multi-analyte MS provides greater specificity and accuracy for steroid measurement so might improve the classification. STUDY DESIGN, SIZE, DURATION: An observational, cross-sectional study of women with PCOS (n = 152) defined by Rotterdam criteria and matched non-PCOS (n = 45) control women was conducted. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum steroid profiles of testosterone (T), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), androstenedione (A4), estradiol (E2), estrone (E1), 17 hydroxy progesterone (17OHP4), progesterone (P4) and cortisol were measured by LC-MS; T_IA and sex hormone binding globulin were measured by immunoassay; and FAI, calculated free testosterone (cFT) and total androgen index (TAI) were calculated. Classification was based on logistic regression with corresponding univariate and multivariate C-statistics. MAIN RESULTS AND THE ROLE OF CHANCE: Serum testosterone by immunoassay demonstrated levels more than 100% higher than that measured by LC-MS. Compared with the controls, women with PCOS had higher serum T, DHEA, A4, TAI, T_IA, cFT, FAI and E2 but not serum DHT, E1, P4, 17OHP4 or cortisol. Univariate C-statistics were highest for FAI (0.89) and T_IA (0.82) compared with other androgens (T [0.72], DHT [0.40]), pro-androgens (A4 [0.74], DHEA[0.71]) or derivatives (cFT [0.75], TAI [0.60]). For all multivariate models, the overall correct predictions (81-86%) featured high sensitivity (92-96%) but low specificity (28-43%). and substituting LC-MS steroid measurements for T_IA and FAI produced only minimal improvements in classification. LIMITATIONS REASONS FOR CAUTION: The study cohort is limited in size and only unconjugated steroids were measured. WIDER IMPLICATIONS OF THE FINDINGS: Multi-analyte steroid profiling of unconjugated circulating steroids provides only limited improvement on direct T_IA in classifying women with and without PCOS. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: N/A.

Maternal factors and the risk of birth defects after IVF and ICSI: a whole of population cohort study.

OBJECTIVE: To assess the contribution of maternal factors to major birth defects after in vitro fertilisation (IVF), intracytoplasmic sperm injection (ICSI), and natural conception. DESIGN: Retrospective cohort study in South Australia for the period January 1986 to December 2002. SETTING: A whole of population study. POPULATION: A census of all IVF and ICSI linked to registries for births, pregnancy terminations, and birth defects (diagnosed before a child's fifth birthday). METHODS: Odds ratios (ORs) for birth defects were calculated among IVF, ICSI, and natural conceptions for maternal age, parity, pre-pregnancy BMI, smoking, pre-existing diseases, and conditions in pregnancy, with adjustment for confounding factors. MAIN OUTCOME MEASURES: Birth defects classified by International Classification of Diseases (ninth revision) and British Paediatric Association (ICD9-BPA) codes. RESULTS: There were 2211 IVF, 1399 ICSI, and 301 060 naturally conceived births. The unadjusted prevalence of any birth defect was 7.1, 9.9, and 5.7% in the IVF, ICSI, and natural conception groups, respectively. As expected, the risk of birth defects increased with maternal age among the natural conceptions. In contrast, for IVF and ICSI combined, relative to natural conceptions, births to women aged ≤29 years had a higher risk (adjusted odds ratio, aOR 1.42; 95% confidence interval, 95% CI 1.04-1.94), births to women aged 35-39 years had no difference in risk (aOR 1.01; 95% CI 0.74-1.37), and births to women aged ≥40 years had a lower risk of defects (aOR 0.45; 95% CI 0.22-0.92). Defects were also elevated for nulliparity, anaemia, and urinary tract infection in births after ICSI, but not after IVF. CONCLUSIONS: The usual age-birth defect relationship is reversed in births after IVF and ICSI, and the associations for other maternal factors and defects vary between IVF and ICSI. TWEETABLE ABSTRACT: Risk of birth defects in women over 40 years is lower after infertility treatment than for natural conceptions.

Resolver problemas y tomar decisiones, esencia de práctica reflexiva en enfermería. Análisis de la literatura / Problem-solving and decision-making, essence of reflexive practice in nursing: A literature review / Resolver problemas e tomar decisões, essência de prática reflexiva em enfermagem. Análise da literatura

Dada la importancia de la formación de profesionales reflexivos, y en el marco de la búsqueda de una nueva epistemología de la práctica de enfermería, este artículo de revisión analiza diversas fuentes teóricas que representan evidencias científicas relativas a la resolución de problemas, toma de decisiones clínicas y su relación con las características de los recién egresados del pregrado, quienes al realizar servicio social (residencias), vivencian un proceso de transición: dejar de ser estudiante, pero a la vez enfrentarse a situaciones de ejercicio profesional que requieren habilidades para resolver problemas y tomar decisiones en situaciones inciertas y complejas. La revisión implicó búsquedas sistemáticas en bases de datos como Medline, CINAHL, Scielo, Lilacs, Cochrane, Cuiden y Redalyc, que permitieron localizar: 3 revisiones sistemáticas, 11 estudios con enfoque cuantitativo, 11 con enfoque cualitativo y 2 mixto, 14 artículos de revisión y 5 libros, publicados en los últimos 15 años. Aunque las publicaciones analizadas proceden de todos los continentes, predominan las de América en un 50%, seguidas por las europeas en un 22%. Se concluye que existen modelos que pueden apoyar el desarrollo de habilidades para los procesos cognitivos referidos, lo que coadyuvaría a un ejercicio profesional reflexivo y autónomo, en lugar de la adhesión a prácticas asistenciales rutinarias. También que las escuelas de Enfermería tienen el compromiso para incorporar en el currículo diversas estrategias deliberadas y progresivas que apoyen el desarrollo de dichas habilidades, así como de generar ambientes de aprendizaje áulicos y clínicos que las promuevan.

Considering the importance of forming reflexive professionals, and also within the frame of a new epistemology of nursing practice, this review explores diverse theoretical sources which represent scientific evidence related to problem-solving and clinical decision-making skills, and also to the characteristics of newly nursing graduates who, during their social service (residency), experience a process of transition facing professional realities which require them to use those skills within complex and uncertain situations. The review included systematic searches in databases such as Medline, CINHAL, Scielo, Lilacs, Cochrane, Cuiden, and Redalyc, and yielded: 3 systematic reviews, 11 studies with quantitative approaches, 11 studies with qualitative ones, 2 with mixed ones, 14 review articles, and 5 books published in the last 15 years. The analyzed publications came from all continents, but there was a higher prevalence of those from America (50%) and Europe (22%). This review suggested that there are models which can support the development of these important skills and thus help consolidate a professional performance which is autonomous-reflexive rather than repetitive. Moreover, the schools of nursing can consider incorporating these models into their curricula and also generate school and clinical environments which further support the development of these skills.

Dada a importância da formação de profissionais reflexivos e no quadro da busca de uma nova epistemologia da prática de enfermagem, este artigo de revisão, analisa diversas fontes teóricas que representam evidencias científicas relativas à resolução de problemas, toma de decisões clínicas e a sua relação com as caraterísticas dos recém-formados da pre-graduação, os quais ao fazer o estágio (residências), vivenciam um processo de transição: deixar de ser estudante, mas ao mesmo tempo confrontar-se a situações de exercício profissional, eles requerem habilidades para resolver problemas e tomar decisões em situações incertas e complexas. A revisão envolveu buscas sistemáticas em bases de dados como Medline, CINAHL, Scielo, Lilacs, Cochrane, Cuiden e Redalyc, que permitiram localizar 3 revisões sistemáticas, 11 estudos com abordagem quantitativa, 11 com abordagem qualitativa e 2 mista, 14 artigos de revisão e 5 livros, publicados nos últimos 15 anos. Ainda que as publicações analisadas procedam de todos os continentes, predominam as da América em um cinquenta por cento, seguidas pelas europeias em vente e dois por cento. Conclui-se que existem modelos que podem apoiar o desenvolvimento de habilidades para os processos cognitivos referidos, o qual contribuiria a um exercício profissional reflexivo e autônomo, em vez da adesão de práticas assistenciais rotineiras. Também que as escolas de Enfermagem têm o compromisso para incorporar no currículo diversas estratégias intencionais e progressivas que apoiem o desenvolvimento de tais habilidades, assim como para gerar ambientes de aprendizagem escolares e clínicos que as promovam.

The association between Polycystic Ovary Syndrome (PCOS) and metabolic syndrome: a statistical modelling approach.

OBJECTIVE: Polycystic ovary syndrome (PCOS) affects 12-21% of women. Women with PCOS exhibit clustering of metabolic features. We applied rigorous statistical methods to further understand the interplay between PCOS and metabolic features including insulin resistance, obesity and androgen status. DESIGN: Retrospective cross-sectional analysis. PATIENTS: Women with PCOS attending reproductive endocrine clinics in South Australia for the treatment of PCOS (n = 172). Women without PCOS (controls) in the same Australian region (n = 335) from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), a national population-based study (age- and BMI-matched within one standard deviation of the PCOS cohort). MEASUREMENTS: The factor structure for metabolic syndrome for women with PCOS and control groups was examined, specifically, the contribution of individual factors to metabolic syndrome and the association of hyperandrogenism with other metabolic factors. RESULTS: Women with PCOS demonstrated clustering of metabolic features that was not observed in the control group. Metabolic syndrome in the PCOS cohort was strongly represented by obesity (standardized factor loading = 0·95, P < 0·001) and insulin resistance factors (loading = 0·92, P < 0·001) and moderately by blood pressure (loading = 0·62, P < 0·001) and lipid factors (loading = 0·67, P = 0·002). On further analysis, the insulin resistance factor strongly correlated with the obesity (r = 0·70, P < 0·001) and lipid factors (r = 0·68, P < 0·001) and moderately with the blood pressure factor (loading = 0·43, P = 0·002). The hyperandrogenism factor was moderately correlated with the insulin resistance factor (r = 0·38, P < 0·003), but did not correlate with any other metabolic factors. CONCLUSIONS: PCOS women are more likely to display metabolic clustering in comparison with age- and BMI-matched control women. Obesity and insulin resistance, but not androgens, are independently and most strongly associated with metabolic syndrome in PCOS.

Vitamin D is independently associated with depression in overweight women with and without PCOS.

BACKGROUND: Depression, anxiety, and inflammation are common in polycystic ovary syndrome (PCOS). Inflammation may adversely impact on mood and vitamin D has been associated with both mood disorders and inflammation in the general population, but these relationships have not been studied in PCOS. The aim of this study was to investigate the association among 25 hydroxy-Vitamin D (25OHVD) status, anxiety, depression, and inflammation in women with and without PCOS. METHODS: Cross-sectional study in overweight or obese premenopausal women with (n = 50) and without (n = 23) PCOS. Primary outcome measures were 25OHVD, mood (Hospital Anxiety and Depression questionnaire), and inflammation (highly sensitive C-reactive protein (hsCRP)). RESULTS: Vitamin D deficiency (25OHVD<50 nmol/L) (46% versus 39%, p = 0.311) and 25OHVD (50.4 ± 22.2 nmol/L versus 51.6 ± 19.0 nmol/L, p = 0.828) were not significantly different in women with and without PCOS. For all women combined, 25OHVD was the only significant independent predictor of depression (ß = -0.063 ± 0.021, p = 0.005) and hsCRP (ß = -0.041 ± 0.015, p = 0.010). CONCLUSIONS: Vitamin D deficiency is common in both women with and without PCOS with no differences between the groups. Vitamin D is independently associated with depression and inflammation in overweight women both with and without PCOS. Further investigation to clarify the interrelationship among vitamin D, inflammation and depression is required to identify optimal prevention and treatment strategies for psychological and metabolic dysfunction in PCOS.

Sleep disturbances in a community-based sample of women with polycystic ovary syndrome.

STUDY QUESTION: Is there an excess of sleep disturbances in women with polycystic ovary syndrome (PCOS) in a community-based sample? STUDY ANSWER: Sleep disturbances are almost twice as common in women with PCOS compared with women of similar age without PCOS, with the association slightly accounted for by body weight and, to a greater extent, by depressive symptoms. WHAT IS KNOWN ALREADY: There is an excess of sleep-disordered breathing in clinical samples of women with PCOS, after accounting for their profile of body weight. Poor sleep patterns increase insulin resistance and thus may exacerbate PCOS symptoms and longer-term risk of metabolic disease. STUDY DESIGN, SIZE, DURATION: A cross-sectional study of 724 women, comprising 74% of a cohort study established retrospectively when women were around age 30 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Comparisons were made between 87 women with PCOS, diagnosed using the Rotterdam criteria, and 637 women without this diagnosis in Adelaide, South Australia. Differences in sleep disturbances, assessed using a modified version of the Jenkins questionnaire, were investigated using ordered logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE: Sleep disturbances were twice as common in women with PCOS compared with those without. Specifically, PCOS was associated with increasing occurrence of difficulty falling asleep (odds ratio (OR) 1.94, 95% confidence interval (CI) 1.28-2.95); this association was attenuated but still statistically significant after accounting for BMI and depressive symptoms. Increasing occurrence of difficulty maintaining sleep (OR 1.92 95% CI 1.12-3.31) was mediated by obesity and depressive symptoms, together. Other factors did not change these findings. LIMITATIONS, REASONS FOR CAUTION: The cross-sectional nature of the study means that the direction of associations between PCOS and sleep disturbances is unclear, although bi-directionality for the mediators is likely based on data in the wider literature. WIDER IMPLICATIONS OF THE FINDINGS: Our results indicate that assessment and management of both sleep and mental health problems in women with PCOS should be undertaken. Longitudinal data would be valuable to see how poor sleep affects longer-term health profiles.

Effect of dietary supplementation with flaxseed oil or vitamin E on sheep experimentally infected with Fasciola hepatica.

The effects of two diets supplemented with flaxseed oil (FO) or vitamin E (VE) were studied in sheep infected with Fasciola hepatica. The control group (CO), not supplemented, had higher weight gain and faecal egg count (P < 0.05) at the end of the study. At necropsy, the number (71.2 ± 26.5) and size of flukes were lower in the FO group (P < 0.01), probably due to the higher levels of white blood cells and lymphocytes (P < 0.01). This group also had higher red blood cell and haematocrit values (P < 0.01). The CO group had more severe hypoproteinaemia and hypoalbuminaemia, due to having the highest fluke burden (123.0 ± 35.2), and also the highest IgG1 titre (P < 0.01). The diet did not affect production or gene expression levels of IFN-γ and IL-4. On the other hand, the supplementation with VE led to a reduction in adult fluke burden (97.7 ± 39.9) and lower lipid oxidation in the liver (P < 0.001).

Effects of linseed and quercetin added to the diet of fattening lambs on the fatty acid profile and lipid antioxidant status of meat samples.

Thirty-two Merino lambs fed barley straw and a concentrate formulated either with palm oil (CTRL group) or with linseed (+LS group), both alone or supplemented with quercetin (+QCT group or +LS+QCT group) were used to assess the effects of these dietary supplements on meat quality attributes. After being slaughtered, the longissimus thoracis muscles were used to study the fatty acid (FA) profile in detail, whilst longissimus lumborum slices were stored under refrigerated conditions to determine the lipid stability. Linseed increased the content of highly unsaturated n-3 long-chain fatty acid (20:5n-3; 22:5n-3; 22:6n-3). Interestingly, a significant increment of rumenic acid content (9c,11t-18:2) was observed when this seed was administered together with dietary quercetin. Moreover, the feeding of quercetin resulted in a reduction in the proportion of saturated FA and a decrease in lipid peroxidation of meat when the lambs were fed linseed. In conclusion, from both a nutritional and a commercial (shelf-life) point of view, it may be useful to include a source of quercetin when lambs are fed linseed diets.

Gestational diabetes and type 2 diabetes in reproductive-aged women with polycystic ovary syndrome.

CONTEXT: Polycystic ovary syndrome (PCOS) affects 6%-21% of women. PCOS has been associated with an increased risk of dysglycemia including gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM). OBJECTIVE: The objective of the study was to assess the prevalence of dysglycemia and the impact of obesity in young reproductive-aged women with and without PCOS in a community-based cohort. DESIGN: This was a cross-sectional analysis of data from a large longitudinal study (the Australian Longitudinal Study on Women's Health). SETTING: The setting for the study was the general community. PARTICIPANTS: Women were randomly selected from the national health insurance database. Standardized data collection occurred at five survey time points (years 1996, 2000, 2003, 2006, and 2009). Data from survey 4 (2006, n = 9145, 62% of original cohort aged 18-23 y) were examined for this study. MAIN OUTCOME MEASURES: Self-reported PCOS, GDM, and T2DM were measured. RESULTS: In women aged 28-33 years, PCOS prevalence was 5.8% [95% confidence interval (CI) 5.3%-6.4%]. The prevalence of GDM (in women reporting prior pregnancy) and T2DM was 11.2% and 5.1% in women with PCOS and 3.8% and 0.3% in women without PCOS, respectively (P for both < .001). PCOS was associated with an increased odds of GDM and T2DM. After adjusting for age, body mass index, hypertension, smoking, and demographic factors, the odds of GDM (odds ratio 2.1, 95% CI 1.1-3.9, P = .02) and T2DM (odds ratio 8.8, 95% CI 3.9-20.1, P < .001) remained increased in women reporting PCOS. CONCLUSIONS: In a large community-based cohort of reproductive-aged women, PCOS was independently associated with a higher risk of GDM and T2DM, independent of body mass index. Aggressive screening, prevention, and management of dysglycemia is clearly warranted in women with PCOS.