Association of early menarche with breast tumor molecular features and recurrence.

BACKGROUND: Early menarche is an established risk factor for breast cancer but its molecular contribution to tumor biology and prognosis remains unclear. METHODS: We profiled transcriptome-wide gene expression in breast tumors (N = 846) and tumor-adjacent normal tissues (N = 666) from women in the Nurses' Health Studies (NHS) to investigate whether early menarche (age < 12) is associated with tumor molecular and prognostic features in women with breast cancer. Multivariable linear regression and pathway analyses using competitive gene set enrichment analysis were conducted in both tumor and adjacent-normal tissue and externally validated in TCGA (N = 116). Subgroup analyses stratified on ER-status based on the tumor were also performed. PAM50 signatures were used for tumor molecular subtyping and to generate proliferation and risk of recurrence scores. We created a gene expression score using LASSO regression to capture early menarche based on 28 genes from FDR-significant pathways in breast tumor tissue in NHS and tested its association with 10-year disease-free survival in both NHS (N = 836) and METABRIC (N = 952). RESULTS: Early menarche was significantly associated with 369 individual genes in adjacent-normal tissues implicated in extracellular matrix, cell adhesion, and invasion (FDR ≤ 0.1). Early menarche was associated with upregulation of cancer hallmark pathways (18 significant pathways in tumor, 23 in tumor-adjacent normal, FDR ≤ 0.1) related to proliferation (e.g. Myc, PI3K/AKT/mTOR, cell cycle), oxidative stress (e.g. oxidative phosphorylation, unfolded protein response), and inflammation (e.g. pro-inflammatory cytokines IFN α and IFN γ ). Replication in TCGA confirmed these trends. Early menarche was associated with significantly higher PAM50 proliferation scores (ß = 0.082 [0.02-0.14]), odds of aggressive molecular tumor subtypes (basal-like, OR = 1.84 [1.18-2.85] and HER2-enriched, OR = 2.32 [1.46-3.69]), and PAM50 risk of recurrence score (ß = 4.81 [1.71-7.92]). Our NHS-derived early menarche gene expression signature was significantly associated with worse 10-year disease-free survival in METABRIC (N = 952, HR = 1.58 [1.10-2.25]). CONCLUSIONS: Early menarche is associated with more aggressive molecular tumor characteristics and its gene expression signature within tumors is associated with worse 10-year disease-free survival among women with breast cancer. As the age of onset of menarche continues to decline, understanding its relationship to breast tumor characteristics and prognosis may lead to novel secondary prevention strategies.

Women's reproductive risk and genetic predisposition in type 2 diabetes: A prospective cohort study.

OBJECTIVE: To assess synergistic effects of reproductive factors and gene-reproductive interaction on type 2 diabetes (T2D) risk, also the extent to which the genetic risk of T2D can be affected by reproductive risk. METHODS: 84,254 women with genetic data and reproductive factors were enrolled between 2006 and 2010 in the UK Biobank. The reproductive risk score (RRS) was conducted based on 17 reproductive items, and genetic risk score (GRS) was based on 149 genetic variants. RESULTS: There were 2300 (2.8 %) T2D cases during an average follow-up of 4.49 years. We found a significant increase in T2D risk across RRS categories (Ptrend < 0.001). Compared with low reproductive risk, high-mediate (adjusted hazard ratio [aHR] 1.38, 95 % CI 1.20-1.58) and high (aHR 1.84, 95 % CI 1.54-2.19) reproductive risk could increase the risk of T2D. We further observed a significant additive interaction between reproductive risk and genetic predisposition. In the situation of high genetic predisposition, women with low reproductive risk had lower risk of T2D than those with high reproductive risk (aHR 0.47, 95 % CI 0.30-0.76), with an absolute risk reduction of 2.98 %. CONCLUSIONS: Our novo developed RRS identified high reproductive risk is associated with elevated risk of women's T2D, which can be magnified by gene-reproductive interaction.

Associations of reproductive risk score and joint exposure to ambient air pollutants with chronic obstructive pulmonary disease: a cohort study in UK Biobank.

BACKGROUND: Reproductive risk factors and air pollution for developing chronic obstructive pulmonary disease (COPD) have been documented separately. However, the combined effects of overall reproductive risk status on COPD and the extent to which this can be impacted by air pollution are unknown. The aim of this study was to construct a reproductive risk score (RRS) and an air pollution score (APS) and assess independent and joint associations between the two with incident COPD risk. METHODS: 78,027 female participants aged 40-69 years without baseline COPD from UK Biobank recruited between 2006 to 2010 were included in this study. RRS was constructed by 17 women's reproductive health-related items, and APS incorporating PM2.5, PM2.5-10, PM10, NO2, and NOx was calculated to assess the joint exposure level. The outcome of the incident COPD was identified through the in-patient hospital register. The associations of RRS and APS with COPD were examined by Cox proportional hazards regression. RESULTS: The risk of COPD reached its highest in the fourth quartile of the RRS (adjusted HR: 2.23, 95% CI: 1.76-2.82, P for trend < 0.001). A dose-response manner can also be observed between higher tertile APS with increased COPD risk and the highest risk was found in the third tertile of the APS (adjusted HR: 1.37, 95% CI: 1.19-1.58, P for trend < 0.001). The relative excess risk due to interaction (RERI) of 0.030 (95% CI: 0.012-0.048) showed additive interaction between RRS and APS on COPD was significant. In the joint analysis, the combinations of both higher RRS and APS signified higher incident COPD risk. CONCLUSION: High RRS and high APS were jointly associated with increased COPD risks in a dose-response pattern. Using comprehensive indicators to identify women's reproductive risk factors, together with the control of air pollution, is effective for COPD prevention.

Monitoring of polycyclic aromatic hydrocarbons emitted from kerosene fuel burning and assessment of health risks among women in selected rural and urban households of South India.

Polycyclic aromatic hydrocarbons (PAHs) are well-known hazardous substances; nevertheless, research on their exposure and health concerns associated with kerosene fuel emissions is limited. In this study, PAH (combined gaseous and particle phase) monitoring was carried out in the kitchen and living room in selected households. Personal exposure and cooking time monitoring were also carried out, simultaneously. The study's findings revealed that BaP, BA, BbF, and Nap were the most prevalent PAHs in both the summer and winter seasons, regardless of urban or rural households. The estimated values of average incremental lifetime cancer risks were found to be greater than the USEPA level, i.e., 1 × 10-6, in both urban and rural households, regardless of seasonal fluctuation. In both seasons, the non-carcinogenic risk for developmental and reproductive effects was higher in rural women than in urban women, and in case of developmental risk it showed greater than unity (rural: 1.11 and urban 1.03) in the winter season. On the other hand, Monte Carlo simulation model revealed that concentrations of PAHs (97.1% and 97.5%) and exposure duration (51.7% and 56.7%) were the most sensitive factors contributed for health risk estimations for urban and rural area in both seasons, respectively. Furthermore, the results clearly showed that women who were using kerosene for cooking were at a greater risk of acquiring both carcinogenic and non-carcinogenic health consequences from PAH exposure from kerosene cookstoves. It was recommended that they should utilize clean fuel, either by using LPG under the PMUY scheme or by using electricity/solar power to reduce health risks for better health.

Genotoxicity and Reproductive Risk in Workers Exposed to Pesticides in Rural Areas of Curicó, Chile: A Pilot Study.

Significant risks to human health have been associated with chronic exposure to low doses of pesticides, a situation which may be frequent among agricultural workers. In this context, and regarding the agricultural-based economy of central Chile, we aimed to explore the genotoxic damage in agricultural workers and reproductive risk among women in rural and urban areas of Curicó, a traditional agricultural district in Chile. Hence, we sampled a group of rural agricultural workers associated with pesticide management (n = 30) and an urban unexposed group (n = 30). Our results showed that the agricultural workers had higher micronuclei frequencies (MN: ß = 13.27; 95% CI low = 11.08, CI high = 15.47) and women had a 40-fold higher risk of reproductive problems (OR = 40.32; 95% CI low = 2.60, CI high = 624.31) than the unexposed group. The factor analysis of mixed data (FAMD) showed that neither the sex nor smoking habits appear to define the ordination of the data. Nevertheless, the exposure level did segregate them in the multidimensional space (explained variance: 35.38% dim-1; 18.63% dim-2). This pilot study highlights the higher risks of biological conditions negatively associated with the health of agricultural workers.

Percepciones sobre maternidad, riesgo obstétrico y planificación familiar en mujeres con enfermedad crónica que fueron madres / Percepções da maternidade, risco obstétrico e planejamento familiar em mulheres com doenças crônicas que eram mães / Perceptions of motherhood, obstetric risk and family planning in women with chronic illness who were mothers

Objective: To analyze the perceptions that a group of women have about maternity, obstetric risk and family planning who, knowing that they were diagnosed with chronic diseases, assumed the experience of pregnancy and childbirth. Methodology: Qualitative study. The informants were summoned through convenience sampling and “snowballing”. Individual semi-structured interviews were applied to nine women who recognized themselves as having a chronic noncommunicable disease. The data analysis was carried out with the Grounded Theory proposal withemergent design. Results: Motherhood is considered an unavoidable event in the life project ofwomen, even those who have been informed of the risk. There is little awareness of the impact thedisease can have on your reproductive life. Family planning is seen as a strategy for procreation,classifying it as a general option for all people, without being able to elucidate its relevance for theirindividual situation. There is also a late identification of risk pregnancies and a delayed prenatalcontrol. Conclusions: The communication of reproductive risk is ineffective because it is constructedoutside the social imaginary of women, family planning is seen as an imposition and not as a human right of women. (AU)

Objetivo: Analizar las percepciones que sobre maternidad, riesgo obstétrico y planificación familiar tiene un grupo de mujeres que sabiéndose diagnosticadas con enfermedades crónicas,asumieron la experiencia del embarazo y parto. Metodología: Estudio cualitativo. Se convocó a lasinformantes mediante muestreo por conveniencia y “bola de nieve”. Se aplicaron entrevistas semiestructuradas individuales a nueve mujeres que se reconocían diagnosticadas con una enfermedadcrónica no transmisible. El análisis de datos se realizó con la propuesta de Teoría Fundamentadacon diseño emergente. Resultados: La maternidad es considerada como un evento ineludible en elproyecto de vida de las mujeres, aun de aquellas que han sido informadas del riesgo. Existe pocaconsciencia del impacto que la enfermedad puede tener sobre su vida reproductiva. La planificaciónfamiliar es vista como una estrategia para la procreación, catalogándola como una opción generalpara todas las personas, sin alcanzar a dilucidar la relevancia que tiene para su situación individual.Existe además una identificación tardía de embarazos de riesgo y un control prenatal retrasado.Conclusiones: La comunicación del riesgo reproductivo es inefectiva porque se construye ajena alos imaginarios sociales de las mujeres, la planificación familiar es vista como una imposición y nocomo un derecho humano de las mujeres. (AU)

Objetivo: Analisar as percepções que um grupo de mulheres tem sobre a maternidade, orisco obstétrico e o planejamento familiar que, sabendo ser diagnosticadas com doenças crônicas,assumiram a experiência da gravidez e do parto. Metodologia: Estudo qualitativo. Os informantesforam convocados por amostragem de conveniência e “bola de neve”. Entrevistas individuaissemiestruturadas foram aplicadas a nove mulheres que se reconheciam portadoras de doençacrônica não transmissível. A análise dos dados foi realizada com a proposta da Teoria Fundamentadanos Dados com desenho emergente. Resultados: a maternidade é considerada um evento inevitávelno projeto de vida das mulheres, mesmo aquelas que foram informadas do risco. Há poucaconsciência do impacto que a doença pode ter em sua vida reprodutiva. O planejamento familiar évisto como uma estratégia de procriação, classificando-o como uma opção geral para todas aspessoas, sem poder elucidar sua relevância para sua situação individual. Há também identificaçãotardia de gestações de risco e controle pré-natal tardio. Conclusões: A comunicação do riscoreprodutivo é ineficaz porque é construída fora do imaginário social da mulher, o planejamentofamiliar é visto como uma imposição e não como um direito humano das mulheres. (AU)

Considerations on the use of carrier screening testing in human reproduction: comparison between recommendations from the Italian Society of Human Genetics and other international societies.

PURPOSE: Carrier screening (CS) is a term used to describe a genetic test performed on individuals without family history of genetic disorders, to investigate the carrier status for pathogenic variants associated with multiple recessive conditions. The advent of next-generation sequencing enabled simultaneous CS for an increasing number of conditions; however, a consensus on which diseases to include in gene panels and how to best develop the provision of CS is far to be reached. Therefore, the provision of CS is jeopardized and inconsistent and requires solving several important issues. METHODS: In 2020, the Italian Society of Human Genetics (SIGU) established a working group composed of clinical and laboratory geneticists from public and private fields to elaborate a document to define indications and best practice of CS provision for couples planning a pregnancy. RESULTS: Hereby, we present the outcome of the Italian working group's activity and compare it with previously published international recommendations (American College of Medical Genetics and Genomics (ACMG), American College of Obstetricians and Gynecologists (ACOG), and Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG)). We determine a core message on genetic counseling and nine main subject categories to explore, spanning from goals and execution to technical scientific, ethical, and socio-economic topics. Moreover, a level of agreement on the most critical points is discussed using a 5-point agreement scale, demonstrating a high level of consensus among the four societies. CONCLUSIONS: This document is intended to provide genetic and healthcare professionals involved in human reproduction with guidance regarding the clinical implementation of CS.

Mitos y realidades sobre la obesidad en el síndrome de ovario poliquístico / Myths and realities about obesity in polycystic ovary syndrome

Introducción: La asociación entre la obesidad y el síndrome de ovario poliquístico es importante porque amplifica los trastornos metabólicos, reproductivos, psicológicos o de la calidad de vida. Sin embargo, es común que se sobrevalore o se emplee como criterio diagnóstico, lo que denota una definición no clara de esta relación. Objetivo: Analizar lo que, en opinión de los autores, pudieran ser "mitos" sobre la obesidad en el síndrome de ovario poliquístico y su coherencia con la evidencia disponible. Métodos: Se realizó una revisión del estado del arte en este tema. Se localizaron 230 artículos en las bases PubMed, Medline, Scielo y Google Académico, y se contrastó con los criterios propios. Conclusiones: Algunas creencias generalizadas sobre la obesidad en el síndrome de ovario poliquístico, aunque tienen cierto grado de certidumbre, se malinterpretan o magnifican, por lo que pueden considerarse "mitos". Entender que las mujeres con síndrome de ovario poliquístico pueden no tener obesidad y, aún así, tener adiposidad abdominal y los efectos que de ella derivan, no niega la evidencia indiscutible de que la obesidad, si está presente, agrava el síndrome. Polemizar sobre el tema pretende contribuir a que se diagnostique el síndrome no solo en mujeres con obesidad y que se considere factor de riesgo para la obesidad. Debe entenderse que la obesidad asociada al síndrome puede revertirse y que se pueden incorporar estilos de vida saludable y un control del peso corporal como pilares del tratamiento en todas las mujeres que padezcan este(AU)

Introduction: The association between obesity and polycystic ovary syndrome is important because it amplifies metabolic, reproductive, psychological, or quality of life disorders. However, it is commonly overestimated or used as a diagnostic criterion, which denotes an unclear definition of this relationship. Objective: To analyze what, in the authors' opinion, could be "myths" about obesity in polycystic ovary syndrome and their consistency with the available evidence. Methods: A state-of-the-art review on this subject was performed and contrasted with own criteria. Conclusions: Some widespread beliefs about obesity in polycystic ovary syndrome, although they have some degree of certainty, are misinterpreted or magnified, so they can be considered "myths". Understanding that the patients may not suffer from obesity and still have abdominal adiposity and the effects that derive from it, does not deny the indisputable evidence that, if present, it aggravates the syndrome. Discussing the subject intends to contribute to diagnose the syndrome not only in women with obesity. The aim is to consider it as a risk factor for obesity and to prevent it, to understand that obesity can be reversed, and to incorporate counseling on healthy lifestyles and body weight control as pillars of treatment in all women with the syndrome, with or without obesity(AU)

Remdesivir impairs mouse preimplantation embryo development at therapeutic concentrations.

Remdesivir (RDV) is the first antiviral drug to be approved by the US Food and Drug Administration for the treatment of COVID-19. While the general safety of RDV has been studied, its reproductive risk, including embryotoxicity, is largely unknown. Here, to gain insights into its embryotoxic potential, we investigated the effects of RDV on mouse preimplantation embryos cultured in vitro at the concentrations comparable to the therapeutic plasma levels. Exposure to RDV (2-8 µM) did not affect the initiation of blastocyst formation, although the maintenance of the cavity failed at 8 µM due to increased cell death. While exposure to 2-4 µM permitted the cavity maintenance, expressions of developmental regulator genes associated with the inner cell mass (ICM) lineage were significantly diminished. Adverse effects of RDV depended on the duration and timing of exposure, as treatment between the 8-cell to early blastocyst stage most sensitively affected cavity expansion, gene expressions, and cell proliferation, particularly of the ICM than the trophectoderm lineage. GS-441524, a major metabolite of RDV, did not impair blastocyst formation or cavity expansion, although it altered gene expressions in a manner differently from RDV. Additionally, RDV reduced the viability of human embryonic stem cells, which were used as a model for the human ICM lineage, more potently than GS-441524. These findings suggest that RDV is potentially embryotoxic to impair the pluripotent lineage, and will be useful for designing and interpreting further in vitro and in vivo studies on the reproductive toxicity of RDV.

Risk factors for breast cancer and their association with molecular subtypes in a population of Northeast Brazil.

BACKGROUND: The risk factors for breast cancer (BC) among women in Brazilian populations are poorly understood. To date, few Brazilian studies have addressed the potential association between risk factors and molecular BC subtypes. This case-control study aimed to identify risk factors for BC in a population of Northeast Brazil. METHODS: Data from 313 patients with invasive BC and 321 healthy controls were obtained from medical records from two cancer treatment centres and personal interviews. Of the 313 BC patients, 224 (71.6%) had reached menopause. The following distribution of subtypes was found among 301 patients: (1) Luminal A: 54 (17.9%); (2) Luminal B: 175 (58.1%); (3) HER2/neu: 29 (9.7%); and (4) triple-negative breast cancer (TNBC): 43 (14.3%). Odds ratios (ORs) and confidence intervals (CIs) were determined using regression analysis. RESULTS: Regression modelling indicated that family history, obesity (≥ 30.0 kg/m2), alcohol consumption and contraceptive use increased the overall risk of BC 1.78 (95% CI: 1.22-2.59), 1.69 (95% CI: 1.08-2.63), 2.21 (95% CI: 1.44-3.39) and 2.99 (95% CI: 2.09-4.28) times, respectively. After stratification for menopausal status, alcohol consumption increased the risk of BC 4.15 (95% CI: 2.13-8.11) times, and obesity, as a single variable, increased the risk of BC 2.02 (95% CI: 1.22-3.37) times, only among postmenopausal women. In a case-control analysis, the risk of TNBC and Luminal B breast cancer were 4.06 (95% CI: 1.58-10.42) and 1.87 times (95% CI: 1.13-3.11) higher, respectively, in obese women than in non-obese women. Furthermore, alcohol consumption increased the risk of Luminal A and B subtypes 7.08 (3.40-14.73) and 1.77 (1.07-2.92) times, respectively. CONCLUSION: Family history, contraceptive use, obesity and alcohol consumption increased the risk of BC. Obesity and alcohol consumption differentially increased risk of TNBC and Luminal molecular subtypes.

Refining reproductive risk for FMR1 premutation carriers in the general obstetric population.

Female FMR1 premutation (FMR1 PM) carriers for fragile X syndrome (FXS) are at risk to have a child with FXS based on their CGG repeat size and AGG interruption number. Studies examining this risk in unselected populations of female PM carriers are lacking. This retrospective cohort study analyzed carrier status, CGG repeat length, AGG interruption result, and reproductive risk refinement in a population of female patients who underwent routine carrier screening for FXS. A total of 1536 PM carriers (0.43%) were identified, 95% of whom had between 55 and 90 CGG repeats. A number of 1334 carriers underwent AGG interruption testing. The majority had at least one AGG interruption and received a lower reproductive risk for FXS following AGG interruption testing (89% and 85%, respectively) as compared to their risk calculated based on CGG repeat size alone. The average change in risk across the population following AGG interruption testing was -3.4%, with a range from -50.8% to 48.9%. This article describes the range of CGG repeats and AGG interruptions in an unselected population of female PM carriers and suggests that most carriers would benefit from AGG interruption testing to refine their reproductive risk of having a child with FXS.

Patient with Mosaic Turner Syndrome and a Derivative X Chromosome with a Variant Triple X Diagnosis in Fetus: A Case Report.

Although Turner syndrome is most often sporadic, multigenerational recurrence has been reported more often in the offspring of women with mosaic or variant forms of Turner syndrome. We present a case in which natural conception in a woman with identified 45,X/46,XX mosaicism resulted in a fetus with a gain of a derivative X chromosome. The unexpected fetal finding prompted further cytogenetic evaluation of the patient and subsequent identification of an additional cell line with the same derivative X chromosome, not observed in the initial study. To our knowledge, this is the first case in which further investigation of an abnormal noninvasive prenatal screen resulted in the identification of both maternal and fetal sex chromosome abnormality. We discuss the discordant finding, similar cases, and potential phenotype with respect to skewed X inactivation. We also highlight the use of multiple testing methodologies to characterize the serendipitous identification of a derivative X chromosome.

Estimated lifetime risk of venous thromboembolism in men and women in a Danish nationwide cohort: impact of competing risk of death.

Incidence of venous thromboembolism (VTE) risk varies by age and sex. Some studies have reported overall higher risk in men, especially when VTEs triggered by female reproductive factors are excluded. However, higher mortality rates in men may have led to overestimation of lifetime VTE risk in men compared with women. Therefore, we estimated the lifetime risk of VTE in men and women in a Danish, nationwide cohort, taking into account the competing risk of death. Within the population of Denmark (> 5 million persons), all first-time VTEs occurring in 1995-2016 were identified from the Danish National Patient Registry covering all Danish hospitals. The cumulative incidences of VTE were estimated in men and women with age as timescale, taking into account the competing risk of death. Estimated lifetime risk was defined as cumulative incidence at age 100. In a simulation study, we excluded the proportion of female cases that could be attributed to reproductive risk factors and re-estimated the cumulative incidence. We identified 123,543 incident VTEs. The cumulative incidence of VTE was 1.9% in women and 1.3% in men at age 50, 4.3% in women and 4.4% in men at age 70, and 9.3% in women and 8.1% in men at age 100. After accounting for VTEs attributed to reproductive factors, the corresponding incidences in women were 1.2% at age 50, 3.2% at age 70, and 8.2% at age 100. In conclusion, the estimated lifetime risk of VTE was slightly higher in women than in men when accounting for competing risk of death. Our simulation study suggested that reproductive risk factors contribute modestly to the estimated lifetime VTE risk in women.

Every mother and every fetus matters: A positive pregnancy test = multiple offerings of reproductive risk screening for personal, family, and specific obstetrical-fetal conditions.

OBJECTIVE: To focus on the evidence-based screening test options and timing as part of the overall "pregnant-woman-centered" preconception and prenatal care journey. The requirement and need for a focused "pregnant-woman-centered" prenatal care process with time for informed consent and shared decision making are important for optimal prenatal care. METHODS: A structured quality improvement (QI) review (Squire 2.0) was undertaken to examine the appropriate reproductive screening process in the periods of preconception and during pregnancy. RESULTS: First, the broader prenatal care structure was evaluated which, second, enabled the directed reproductive risk screening processes to be offered within an informed consent process. Four international preconception and prenatal evidence-based guidance consensus would routinely offer specific gestational age reproductive risk screening elements: totaling 21 screening elements (three preconception; nine first trimester; three second trimester; four third trimester; one intrapartum; and one postpartum). CONCLUSION: The best evidence-based opportunity for comprehensive and collaborative prenatal care with appropriate screening elements requires: a single national access healthcare system; expert evidence-based guideline creation; collaborative maternity care providers based for risk assessment, triage, and management; a pregnant-woman-centered care model of maternity care; clearly identified evidence-based gestational age directed screening elements; international preconception and prenatal guideline consensus.

Association of reproductive risk factors and comorbidities among molecular subtypes of Breast cancer in a Tertiary care Hospital

The reasons for the recently observed increase in the incidence of breast cancer in the Indian population are not clearly understood, but thought to be largely explained by westernization of lifestyles and changes in reproductive behavior, which characterize exposure to hormones. Our aim is to review the reproductive risk factors and comorbidities and evaluate the association between molecular subtypes of breast cancer. A hospital-based analytical case-control study was conducted among the breast cancer cases with controls in a multispecialty teaching hospital for a period of one year. Totally, 130 subjects were recruited and an interview was conducted using a structured questionnaire to obtain demographic and risk factor data, including tissue marker status (ER, PR and HER-2) obtained from case files. Data were analyzed with SPSS-20 version. Results: The highest age group reported in this study was 51- 60 years which has a 3.8 times increased risk compared to other age and the age group of 31- 40 have a decrease risk of 0.33. In this study, the percentage of post menopause (68%) and mothers not breastfeeding (10%) was higher in cases compared to controls and a noted increase in the risk of breast cancer with odds ratio (OR) of 2.745 (p= <0.0001) and 9.08 (p=0.01) respectively. Duration of breastfeeding showed significantly (p=<0.0001)) moderate positive correlation (r=0.549, 0.457, 0.418 and 0.636) for luminal A, luminal B, HER+, and triple negative respectively. This study found that all the reproductive risk factors do not have correlation with a molecular subtype of breast cancer except breastfeeding. Post menopause and breastfeeding were common factors associated with all people and could be modifiable to prevent the occurrence of breast cancer through lifestyle change

The distribution of reproductive risk factors disclosed the heterogeneity of receptor-defined breast cancer subtypes among Tanzanian women.

BACKGROUND: Recent epidemiological studies suggest that reproductive factors are associated with breast cancer (BC) molecular subtypes. However, these associations have not been thoroughly studied in the African populations. The present study aimed to investigate the prevalence of BC molecular subtypes and assess their association with reproductive factors in Tanzanian BC patients. METHODS: This hospital-based case-only cross-sectional study consisted of 263 histologically confirmed BC patients in Tanzania. Clinico-pathological data, socio-demographic characteristics, anthropometric measurements, and reproductive risk factors were examined using the Chi-square test and one-way ANOVA. The association among reproductive factors and BC molecular subtypes was analyzed using multinomial logistic regression. The heterogeneity of the associations was assessed using the Wald test. RESULTS: We found evident subtype heterogeneity for reproductive factors. We observed that post-menopausal status was more prevalent in luminal-A subtype, while compared to luminal-A subtype, luminal-B and HER-2 enriched subtypes were less likely to be found in post-menopausal women (OR: 0.21, 95%CI 0.10-0.41, p = 0.001; OR: 0.39, 95%CI 0.17-0.89, p = 0.026, respectively). Also, the luminal-B subtype was more likely to be diagnosed in patients aged ≤ 40 years than the luminal-A subtype (OR: 2.80, 95%CI 1.46-5.32, p = 0.002). Women who had their first full-term pregnancy at < 30 years were more likely to be of luminal-B (OR: 2.71, 95%CI 1.18-4.17, p = 0.018), and triple-negative (OR: 2.28, 95%CI 1.02-4.07, p = 0.044) subtypes relative to luminal-A subtype. Furthermore, we observed that breastfeeding might have reduced odds of developing luminal-A, luminal-B and triple-negative subtypes. Women who never breastfed were more likely to be diagnosed with luminal-B and triple-negative subtypes when compared to luminal-A subtype (OR: 0.46, 95%CI 0.22-0.95, p = 0.035; OR: 0.41, 95%CI 0.20-0.85, p = 0.017, respectively). . CONCLUSION: Our results are the first data reporting reproductive factors heterogeneity among BC molecular subtypes in Tanzania. Our findings suggest that breast-feeding may reduce the likelihood of developing luminal-A, luminal-B, and triple-negative subtypes. Meanwhile, the first full-term pregnancy after 30 years of age could increase the chance of developing luminal-A subtype, a highly prevalent subtype in Tanzania. More interventions to promote modifiable risk factors across multiple levels may most successfully reduce BC incidence in Africa.

Intervención neuropsicológica para la modificación de la conducta de riesgo sexual y de la función reproductiva en adolescentes / Neuropsychological intervention for the modification of sexual risk behavior and reproductive function in adolescents / Intervenção neuropsicológica para a modificação do comportamento sexual de risco e função reprodutiva em adolescentes

RESUMEN Se realizóuna revisión sobre el objeto de estudio: los métodos de modificación de la conducta de riesgo sexual y de la función reproductiva en adolescentes. A juzgar por la cantidad de publicaciones en este campo, se podría afirmar engañosamente que este tópico ha sido exhaustivamente estudiado, sin embargo, sólo hay limitada información sobre las intervenciones neuropsicológicas, por lo que los investigadores se propusieron diseñar y validar un modelo de intervención neuropsicológica para la modificación de la conducta de riesgo sexual y de la función reproductiva en adolescentes. Para ello se modeló una intervención original mediante el condicionamiento operante, que se someterá a evaluación de expertos, y luego se validará experimentalmente en el policlínico No 3 de Manzanillo, en el período comprendido desde enero del 2021 hasta enero del 2023. El universo estará formado por adolescentes entre las edades de 15 a 17años con conducta de riesgo sexual y de la función reproductiva, las unidades muestrales se seleccionarán por el método aleatorio simple. La prueba estadística a usar será el Cross over y la prueba de los signos para probar los cambios en variables relevantes de la conducta antes y después de intervenir. El método de análisis histórico lógico permitió identificar un problema científico trascendente: Existen insuficiencias en los métodos para la modificación de la conducta de riesgo sexual y la función reproductiva en adolescentes. Se expone el modelo de intervención neuropsicológica y la metodología integral de validación.

ABSTRACT A review was carried out on the object of study: The methods of modifying sexual risk behavior and reproductive function in adolescents. Judging from the number of publications in this field, it could be misleadingly stated that this topic has been extensively studied, however, there is only limited information on neuropsychological interventions. Therefore, the researchers set out to design and validate a neuropsychological intervention model for modifying sexual risk behavior and reproductive function in adolescents. For this, an original intervention was modeled through operant conditioning, which will be subject to expert evaluation, and then will be experimentally validated at the Manzanillo polyclinic No. 3, in the period from January 2021 to January 2023. The universe will be made up of adolescents between the ages of 15 to 17 years with sexual risk behavior and reproductive function, the sample units will be selected by the simple random method. The statistical test to be used will be the Cross over and the test of the signs to test the changes in relevant variables of the behavior before and after the intervention. The logical historical analysis method allowed the identification of a transcendent scientific problem: There are shortcomings in the methods for modifying sexual risk behavior and reproductive function in adolescents. The neuropsychological intervention model and the comprehensive validation methodology are exposed.

RESUMO Foi realizada uma revisão sobre o objeto de estudo: Os métodos de modificação do comportamento sexual de risco e da função reprodutiva em adolescentes. A julgar pelo número de publicações neste campo, pode ser erroneamente declarado que este tópico foi extensivamente estudado, no entanto, há apenas informações limitadas sobre intervenções neuropsicológicas. Portanto, os pesquisadores se propuseram a projetar e validar um modelo de intervenção neuropsicológica para modificar o comportamento sexual de risco e a função reprodutiva em adolescentes. Para isso, foi modelada uma intervenção original por meio de condicionamento operante, que será submetida à avaliação de especialistas, e a seguir será validada experimentalmente na policlínica de Manzanillo nº 3, no período de janeiro de 2021 a janeiro de 2023. O universo será formado por adolescentes de 15 a 17 anos com comportamento sexual de risco e função reprodutiva, as unidades amostrais serão selecionadas pelo método aleatório simples. O teste estatístico a ser utilizado será o Cross over e o teste dos sinais para testar as alterações nas variáveis ​​relevantes do comportamento antes e depois da intervenção. O método lógico de análise histórica permitiu a identificação de um problema científico transcendente: Existem lacunas nos métodos para modificar o comportamento sexual de risco e a função reprodutiva em adolescentes. O modelo de intervenção neuropsicológica e a metodologia de validação abrangente são expostos.

Genetic Counseling and NGS Screening for Recessive LGMD2A Families.

: Genetic counseling applied to limb-girdle muscular dystrophies (LGMDs) can be very challenging due to their clinical and genetic heterogeneity and the availability of different molecular assays. Genetic counseling should therefore be addressed to select the most suitable approach to increase the diagnostic rate and provide an accurate estimation of recurrence risk. This is particularly true for families with a positive history for recessive LGMD, in which the presence of a known pathogenetic mutation segregating within the family may not be enough to exclude the risk of having affected children without exploring the genetic background of phenotypically unaffected partners. In this work, we presented a family with a positive history for LGMD2A (OMIM #253600, also known as calpainopathy) characterized by compound heterozygosity for two CAPN3 mutations. The genetic specialist suggested the segregation analysis of both mutations within the family as a first-level analysis. Sequentially, next-generation sequencing (NGS) analysis was performed in the partners of healthy carriers to provide an accurate recurrence/reproductive risk estimation considering the genetic background of the couple. Finally, this work highlighted the importance of providing a genetic counseling/testing service even in unaffected individuals with a carrier partner. This approach can support genetic counselors in estimating the reproductive/recurrence risk and eventually, suggesting prenatal testing, early diagnosis or other medical surveillance strategies.

Whole-genome mate-pair sequencing of apparently balanced chromosome rearrangements reveals complex structural variations: two case studies.

BACKGROUND: Apparently balanced chromosome rearrangements (ABCRs) in non-affected individuals are well-known to possess high reproductive risks such as infertility, abnormal offspring, and pregnancy loss. However, caution should be exercised in genetic counseling and reproductive intervention because cryptic unbalanced defects and genome structural variations beyond the resolution of routine cytogenetics may not be detected. CASE PRESENTATION: Here, we studied two familial cases of ABCRs were recruited in this study. In family 1, the couple suffered two abortions pregnancies and underwent labor induction. Single nucleotide polymorphism (SNP) array analysis of the aborted sample from the second pregnancy revealed a 10.8 Mb heterozygous deletion at 10q26.13q26.3 and a 5.5 Mb duplication at 19q13.41-q13.43. The non-affected father was identified as a carrier of three-way complex chromosomal rearrangement [t (6;10;19)(p22;q26;q13)] by karyotyping. Whole-genome mate-pair sequencing revealed a cryptic breakpoint on the derivative chromosome 19 (der19), indicating that the karyotype was a more complex structural rearrangement comprising four breakpoints. Three genes, FAM24B, CACNG8, and KIAA0556, were disrupted without causing any abnormal phenotype in the carrier. In family 2, the couple suffered from a spontaneous miscarriage. This family had an affected child with multiple congenital deformities and an unbalanced karyotype, 46,XY,der (11) t (6;11)(q13;p11.2). The female partner was identified as a balanced translocation carrier with the karyotype 46,XX,t (6;11)(q13;p11.2) dn. Further SNP array and fluorescent in situ hybridization (FISH) indicated a cryptic insertion between chromosome 6 and chromosome 11. Finally, whole-genome mate-pair sequencing revealed an extremely complex genomic structural variation, including a cryptic deletion and 12 breakpoints on chromosome 11, and 1 breakpoint on chromosome 6 . CONCLUSIONS: Our study investigated two rare cases of ABCRs and demonstrated the efficacy of whole-genome mate-pair sequencing in analyzing the genome complex structural variation. In case of ABCRs detected by conventional cytogenetic techniques, whole genome sequencing (WGS) based approaches should be considered for accurate diagnosis, effective genetic counseling, and correct reproductive intervention to avoid recurrence risks.

Reproductive factors and risk of breast cancer by tumor subtypes among Ghanaian women: A population-based case-control study.

Higher proportions of early-onset and estrogen receptor (ER) negative cancers are observed in women of African ancestry than in women of European ancestry. Differences in risk factor distributions and associations by age at diagnosis and ER status may explain this disparity. We analyzed data from 1,126 cases (aged 18-74 years) with invasive breast cancer and 2,106 controls recruited from a population-based case-control study in Ghana. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for menstrual and reproductive factors using polytomous logistic regression models adjusted for potential confounders. Among controls, medians for age at menarche, parity, age at first birth, and breastfeeding/pregnancy were 15 years, 4 births, 20 years and 18 months, respectively. For women ≥50 years, parity and extended breastfeeding were associated with decreased risks: >5 births vs. nulliparous, OR 0.40 (95% CI 0.20-0.83) and 0.71 (95% CI 0.51-0.98) for ≥19 vs. <13 breastfeeding months/pregnancy, which did not differ by ER. In contrast, for earlier onset cases (<50 years) parity was associated with increased risk for ER-negative tumors (p-heterogeneity by ER = 0.02), which was offset by extended breastfeeding. Similar associations were observed by intrinsic-like subtypes. Less consistent relationships were observed with ages at menarche and first birth. Reproductive risk factor distributions are different from European populations but exhibited etiologic heterogeneity by age at diagnosis and ER status similar to other populations. Differences in reproductive patterns and subtype heterogeneity are consistent with racial disparities in subtype distributions.