Predictors of Anti-Müllerian hormone, a biomarker of ovarian reserve: A systematic review of the literature

Purpose: Anti-Müllerian hormone (AMH) is a novel biomarker of ovarian reserve, or the size of the ovarian follicle pool. Follicle stimulating hormone (FSH) and inhibin B have been the gold standard measures of ovarian reserve. However, changes in FSH and inhibin B levels are not detectable in serum until there is a significant reduction in the follicle pool (Steiner, 2013), making timely detection and intervention challenging. Several studies have explored the influence of both reproductive and lifestyle determinants on AMH concentrations (Dolleman et al., 2013; Freeman et al., 2007; La Marca et al., 2010; La Marca, Stabile, Artenisio, & Volpe, 2006; Malhotra, Bahadur, Singh, Kalaivani, & Mittal, 2013; Nelson, Stewart, Fleming, & Freeman, 2010; Steiner, Stanczyk, Patel, & Edelman, 2010; Tsepelidis et al., 2007). A systematic review of factors associated with AMH levels has not been conducted. A high level summary of the evidence is needed to evaluate the usefulness of AMH as a biomarker of ovarian reserve. Ovarian reserve is established during fetal life. At birth, the number of primordial follicles is estimated at 1 million. This number decreases steadily during a female s lifespan and is reduced to approximately 300,000-500,000 at menarche. Throughout a female s reproductive years, follicles are recruited from the primordial pool and progress through the various stages of follicular growth. At the start of each menstrual cycle, one dominant follicle is selected for ovulation (Visser, de Jong, Laven, & Themmen, 2006). While it has proven challenging to quantify ovarian reserve, a new biomarker, anti-Müllerian hormone (AMH), has shown considerable promise (Dewailly et al., 2014). AMH is secreted by growing follicles, and is therefore reflective of the size of the primordial follicular pool. Measurable in serum, AMH offers a promising non-invasive marker of ovarian reserve. In addition, AMH levels are the earliest detectable change that occurs in the sequence of events associated with ovarian aging (Sills, Alper, & Walsh, 2009). The hormone is also ideal as a research and clinical measure because concentrations do not fluctuate across the menstrual cycle, and are independent of FSH, LH, and E2 levels (La Marca et al., 2010; Shaw et al., 2011; Tran, Cedars, & Rosen, 2011). While ovarian reserve naturally declines with age, age alone is not predictive of ovarian age or reproductive status. The decline of ovarian reserve is primarily due to apoptotic loss of oocytes (programmed cell death) rather than ovulation (Tremellen, Kolo, Gilmore, & Lekamge, 2005). Thirty-four percent of the variation in AMH concentrations is due to age, meaning that the remaining 66% is due to other factors (Kelsey, Wright, Nelson, Anderson, & Wallace, 2011). Identifying these factors may help to elucidate predictors of reproductive dysfunction and disease. Understanding factors that influence AMH levels in normo-ovulatory women will also help to establish reliable normative age ranges for use in clinical practice and research. While numerous studies have examined factors associated with AMH concentrations, the sensitivity of the biomarker depends on an understanding of the complex interplay of factors that influence its concentrations. The purpose of this systematic review is to provide a high level summary of the evidence on the factors associated with AMH concentrations and to develop a conceptual model based on the strengths of association for future hypothesis testing. Methods: This systematic review will be conducted according to the PRISMA guidelines. A comprehensive literature search will be conducted using anti-Müllerian hormone as the search term in PubMed. Studies will be included if they meet the follow criteria: 1) published in the last 10 years, 2) human subjects research, 3) research conducted with healthy females. Reference lists of selected studies will also be searched in order to identify any relevant studies missed in the primary search. Results: Two researchers will read and independently judge all selected studies. Studies will be grouped by the factors that emerge from the systematic review. Once all relevant factors have been reviewed, a conceptual model will be developed based on the strengths of association. If there is contradicting evidence, several potential models may be proposed. Conclusion: The conceptual models developed through this systematic review will provide the foundation for future hypothesis testing, and may improve the usefulness of AMH as a biomarker of ovarian reserve

A Prospective Longitudinal Study of the Clinical Outcomes from Cryptococcal Meningitis following Treatment Induction with 800 mg Oral Fluconazole in Blantyre, Malawi

Introduction: Cryptococcal meningitis is the most common neurological infection in HIV infected patients in Sub Saharan Africa, where gold standard treatment with intravenous amphotericin B and 5 flucytosine is often unavailable or difficult to administer. Fluconazole monotherapy is frequently recommended in national guidelines but is a fungistatic drug compromised by uncertainty over optimal dosing and a paucity of clinical end-point outcome data. Methods: From July 2010 until March 2011, HIV infected adults with a first episode of cryptococcal meningitis were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Patients were treated with oral fluconazole monotherapy 800 mg daily, as per national guidelines. ART was started at 4 weeks. Outcomes and factors associated with treatment failure were assessed 4, 10 and 52 weeks after fluconazole initiation. Results: Sixty patients were recruited. 26/60 (43%) died by 4 weeks. 35/60 (58.0%) and 43/56 (77%) died or failed treatment by 10 or 52 weeks respectively. Reduced consciousness (Glasgow Coma Score ,14 of 15), moderate/severe neurological disability (modified Rankin Score .3 of 5) and confusion (Abbreviated Mental Test Score ,8 of 10) were all common at baseline and associated with death or treatment failure. ART prior to recruitment was not associated with better outcomes. Conclusions: Mortality and treatment failure from cryptococcal meningitis following initiation of treatment with 800 mg oral fluconazole is unacceptably high. To improve outcomes, there is an urgent need for better therapeutic strategies and point-of-care diagnostics, allowing earlier diagnosis before development of neurological deficit

The Relationship of Anti-Mullerian Hormone Levels and Urine Cortisol in Women with Chronic Abdominal Pain

Context: Persistent and intense stress leads to chronic activation of the hypothalamic-pituitary-adrenal (HPA) axis, placing an individual at increased risk for the development of disease. HPA activity inhibits ovarian functioning, and may contribute to female infertility. Objective: The objective of the study was to explore the association of HPA activity with ovarian functioning in female participants with and without chronic abdominal pain (CAP). Design/setting/and subjects: A secondary data analysis was performed using data from female participants in a natural history protocol at the National Institutes of Health. A total of 36 females (19–39 years, mean 27.11) were included in the study. Main outcome measurements: Whole blood was drawn for determination of serum levels of anti-Mullerian hormone (AMH), luteinizing hormone, follicle stimulating hormone, and cortisol. Urine samples were collected over a five hour period for determination of cortisol levels. CAP was defined as presence or absence of chronic abdominal pain for \u3e6 months and was determined via self-report. Results: AMH concentrations declined significantly with age as expected. When AMH levels were dichotomized as normal or abnormal (defined as higher or lower than age-specific normative ranges), there were significant associations between abnormal AMH levels and CAP and urine cortisol levels. Subjects with CAP or low urine cortisol levels were significantly more likely to have abnormal AMH levels. Conclusions: Results suggest that chronic pain and HPA dysregulation may be associated with abnormal AMH levels

Core Outcome Measures for Adults with Neurologic Conditions: Pilot Implementation in Hospital-Based Outpatient Clinic.

This residency capstone project’s objective was implementation of 3 of the core neuro outcome measures within a small outpatient clinic, as they were being used inconsistently and heterogeneously. The project included 3 phases: preparation/development, education, and implementation, followed by analyzing and reporting on the project’s and resident’s outcomes

Core Outcome Measures for Adults with Neurologic Conditions: Pilot Implementation in Hospital-Based Outpatient Clinic.

Purpose: To describe a pilot implementation project of 3 of the core neuro outcome measures (OMs) within a small outpatient clinic. Description: OMs provide standardized methods to track patient progress and functional status across levels of care. As the PT profession continues implementing standardized and evidence-based clinical practice guidelines (CPGs) to reflect expertise in the movement system, consistent use of OMs is crucial.1-3 A core set of OMs (COMs) CPG was developed for adults with neurologic conditions; tools to facilitate its use are being produced through the Academy of Neurologic PT (ANPT).4-6 PTs from new grads to clinical specialists should have adequate exposure to COMs and be able to administer them competently.7 Components of DPT education should be upheld once in the clinic. This capstone residency project is helping bridge that gap, bringing didactic and skills training into the clinic to refresh PTs’ OM exposure and facilitate standard and consistent use. Summary of Use: Needs assessment identified that the clinic (10-15 therapists) was not equipped to use COMs according to ANPT recommendations, and OMs were being used inconsistently. However, staff expressed willingness to begin adopting the CPG recommendations. Clinicians were provided ANPT administration guides and electronic medical record (EMR) documentation phrases. To introduce the CPG and COMs, an education session was given emphasizing recommended COM use, standardization of methods and interpretations, and group work for clinical decision-making with certain patient presentations. The session concluded with a departmental discussion on barriers to using OMs and a plan to address them, with the goal for intentional and consistent use beginning with 3 of the COMs. The department was equipped with a binder with laminated copies of ANPT guides, and the clinic was set up to standardize COM administration. For lab training, clinicians were provided copies of the 3 ANPT guides and a competency checklist, and each OM was demonstrated by the resident. During the lab, clinicians role-played alternating as therapist, patient, and observer for each OM to complete the checklist. Next steps of roll-out are currently in progress, beginning with a 5-week period to collect data, followed by data analysis. Implementation of the measures will occur during the 5 weeks, tracking frequency of OM use, documentation in the EMR, and incorporation into the plan of care as collected through a chart audit tool and weekly check-ins. It will also include a subjective pre/post survey to assess clinician learning outcomes and perceptions. Importance to Members: Barriers to OM administration are clinic-wide, and changing practice patterns may often be met with resistance.5,6,8-11 This pilot project may reflect a feasible way to standardize implementation of the COMs into hospital-based outpatient clinics in a way that is not overwhelming to clinicians nor overtly costly to management. This type of standardized OM implementation may also be able to aid in nation-wide outcomes tracking

Chronic Stress and Ovarian Function in Female Childhood Cancer Survivors

Objectives: To explore the relationships among perceived stress, biomarkers of hypothalamic–pituitary–adrenal (HPA) activity, gonadotropin levels, and anti-Müllerian hormone (AMH) in female childhood cancer survivors (CCSs). Sample & Setting: 24 female CCSs from the Royal Hospital for Sick Children in Edinburgh, Scotland, were included in the study. Methods & Variables: Perceived stress was measured using the Perceived Stress Scale. HPA activity was measured using salivary cortisol and hair cortisol. Ovarian function was measured using serum gonadotropin levels and serum AMH levels. Latent growth curve modeling was used to determine diurnal cortisol slope and intercept. Bayesian structural equation modeling was used to explore the relationship among perceived stress, biomarkers of HPA activity, and ovarian function. Results: The authors found an inverse association between perceived stress and ovarian function and a positive association between biomarkers of HPA activity and ovarian function. Implications for Nursing: Further research is needed to understand factors contributing to risk for post-treatment reproductive dysfunction in female CCSs

Hematocrit Self-Testing in Patients with Polycythemia Vera and Other Hematological Conditions: Assessing the Accuracy of the StatStrip Xpress® 2 LAC/Hb/Hct Device and User Opinion about the Device in Real-World Clinical Practice.

Maintaining hematocrit (Hct) levels below 45% can reduce morbidity and mortality in patients with polycythemia vera (PV). A device that patients can use to self-monitor Hct levels could enable timely interventions if Hct levels increase above 45%, and could improve quality of life (QoL). This study evaluated the accuracy of the StatStrip Xpress® 2 LAC/Hb/Hct meter (Hb/Hct meter) when used by healthcare professionals (HCPs) or patients in clinical practice. Blood samples from 68 visits for 60 patients with PV or other hematological conditions were collected and analyzed by HCPs using a laboratory hematological analyzer, and by patients (self-test) and HCPs (professional test) using the Hb/Hct meter at two Swiss centers. Accuracy was assessed as the mean difference in readings between two users/methods (mdiff, 90% confidence interval; Spearman correlation [r]). The Hct values were similar between the professional test and analyzer (n = 66 comparisons, mdiff = 0.1% [-0.5 to 0.8]; r = 0.95, p < 0.001), the self-test and professional test (n = 62 comparisons, mdiff = -0.2% [-1.1 to 0.7]; r = 0.93, p < 0.001), and the self-test and analyzer (n = 63 comparisons, mdiff = 0.0% [-0.8 to 0.7]; r = 0.94, p < 0.001). The hemoglobin values across users/methods were also similar. Reporting their opinion on the Hb/Hct meter at visit 1, 100% of the patients found it easy to use, and 97% were willing to use it at home. Of the patients with PV, approximately 71% and 56%, respectively, stated that they would feel safer using a self-testing device, and that it would improve their QoL. These findings demonstrate the potential of the Hb/Hct meter for HCP and patient use in real-world settings

Mental/Behavioural Health and Educational Outcomes of Grandchildren Raised by Custodial Grandparents: A Mixed Methods Systematic Review

Grandparents caring for grandchildren has increased globally in the past two decades, but we have a limited understanding of its effects on custodial grandchildren\u27s mental/behavioural health and educational outcomes. This mixed methods systematic review aims to synthesise mental/behavioural health and educational outcomes of custodial grandchildren within custodial grandparent-headed families and with comparison to other types of household structure and further examine factors associated with these outcomes. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was conducted. We searched ERIC, Family Studies Abstracts, PsycINFO, PubMed, Scopus, Social Work Abstract and SocINDEX in March 2021 and screened 14,515 articles, which resulted in the inclusion of 42 studies, including 33 quantitative, seven qualitative and two mixed methods studies. The quality of included studies was assessed. This review covered 10 countries, yet most studies revealed that grandchildren raised by grandparents had adverse mental/behavioural health and educational outcomes compared to their peers raised by biological parents. This review further identified multi-level factors contributing to custodial grandchildren\u27s adverse outcomes. Methodological limitations and implications for future practice and research were discussed

Common Genetic Variants Are Associated with Accelerated Bone Mineral Density Loss after Hematopoietic Cell Transplantation

BACKGROUND: Bone mineral density (BMD) loss commonly occurs after hematopoietic cell transplantation (HCT). Hypothesizing that genetic variants may influence post-HCT BMD loss, we conducted a prospective study to examine the associations of single nucleotide polymorphisms (SNP) in bone metabolism pathways and acute BMD loss after HCT. METHODS AND FINDINGS: We genotyped 122 SNPs in 45 genes in bone metabolism pathways among 121 autologous and allogeneic HCT patients. BMD changes from pre-HCT to day +100 post-HCT were analyzed in relation to these SNPs in linear regression models. After controlling for clinical risk factors, we identified 16 SNPs associated with spinal or femoral BMD loss following HCT, three of which have been previously implicated in genome-wide association studies of bone phenotypes, including rs2075555 in COL1A1, rs9594738 in RANKL, and rs4870044 in ESR1. When multiple SNPs were considered simultaneously, they explained 5-35% of the variance in post-HCT BMD loss. There was a significant trend between the number of risk alleles and the magnitude of BMD loss, with patients carrying the most risk alleles having the greatest loss. CONCLUSION: Our data provide the first evidence that common genetic variants play an important role in BMD loss among HCT patients similar to age-related BMD loss in the general population. This infers that the mechanism for post-HCT bone loss is a normal aging process that is accelerated during HCT. A limitation of our study comes from its small patient population; hence future larger studies are warranted to validate our findings

Reconstruction of primary vertices at the ATLAS experiment in Run 1 proton–proton collisions at the LHC

This paper presents the method and performance of primary vertex reconstruction in proton–proton collision data recorded by the ATLAS experiment during Run 1 of the LHC. The studies presented focus on data taken during 2012 at a centre-of-mass energy of √s=8 TeV. The performance has been measured as a function of the number of interactions per bunch crossing over a wide range, from one to seventy. The measurement of the position and size of the luminous region and its use as a constraint to improve the primary vertex resolution are discussed. A longitudinal vertex position resolution of about 30μm is achieved for events with high multiplicity of reconstructed tracks. The transverse position resolution is better than 20μm and is dominated by the precision on the size of the luminous region. An analytical model is proposed to describe the primary vertex reconstruction efficiency as a function of the number of interactions per bunch crossing and of the longitudinal size of the luminous region. Agreement between the data and the predictions of this model is better than 3% up to seventy interactions per bunch crossing