Clinical Applications of Serum Anti-Müllerian Hormone

During the fifth week of fetal life, formation of the genital ridges starts in the posterior abdominal wall, in response to colonization by primordial germ cells, migrating from the yolk sac. By the end of the sixth week, the male and female gonads are indifferent. Differentiation of the gonads is triggered by the sex-determining-region on the Y-chromosome. The first step in male gonadal development is differentiation of Sertoli cells, which produce anti-Müllerian hormone (AMH). Subsequently, between the eighth and tenth week, AMH induces regression of the Müllerian ducts. Thereafter, mesenchymal cells differentiate into Leydig cells, which produce testosterone. Further differentiation of the urogenital system into male derivatives is then ensured by testosterone. In absence of the sex-determining-region on the Y-chromosome, producing the testis determining factor, the gonad differentiates into a female genital system. In addition, production of AMH is lacking and Müllerian ducts, also called the paramesonephric ducts, continue to differentiate into fallopian tubes, uterus and upper part of the vagina. From the seventh week of fetal life onwards, germ cells differentiate into oogonia. Through mitotic cell divisions, the number of oogonia increases steadily and during the third month, the first oogonia begin to transform into oocytes. From the fifth month onwards, the oogonia enter meiosis. In addition, the oocytes are encapsuled by a single layer of pregranulosa cells, forming the primordial follicles. Meiosis is arrested during the first prophase of the first meiotic division, when the homologous chromosomes pair and the primordial follicles enter a dormant state

A blended preconception lifestyle programme for couples undergoing IVF:lessons learned from a multicentre randomized controlled trial

Study question: What is the effect of a blended preconception lifestyle programme on reproductive and lifestyle outcomes of couples going through their first 12 months of IVF as compared to an attention control condition?Summery answer:This randomized controlled trial (RCT) was stopped prematurely because of the coronavirus disease 2019 (Covid-19) pandemic but the available data did not suggest that a blended preconception lifestyle programme could meaningfully affect time to ongoing pregnancy or other reproductive and lifestyle outcomes.What is know already:Increasing evidence shows associations between a healthy lifestyle and IVF success rates. Lifestyle programmes provided through a mobile phone application have yet to be evaluated by RCTs in couples undergoing IVF.Study design, size, duration:A multicentre RCT (1:1) was carried out. The RCT started in January 2019 and was prematurely stopped because of the Covid-19 pandemic, leading to a reduced sample size (211 couples initiating IVF) and change in primary outcome (cumulative ongoing pregnancy to time to ongoing pregnancy).Participants/materials, setting, methods:Heterosexual couples initiating IVF in five fertility clinics were randomized between an attention control arm and an intervention arm for 12 months. The attention control arm received treatment information by mobile phone in addition to standard care. The intervention arm received the blended preconception lifestyle (PreLiFe)-programme in addition to standard care. The PreLiFe-programme included a mobile application, offering tailored advice and skills training on diet, physical activity and mindfulness, in combination with motivational interviewing over the telephone. The primary outcome was 'time to ongoing pregnancy'. Secondary reproductive outcomes included the Core Outcome Measures for Infertility Trials and IVF discontinuation. Changes in the following secondary lifestyle outcomes over 3 and 6 months were studied in both partners: diet quality, fruit intake, vegetable intake, total moderate to vigorous physical activity, sedentary behaviour, emotional distress, quality of life, BMI, and waist circumference. Finally, in the intervention arm, acceptability of the programme was evaluated and actual use of the mobile application part of the programme was tracked. Analysis was according to intention to treat.Main results and the role of chance:A total of 211 couples were randomized (105 control arm, 106 intervention arm). The hazard ratio of the intervention for time to ongoing pregnancy was 0.94 (95% CI 0.63 to 1.4). Little to no effect on other reproductive or lifestyle outcomes was identified. Although acceptability of the programme was good (6/10), considerable proportions of men (38%) and 9% of women did not actively use all the modules of the mobile application (diet, physical activity, or mindfulness).Limitations, reasons for caution:The findings of this RCT should be considered exploratory, as the Covid-19 pandemic limited its power and the actual use of the mobile application was low.Wider implications of the findings:This is the first multicentre RCT evaluating the effect of a blended preconception lifestyle programme for women and their partners undergoing IVF on both reproductive and lifestyle outcomes. This exploratory RCT highlights the need for further studies into optimal intervention characteristics and actual use of preconception lifestyle programmes, as well as RCTs evaluating effectiveness.Study fonding/competing intrest(s):Supported by the Research foundation Flanders (Belgium) (FWO-TBM; reference: T005417N). No competing interests to declare.Trial registration number:ClinicalTrials.gov Identifier: NCT03790449TRIAL REGISTRATION DATE 31 December 2018DATE OF FIRST PATIENT'S ENROLMENT 2 January 201

A nationwide study on reproductive function, ovarian reserve, and risk of premature menopause in female survivors of childhood cancer: design and methodological challenges

<p>Abstract</p> <p>Background</p> <p>Advances in childhood cancer treatment over the past decades have significantly improved survival, resulting in a rapidly growing group of survivors. However, both chemo- and radiotherapy may adversely affect reproductive function. This paper describes the design and encountered methodological challenges of a nationwide study in the Netherlands investigating the effects of treatment on reproductive function, ovarian reserve, premature menopause and pregnancy outcomes in female childhood cancer survivors (CCS), the DCOG LATER-VEVO study.</p> <p>Methods</p> <p>The study is a retrospective cohort study consisting of two parts: a questionnaire assessing medical, menstrual, and obstetric history, and a clinical assessment evaluating ovarian and uterine function by hormonal analyses and transvaginal ultrasound measurements. The eligible study population consists of adult female 5-year survivors of childhood cancer treated in the Netherlands, whereas the control group consists of age-matched sisters of the participating CCS. To date, study invitations have been sent to 1611 CCS and 429 sister controls, of which 1215 (75%) and 333 (78%) have responded so far. Of these responders, the majority consented to participate in both parts of the study (53% vs. 65% for CCS and sister controls respectively). Several challenges were encountered involving the study population: dealing with bias due to the differences in characteristics of several types of (non-) participants and finding an adequately sized and well-matched control group. Moreover, the challenges related to the data collection process included: differences in response rates between web-based and paper-based questionnaires, validity of self-reported outcomes, interpretation of clinical measurements of women using hormonal contraceptives, and inter- and intra-observer variation of the ultrasound measurements.</p> <p>Discussion</p> <p>The DCOG LATER-VEVO study will provide valuable information about the reproductive potential of paediatric cancer patients as well as long-term survivors of childhood cancer. Other investigators planning to conduct large cohort studies on late effects may encounter similar challenges as those encountered during this study. The solutions to these challenges described in this paper may be useful to these investigators.</p> <p>Trial registration</p> <p>NTR2922; <url>http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2922</url></p

Preoperative predictors for residual tumor after surgery in patients with ovarian carcinoma

Objectives: Suboptimal debulking (>1 cm residual tumor) results in poor survival rates for patients with an advanced stage of ovarian cancer. The purpose of this study was to develop a prediction model, based on simple preoperative parameters, for patients with an advanced stage of ovarian cancer who are at risk of suboptimal cytoreduction despite maximal surgical effort. Methods: Retrospective analysis of 187 consecutive patients with a suspected clinical diagnosis of advanced-stage ovarian cancer undergoing upfront debulking between January 1998 and December 2003. Preoperative parameters were Karnofsky performance status, ascites and serum concentrations of CA 125, hemoglobin, albumin, LDH and blood platelets. The main outcome parameter was residual tumor >1 cm. Univariate and multivariate logistic regression was employed for testing possible prediction models. A clinically applicable graphic model (nomogram) for this prediction was to be developed. Results: Serum concentrations of CA 125 and blood platelets in the group with residual tumor >1 cm were higher in comparison to the optimally cytoreduced group (p 1 cm based on serum levels of CA 125 and albumin was established. Conclusion: Postoperative residual tumor despite maximal surgical effort can be predicted by preoperative CA 125 and serum albumin levels. With a nomogram based on these two parameters, probability of postoperative residual tumor in each individual patient can be predicted. This proposed nomogram may be valuable in daily routine practice for counseling and to select treatment modality. Copyrigh

An evaluation of 9-1-1 calls to assess the effectiveness of dispatch-assisted cardiopulmonary resuscitation (CPR) instructions: design and methodology

<p>Abstract</p> <p>Background</p> <p>Cardiac arrest is the leading cause of mortality in Canada, and the overall survival rate for out-of-hospital cardiac arrest rarely exceeds 5%. Bystander cardiopulmonary resuscitation (CPR) has been shown to increase survival for cardiac arrest victims. However, bystander CPR rates remain low in Canada, rarely exceeding 15%, despite various attempts to improve them. Dispatch-assisted CPR instructions have the potential to improve rates of bystander CPR and many Canadian urban communities now offer instructions to callers reporting a victim in cardiac arrest. Dispatch-assisted CPR instructions are recommended by the International Guidelines on Emergency Cardiovascular Care, but their ability to improve cardiac arrest survival remains unclear.</p> <p>Methods/Design</p> <p>The overall goal of this study is to better understand the factors leading to successful dispatch-assisted CPR instructions and to ultimately save the lives of more cardiac arrest patients. The study will utilize a before-after, prospective cohort design to specifically: 1) Determine the ability of 9-1-1 dispatchers to correctly diagnose cardiac arrest; 2) Quantify the frequency and impact of perceived agonal breathing on cardiac arrest diagnosis; 3) Measure the frequency with which dispatch-assisted CPR instructions can be successfully completed; and 4) Measure the impact of dispatch-assisted CPR instructions on bystander CPR and survival rates.</p> <p>The study will be conducted in 19 urban communities in Ontario, Canada. All 9-1-1 calls occurring in the study communities reporting out-of-hospital cardiac arrest in victims 16 years of age or older for which resuscitation was attempted will be eligible. Information will be obtained from 9-1-1 call recordings, paramedic patient care reports, base hospital records, fire medical records and hospital medical records. Victim, caller and system characteristics will be measured in the study communities before the introduction of dispatch-assisted CPR instructions (before group), during the introduction (run-in phase), and following the introduction (after group).</p> <p>Discussion</p> <p>The study will obtain information essential to the development of clinical trials that will test a variety of educational approaches and delivery methods for telephone cardiopulmonary resuscitation instructions. This will be the first study in the world to clearly quantify the impact of dispatch-assisted CPR instructions on survival to hospital discharge for out-of-hospital cardiac arrest victims.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00664443</p

A genome-wide association study identifies risk alleles in plasminogen and P4HA2 associated with giant cell arteritis

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analysed in 2,134 cases and 9,125 unaffected controls from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, P = 1.94E-54, per-allele OR = 1.79; and rs9275592, P = 1.14E-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, P = 1.23E-10, OR = 1.28; and rs128738, P = 4.60E-09, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis

Preemptive use of lamivudine reduces hepatitis B exacerbation after allogeneic hematopoietic cell transplantation

Exacerbation of hepatitis B virus (HBV) is a serious cause of morbidity and mortality in hepatitis B surface antigen (HBsAg)-positive patients undergoing transplantation. Our aim was to evaluate the effectiveness of lamivudine to prevent hepatitis due to exacerbation of HBV in HBsAg-positive patients treated with allogeneic hematopoietic cell transplantation. We studied 20 consecutive HBsAg-positive recipients of allogeneic hematopoietic cell transplantation who received lamivudine 100 mg daily starting one week before transplantation until week 52 after transplantation (group 1). Serial serum alanine aminotransferase and HBV DNA levels were measured before and after transplantation at 4- to 8-week intervals for the first year and then 4- to 12-week intervals. Their virologic and clinical outcomes were compared with 20 case-matched recipients who did not receive any antiviral therapy to HBV (anti-HBV) before and after hematopoietic cell transplantation (group 2). After transplantation, 9 patients (45%) in group 2 and one patient (5%) in group 1 had hepatitis due to exacerbation of HBV (P < .008), with 3 hepatic failures in group 2 and none in group 1. The one-year actuarial probability of survival without hepatitis due to exacerbation of HBV was higher in group 1 than group 2 (94.1% vs. 54.3%, P = .002). By multivariate Cox analysis, preemptive use of lamivudine effectively reduced hepatitis due to exacerbation of HBV (adjusted hazards ratio, 0.09; P = .021). In conclusion, preemptive lamivudine reduced HBV exacerbation. The use of lamivudine with other immunosuppressive regimens to prevent exacerbation of HBV should be further explored.link_to_OA_fulltex

Translation and validation of the functional assessment of cancer therapy-bone marrow transplant (FACT-BMT) version 4 quality of life instrument into traditional Chinese

The need for a culturally sensitive instrument to assess quality of life (QOL) of patients in international oncology clinical trials has been well documented. This study was designed to evaluate the psychometric properties of the traditional Chinese translation (TCHI) of the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Version 4. The FACT-BMT consists of the FACT-General and treatment-specific concerns of bone marrow transplantation. The Chinese translation follows the standard Functional Assessment of Chronic Illness Therapy (FACIT) translation methodology. Bilingual teams from the United States and Hong Kong reviewed the translation to develop a provisional TCHI FACT-BMT, which was then pre-tested by interviewing 20 native Chinese-speaking BMT patients in Hong Kong. The pre-test results indicated good content coverage and overall comprehensibility. A refined translation, taking into account patient comments, was validated by 134 BMT patients in Hong Kong. The results indicated the high internal consistency of the TCHI FACT-BMT scales, with Cronbach's alpha coefficients ranging from 0.71 (emotional well-being) to 0.92 (FACT-BMT total). The FACT-BMT also demonstrated good construct validity when correlated with SF-36 Health Survey scales. The QOL of Chinese BMT patients can now be evaluated using a well-validated international QOL instrument in their own language.link_to_OA_fulltex

Pregnancy outcome in female childhood cancer survivors

BACKGROUND: The number of childhood cancer survivors has dramatically increased and consequently, an increasing number of survivors may now wish to conceive. Recently, several studies have described that previous treatment with abdominal radiotherapy may increase the risk of adverse pregnancy outcome.METHODSWe conducted a retrospective single centre cohort study of childhood cancer survivors with a singleton live birth between January 2000 and December 2005. Pregnancy outcome was compared with data from the Netherlands Perinatal Registry, a nationwide database of pregnancy outcome parameters of all births in the Netherlands registered by midwives, obstetricians and paediatricians.RESULTSData were available on 40 survivors and 9031 controls. Median age at diagnosis was 6.9 years (range 0.1-16.8 years). The median interval between diagnosis and date of delivery was 21.6 years (range 7.4-36.1 years). In the whole cohort, pregnancy outcome was not different between survivors and controls. However, survivors treated with abdominal radiotherapy delivered preterm and had post-partum haemorrhage (mean gestational age in survivors = 34.9 versus 39.2 weeks in controls, P = 0.001; 33 in survivors versus 5 in controls, P = 0.007, respectively). The offspring of su