Expectant management versus IUI in unexplained subfertility and a poor pregnancy prognosis (EXIUI study) : a randomized controlled trial

Funding The study received a grant from The Netherlands Organisation for Health Research and Development (ZonMw; www.zonmw.nl). ZonMw has no role in the design of the study, collection, analysis and interpretation of data or writing of the manuscript.Peer reviewedPublisher PD

Is home-based monitoring of ovulution to time frozen embryo transfer a cost-effective alternative for hospital-based monitoring of ovulation? Study protocol of the multicentre, non-inferiority Antarctica-2 randomised controlled trial

STUDY QUESTION: The objective of this trial is to compare the effectiveness and costs of true natural cycle (true NC-) frozen embryo transfer (FET) using urinary LH tests to modified NC-FET using repeated ultrasound monitoring and ovulation trigger to time FET in the NC. Secondary outcomes are the cancellation rates of FET (ovulation before hCG or no dominant follicle, no ovulation by LH urine test, poor embryo survival), pregnancy outcomes (miscarriage rate, clinical pregnancy rates, multiple ongoing pregnancy rates, live birth rates, costs) and neonatal outcomes (including gestational age, birthweight and sex, congenital abnormalities or diseases of babies born). WHAT IS KNOWN ALREADY: FET is at the heart of modern IVF. To allow implantation of the thawed embryo, the endometrium must be prepared either by exogenous oestrogen and progesterone supplementation (artificial cycle (AC)-FET) or by using the NC to produce endogenous oestradiol before and progesterone after ovulation to time the transfer of the thawed embryo (NC-FET). During an NC-FET, women visit the hospital repeatedly and receive an ovulation trigger to time FET (i.e. modified (m)NC-FET or hospital-based monitoring). From the woman’s point of view, a more natural approach using home-based monitoring of the ovulation with LH urine tests to allow a natural ovulation to time FET may be desired (true NC-FET or home-based monitoring). STUDY DESIGN, SIZE, DURATION: This is a multicentre, non-inferiority prospective randomised controlled trial design. Consenting women will undergo one FET cycle using either true NC-FET or mNC-FET based on randomisation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on our sample size calculation, the study group will consist of 1464 women between 18 and 45 years old who are scheduled for FET. Women with anovulatory cycles, women who need ovulation induction and women with a contra indication for pregnancy will be excluded. The primary outcome is ongoing pregnancy. Secondary outcomes are cancellation rates of FET, pregnancy outcomes (including miscarriage rate, clinical pregnancy, multiple pregnancy rate and live birth rate). Costs will be estimated by counting resource use and calculating unit prices. STUDY FUNDING/COMPETING INTEREST(S): The study received a grant from the Dutch Organisation for Health Research and Development (ZonMw 843002807; www.zonmw.nl). ZonMw has no role in the design of the study, collection, analysis, and interpretation of data or writing of the manuscript. F.B. reports personal fees from member of the external advisory board for Merck Serono, grants from Research support grant Merck Serono, outside the submitted work. A.E.P.C. reports and Unrestricted grant of Ferring B.V. to the Center for Reproductive medicine, no personal fee. Author up-to-date on Hyperthecosis. Congress meetings 2019 with Ferring B.V. and Theramex B.V. M.G. reports Department research and educational grants from Guerbet, Merck and Ferring (location VUMC) outside the submitted work. E.R.G. reports personal fees from Titus Health Care, outside the submitted work. C.B.L. reports grants from Ferring, grants from Merck, from Guerbet, outside the submitted work. The other authors have none to declare. TRIAL REGISTRATION NUMBER: Dutch Trial Register (Trial NL6414 (NTR6590), https://www.trialregister.nl/). TRIAL REGISTRATION DATE: 23 July 2017 DATE OF FIRST PATIENT’S ENROLMENT: 10 April 201

Cost-effectiveness of stereotactic large-core needle biopsy for nonpalpable breast lesions compared to open-breast biopsy

This paper demonstrates that the introduction of large-core needle biopsy (LCNB) replacing needle-localised breast biopsy (NLBB) for nonpalpable (screen-detected) breast lesions could result in substantial cost savings at the expense of a possible slight increase in breast cancer mortality. The cost-effectiveness of LCNB and NLBB was estimated using a microsimulation model. The sensitivity of LCNB (0.97) and resource use and costs of LCNB and NLBB were derived from a multicentre consecutive cohort study among 973 women who consented in getting LCNB and NLBB, if LCNB was negative. Sensitivity analyses were performed. Replacing NLBB with LCNB would result in approximately six more breast cancer deaths per year (in a target population of 2.1 million women), or in 1000 extra life-years lost from breast cancer (effect over 100 years). The total costs of management of breast cancer (3% discounted) are estimated at £4676 million with NLBB; introducing LCNB would save £13 million. The incremental cost-effectiveness ratio of continued NLBB vs LCNB would be £12 482 per additional life-year gained (3% discounted); incremental costs range from £-21 687 (low threshold for breast biopsy) to £74 378 (high sensitivity of LCNB)

Interpreting Overdiagnosis Estimates in Population-based Mammography Screening

Estimates of overdiagnosis in mammography screening range from 1% to 54%. This review explains such variations using gradual implementation of mammography screening in the Netherlands as an example. Breast cancer incidence without screening was predicted with a micro-simulation model. Observed breast cancer incidence (including ductal carcinoma in situ and invasive breast cancer) was modeled and compared with predicted incidence without screening during various phases of screening program implementation. Overdiagnosis was calculated as the difference between the modeled number of breast cancers with and the predicted number of breast cancers without screening. Estimating overdiagnosis annually between 1990 and 2006 illustrated the importance of the time at which overdiagnosis is measured. Overdiagnosis was also calculated using several estimators identified from the literature. The estimated overdiagnosis rate peaked during the implementation phase of screening, at 11.4% of all predicted cancers in women aged 0–100 years in the absence of screening. At steady-state screening, in 2006, this estimate had decreased to 2.8%. When different estimators were used, the overdiagnosis rate in 2006 ranged from 3.6% (screening age or older) to 9.7% (screening age only). The authors concluded that the estimated overdiagnosis rate in 2006 could vary by a factor of 3.5 when different denominators were used. Calculations based on earlier screening program phases may overestimate overdiagnosis by a factor 4. Sufficient follow-up and agreement regarding the chosen estimator are needed to obtain reliable estimates

Endometrial scratching in women with one failed IVF/ICSI cycle-outcomes of a randomised controlled trial (SCRaTCH)

STUDY QUESTION: Does endometnal scratching in women with one failed IVF/ICSI treatment affect the chance of a live birth of the subsequent fresh IVF/ICSI cycle? SUMMARY ANSWER: In this study, 4.6% more live births were observed in the scratch group, with a likely certainty range between -0.7% and +9.9%. WHAT IS KNOWN ALREADY: Since the first suggestion that endometrial scratching might improve embryo implantation during IVF/ICSI, many clinical trials have been conducted. However, due to limitations in sample size and study quality, it remains unclear whether endometrial scratching improves IVF/ICSI outcomes. STUDY DESIGN, SIZE, DURATION: The SCRaTCH trial was a non-blinded randomised controlled trial in women with one unsuccessful IVF/ICSI cycle and assessed whether a single endometrial scratch using an endometrial biopsy catheter would lead to a higher live birth rate after the subsequent IVF/ICSI treatment compared to no scratch. The study took place in 8 academic and 24 general hospitals. Participants were randomised between January 2016 and July 2018 by a web-based randomisation programme. Secondary outcomes included cumulative 12-month ongoing pregnancy leading to live birth rate. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with one previous failed IVF/ICSI treatment and planning a second fresh IVF/ICSI treatment were eligible. In total, 933 participants out of 1065 eligibles were included (participation rate 88%). MAIN RESULTS AND THE ROLE OF CHANCE: After the fresh transfer, 4.6% more live births were observed in the scratch compared to control group (110/465 versus 88/461, respectively, risk ratio (RR) 1.24 [95% CI 0.96-1.59]). These data are consistent with a true difference of between - 0.7% and 9.9% (95% CI), indicating that while the largest proportion of the 95% CI is positive, scratching could have no or even a small negative effect. Biochemical pregnancy loss and miscarriage rate did not differ between the two groups: in the scratch group 27/153 biochemical pregnancy losses and 14/126 miscarriages occurred, while this was 19/130 and 17/11 I for the control group (RR 1.21 (95% CI 0.71-2.07) and RR 0.73 (95% CI 0.38-1.40), respectively). After 12 months of follow-up, 5.1% more live births were observed in the scratch group (202/467 versus 178/466), of which the true difference most likely lies between -1.2% and +11.4% (95% CI). LIMITATIONS, REASONS FOR CAUTION: This study was not blinded. Knowledge of allocation may have been an incentive for participants allocated to the scratch group to continue treatment in situations where they may otherwise have cancelled or stopped. In addition, this study was powered to detect a difference in live birth rate of 9%. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study are an incentive for further assessment of the efficacy and clinical implications of endometrial scratching. If a true effect exists, it may be smaller than previously anticipated or may be limited to specific groups of women undergoing IVF/ICSI. Studying this will require larger sample sizes, which will be provided by the ongoing international individual participant data-analysis (PROSPERO CRD42017079120). At present, endometrial scratching should not be performed outside of clinical trials

Combined Risk Allele Score of Eight Type 2 Diabetes Genes Is Associated With Reduced First-Phase Glucose-Stimulated Insulin Secretion During Hyperglycemic Clamps

OBJECTIVE - At least 20 type 2 diabetes loci have now been identified, and several of these are associated with altered β-cell function. In this study, we have investigated the combined effects of eight known β-cell loci on insulin secretion stimulated by three different secretagogues during hyperglycemic clamps. RESEARCH DESIGN AND METHODS - A total of 447 subjects originating from four independent studies in the Netherlands and Germany (256 with normal glucose tolerance [NGT]/ 191 with impaired glucose tolerance [IGT]) underwent a hyperglycemic clamp. A subset had an extended clamp with additional glucagon-like peptide (GLP)-1 and arginine (n = 224). We next genotyped single nucleotide polymorphisms in TCF7L2, KCNJ11, CDKAL1, IGF2BP2, HHEX/IDE, CDKN2A/B, SLC30A8, and MTNR1B and calculated a risk allele score by risk allele counting. RESULTS - The risk allele score was associated with lower first-phase glucose-stimulated insulin secretion (GSIS) (P = 7.1 × 1

Two Isoforms of the mRNA Binding Protein IGF2BP2 Are Generated by Alternative Translational Initiation

IGF2BP2 is a member of a family of mRNA binding proteins that, collectively, have been shown to bind to several different mRNAs in mammalian cells, including one of the mRNAs encoding insulin-like growth factor-2. Polymorphisms in the Igf2bp2 gene are associated with risk of developing type 2 diabetes, but detailed functional characterisation of IGF2BP2 protein is lacking. By immunoblotting with C-terminally reactive antibodies we identified a novel IGF2BP2 isoform with a molecular weight of 58 kDa in both human and rodents, that is expressed at somewhat lower levels than the full-length 65 kDa protein. We demonstrated by mutagenesis that this isoform is generated by alternative translation initiation at the internal Met69. It lacks a conserved N-terminal RNA Recognition Motif (RRM) and would be predicted to differ functionally from the canonical full length isoform. We further investigated IGF2BP2 mRNA transcripts by amplification of cDNA using 5′-RACE. We identified multiple transcription start sites of the human, mouse and rat Igf2bp2 genes in a highly conserved region only 50–90 nts upstream of the major translation start site, ruling out the existence of N-terminally extended isoforms. We conclude that structural heterogeneity of IGF2BP2 protein should be taken into account when considering cellular function

A prediction model for primary aldosteronism when the salt loading test is inconclusive

Objective: To develop a prediction model to confirm or exclude primary aldosteronism (PA) in patients with an inconclusive salt loading test (SLT). Context: Diagnosis in patients with a suspicion of PA can be confirmed using an SLT. In case of inconclusive test results the decision about how to manage the patient is usually based on contextual clinical data. Design: We included a retrospective cohort of 276 patients in the final analysis. Methods: All patients underwent an SLT between 2005 and 2016 in our university medical center. The SLT was inconclusive (post-infusion aldosterone levels 140–280 pmol/L) in 115 patients. An expert panel then used contextual clinical data to diagnose PA in 45 of them. Together with 101 patients with a positive SLT this resulted in a total of 146 patients with PA. A total of 11 variables were used in a multivariable logistic regression analysis. We assessed internal validity by bootstrapping techniques. Results: The following variables were independently associated with PA: more intense potassium supplementation, lower plasma potassium concentration, lower plasma renin concentration before SLT and higher plasma aldosterone concentration after SLT. The resulting prediction model had a sensitivity of 84.4% and a specificity of 94.3% in patients with an inconclusive SLT. The positive and negative predictive values were 90.5 and 90.4%, respectively. Conclusions: We developed a prediction model for the diagnosis of PA in patients with an inconclusive SLT that results in a diagnosis that was in high agreement with that of an expert panel

Deletion of CDKAL1 Affects Mitochondrial ATP Generation and First-Phase Insulin Exocytosis

A variant of the CDKAL1 gene was reported to be associated with type 2 diabetes and reduced insulin release in humans; however, the role of CDKAL1 in β cells is largely unknown. Therefore, to determine the role of CDKAL1 in insulin release from β cells, we studied insulin release profiles in CDKAL1 gene knockout (CDKAL1 KO) mice.Total internal reflection fluorescence imaging of CDKAL1 KO β cells showed that the number of fusion events during first-phase insulin release was reduced. However, there was no significant difference in the number of fusion events during second-phase release or high K(+)-induced release between WT and KO cells. CDKAL1 deletion resulted in a delayed and slow increase in cytosolic free Ca(2+) concentration during high glucose stimulation. Patch-clamp experiments revealed that the responsiveness of ATP-sensitive K(+) (K(ATP)) channels to glucose was blunted in KO cells. In addition, glucose-induced ATP generation was impaired. Although CDKAL1 is homologous to cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1, there was no difference in the kinase activity of CDK5 between WT and CDKAL1 KO islets.We provide the first report describing the function of CDKAL1 in β cells. Our results indicate that CDKAL1 controls first-phase insulin exocytosis in β cells by facilitating ATP generation, K(ATP) channel responsiveness and the subsequent activity of Ca(2+) channels through pathways other than CDK5-mediated regulation