Top 10 priorities for future infertility research: an international consensus development study† ‡.

STUDY QUESTION: Can the priorities for future research in infertility be identified? SUMMARY ANSWER: The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care for people with fertility problems were identified. WHAT IS KNOWN ALREADY: Many fundamental questions regarding the prevention, management and consequences of infertility remain unanswered. This is a barrier to improving the care received by those people with fertility problems. STUDY DESIGN, SIZE, DURATION: Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines and Cochrane systematic reviews. A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research priorities for each of the categories male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, people with fertility problems and others (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process using formal consensus methods advocated by the James Lind Alliance. MAIN RESULTS AND THE ROLE OF CHANCE: The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions. A rationalized list of 231 confirmed research uncertainties was entered into an interim prioritization survey completed by 317 respondents from 43 countries. The top 10 research priorities for each of the four categories male infertility, female and unexplained infertility (including age-related infertility, ovarian cysts, uterine cavity abnormalities and tubal factor infertility), medically assisted reproduction (including ovarian stimulation, IUI and IVF) and ethics, access and organization of care were identified during a consensus development meeting involving 41 participants from 11 countries. These research priorities were diverse and seek answers to questions regarding prevention, treatment and the longer-term impact of infertility. They highlight the importance of pursuing research which has often been overlooked, including addressing the emotional and psychological impact of infertility, improving access to fertility treatment, particularly in lower resource settings and securing appropriate regulation. Addressing these priorities will require diverse research methodologies, including laboratory-based science, qualitative and quantitative research and population science. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations, including the representativeness of the participant sample, methodological decisions informed by professional judgment and arbitrary consensus definitions. WIDER IMPLICATIONS OF THE FINDINGS: We anticipate that identified research priorities, developed to specifically highlight the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems and others, will help research funding organizations and researchers to develop their future research agenda. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Auckland Medical Research Foundation, Catalyst Fund, Royal Society of New Zealand and Maurice and Phyllis Paykel Trust. G.D.A. reports research sponsorship from Abbott, personal fees from Abbott and LabCorp, a financial interest in Advanced Reproductive Care, committee membership of the FIGO Committee on Reproductive Medicine, International Committee for Monitoring Assisted Reproductive Technologies, International Federation of Fertility Societies and World Endometriosis Research Foundation, and research sponsorship of the International Committee for Monitoring Assisted Reproductive Technologies from Abbott and Ferring. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and editor for the Cochrane Gynaecology and Fertility Group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. A.W.H. reports research sponsorship from the Chief Scientist's Office, Ferring, Medical Research Council, National Institute for Health Research and Wellbeing of Women and consultancy fees from AbbVie, Ferring, Nordic Pharma and Roche Diagnostics. M.L.H. reports grants from Merck, grants from Myovant, grants from Bayer, outside the submitted work and ownership in Embrace Fertility, a private fertility company. N.P.J. reports research sponsorship from AbbVie and Myovant Sciences and consultancy fees from Guerbet, Myovant Sciences, Roche Diagnostics and Vifor Pharma. J.M.L.K. reports research sponsorship from Ferring and Theramex. R.S.L. reports consultancy fees from AbbVie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. E.H.Y.N. reports research sponsorship from Merck. C.N. reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring and retains a financial interest in NexHand. J.S. reports being employed by a National Health Service fertility clinic, consultancy fees from Merck for educational events, sponsorship to attend a fertility conference from Ferring and being a clinical subeditor of Human Fertility. A.S. reports consultancy fees from Guerbet. J.W. reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. A.V. reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and the journal Reproduction. His employing institution has received payment from Human Fertilisation and Embryology Authority for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the present work. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: N/A.

Developing a core outcome set for future infertility research: an international consensus development study† ‡.

STUDY QUESTION: Can a core outcome set to standardize outcome selection, collection and reporting across future infertility research be developed? SUMMARY ANSWER: A minimum data set, known as a core outcome set, has been developed for randomized controlled trials (RCTs) and systematic reviews evaluating potential treatments for infertility. WHAT IS KNOWN ALREADY: Complex issues, including a failure to consider the perspectives of people with fertility problems when selecting outcomes, variations in outcome definitions and the selective reporting of outcomes on the basis of statistical analysis, make the results of infertility research difficult to interpret. STUDY DESIGN, SIZE, DURATION: A three-round Delphi survey (372 participants from 41 countries) and consensus development workshop (30 participants from 27 countries). PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus science methods. MAIN RESULTS AND THE ROLE OF CHANCE: The core outcome set consists of: viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin and higher multiple pregnancy); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Time to pregnancy leading to live birth should be reported when applicable. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods which have inherent limitations, including the representativeness of the participant sample, Delphi survey attrition and an arbitrary consensus threshold. WIDER IMPLICATIONS OF THE FINDINGS: Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection and reporting of core outcomes. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and over 80 specialty journals, including the Cochrane Gynaecology and Fertility Group, Fertility and Sterility and Human Reproduction, have committed to implementing this core outcome set. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. The funder had no role in the design and conduct of the study, the collection, management, analysis or interpretation of data, or manuscript preparation. B.W.J.M. is supported by a National Health and Medical Research Council Practitioner Fellowship (GNT1082548). S.B. was supported by University of Auckland Foundation Seelye Travelling Fellowship. S.B. reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. J.M.L.K. reports research sponsorship from Ferring and Theramex. R.S.L. reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.J.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. C.N. reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. A.S. reports consultancy fees from Guerbet. E.H.Y.N. reports research sponsorship from Merck. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: Core Outcome Measures in Effectiveness Trials Initiative: 1023.

Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study† ‡.

STUDY QUESTION: Can consensus definitions for the core outcome set for infertility be identified in order to recommend a standardized approach to reporting? SUMMARY ANSWER: Consensus definitions for individual core outcomes, contextual statements and a standardized reporting table have been developed. WHAT IS KNOWN ALREADY: Different definitions exist for individual core outcomes for infertility. This variation increases the opportunities for researchers to engage with selective outcome reporting, which undermines secondary research and compromises clinical practice guideline development. STUDY DESIGN, SIZE, DURATION: Potential definitions were identified by a systematic review of definition development initiatives and clinical practice guidelines and by reviewing Cochrane Gynaecology and Fertility Group guidelines. These definitions were discussed in a face-to-face consensus development meeting, which agreed consensus definitions. A standardized approach to reporting was also developed as part of the process. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus development methods. MAIN RESULTS AND THE ROLE OF CHANCE: Forty-four potential definitions were inventoried across four definition development initiatives, including the Harbin Consensus Conference Workshop Group and International Committee for Monitoring Assisted Reproductive Technologies, 12 clinical practice guidelines and Cochrane Gynaecology and Fertility Group guidelines. Twenty-seven participants, from 11 countries, contributed to the consensus development meeting. Consensus definitions were successfully developed for all core outcomes. Specific recommendations were made to improve reporting. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations. There was limited representation from low- and middle-income countries. WIDER IMPLICATIONS OF THE FINDINGS: A minimum data set should assist researchers in populating protocols, case report forms and other data collection tools. The generic reporting table should provide clear guidance to researchers and improve the reporting of their results within journal publications and conference presentations. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials statement, and over 80 specialty journals have committed to implementing this core outcome set. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility Group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. R.S.L. reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. C.N. reports being the Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and a financial interest in NexHand. E.H.Y.N. reports research sponsorship from Merck. A.S. reports consultancy fees from Guerbet. J.W. reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. A.V. reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and of the journal Reproduction. His employing institution has received payment from Human Fertilisation and Embryology Authority for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: Core Outcome Measures in Effectiveness Trials Initiative: 1023.

Quality control of ultrasound for fetal biometry: results from the INTERGROWTH-21st Project.

OBJECTIVE: To assess a comprehensive package of ultrasound quality control in the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project, a large multicenter study of fetal growth. METHODS: Quality control (QC) measures were performed for 20 313 ultrasound scan images obtained prospectively from 4321 fetuses at 14-41 weeks' gestation in eight geographical locations. At the time of each ultrasound examination, three fetal biometric variables (head circumference (HC), abdominal circumference (AC) and femur length (FL)) were measured in triplicate on separately generated images. All measurements were taken in a blinded fashion. QC had two elements: (1) qualitative QC: visual assessment by sonographers at each study site of their images based on specific criteria, with 10% of images being re-assessed at the Oxford-based Ultrasound Quality Unit (compared using an adjusted kappa statistic); and (2) quantitative QC: assessment of measurement data by comparing the first, second and third measurements (intraobserver variability), remeasurement of caliper replacement in 10% (interobserver variability), both by Bland-Altman plots and plotting frequency histograms of the SD of triplicate measurements and assessing how many were above or below 2 SD of the expected distribution. The system allowed the sonographers' performances to be monitored regularly. RESULTS: A high level of agreement between self- and external scoring was demonstrated for all measurements (κ = 0.99 (95% CI, 0.98-0.99) for HC, 0.98 (95% CI, 0.97-0.99) for AC and 0.96 (95% CI, 0.95-0.98) for FL). Intraobserver 95% limits of agreement (LoA) of ultrasound measures for HC, AC and FL were ± 3.3%, ± 5.6% and ± 6.2%, respectively; the corresponding values for interobserver LoA were ± 4.4%, ± 6.0% and ± 5.6%. The SD distribution of triplicate measurements for all biometric variables showed excessive variability for three of 31 sonographers, allowing prompt identification and retraining. CONCLUSIONS: Qualitative and quantitative QC monitoring was feasible and highly reproducible in a large multicenter research study, which facilitated the production of high-quality ultrasound images. We recommend that the QC system we developed is implemented in future research studies and clinical practice. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Reproducibility of measuring amniotic fluid index and single deepest vertical pool throughout gestation.

OBJECTIVE: The aim of this study is to assess the intraobserver and interobserver reproducibility of measurement of amniotic fluid index (AFI) and single deepest vertical pool (SDVP), also known as the maximal vertical pocket. METHODS: A total of 175 fetuses were evaluated. For each fetus, two observers acquired duplicate sets of AFI and SDVP. Measurement differences were expressed as actual and percentage values. For all comparisons, Bland-Altman plots were used to compare differences, and limits of agreement were calculated. RESULTS: Intraobserver and interobserver agreement remained fairly constant with gestation, both for AFI and SDVP. The intraobserver limits of agreement for AFI were -5.2 to 5 cm or -39% to 37%; whereas for SDVP, these were -2.6 to 2.4 cm or -52% to 48%. The interobserver limits of agreement for AFI measurement were -7.3 to 7.1 cm or -54% to 53% and for SDVP measurement were -2.5 to 2.5 cm or -51% to 52%. Intraobserver coefficient of variation for SDVP was 14% and for AFI was 19%; the interobserver coefficient was 19% for both AFI and SDVP. CONCLUSION: Limits of agreement for both methods are wide. The choice of method should be dictated by clinical considerations other than method reproducibility.

Standardisation of crown-rump length measurement.

Correct estimation of gestational age is essential for any study of ultrasound biometry and for everyday clinical practice. However, inconsistency in pregnancy dating may occur through differences in measurement methods or errors during measurement. In the INTERGROWTH-21(st) Project, pregnancies are dated by the last menstrual period, provided that it is certain and associated with a regular menstrual cycle, and the gestational age by dates concurs with a first-trimester ultrasound crown-rump length (CRL) estimation. Hence, there was a need to standardise CRL measurement methodology across the study sites in this international, multicentre project to avoid systematic differences in dating. To achieve uniformity we undertook the following steps: the ultrasound technique was standardised by disseminating an illustrated, operating manual describing CRL plane landmarks and calliper application, and posters describing the correct acquisition technique were disseminated for quick reference. To ensure that all ultrasonographers understood the methodology, they forwarded a log-book to the INTERGROWTH-21(st) Ultrasound Coordinating Unit, containing the answers to a written test on the manual material and five images of a correctly acquired CRL. Interpretation of CRL was also standardised by ensuring that the same CRL regression formula was used across all study sites. These methods should minimise potential systematic errors in dating associated with pooling data from different health institutions, and represent a model for standardising CRL measurement in future studies.

Ultrasound methodology used to construct the fetal growth standards in the INTERGROWTH-21st Project.

A unified protocol is essential to ensure that fetal ultrasound measurements taken in multicentre research studies are accurate and reproducible. This paper describes the methodology used to take two-dimensional, ultrasound measurements in the longitudinal, fetal growth component of the INTERGROWTH-21(st) Project. These standardised methods should minimise the systematic errors associated with pooling data from different study sites. They represent a model for carrying out similar research studies in the future.

Standardisation and quality control of ultrasound measurements taken in the INTERGROWTH-21st Project.

Meticulous standardisation and ongoing monitoring of adherence to measurement protocols during data collection are essential to ensure consistency and to minimise systematic error in multicentre studies. Strict ultrasound fetal biometric measurement protocols are used in the INTERGROWTH-21(st) Project so that data of the highest quality from different centres can be compared and potentially pooled. A central Ultrasound Quality Unit (USQU) has been set up to oversee this process. After initial training and standardisation, the USQU monitors the performance of all ultrasonographers involved in the project by continuously assessing the quality of the images and the consistency of the measurements produced. Ultrasonographers are identified when they exceed preset maximum allowable differences. Corrective action is then taken in the form of retraining or simply advice regarding changes in practice. This paper describes the procedures used, which can form a model for research settings involving ultrasound measurements.

Fetal biometry: how well can offline measurements from three-dimensional volumes substitute real-time two-dimensional measurements?

OBJECTIVES: To assess the feasibility, accuracy and reproducibility of manipulating three-dimensional (3D) volume sets in order to reconstruct optimal two-dimensional (2D) planes for fetal biometry throughout gestation and compare them with those derived from real-time 2D scanning. METHODS: Sixty-five fetuses were evaluated at a gestational age of 14-41 weeks. For each fetus a duplicate set of seven standard fetal measurements was taken by an experienced operator using 2D ultrasound and then 20 intentionally suboptimal 3D volumes from different predefined angles were captured and stored. These were manipulated and measured. The time taken to complete a full scan, with both 2D and 3D ultrasound, was recorded. All measurement differences were expressed as gestational age-specific Z-scores. For all comparisons Bland-Altman plots were used and limits of agreement were calculated. The means and variances of the measurements were tested with a paired t-test and Pitman's test for differences in variance, respectively. The difference between the time taken to perform a 2D and a 3D scan was tested using the Wilcoxon signed-ranks test. RESULTS: Mean agreement between 2D and 3D ultrasound measurements was good, with no statistically significant differences (i.e. no systematic error) unless the head was facing anteroposteriorly, or the long axis of the femur was at 60-90° to the transducer. The variance (random error) for 3D measurements was similar to that for 2D measurements. Planes from some volumes could not be extracted (7% for head circumference, 9% for abdominal circumference and 11% for femur length). The median time required to perform a full fetal biometric scan was significantly higher for 3D than for 2D (3:04 min vs 1:57 min, respectively; P < 0.001). CONCLUSIONS: Fetal measurements derived from 3D volume acquisitions exhibited good agreement with those obtained by real-time 2D scanning, with no extra systematic or random error. However, they were slower to obtain, not all volumes were amenable to extraction of planes and measurements that came from a head facing anteroposteriorly or that were obtained with the long axis of the femur at 60-90° to the transducer were systematically smaller.

Conservative treatment may be still considered a viable therapeutic option for patients with spontaneous non-specific pyogenic spondylodiscitis. A retrospective audit study of 47 patients.

Background: Spontaneous non-specific pyogenic spondylodiscitis (SNPS) is a rare medical condition, whose optimal treatment remains controversial. We evaluated the multidisciplinary protocol implemented at our department for the conservative treatment of patients with SNPS. Methods: Patients with lumbar or thoracic SNPS, whose treatment was initiated conservatively and had at least six months of follow-up, were enrolled in this retrospective audit study. Patients with specific, postoperative, or iatrogenic spondylodiscitis or necessitating immediate operative treatment were excluded. The location of the infection, initial symptoms, co-morbidities, pathogens, duration of antibiotic treatment, hospitalization and follow-up, and outcome were retrieved. The visual analogue scale (VAS) score was used to register pain improvement after treatment. Results: Between January 2011 and December 2021, forty-seven patients (male: 26, mean age: 68.5 years) with SNPS (lumbar: 29, thoracic: 18) were hospitalized. The main co-morbidity was diabetes mellitus (23 patients). Pain was the predominant (46 patients), and fever was the second most common (19 patients) symptom. The most frequent causative microorganism was staphylococcus aureus (29 patients); no pathogen was identified in ten patients. The mean hospitalization duration for patients completing their conservative treatment (43/47) was 27 (range: 22-41) days. They received antibiotics for a mean period of 23 days intravenously (range: 21-29), 23.8 days per os (range: 21-35), and 46.8 days in total (range: 42-63). Conservative treatment was discontinued in two females. Two male patients died due to septic shock. The mean follow-up was 11.5 months (range: 6-15). During follow-up, no one developed any neurologic deficit and/or recurrence. There was a significant improvement in the mean VAS, from 8.3 ± 0.8 pre-treatment to 1.6 ± 0.5 at the latest follow-up (p <0.001). Conclusions: Although treatment is gradually shifting towards surgical intervention, conservative therapeutic management of SNPS patients with antibiotic administration, bed rest, and careful mobilization remains a viable and efficacious option. HIPPOKRATIA 2023, 27 (2):106-111.

Systematic review of methodology used in ultrasound studies aimed at creating charts of fetal size.

BACKGROUND: Reliable ultrasound charts are necessary for the prenatal assessment of fetal size, yet there is a wide variation of methodologies for the creation of such charts. OBJECTIVE: To evaluate the methodological quality of studies of fetal biometry using a set of predefined quality criteria of study design, statistical analysis and reporting methods. SEARCH STRATEGY: Electronic searches in MEDLINE, EMBASE and CINAHL, and references of retrieved articles. SELECTION CRITERIA: Observational studies whose primary aim was to create ultrasound size charts for bi-parietal diameter, head circumference, abdominal circumference and femur length in fetuses from singleton pregnancies. DATA COLLECTION AND ANALYSIS: Studies were scored against a predefined set of independently agreed methodological criteria and an overall quality score was given to each study. Multiple regression analysis between quality scores and study characteristics was performed. MAIN RESULTS: Eighty-three studies met the inclusion criteria. The highest potential for bias was noted in the following fields: 'Inclusion/exclusion criteria', as none of the studies defined a rigorous set of antenatal or fetal conditions which should be excluded from analysis; 'Ultrasound quality control measures', as no study demonstrated a comprehensive quality assurance strategy; and 'Sample size calculation', which was apparent in six studies only. On multiple regression analysis, there was a positive correlation between quality scores and year of publication: quality has improved with time, yet considerable heterogeneity in study methodology is still observed today. CONCLUSIONS: There is considerable methodological heterogeneity in studies of fetal biometry. Standardisation of methodologies is necessary in order to make correct interpretations and comparisons between different charts. A checklist of recommended methodologies is proposed.

Intra- and interobserver variability in fetal ultrasound measurements.

OBJECTIVE: To assess intra- and interobserver variability of fetal biometry measurements throughout pregnancy. METHODS: A total of 175 scans (of 140 fetuses) were prospectively performed at 14-41 weeks of gestation ensuring an even distribution throughout gestation. From among three experienced sonographers, a pair of observers independently acquired a duplicate set of seven standard measurements for each fetus. Differences between and within observers were expressed in measurement units (mm), as a percentage of fetal dimensions and as gestational age-specific Z-scores. For all comparisons, Bland-Altman plots were used to quantify limits of agreement. RESULTS: When using measurement units (mm) to express differences, both intra- and interobserver variability increased with gestational age. However, when measurement of variability took into account the increasing fetal size and was expressed as a percentage or Z-score, it remained constant throughout gestation. When expressed as a percentage or Z-score, the 95% limits of agreement for intraobserver difference for head circumference (HC) were ± 3.0% or 0.67; they were ± 5.3% or 0.90 and ± 6.6% or 0.94 for abdominal circumference (AC) and femur length (FL), respectively. The corresponding values for interobserver differences were ± 4.9% or 0.99 for HC, ± 8.8% or 1.35 for AC and ± 11.1% or 1.43 for FL. CONCLUSIONS: Although intra- and interobserver variability increases with advancing gestation when expressed in millimeters, both are constant as a percentage of the fetal dimensions or when reported as a Z-score. Thus, measurement variability should be considered when interpreting fetal growth rates.

Blood flow and diameter effect in the navigation process of magnetic nanocarriers inside the carotid artery.

BACKGROUND AND OBJECTIVE: Serious side effects are occurred during the cancer therapy. Magnetic driving of nanoparticles is a novel method for the elimination of these effects by supplying with anticancer drug or increase the temperature of the infected area. For this reason, a numerical model for optimal guidance of nanoparticles, through the gradient magnetic field, inside the human artery system is presented in this study. METHODS: The present method couples Computational Fluid Dynamics (CFD) and Discrete Element Method (DEM) techniques. In addition, the optimum magnetic intensity each time is evaluated by using the covariance matrix adaptation evolution strategy (CMA-ES). Under five feature blood flow velocities in cardiac cycle, the developed method evaluate and select the optimum gradient magnetic field in order to eliminate the deviation of the guided nanoparticles from a pre-described trajectory. RESULTS: Results of the simulations indicate both the influence of the blood flow and the volume of nanocarriers in the magnetic driving process in real conditions. Specifically, the blood flow and the volume of particles are inversely proportional parameters in the magnetic navigation process. As the blood flow is decreased, the deviation of nanoparticles compared to the desired path is minimized. On the contrary, the decrease of the volume of nanocarriers increase the distance of particles from the described trajectory. However, greater magnetic gradient values are needed as the blood flow is increased. Furthermore, the imposed gradient magnetic values are strongly connected with the position of the nanoparticles and the blood blow velocity. CONCLUSIONS: Based on the results of the present study, the most important parameter in the navigation process is the magnetic volume of particles. Under real conditions, the effect of the blood flow is insignificant compared to the volume of particles in the navigation process. In addition, great differences in the optimized magnetic sequence are presented both among the different blood flows and the volume of particles.

A review of fetal volumetry: the need for standardization and definitions in measurement methodology.

Volume charts of fetal organs and structures vary considerably among studies. This review identified 42 studies reporting normal volumes, namely for fetal brain (n = 3), cerebellum (n = 4), liver (n = 6), femur (n = 2), lungs (n = 15), kidneys (n = 3) and first-trimester embryo (n = 9). The differences among median volumes were expressed both in percentage form and as standard deviation scores. Wide discrepancies in reported normal volumes make it extremely difficult to diagnose pathological organ growth reliably. Given its magnitude, this variation is likely to be due to inconsistencies in volumetric methodology, rather than population differences. Complicating factors include the absence of clearly defined anatomical landmarks for measurement; inadequate assessment and reporting of method repeatability; the inherent difficulty in validating fetal measurements in vivo against a reference standard; and a multitude of mutually incompatible three-dimensional (3D) imaging formats and software measuring tools. An attempt to standardize these factors would improve intra- and inter-researcher agreement concerning reported volumetric measures, would allow generalization of reference data across different populations and different ultrasound systems, and would allow quality assurance in 3D fetal biometry. Failure to ensure a quality control process may hamper the wide use of 3D ultrasound.

Surface area measurement using rendered three-dimensional ultrasound imaging: an in-vitro phantom study.

OBJECTIVE: Cranial sutures and fontanelles can be reliably demonstrated using three-dimensional (3D) ultrasound with rendering. Our objective was to assess the repeatability and validity of fontanelle surface area measurement on rendered 3D images. METHODS: This was an in-vitro phantom validation study. Four holes, representing fontanelles, were cut on a flat vinyl tile. The phantom was scanned in a test-tank by two sonographers, at four different depths and using two different 3D sweep directions. The surface areas were measured on scan images and also directly from the phantom for comparison. Coefficients of variation (CVs), intraclass correlation coefficients (ICCs) and Bland-Altman plots were used for repeatability analysis. Validity was expressed as the percentage difference of the measured area from the true surface area. RESULTS: Validity of measurement was satisfactory with a mean percentage difference of - 5.9% (median = - 3.5%). The 95% limits of agreement were - 23.9 to 12.1%, suggesting that random error is introduced during image generation and measurement. Repeatability of caliper placement on the same image was higher (intraobserver CV = 1.6%, ICC = 0.999) than for measurement of a newly generated scan image (intraobserver CV = 5.5%, ICC = 0.992). Reduced accuracy was noted for the smallest shape tested. CONCLUSION: Surface area measurements on rendered 3D ultrasound images are accurate and reproducible in vitro.

Standardization of fetal ultrasound biometry measurements: improving the quality and consistency of measurements.

OBJECTIVE: To assess whether a standardization exercise prior to commencing a fetal growth study involving multiple sonographers can reduce interobserver variation. METHODS: In preparation for an international study assessing fetal growth, nine experienced sonographers from eight countries participated in a standardization exercise consisting of theoretical and practical sessions. Each performed a set of seven standard fetal measurements on pregnant volunteers at 20-37 weeks' gestation, and these were repeated by the lead sonographer; all measurements were taken in a blinded fashion. After this the sonographers had hands-on practice and feedback sessions on other volunteers. This process was repeated three times. Measurement differences between sonographers and the lead sonographer, expressed as a gestational-age-specific Z-score, between the first and third scans were compared using the Wilcoxon signed ranks test, and variance was assessed using Pitman's test. Interobserver agreement was also assessed using the intraclass correlation coefficient (ICC), and all images were scored for quality in a blinded fashion. RESULTS: At baseline the level of agreement and image scoring were high. A significant reduction in the differences between sonographers and the lead sonographer were seen for fetal biometry overall (head circumference, abdominal circumference and femur length) between the first and third scans (median Z-scores, 0.46 and 0.24; P = 0.005), and a reduction in the variance was also observed (P < 0.001). The ICCs for measurement pairs for every fetal measurement showed a clear trend of increasing ICC (better agreement) with consecutive training scan sessions, although no improvement in image scores was seen. CONCLUSION: Even for experienced sonographers, a standardization exercise before starting a study of fetal biometry can improve consistency of measurements. This could be of relevance for studies assessing fetal growth in multicenter sites.

Uncertainty quantification implementations in human hemodynamic flows.

BACKGROUND AND OBJECTIVE: Human hemodynamic modeling is usually influenced by uncertainties occurring from a considerable unavailability of information linked to the boundary conditions and the physical properties used in the numerical models. Calculating the effect of these uncertainties on the numerical findings along the cardiovascular system is a demanding process due to the complexity of the morphology of the body and the area dynamics. To cope with all these difficulties, Uncertainty Quantification (UQ) methods seem to be an ideal tool. RESULTS: This study focuses on analyzing and summarizing some of the recent research efforts and directions of implementing UQ in human hemodynamic flows by analyzing 139 research papers. Initially, the suitability of applying this approach is analyzed and demonstrated. Then, an overview of the most significant research work in various fields of biomedical hemodynamic engineering is presented. Finally, it is attempted to identify any possible forthcoming directions for research and methodological progress of UQ in biomedical sciences. CONCLUSION: This review concludes that by finding the best statistical methods and parameters to represent the propagated uncertainties, while achieving a good interpretation of the interaction between input-output, is crucial for implementing UQ in biomedical sciences.

On the magnetic aggregation of Fe3O4 nanoparticles.

Background and objective In-vivo MRI-guided drug delivery concept is a personalized technique towards cancer treatment. A major bottleneck of this method, is the weak magnetic response of nanoparticles. A crucial improvement is the usage of paramagnetic nanoparticles aggregates since they can easier manipulated in human arteries than isolated particles. However its significance, not a comprehensive study to estimate the mean length and time to aggregate exists. Methods The present detailed numerical study includes all major discrete and continues forces and moments of the nanoscale in a global model. The effort is given in summarizing the effects of particle diameter and concentration, and magnetic field magnitude to comprehensive relations. Therefore, several cases with nanoparticles having various diameters and concentrations are simulated as magnetic field increases. Results It is found that aggregations with maximum length equal to 2000nm can be formed. In addition, the increase of the concentration leads to a decrease in the amount of the isolated particles. Consequently, 33% of the particles are isolated for the concentration of 2.25mg/ml while 13% for the concentration of 10mg/ml. Moreover, the increase of the permanent magnetic field and diameter of particles gives rise to an asymptotic behavior in the number of isolated particles. Furthermore, the mean length of aggregates scales linear with diameter and magnetic field, however, concentration increase results in a weaker effect. The larger aggregation that is formed is composed by 21 particles. Smaller time is needed for the completion of the aggregation process with larger particles. Additionally, the increase of the magnitude of the magnetic field leads to a decrease in the aggregation time process. Therefore, 8.5ms are needed for the completion of the aggregation process for particles of 100nm at B0=0.1T while 7ms at B0=0.9T. Surprisedly, the mean time to aggregate is of the same order as in microparticles, although, with an opposite trend. Conclusions In this study, the evolution of the mean length of aggregations as well as the completion time of the aggregation process in the nano and micro range is evaluated. The present results could be useful to improve the magnetic nanoparticles assisted drug delivery method in order to minimize the side effects from the convectional cancer treatments like radiation and chemotherapy.

Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study.

STUDY QUESTION: Can consensus definitions for the core outcome set for infertility be identified in order to recommend a standardized approach to reporting? SUMMARY ANSWER: Consensus definitions for individual core outcomes, contextual statements, and a standardized reporting table have been developed. WHAT IS KNOWN ALREADY: Different definitions exist for individual core outcomes for infertility. This variation increases the opportunities for researchers to engage with selective outcome reporting, which undermines secondary research and compromises clinical practice guideline development. STUDY DESIGN, SIZE, DURATION: Potential definitions were identified by a systematic review of definition development initiatives and clinical practice guidelines and by reviewing Cochrane Gynaecology and Fertility Group guidelines. These definitions were discussed in a face-to-face consensus development meeting, which agreed consensus definitions. A standardized approach to reporting was also developed as part of the process. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, researchers, and people with fertility problems were brought together in an open and transparent process using formal consensus development methods. MAIN RESULTS AND THE ROLE OF CHANCE: Forty-four potential definitions were inventoried across four definition development initiatives, including the Harbin Consensus Conference Workshop Group and International Committee for Monitoring Assisted Reproductive Technologies, 12 clinical practice guidelines, and Cochrane Gynaecology and Fertility Group guidelines. Twenty-seven participants, from 11 countries, contributed to the consensus development meeting. Consensus definitions were successfully developed for all core outcomes. Specific recommendations were made to improve reporting. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations. There was limited representation from low- and middle-income countries. WIDER IMPLICATIONS OF THE FINDINGS: A minimum data set should assist researchers in populating protocols, case report forms, and other data collection tools. The generic reporting table should provide clear guidance to researchers and improve the reporting of their results within journal publications and conference presentations. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials statement, and over 80 specialty journals have committed to implementing this core outcome set. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund, and Maurice and Phyllis Paykel Trust. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility group. Hans Evers reports being the Editor Emeritus of Human Reproduction. Richard Legro reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. Ben Mol reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. Craig Niederberger reports being the Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and a financial interest in NexHand. Ernest Ng reports research sponsorship from Merck. Annika Strandell reports consultancy fees from Guerbet. Jack Wilkinson reports being a statistical editor for the Cochrane Gynaecology and Fertility group. Andy Vail reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and of the journal Reproduction. His employing institution has received payment from HFEA for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. Lan Vuong reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: Core Outcome Measures in Effectiveness Trials Initiative: 1023.

Top 10 priorities for future infertility research: an international consensus development study.

STUDY QUESTION: Can the priorities for future research in infertility be identified? SUMMARY ANSWER: The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction, and ethics, access, and organization of care for people with fertility problems were identified. WHAT IS KNOWN ALREADY: Many fundamental questions regarding the prevention, management, and consequences of infertility remain unanswered. This is a barrier to improving the care received by those people with fertility problems. STUDY DESIGN, SIZE, DURATION: Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines, and Cochrane systematic reviews. A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research priorities for each of the categories male infertility, female and unexplained infertility, medically assisted reproduction, and ethics, access, and organization of care. PARTICIPANTS/MATERIALS, SETTING, METHODS: Healthcare professionals, people with fertility problems, and others (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process using formal consensus methods advocated by the James Lind Alliance. MAIN RESULTS AND THE ROLE OF CHANCE: The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions. A rationalized list of 231 confirmed research uncertainties were entered into an interim prioritization survey completed by 317 respondents from 43 countries. The top 10 research priorities for each of the four categories male infertility, female and unexplained infertility (including age-related infertility, ovarian cysts, uterine cavity abnormalities, and tubal factor infertility), medically assisted reproduction (including ovarian stimulation, IUI, and IVF), and ethics, access, and organization of care, were identified during a consensus development meeting involving 41 participants from 11 countries. These research priorities were diverse and seek answers to questions regarding prevention, treatment, and the longer-term impact of infertility. They highlight the importance of pursuing research which has often been overlooked, including addressing the emotional and psychological impact of infertility, improving access to fertility treatment, particularly in lower resource settings, and securing appropriate regulation. Addressing these priorities will require diverse research methodologies, including laboratory-based science, qualitative and quantitative research, and population science. LIMITATIONS, REASONS FOR CAUTION: We used consensus development methods, which have inherent limitations, including the representativeness of the participant sample, methodological decisions informed by professional judgement, and arbitrary consensus definitions. WIDER IMPLICATIONS OF THE FINDINGS: We anticipate that identified research priorities, developed to specifically highlight the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems, and others, will help research funding organizations and researchers to develop their future research agenda. STUDY FUNDING/ COMPETING INTEREST(S): The study was funded by the Auckland Medical Research Foundation, Catalyst Fund, Royal Society of New Zealand, and Maurice and Phyllis Paykel Trust. Geoffrey Adamson reports research sponsorship from Abbott, personal fees from Abbott and LabCorp, a financial interest in Advanced Reproductive Care, committee membership of the FIGO Committee on Reproductive Medicine, International Committee for Monitoring Assisted Reproductive Technologies, International Federation of Fertility Societies, and World Endometriosis Research Foundation, and research sponsorship of the International Committee for Monitoring Assisted Reproductive Technologies from Abbott and Ferring. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and editor for the Cochrane Gynaecology and Fertility Group. Hans Evers reports being the Editor Emeritus of Human Reproduction. Andrew Horne reports research sponsorship from the Chief Scientist's Office, Ferring, Medical Research Council, National Institute for Health Research, and Wellbeing of Women and consultancy fees from Abbvie, Ferring, Nordic Pharma, and Roche Diagnostics. M. Louise Hull reports grants from Merck, grants from Myovant, grants from Bayer, outside the submitted work and ownership in Embrace Fertility, a private fertility company. Neil Johnson reports research sponsorship from Abb-Vie and Myovant Sciences and consultancy fees from Guerbet, Myovant Sciences, Roche Diagnostics, and Vifor Pharma. José Knijnenburg reports research sponsorship from Ferring and Theramex. Richard Legro reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. Ben Mol reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. Ernest Ng reports research sponsorship from Merck. Craig Niederberger reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. Jane Stewart reports being employed by a National Health Service fertility clinic, consultancy fees from Merck for educational events, sponsorship to attend a fertility conference from Ferring, and being a clinical subeditor of Human Fertility. Annika Strandell reports consultancy fees from Guerbet. Jack Wilkinson reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. Andy Vail reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and of the journal Reproduction. His employing institution has received payment from HFEA for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. Lan Vuong reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the present work. All authors have completed the disclosure form. TRIAL REGISTRATION NUMBER: Not applicable.