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.

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.

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.

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 (RCT) 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, Ferility 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. 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. 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. 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. Annika Strandell reports consultancy fees from Guerbet. Ernest Ng reports research sponsorship from Merck. 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.

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.

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.

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.

Rheological properties of synovial fluid due to viscosupplements: A review for osteoarthritis remedy.

The synovial fluid is a transparent electrolyte solution included in joints to provide lubrication helping the proper movement. It exhibits complex rheological properties due to the interaction among its constituents i.e. hyaluronic acid, albumin, lubricin and phospholipids. In degenerative osteoarthritis and inflammatory rheumatoid arthritis diseases, the quantity of synovial fluid and lubrication efficiency significantly deteriorates. In that case, viscosupplementation with intra-articular hyaluronic acid may be prescribed to replenish the concentration, the molecular weight and the rheological properties of natural synovial fluid. The present review concentrates on the recent advancements in viscosupplementation with emphasis into their rheological properties, its effects on the rheological behavior of synovial fluid, and finally its clinical effectiveness. Initially, the properties of synovial fluid are summarized, and then a discussion on commercial viscosupplements, the role of polymeric properties and their rheological properties are reviewed. Moreover, a detailed discussion on the clinical effectiveness and challenges of viscosupplements are provided.

Effect of fractal-shaped outer boundary of glioblastoma multiforme on drug delivery.

BACKGROUND AND OBJECTIVE: The present study investigates the transport of drugs in the proximity of the glioblastoma multiforme, a brain neoplasm which is regarded to be the most aggressive type of cancer. In such a small distance from the tumor, diffusion dominates and is driven by the concentration gradient of drug that acquires its maximum at regions where the drugs are released and its minimum at the cancer cell boundary. Undoubtedly, the morphology of the aforementioned boundary is going to play a crucial role in the drug delivery and should be taken into account for the optimal design of the treatment. As first step in order to simulate the topography of glioblastoma multiforme, a fractal boundary is examined which mimics an acceptable model-problem for prognosis and diagnosis of a number of cancer tumors in breast, lungs and brain. METHODS: The drug diffusion is investigated for two concentrations, namely a strong and a mild diffusion, while the outer boundary of the glioblastoma multiforme is approximated via triangular Von Koch shapes. Besides, a Finite Element Method is utilized via FEniCS, which is a Python-based open-source computing platform. Finally, after ascertaining the accuracy of the present numerical model, the concentration of the drug, the entropy production and the mass fluxes in the horizontal and vertical directions are estimated up to the fifth order of Von Koch fractal iterations. RESULTS: It is ascertained that as the boundaries become more and more irregular, the entropy production in specific areas increases and as a consequence the delivery of the drug is facilitated. Hence, the mass fluxes in these sites appear to be larger comparing to the rest of the boundary and increase, as expected, for the case of strong diffusion. CONCLUSIONS: These active regions, which are referred as "hot spots", are of great importance since they seem to be the sites where the drug ultimately penetrates the glioblastoma. This first-principles investigation is anticipated to shed light on a very significant part of drug delivery, which deals with the vicinity of the glioblastoma multiforme, stress the importance of the topography and give rise to future studies to be conducted based on subject-specific geometries.

Development of a new theoretical model for blood-CNTs effective thermal conductivity pertaining to hyperthermia therapy of glioblastoma multiform.

BACKGROUND AND OBJECTIVE: The present study deals with the hyperthermia therapy, which is the type of treatment in which tissues are exposed to high temperatures in order to destroy cancer cells with minimal injury to healthy tissues. In particular, it focuses on glioblastoma multiform, which is the most aggressive cancer that begins within the brain. Conventional treatments display limitations that can be overcome by using nanoparticles for targeted heating. Out of the proposed nanoparticles, this investigation focuses on a new field that utilizes carbon nanotubes (CNTs) which are able to selectively heat the cancer cells since they can convert near infrared light into heat. In the absence of any experiment or theoretical model for the estimation of an effective thermal conductivity of blood and CNTs, a first principle model is developed in this study which takes into account the blood micro-structure. Besides, a number of factors are included, namely the shape and the size of the nanoparticles, the interfacial layer formed around them and their volume fraction. METHODS: Firstly, assuming that the blood consists of blood cells and plasma, the thermal conductivity of the former is estimated. Then, the effective thermal conductivity of plasma/CNTs is calculated for various parameters. Finally, the resulting "bio-nanofluid" consisting of plasma/CNTs and blood cells is formed. RESULTS: It is ascertained that thin and elongated CNTs with relatively large nanolayer thickness as well as large concentrations of CNTs contribute to the increase of the thermal conductivity and, thus, in the enhancement of the heat transfer. CONCLUSIONS: Investigating of how design parameters pertaining to CNTs, such as their size and shape, affect the effective thermal conductivity of blood-CNTs, possible regulating ways are suggested regarding the hyperthermic treatment. Finally, the present simple estimation of the effective thermal conductivity can be used as an effective property of the nanofluid when it comes to numerical investigations regarding heat transfer occurring during hyperthermia or other potential clinical uses (for example targeted heat of living tissues).

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.

A numerical model for aggregations formation and magnetic driving of spherical particles based on OpenFOAM®.

BACKGROUND AND OBJECTIVE: This work presents a numerical model for the formation of particle aggregations under the influence of a permanent constant magnetic field and their driving process under a gradient magnetic field, suitably created by a Magnetic Resonance Imaging (MRI) device. METHODS: The model is developed in the OpenFOAM platform and it is successfully compared to the existing experimental and numerical results in terms of aggregates size and their motion in water solutions. Furthermore, several series of simulations are performed for two common types of particles of different diameter in order to verify their aggregation and flow behaviour, under various constant and gradient magnetic fields in the usual MRI working range. Moreover, the numerical model is used to measure the mean length of aggregations, the total time needed to form and their mean velocity under different permanent and gradient magnetic fields. RESULTS: The present model is found to predict successfully the size, velocity and distribution of aggregates. In addition, our simulations showed that the mean length of aggregations is proportional to the permanent magnetic field magnitude and particle diameter according to the relation : l¯a=7.5B0di3/2. The mean velocity of the aggregations is proportional to the magnetic gradient, according to : u¯a=6.63G˜B0 and seems to reach a steady condition after a certain period of time. The mean time needed for particles to aggregate is proportional to permanent magnetic field magnitude, scaled by the relationship : t¯a∝7B0. CONCLUSIONS: A numerical model to predict the motion of magnetic particles for medical application is developed. This model is found suitable to predict the formation of aggregations and their motion under the influence of permanent and gradient magnetic fields, respectively, that are produced by an MRI device. The magnitude of the external constant magnetic field is the most important parameter for the aggregations formation and their driving.

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 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.

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 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.

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.

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.