The peak force to push a trial tibial insert into position cannot be used to select the correct thickness in total knee arthroplasty.

An objective of a total knee arthroplasty (TKA) is to restore native (i.e. healthy) function, and a crucial step is determining the correct insert thickness for each patient. If the insert is too thick, then stiffness results, and if too thin, then instability results. Two methods to determine the insert thickness are by manually assessing the joint laxity and by using a trial insert with goniometric markings that measures the internal-external rotation of the trial with respect to a mark on the femoral component. The former is qualitative and depends on the surgeon's experience and 'feel' and while the latter is quantitative, it can be used only with an insert with medial ball-in-socket conformity. An unexplored method is to measure the force required to push a trial insert into position. To determine whether this method has merit, the push force was measured in 30 patients undergoing unrestricted kinematically aligned TKA using an insert with ball-in-socket medial conformity, a flat lateral surface, and retention of the posterior cruciate ligament. During surgery, the surgeon determined three appropriate thicknesses to test from a selection ranging from 10 mm to 14 mm in 1 mm increments. The peak push forces going from an insert 1 mm thinner than the correct thickness as determined by an insert goniometer and from the correct thickness to 1 mm thicker were measured. Mean peak forces for the different insert thicknesses were 127 ± 104 N, 127 ± 95 N, and 144 ± 96 N for 1 mm thinner, correct, and 1 mm thicker, respectively, and did not differ (p = 0.3210). As a result, measurement of peak force during trial positioning of a tibial insert cannot be used to identify the correct thickness for all insert designs.

Posterior cruciate ligament retention with medial ball-in-socket conformity promotes internal tibial rotation and knee flexion while providing high clinical outcome scores.

BACKGROUND: Although retaining the posterior cruciate ligament (PCL) is advantageous in unrestricted kinematically aligned TKA, it is often excised with a medial stabilized implant. The primary objectives were to determine whether PCL retention using an insert with ball-in-socket (B-in-S) medial conformity to maximize A-P stability promotes internal tibial rotation and flexion while providing high patient-reported outcome scores. METHODS: Two cohorts of 25 patients each were treated with unrestricted kinematically aligned (KA) TKA using a tibial insert with B-in-S medial conformity and a flat lateral articular surface. One cohort retained the PCL; the other had it excised. Patients performed deep knee bend and step-up exercises during fluoroscopic imaging. Following 3D model-to-2D image registration, anterior-posterior (A-P) positions of the femoral condyles and tibial rotation were determined. RESULTS: For deep knee bend, mean internal tibial rotation with PCL retention was significantly greater at maximum flexion (17.7° ± 5.7° versus 10.4° ± 6.5°, p < 0.001) and significantly greater at 30°, 60°, and 90° flexion as well (p ≤ 0.0283). For step-up, mean internal tibial rotation with PCL retention was significantly greater at at 15°, 30°, and 45° flexion (p ≤ 0.0049) but was marginally not significantly greater at 60° (i.e. maximum) flexion (12.3° ± 4.4° versus 10.1° ± 5.4°, p = 0.0794). Mean flexion during active knee flexion with PCL retention was significantly greater (127° ± 8° versus 122° ± 6°, p = 0.0400). Both cohorts had high median Oxford Knee, WOMAC, and Forgotten Joint Scores that were not significantly different (p = 0.0918, 0.1448, and 0.0855, respectively) CONCLUSION: Surgeons that perform unrestricted KA TKA should retain the PCL with an insert that has B-in-S medial conformity, as this maintains extension and flexion gaps while also promoting internal tibial rotation and knee flexion as well as providing high clinical outcome scores.

Safety and acceptability of intravaginal rings releasing estradiol and progesterone.

OBJECTIVE: This study aimed to evaluate the safety and acceptability of two fixed-dose 28-day vaginal ring formulations of 17ß-estradiol (E2) and progesterone (P4) to treat vasomotor symptoms (VMS) and the genitourinary syndrome of menopause. DESIGN: DARE HRT1-001 was the first-in-woman study of 28-day exposure to two 28-day intravaginal rings (IVRs) designed to release 80 µg/day E2 + 4 mg/day P4 (IVR1) or 160 µg/day E2 + 8 mg/day P4 (IVR2) compared with oral E2 1 mg/day + oral P4 100 mg/day. To assess safety, participants completed a daily diary to record treatment emergent adverse events (TEAEs). To determine acceptability, at the end of treatment IVR users completed a questionnaire assessing tolerability and usability. RESULTS: Enrolled women (n = 34) were randomized to use IVR1 (n = 10), IVR2 (n = 12) or oral (n = 12). Thirty-one participants (IVR1 = 10, IVR2 = 10, oral = 11) completed the study. The TEAE profile of those in the IVR groups were similar to the referent oral regimen. TEAEs related to the study product were more common with IVR2 use. Endometrial biopsies were not performed unless endometrial thickness was >4 mm or for clinically significant postmenopausal bleeding. One IVR1 participant had an endometrial stripe increase from 4 mm at screening to 8 mm at the end of treatment. The biopsy indicated no evidence of plasma cells or endometritis and no evidence of atypia, hyperplasia or malignancy. Two other endometrial biopsies were performed for postmenopausal bleeding with similar findings. There were no clinically meaningful laboratory or vital sign abnormalities or trends identified in observed values or changes from baseline. Pelvic speculum examination identified no clinically significant abnormalities in any participant at any visit. Tolerability and usability data demonstrated that both IVRs were generally highly acceptable. CONCLUSIONS: Both IVR1 and IVR2 were safe and well tolerated in healthy postmenopausal women. TEAE profiles were comparable to the referent oral regimen.

Joint Coordinate System Using Functional Axes Achieves Clinically Meaningful Kinematics of the Tibiofemoral Joint as Compared to the International Society of Biomechanics Recommendation.

Quantification of clinically meaningful tibiofemoral motions requires a joint coordinate system (JCS) with motions free from kinematic crosstalk errors. The objectives were to use a JCS with literature-backed functional axes (FUNC) and a JCS recommended by the International Society of Biomechanics (ISB) to determine tibiofemoral kinematics of the native (i.e., healthy) knee, determine variability associated with each JCS, and determine whether the FUNC JCS significantly reduced kinematic crosstalk errors compared to the ISB JCS. Based on a kinematic model consisting of a three-cylindric joint chain, the FUNC JCS included functional flexion-extension (F-E) and internal-external (I-E) tibial rotation axes. In contrast, the ISB JCS included F-E and I-E axes defined using anatomic landmarks. Single-plane fluoroscopic images in 13 subjects performing a weighted deep knee bend were analyzed. Tibiofemoral kinematics using the FUNC JCS fell within the physiological range of motion in all six degrees-of-freedom. Internal tibial rotation averaged 13 deg for the FUNC JCS versus 10 deg for the ISB JCS and motions in the other four degrees-of-freedom (collectively termed off-axis motions) were minimal as expected based on biomechanical constraints. Off-axis motions for the ISB JCS were significantly greater; maximum valgus rotation was 4 deg and maximum anterior and distraction translations were 9 mm and 25 mm, respectively, which is not physiologic. Variabilities in off-axis motions were significantly greater with the ISB JCS (p < 0.0002). The FUNC JCS achieved clinically meaningful kinematics by significantly reducing kinematic crosstalk errors and is the more suitable coordinate system for quantifying tibiofemoral motions.

Errors in using fixed flexion facet centers to determine tibiofemoral kinematics increase fourfold for multi-radius femoral component designs with early versus late decreases in the radius of curvature.

BACKGROUND: One method to determine tibiofemoral joint kinematics following total knee arthroplasty (TKA) is to quantify movement of the anterior-posterior (AP) position of the flexion facet center (FFC) on each femoral condyle relative to the tibia during knee flexion. The primary objective was to determine how closely AP positions of fixed FFCs approximate AP positions of variable FFCs of multi-radius femoral component designs with early versus late initial transition angles (i.e. earliest flexion angle where the radius of curvature decreases markedly). METHODS: Variable FFCs were determined for each femoral condyle as centers of best-fit circles to 20° segments of the sagittal profile from 0° to 120° of flexion in 15° increments. The fixed FFC of each condyle was the center of the best-fit circle from 0° to 120° of flexion. Errors in AP positions were differences between AP positions of fixed FFCs and variable FFCs. RESULTS: For profiles with a late initial transition angle of 120° of flexion, the root mean square error (RMSE) was limited to 0.7 mm. For profiles with an early initial transition angle of 60° of flexion, the RMSE was 2.7 mm, nearly a fourfold increase. CONCLUSIONS: To determine whether fixed FFCs can be used to indicate AP positions of femoral condyles with minimal RMSE < 1 mm, the initial transition angle should be found as an important first step. Condylar AP positions for designs with an early initial transition angle should not be approximated by AP positions of fixed FFCs when determining tibiofemoral kinematics.

Can a 2D planar model more accurately determine locations of contact developed by the femoral condyles on the tibial insert in total knee arthroplasty than the penetration method?

Knowledge of the anterior-posterior (AP) tibial contact locations is useful in assessing wear of tibial inserts and detecting posterior rim loading. The objectives of this study were to 1) create a new 2D planar model to determine AP tibial contact locations, 2) use the 2D planar model to determine AP tibial contact locations for cadaveric TKA knees, and 3) determine whether errors of the 2D planar model are lower than those of the penetration method. A slopes-of-sagittal profiles (SSP) model was created using mathematical functions to simulate articular surfaces of the tibial insert and femoral condyles. AP tibial contact locations were computed using the model and the penetration method and simultaneously measured with a custom tibial force sensor in 10 cadaveric TKA knees at 0°, 30°, 60°, and 90° of flexion in each compartment during passive motion. For each method, the overall bias, overall precision, and overall root mean square error (RMSE) were calculated from the differences between the computed AP tibial contact locations and the measured locations. The SSP model had an overall bias of 0.6 mm and precision of 2.8 mm which were significantly greater than the overall bias of -0.1 mm (p = 0.0369) and overall precision of 2.0 mm (p = 0.0021) of the penetration method. A planar model based on the analysis of single-plane radiographs did not decrease overall errors in AP tibial contact locations compared to the penetration method.

Agreement Between Two Methods for Computing the Anterior-Posterior Positions of Native Femoral Condyles Using Three-Dimensional Bone Models With and Without Articular Cartilage and Smoothing.

Knowledge of anterior-posterior (AP) movement of the femoral condyles on the tibia in healthy knees serves to assess whether an artificial knee restores natural movement. Two methods for identifying AP positions and hence condylar movements include: (1) the flexion facet center (FFC) and (2) the lowest point (LP) methods. The objectives were to determine (1) agreement between the two methods and (2) whether addition of articular cartilage and/or smoothing significantly affects AP positions. Magnetic resonance (MR) images of healthy knees were obtained from eleven subjects, who subsequently performed a dynamic, weight-bearing deep knee bend under fluoroscopy. Four different types of MR models of the distal femur were created: femur, smoothed femur, femur with articular cartilage, and femur with smoothed articular cartilage. In the medial and lateral compartments for the femur with smoothed articular cartilage at 0 deg flexion, mean AP positions of the LPs were 7.7 mm and 5.4 mm more anterior than those of the FFCs, respectively (p < 0.0001, p = 0.0002) and limits of agreement were ±5.5 mm. In the flexion range 30 deg to 90 deg, differences in mean AP positions were 1.5 mm or less and limits of agreement were bounded by ±2.4 mm. Differences in mean AP positions between model types were <1.3 mm for both LPs and FFCs. Since omitting articular cartilage from three-dimensional (3D) models of the femur minimally affected AP positions, faster and less expensive imaging techniques such as computed-tomography (CT) can be used to generate 3D bone models for kinematic analysis. In addition, the LP method is preferred over the FFC method because of its inherent accuracy in indicating the AP position of the instant center of curvature of the femoral condyles which varies with the knee in extension versus flexion.

Circle-based model to estimate error in using the lowest points to indicate locations of contact developed by the femoral condyles on the tibial insert in total knee arthroplasty.

A common method used to study tibiofemoral joint biomechanics following total knee arthroplasty (TKA) is the lowest point method, which finds the lowest points of each femoral condyle in relation to the plane of the resected tibia. The objectives of this paper were twofold: 1) to use a circle-based model to demonstrate the large inherent error introduced when the lowest points are used to indicate anterior-posterior (AP) positions of contact by the femur on the tibial insert, 2) to use the circle-based model to estimate the magnitude of error. A circle-based model was created to simulate articular surfaces of the tibial insert and condyles of the femoral component and to demonstrate the error. Equations relating the error to radii of tibial and femoral articular surfaces were derived. The magnitude of the error was estimated for common low-conforming TKA components by determining radii using best-fit circles to approximate curvature of articular surfaces. Error in AP tibial insert contact locations is caused by the slope of the tibial articular surface and the magnitude increases with increasing slope and increasing radius of the femoral condyle. For radii approximating articular surfaces of common low-conforming components, relative errors range from 45% to 109%. The circle-based model effectively demonstrates the cause of the large error in using lowest points to indicate AP tibial insert contact locations and enables an estimate of relative error. Because relative error exceeds 45%, the lowest point method should not be used to indicate the AP tibial insert contact locations.

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.

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.

A core outcome set for future endometriosis research: an international consensus development study.

OBJECTIVE: To develop a core outcome set for endometriosis. DESIGN: Consensus development study. SETTING: International. POPULATION: One hundred and sixteen healthcare professionals, 31 researchers and 206 patient representatives. METHODS: Modified Delphi method and modified nominal group technique. RESULTS: The final core outcome set includes three core outcomes for trials evaluating potential treatments for pain and other symptoms associated with endometriosis: overall pain; improvement in the most troublesome symptom; and quality of life. In addition, eight core outcomes for trials evaluating potential treatments for infertility associated with endometriosis were identified: viable intrauterine pregnancy confirmed by ultrasound; pregnancy loss, including ectopic pregnancy, miscarriage, stillbirth and termination of pregnancy; live birth; time to pregnancy leading to live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital abnormalities. Two core outcomes applicable to all trials were also identified: adverse events and patient satisfaction with treatment. CONCLUSIONS: Using robust consensus science methods, healthcare professionals, researchers and women with endometriosis have developed a core outcome set to standardise outcome selection, collection and reporting across future randomised controlled trials and systematic reviews evaluating potential treatments for endometriosis. TWEETABLE ABSTRACT: @coreoutcomes for future #endometriosis research have been developed @jamesmnduffy.

Prediction of Future Chronic Opioid Use Among Hospitalized Patients.

BACKGROUND: Opioids are commonly prescribed in the hospital; yet, little is known about which patients will progress to chronic opioid therapy (COT) following discharge. We defined COT as receipt of ≥ 90-day supply of opioids with < 30-day gap in supply over a 180-day period or receipt of ≥ 10 opioid prescriptions over 1 year. Predictive tools to identify hospitalized patients at risk for future chronic opioid use could have clinical utility to improve pain management strategies and patient education during hospitalization and discharge. OBJECTIVE: The objective of this study was to identify a parsimonious statistical model for predicting future COT among hospitalized patients not on COT before hospitalization. DESIGN: Retrospective analysis electronic health record (EHR) data from 2008 to 2014 using logistic regression. PATIENTS: Hospitalized patients at an urban, safety net hospital. MAIN MEASUREMENTS: Independent variables included medical and mental health diagnoses, substance and tobacco use disorder, chronic or acute pain, surgical intervention during hospitalization, past year receipt of opioid or non-opioid analgesics or benzodiazepines, opioid receipt at hospital discharge, milligrams of morphine equivalents prescribed per hospital day, and others. KEY RESULTS: Model prediction performance was estimated using area under the receiver operator curve, accuracy, sensitivity, and specificity. A model with 13 covariates was chosen using stepwise logistic regression on a randomly down-sampled subset of the data. Sensitivity and specificity were optimized using the Youden's index. This model predicted correctly COT in 79% of the patients and no COT correctly in 78% of the patients. CONCLUSIONS: Our model accessed EHR data to predict 79% of the future COT among hospitalized patients. Application of such a predictive model within the EHR could identify patients at high risk for future chronic opioid use to allow clinicians to provide early patient education about pain management strategies and, when able, to wean opioids prior to discharge while incorporating alternative therapies for pain into discharge planning.

Do varus or valgus outliers have higher forces in the medial or lateral compartments than those which are in-range after a kinematically aligned total knee arthroplasty? limb and joint line alignment after kinematically aligned total knee arthroplasty.

AIMS: The aims of this study were to determine the proportion of patients with outlier varus or valgus alignment in kinematically aligned total knee arthroplasty (TKA), whether those with outlier varus or valgus alignment have higher forces in the medial or lateral compartments of the knee than those with in-range alignment and whether measurements of the alignment of the limb, knee and components predict compartment forces. PATIENTS AND METHODS: The intra-operative forces in the medial and lateral compartments were measured with an instrumented tibial insert in 67 patients who underwent a kinematically aligned TKA during passive movement. The mean of the forces at full extension, 45° and 90° of flexion determined the force in the medial and lateral compartments. Measurements of the alignment of the limb and the components included the hip-knee-ankle (HKA) angle, proximal medial tibial angle (PMTA), and distal lateral femoral angle (DLFA). Measurements of the alignment of the knee and the components included the tibiofemoral angle (TFA), tibial component angle (TCA) and femoral component angle (FCA). Alignment was measured on post-operative, non-weight-bearing anteroposterior (AP) scanograms and categorised as varus or valgus outlier or in-range in relation to mechanically aligned criteria. RESULTS: The proportion of patients with outlier varus or valgus alignment was 16%/24% for the HKA angle, 55%/0% for the PMTA, 0%/57% for the DLFA, 25%/12% for the TFA, 100%/0% for the TCA, and 0%/64% for the FCA. In general, the forces in the medial and lateral compartments of those with outlier alignment were not different from those with in-range alignment except for the TFA, in which patients with outlier varus alignment had a mean paradoxical force which was 6 lb higher in the lateral compartment than those with in-range alignment. None of the measurements of alignment of the limb, knee and components predicted the force in the medial or lateral compartment. CONCLUSION: Although kinematically aligned TKA has a high proportion of varus or valgus outliers using mechanically aligned criteria, the intra-operative forces in the medial and lateral compartments of patients with outlier alignment were comparable with those with in-range alignment, with no evidence of overload of the medial or lateral compartment of the knee. Cite this article: Bone Joint J 2017;99-B:1319-28.

Anterior laxity and patient-reported outcomes 7 years after ACL reconstruction with a fresh-frozen tibialis allograft.

PURPOSE: After reconstructing a torn ACL with a soft tissue allograft, the long-term healing process of graft maturation following the short-term healing process of graft incorporation into the bone tunnels might lead to recurring instability and concomitant decreases in the activity level, function, and patient satisfaction. Relying on roentgen stereophotogrammetric analysis (RSA), the primary purpose was to determine whether anterior laxity increased and whether patient-reported outcomes declined between 1 and 7 years for a particular graft construct, surgical technique, and rehabilitation programme. METHODS: Eighteen of 19 patients, who participated in an earlier RSA study which extended to 1 year after the surgical procedure, were contacted 7 years after the surgical procedure. An examiner, different from the treating surgeon, measured anterior laxity under 150 N of anterior force using RSA in 16 patients and obtained outcome scores in 17 patients. One patient moved abroad and could not be contacted. One patient reinjured his reconstructed ACL and was excluded. RESULTS: The average increase in anterior laxity of 1.5 ± 2.1 mm between 1 and 7 years after surgery was not significant (p = 0.08), and the average increase in anterior laxity of 2.7 ± 2.3 mm between the day of surgery and 7 years was significant (p < 0.001). There were no significant declines in activity (median Tegner score, 6 at 1 year, 6 at 7 years), function (average Lysholm score, 94 at 1 year, 91 at 7 years), and subjective satisfaction (average International Knee Documentation Committee score, 90 at 1 year, 87 at 7 years) between 1 and 7 years after surgery. CONCLUSION: In demonstrating that the ACL graft construct remains functional in the long term, this study supports the use of a fresh-frozen tibialis allograft in patients with an average age of 37 years at the time of surgery when used in conjunction with a surgical technique which avoids roof and PCL impingement, uses slippage-resistant fixation devices, and allows brace-free, self-paced rehabilitation. LEVEL OF EVIDENCE: IV.

Design, calibration and validation of a novel 3D printed instrumented spatial linkage that measures changes in the rotational axes of the tibiofemoral joint.

An accurate axis-finding technique is required to measure any changes from normal caused by total knee arthroplasty in the flexion-extension (F-E) and longitudinal rotation (LR) axes of the tibiofemoral joint. In a previous paper, we computationally determined how best to design and use an instrumented spatial linkage (ISL) to locate the F-E and LR axes such that rotational and translational errors were minimized. However, the ISL was not built and consequently was not calibrated; thus the errors in locating these axes were not quantified on an actual ISL. Moreover, previous methods to calibrate an ISL used calibration devices with accuracies that were either undocumented or insufficient for the device to serve as a gold-standard. Accordingly, the objectives were to (1) construct an ISL using the previously established guidelines,(2) calibrate the ISL using an improved method, and (3) quantify the error in measuring changes in the F-E and LR axes. A 3D printed ISL was constructed and calibrated using a coordinate measuring machine, which served as a gold standard. Validation was performed using a fixture that represented the tibiofemoral joint with an adjustable F-E axis and the errors in measuring changes to the positions and orientations of the F-E and LR axes were quantified. The resulting root mean squared errors (RMSEs) of the calibration residuals using the new calibration method were 0.24, 0.33, and 0.15 mm for the anterior-posterior, medial-lateral, and proximal-distal positions, respectively, and 0.11, 0.10, and 0.09 deg for varus-valgus, flexion-extension, and internal-external orientations, respectively. All RMSEs were below 0.29% of the respective full-scale range. When measuring changes to the F-E or LR axes, each orientation error was below 0.5 deg; when measuring changes in the F-E axis, each position error was below 1.0 mm. The largest position RMSE was when measuring a medial-lateral change in the LR axis (1.2 mm). Despite the large size of the ISL, these calibration residuals were better than those for previously published ISLs, particularly when measuring orientations, indicating that using a more accurate gold standard was beneficial in limiting the calibration residuals. The validation method demonstrated that this ISL is capable of accurately measuring clinically important changes (i.e. 1 mm and 1 deg) in the F-E and LR axes.

Optimized design of an instrumented spatial linkage that minimizes errors in locating the rotational axes of the tibiofemoral joint: a computational analysis.

An accurate method to locate of the flexion-extension (F-E) axis and longitudinal rotation (LR) axis of the tibiofemoral joint is required to accurately characterize tibiofemoral kinematics. A method was recently developed to locate these axes using an instrumented spatial linkage (ISL) (2012, "On the Estimate of the Two Dominant Axes of the Knee Using an Instrumented Spatial Linkage," J. Appl. Biomech., 28(2), pp. 200-209). However, a more comprehensive error analysis is needed to optimize the design and characterize the limitations of the device before using it experimentally. To better understand the errors in the use of an ISL in finding the F-E and LR axes, our objectives were to (1) develop a method to computationally determine the orientation and position errors in locating the F-E and LR axes due to transducer nonlinearity and hysteresis, ISL size and attachment position, and the pattern of applied tibiofemoral motion, (2) determine the optimal size and attachment position of an ISL to minimize these errors, (3) determine the best pattern of pattern of applied motion to minimize these errors, and (4) examine the sensitivity of the errors to range of flexion and internal-external (I-E) rotation. A mathematical model was created that consisted of a virtual "elbow-type" ISL that measured motion across a virtual tibiofemoral joint. Two orientation and two position errors were computed for each axis by simulating the axis-finding method for 200 iterations while adding transducer errors to the revolute joints of the virtual ISL. The ISL size and position that minimized these errors were determined from 1080 different combinations. The errors in locating the axes using the optimal ISL were calculated for each of three patterns of motion applied to the tibiofemoral joint, consisting of a sequential pattern of discrete tibiofemoral positions, a random pattern of discrete tibiofemoral positions, and a sequential pattern of continuous tibiofemoral positions. Finally, errors as a function of range of flexion and I-E rotation were determined using the optimal pattern of applied motion. An ISL that was attached to the anterior aspect of the knee with 300-mm link lengths had the lowest maximum error without colliding with the anatomy of the joint. A sequential pattern of discrete tibiofemoral positions limited the largest orientation or position error without displaying large bias error. Finally, the minimum range of applied motion that ensured all errors were below 1 deg or 1 mm was 30 deg flexion with ±15 deg I-E rotation. Thus a method for comprehensive analysis of error when using this axis-finding method has been established, and was used to determine the optimal ISL and range of applied motion; this method of analysis could be used to determine the errors for any ISL size and position, any applied motion, and potentially any anatomical joint.

Validation of a new method for finding the rotational axes of the knee using both marker-based roentgen stereophotogrammetric analysis and 3D video-based motion analysis for kinematic measurements.

In a previous paper, we reported the virtual axis finder, which is a new method for finding the rotational axes of the knee. The virtual axis finder was validated through simulations that were subject to limitations. Hence, the objective of the present study was to perform a mechanical validation with two measurement modalities: 3D video-based motion analysis and marker-based roentgen stereophotogrammetric analysis (RSA). A two rotational axis mechanism was developed, which simulated internal-external (or longitudinal) and flexion-extension (FE) rotations. The actual axes of rotation were known with respect to motion analysis and RSA markers within ± 0.0006 deg and ± 0.036 mm and ± 0.0001 deg and ± 0.016 mm, respectively. The orientation and position root mean squared errors for identifying the longitudinal rotation (LR) and FE axes with video-based motion analysis (0.26 deg, 0.28 m, 0.36 deg, and 0.25 mm, respectively) were smaller than with RSA (1.04 deg, 0.84 mm, 0.82 deg, and 0.32 mm, respectively). The random error or precision in the orientation and position was significantly better (p=0.01 and p=0.02, respectively) in identifying the LR axis with video-based motion analysis (0.23 deg and 0.24 mm) than with RSA (0.95 deg and 0.76 mm). There was no significant difference in the bias errors between measurement modalities. In comparing the mechanical validations to virtual validations, the virtual validations produced comparable errors to those of the mechanical validation. The only significant difference between the errors of the mechanical and virtual validations was the precision in the position of the LR axis while simulating video-based motion analysis (0.24 mm and 0.78 mm, p=0.019). These results indicate that video-based motion analysis with the equipment used in this study is the superior measurement modality for use with the virtual axis finder but both measurement modalities produce satisfactory results. The lack of significant differences between validation techniques suggests that the virtual sensitivity analysis previously performed was appropriately modeled. Thus, the virtual axis finder can be applied with a thorough understanding of its errors in a variety of test conditions.