The effect of polymorphisms in FSHR and FSHB genes on ovarian response: a prospective multicenter multinational study in Europe and Asia.

STUDY QUESTION: Does the presence of single nucleotide polymorphisms (SNPs) in the FSH receptor gene (FSHR) and/or FSH beta subunit-encoding gene (FSHB) influence ovarian response in predicted normal responders treated with rFSH? SUMMARY ANSWER: The presence of FSHR SNPs (rs6165, rs6166, rs1394205) has a statistically significant impact in ovarian response, although this effect is of minimal clinical relevance in predicted normal responders treated with a fixed dose of 150 IU rFSH. WHAT IS KNOWN ALREADY: Ovarian reserve markers have been a breakthrough in response prediction following ovarian stimulation. However, a significant percentage of patients show a disproportionate lower ovarian response, as compared with their actual ovarian reserve. Studies on pharmacogenetics have demonstrated a relationship between FSHR or FSHB genotyping and drug response, suggesting a potential effect of individual genetic variability on ovarian stimulation. However, evidence from these studies is inconsistent, due to the inclusion of patients with variable ovarian reserve, use of different starting gonadotropin doses, and allowance for dose adjustments during treatment. This highlights the necessity of a well-controlled prospective study in a homogenous population treated with the same fixed protocol. STUDY DESIGN, SIZE, DURATION: We conducted a multicenter multinational prospective study, including 368 patients from Vietnam, Belgium, and Spain (168 from Europe and 200 from Asia), from November 2016 until June 2019. All patients underwent ovarian stimulation followed by oocyte retrieval in an antagonist protocol with a fixed daily dose of 150 IU rFSH until triggering. Blood sampling and DNA extraction was performed prior to oocyte retrieval, followed by genotyping of four SNPs from FSHR (rs6165, rs6166, rs1394205) and FSHB (rs10835638). PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible were predicted normal responder women <38 years old undergoing their first or second ovarian stimulation cycle. Laboratory staff and clinicians were blinded to the clinical results and genotyping, respectively. The prevalence of hypo-responders, the number of oocytes retrieved, the follicular output rate (FORT), and the follicle to oocyte index (FOI) were compared between different FSHR and FSHB SNPs genotypes. MAIN RESULTS AND THE ROLE OF CHANCE: The prevalence of derived allele homozygous SNPs in the FSHR was rs6166 (genotype G/G) 15.8%, rs6165 (genotype G/G) 34.8%, and rs1394205 (genotype A/A) 14.1%, with significant differences between Caucasian and Asian women (P < 0.001). FSHB variant rs10835638 (c.-211 G>T) was very rare (0.5%). Genetic model analysis revealed that the presence of the G allele in FSHR variant rs6166 resulted in less oocytes retrieved when compared to the AA genotype (13.54 ± 0.46 vs 14.81 ± 0.61, estimated mean difference (EMD) -1.47 (95% CI -2.82 to -0.11)). In FSHR variant rs1394205, a significantly lower number of oocytes was retrieved in patients with an A allele when compared to G/G (13.33 ± 0.41 vs 15.06 ± 0.68, EMD -1.69 (95% CI -3.06 to -0.31)). A significantly higher prevalence of hypo-responders was found in patients with the genotype A/G for FSHR variant rs6166 (55.9%, n = 57) when compared to A/A (28.4%, n = 29), ORadj 1.87 (95% CI 1.08-3.24). No significant differences were found regarding the FORT across the genotypes for FSHR variants rs6166, rs6165, or rs1394205. Regarding the FOI, the presence of the G allele for FSHR variant rs6166 resulted in a lower FOI when compared to the A/A genotype, EMD -13.47 (95% CI -22.69 to -4.24). Regarding FSHR variant rs6165, a lower FOI was reported for genotype A/G (79.75 ± 3.35) when compared to genotype A/A (92.08 ± 6.23), EMD -13.81 (95% CI -25.41 to -2.21). LIMITATIONS, REASONS FOR CAUTION: The study was performed in relatively young women with normal ovarian reserve to eliminate biases related to age-related fertility decline; thus, caution is needed when extrapolating results to older populations. In addition, no analysis was performed for FSHB variant rs10835638 due to the very low prevalence of the genotype T/T (n = 2). WIDER IMPLICATIONS OF THE FINDINGS: Based on our results, genotyping FSHR SNPs rs6165, rs6166, rs1394205, and FSHB SNP rs10835638 prior to initiating an ovarian stimulation with rFSH in predicted normal responders should not be recommended, taking into account the minimal clinical impact of such information in this population. Future research may focus on other populations and other genes related to folliculogenesis or steroidogenesis. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by an unrestricted grant by Merck Sharp & Dohme (MSD). N.P.P. reports grants and/or personal fees from MSD, Merck Serono, Roche Diagnostics, Ferring International, Besins Healthcare, Gedeon Richter, Theramex, and Institut Biochimique SA (IBSA). N.L.V. and M.T.H. report consultancy and conference fees from Merck, Ferring, and MSD, outside the submitted work. P.D. has received honoraria for lecturing and/or research grants from MSD, Ferring International, and Merck. D.S. reports grants and/or personal fees from MSD, Ferring International, Merck Serono, Cook, and Gedeon Richter. A.R.N., B.A.M., C.S., J.M., L.H.L., P.Q.M.M., H.T., and S.G. report no conflict of interests. TRIAL REGISTRATION NUMBER: NCT03007043.

Alveolar Bone Segmentation in Intraoral Ultrasonographs with Machine Learning.

The use of intraoral ultrasound imaging has received great attention recently due to the benefits of being a portable and low-cost imaging solution for initial and continuing care that is noninvasive and free of ionizing radiation. Alveolar bone is an important structure in the periodontal apparatus to support the tooth. Accurate assessment of alveolar bone level is essential for periodontal diagnosis. However, interpretation of alveolar bone structure in ultrasound images is a challenge for clinicians. This work is aimed at automatically segmenting alveolar bone and locating the alveolar crest via a machine learning (ML) approach for intraoral ultrasound images. Three convolutional neural network-based ML methods were trained, validated, and tested with 700, 200, and 200 images, respectively. To improve the robustness of the ML algorithms, a data augmentation approach was introduced, where 2100 additional images were synthesized through vertical and horizontal shifting as well as horizontal flipping during the training process. Quantitative evaluations of 200 images, as compared with an expert clinician, showed that the best ML approach yielded an average Dice score of 85.3%, sensitivity of 88.5%, and specificity of 99.8%, and identified the alveolar crest with a mean difference of 0.20 mm and excellent reliability (intraclass correlation coefficient ≥0.98) in less than a second. This work demonstrated the potential use of ML to assist general dentists and specialists in the visualization of alveolar bone in ultrasound images.

Improvement on the Accuracy and Reliability of Ultrasound Coronal Curvature Measurement on Adolescent Idiopathic Scoliosis With the Aid of Previous Radiographs.

STUDY DESIGN: Retrospective study of the coronal curvature measurement on ultrasound (US) images with the aid of previous radiographs. OBJECTIVE: To compare the reliability and accuracy of the coronal curvature measurements from US images on children who have adolescent idiopathic scoliosis (AIS) with and without the knowledge of previous radiographs. SUMMARY OF BACKGROUND DATA: Using US imaging technique to measure coronal curvature on children with AIS has demonstrated high intra- and interrater reliabilities. However, the selection of end-vertebrae and the measurement difference between radiography and the US method were only moderately reliable. METHODS: Two raters measured the coronal curvatures from 65 AIS standing US spine images, without (measured one time) and with the aid of previous standing radiographs (measured two times). The intra- and interrater reliability, the correlation and the difference between the radiographic and US measurements, and the error index of the end-vertebrae selection were assessed. RESULTS: Overall, 109 curves were investigated. The intraclass correlation coefficients (ICC) of intra- and interrater reliability of the US coronal curvature measurement with the aid of previous radiographs (AOR) were 0.95 and 0.91, respectively. In comparison with the radiographic measurements, the correlation of AOR method (R) was 0.90 and the MAD was 2.8°; the corresponding results of the US measurement without the AOR (blinded US method) were 0.73° and 4.8°, respectively. The average error index on end-vertebral selection improved 43% with the AOR. CONCLUSION: The AOR method significantly improved reliability and accuracy of the spinal curvature measurement on US images compared with the blinded US method (P<0.001). It indicates that US standing images with the AOR can be used as a reliable and accurate nonionizing imaging method to monitor children with AIS. LEVEL OF EVIDENCE: 3.

Micro-scale finite element modeling of ultrasound propagation in aluminum trabecular bone-mimicking phantoms: A comparison between numerical simulation and experimental results.

The present study investigated the accuracy of micro-scale finite element modeling for simulating broadband ultrasound propagation in water-saturated trabecular bone-mimicking phantoms. To this end, five commercially manufactured aluminum foam samples as trabecular bone-mimicking phantoms were utilized for ultrasonic immersion through-transmission experiments. Based on micro-computed tomography images of the same physical samples, three-dimensional high-resolution computational samples were generated to be implemented in the micro-scale finite element models. The finite element models employed the standard Galerkin finite element method (FEM) in time domain to simulate the ultrasonic experiments. The numerical simulations did not include energy dissipative mechanisms of ultrasonic attenuation; however, they expectedly simulated reflection, refraction, scattering, and wave mode conversion. The accuracy of the finite element simulations were evaluated by comparing the simulated ultrasonic attenuation and velocity with the experimental data. The maximum and the average relative errors between the experimental and simulated attenuation coefficients in the frequency range of 0.6-1.4 MHz were 17% and 6% respectively. Moreover, the simulations closely predicted the time-of-flight based velocities and the phase velocities of ultrasound with maximum relative errors of 20 m/s and 11 m/s respectively. The results of this study strongly suggest that micro-scale finite element modeling can effectively simulate broadband ultrasound propagation in water-saturated trabecular bone-mimicking structures.

Simplified inverse filter tracking algorithm for estimating the mean trabecular bone spacing.

Ultrasonic backscatter signals provide useful information relevant to bone tissue characterization. Trabecular bone microstructures have been considered as quasi-periodic tissues with a collection of regular and diffuse scatterers. This paper investigates the potential of a novel technique using a simplified inverse filter tracking (SIFT) algorithm to estimate mean trabecular bone spacing (MTBS) from ultrasonic backscatter signals. In contrast to other frequency-based methods, the SIFT algorithm is a time-based method and utilizes the amplitude and phase information of backscatter echoes, thus retaining the advantages of both the autocorrelation and the cepstral analysis techniques. The SIFT algorithm was applied to backscatter signals from simulations, phantoms, and bovine trabeculae in vitro. The estimated MTBS results were compared with those of the autoregressive (AR) cepstrum and quadratic transformation (QT) . The SIFT estimates are better than the AR cepstrum estimates and are comparable with the QT values. The study demonstrates that the SIFT algorithm has the potential to be a reliable and robust method for the estimation of MTBS in the presence of a small signal-to-noise ratio, a large spacing variation between regular scatterers, and a large scattering strength ratio of diffuse scatterers to regular ones.

Computer-assisted Cobb angle measurement on posteroanterior radiographs.

The Cobb angle method is the gold standard to assess severity of scoliosis. A computer-aided method was developed to provide a semi-automatic Cobb angle measurement during a scoliosis clinic. This study was to evaluate the reliability and accuracy of the developed method. Curve types were also tested. The computer method required enhancement of the contrast, normalization of the image size, and selection of the end-vertebrae on the radiographs before the automatic measurement started. The computer-aided process automatically identified the line segments that fitted to the endplates of the end-vertebrae. The Cobb angle was then calculated from the slopes of these lines. Seventy-six radiographs were randomly selected and categorized with Lenke's classification. Among them, 75 cases were used and categorized into 4 types: 1, 3, 5 and 6. One type 2 case was excluded. An orthopedic spine surgeon measured the radiographs manually, serving as the reference standard. Two observers used the developed method and measured twice. For each curve type, the inter-method, inter-observer, and intra-observer variability were analyzed by Intraclass correlation coefficients (ICC[2,1]). The ICC values were higher than 0.90 in all these types. The developed method was reliable to measure the Cobb angle and was not dependent on the curve type.

Phase II multicenter open-label study of carboplatin and pegylated liposomal doxorubicin in uterine and cervical malignancies.

The results of a multicenter phase II study investigating carboplatin and pegylated liposomal doxorubicin (PLD) in patients with recurrent/metastatic uterine and cervical malignancies (UCM) are presented here. Fifty-three subjects with measurable, untreated, advanced UCM were enrolled. Fifty-one were evaluable for response. Prior combined-modality treatment was permitted if a component of primary therapy. Patients received carboplatin AUC = 5 with PLD 35 mg/m(2) intravenously once every 4 weeks. Overall response rate was 33% (35% stable disease). Overall survival (OS) at six months was 86% (95% CI 76%-96%). Six-month progression-free survival (PFS) was 43% (95% CI 30%-57%). Median PFS was 22.9 weeks (range 16.0-35.3) and median OS was 49.1 weeks (range 41.4-75.1). The most frequent grade 3-4 nonhematological adverse events were: abdominal pain (n = 7), fatigue (4), vomiting (4), nausea (3), and shortness of breath (3). There was 1 report of grade 3 hand-foot syndrome and none of grade 4. Twelve patients had first infusion reactions with only 1 discontinuing treatment. Grade 3-4 neutropenia occurred in 26/230 cycles (11.3%). There were no treatment-related deaths. The combination of carboplatin and PLD is well tolerated with sufficient activity to justify additional evaluation in clinical trials and might be suited to the addition of a taxane.

Partial failure of sternal fusion in an adolescent.

We describe the case of an adolescent girl who had an isolated cranial sternal cleft without any associated abnormalities; the cleft had been well tolerated since her birth. A review of the literature shows that such cases are uncommon. In such cases, surgery is only for cosmetic reasons.

Mediastinal lipomatosis.

Mediastinal lipomatosis is a benign condition characterized by a large amount of mature adipose tissue within the mediastinum. It widens the mediastinum and may simulate mass lesions, thus leading to diagnostic errors. We describe a new case of a huge mediastinal lipomatosis and review 36 cases previously reported in the literature. Computed tomography has an important role in the diagnosis of this disease. To avoid invasive and unnecessary procedures, this diagnosis should be considered in any patient with Cushing's syndrome.

An investigation of pulse-timing techniques for broadband ultrasonic velocity determination in cancellous bone: a simulation study.

Berlage wavelets are used to simulate ultrasonic pulses in an unbounded, homogeneous, isotropic and absorptive medium. Intrinsic absorption of the medium is properly described by Kolsky's attenuation, which considers velocity dispersion to meet the causality condition. Several current time-domain velocity measurement techniques have been investigated using numerically simulated pulses for three normalized BUA values: 20, 40 and 60 dB MHz(-1) cm(-1), which mimic experimentally determined values for cancellous bone. The velocities, calculated using first motion transit times, are used as references supported by the Fermat principle of least time. The simulated results for fixed sample thickness indicate that pulse-broadening increases with the transit time of the reference point and the intrinsic absorption of the medium. Comparison shows that the first zero-crossing method yields 3-6% errors in velocity results, better than the cross-correlation method. However, the zero-crossing method gives inconsistent velocity measurement for a medium of 40 dB MHz(-1) cm(-1)1 absorption and three different thicknesses: 0.2, 0.4 and 0.6 cm. A novel technique for velocity measurement is presented using the peak of the envelope of a signal as a reference point to measure transit time difference. The envelope of a signal represents the instantaneous amplitude of the associated analytic signal. The velocities derived using this method differ from the true velocities by only 1.2-2.4%, more accurate than those obtained by the first zero-crossing method. The envelope peak has the additional merits of easy detection and robustness. Most importantly, the envelope technique may be used to yield accurate velocity measurement in cases where an accurate determination of the first motion transit time is sometimes prohibited due to the presence of noise.

[Endobronchial lipoma: apropos of a case with dual localization]. / Le lipome endobronchique: à propos d'un cas à double localisation.

Endobronchial lipoma is an uncommon benign tumor. It is composed of fat tissue and is visible on CT scanner. We report an unusual case of a patient who developed two endobronchial lipomas. The first lipoma was removed 10 years earlier. We emphasize the contribution of computed tomography in the diagnosis of endobronchial lipoma. Cases of multiple lipomas are very scarce in the literature.

Approximating the acoustic reflection coefficient of lossy biological tissues.

The amplitude acoustic reflection coefficient of an interface between two lossy biological tissues can be approximated as Rlossy approximately Rlossless + i delta/2 where Rlossless is the lossless acoustic reflection coefficient and delta is the change in alpha/kappa (absorption coefficient per wavenumber) across the tissue interface. This approximation is shown to be valid for both normal and oblique angles of incidence.