Dydrogesterone supplementation in addition to routine micronized progesterone administration for luteal support in cycles triggered with lone GnRH agonist results in an acceptable pregnancy rate and avoids the need to freeze embryos.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is reduced when using antagonist cycle with gonadotrophin releasing hormone (GnRH) agonist trigger before ovum pick up. This trigger induces short luteinizing hormone (LH) and follicle stimulating hormone (FSH) peaks, resulting in an inadequate luteal phase and a reduced implantation rate. We assessed whether the luteal phase can be rescued by supplementing with oral dydrogesterone (duphaston) in antagonist cycles after a lone GnRH agonist trigger. METHODS: A retrospective cohort study. The study group (N.=123) included women who underwent IVF. Patients received a GnRH-antagonist with a lone GnRH-agonist trigger due to imminent OHSS. The control group (N.=374) included patients who underwent a standard antagonist protocol with a dual trigger of a GnRH-agonist and human chorionic gonadotrophin (hCG). All the patients were treated with micronized progesterone (utrogestan) for luteal phase support. Study patients were given duphaston in addition. RESULTS: The fertilization rate was comparable between the two groups. The mean number of embryos transferred, the clinical pregnancy rate and the take-home baby rate were comparable between groups (1.5±0.6 vs. 1.5±0.5 and 46.3% vs. 41.2%, and 66.7% vs. 87.7%, respectively). No OHSS event was reported in either group. CONCLUSIONS: This study was the first to evaluate outcomes of duphaston supplementation for luteal support in an antagonist cycle with lone GnRH agonist trigger. The functionality of the luteal phase of those cycles could be restored by adding duphaston. This approach was found to be safe and prevented the need to postpone embryo transfer in case of pending OHSS.

Fast and slow EQCM response of zwitterionic weak electrolytes to changes in the electrode potential: a pH-mediated mechanism.

Using a fast electrochemical quartz crystal microbalance (EQCM), zwitterionic electrolytes were studied with regard to changes of resonance frequency and resonance bandwidth after the electrode potential was switched. In addition to a fast change of frequency (within milliseconds), a further, slower process with opposite direction is observed. Both the fast and the slow process change sign when the pH is varied across the isoelectric point (pI). The fast process can be attributed to double layer recharging. Its characteristic time is slightly larger than the charge response time (the RC-time) as inferred from electrochemical impedance spectroscopy (EIS). With regard to the slow process, amino acids with moderate concentration behave markedly different from concentrated solutions of proteins. For amino acids, the slow process is larger in amplitude than the fast process and the QCM response is Sauerbrey-like. The shift in half bandwidth is smaller than the shift in frequency and the overtone-normalized frequency shifts agree between overtones (-Δf/n ≈ const. with n the overtone order). This can be explained with a viscosity change in the diffuse double layer. Independent measurements show that the viscosities of these electrolytes are higher than the average in a pH range around the pI. Presumably, the slow process reflects a rearrangement of molecules after the net charge on the molecule has increased or decreased, changing the degree of dipolar coupling and, in consequence, the viscosity. For concentrated solutions of bovine serum albumin (BSA), the QCM response does not follow Sauerbrey behaviour, which can be explained with viscoelasticity and viscoelastic dispersion. The slow process lets the frequency and the bandwidth relax towards a baseline, which is the same for jumps to more positive and to more negative potentials. Presumably, the slow process in this case is caused by a reorientation of molecules inside the Helmholtz layer, such that they screen the electric field more efficiently than immediately after the voltage jump.

Management of spinal deformities and tibial pseudarthrosis in children with neurofibromatosis type 1 (NF-1).

The skeletal system is affected in up to 60% of patients with neurofibromatosis type 1. The most commonly observed entities are spinal deformities and tibial dysplasia. Early recognition of radiologic osseous dystrophy signs is of utmost importance because worsening of the deformities without treatment is commonly observed and surgical intervention is often necessary. Due to the relative rarity and the heterogenic presentation of the disease, evidence regarding the best surgical strategy is still lacking. PURPOSE: To report our experience with the treatment of skeletal manifestations in pediatric patients with (neurofibromatosis type 1) NF-1 and to present the results with our treatment protocols. MATERIALS AND METHODS: This is a retrospective, single expert center study on children with spinal deformities and tibial dysplasia associated with NF-1 treated between 2006 and 2020 in a tertiary referral institution. RESULTS: Spinal deformity: Thirty-three patients (n = 33) were included. Mean age at index surgery was 9.8 years. In 30 patients (91%), the deformity was localized in the thoracic and/or lumbar spine, and in 3 patients (9%), there was isolated involvement of the cervical spine. Eleven patients (33%) received definitive spinal fusion as an index procedure and 22 (67%) were treated by means of "growth-preserving" spinal surgery. Halo-gravity traction before index surgery was applied in 11 patients (33%). Progression of deformity was stopped in all patients and a mean curve correction of 60% (range 23-98%) was achieved. Mechanical problems with instrumentation requiring revision surgery were observed in 55% of the patients treated by growth-preserving techniques and in none of the patients treated by definitive fusion. One patient (3%) developed a late incomplete paraplegia due to a progressive kyphotic deformity. Tibial dysplasia: The study group comprised of 14 patients. In 5 of them (36%) pathological fractures were present on initial presentation. In the remaining 9 patients (64%), anterior tibial bowing without fracture was observed initially. Four of them (n = 4, 28%) subsequently developed a pathologic fracture despite brace treatment. Surgical treatment was indicated in 89% of the children with pathological fractures. This involved resection of the pseudarthrosis, autologous bone grafting, and intramedullary nailing combined with external fixation in some of the cases. In 50% of the patients, bone morphogenic protein was used "off-label" in order to promote union. Healing of the pseudarthrosis was achieved in all of the cases and occurred between 5 to 13 months after the index surgical intervention. Four of the patients treated surgically needed more than one surgical intervention in order to achieve union; one patient had a re-fracture. All patients had a good functional result at last follow-up. CONCLUSION: Early surgical intervention is recommended for the treatment dystrophic spinal deformity in children with NF-1. Good and sustainable curve correction without relevant thoracic growth inhibition can be achieved with growth-preserving techniques alone or in combination with short spinal fusion at the apex of the curve. Preoperative halo-gravity traction is a safe and very effective tool for the correction of severe and rigid deformity in order to avoid neurologic injury. Fracture union in tibial dysplasia with satisfactory functional results can be obtained in over 80% of the children by means of surgical resection of the pseudarthrosis, intramedullary nailing, and bone grafting. Wearing a brace until skeletal maturity is achieved is mandatory in order to minimize the risk of re-fracture.

Biofilm formation on different dental restorative materials in the oral cavity.

BACKGROUND: Bacterial biofilms adhere to all tissues and surfaces in the oral cavity. Oral biofilms are responsible for the decay of human dental structures and the inflammatory degeneration of the alveolar bone. Moreover, oral biofilms on artificial materials influence the lifespan of dental prostheses and restoratives. METHODS: To investigate in vivo oral biofilm formation and growth, five different dental restorative materials were analyzed and compared to human enamel. The roughness of the materials and the human enamel control probe were measured at the start of the study. The dental restorative materials and the human enamel control probe were placed in dental splints and worn for 3 h, 24 h and 72 h. RESULTS: Scanning electron microscopy (SEM) revealed major differences between oral biofilm formation and growth on the materials compared to those on human enamel. Microbiological analyses showed that bacterial strains differed between the materials. Significant differences were observed in the roughness of the dental materials. CONCLUSIONS: It can be concluded that material roughness affects biofilm formation on dental surfaces and restoratives, but other factors, such as surface charge, surface energy and material composition, may also have an influence.

Freewater estimatoR using iNtErpolated iniTialization (FERNET): Characterizing peritumoral edema using clinically feasible diffusion MRI data.

Characterization of healthy versus pathological tissue in the peritumoral area is confounded by the presence of edema, making free water estimation the key concern in modeling tissue microstructure. Most methods that model tissue microstructure are either based on advanced acquisition schemes not readily available in the clinic or are not designed to address the challenge of edema. This underscores the need for a robust free water elimination (FWE) method that estimates free water in pathological tissue but can be used with clinically prevalent single-shell diffusion tensor imaging data. FWE in single-shell data requires the fitting of a bi-compartment model, which is an ill-posed problem. Its solution requires optimization, which relies on an initialization step. We propose a novel initialization approach for FWE, FERNET, which improves the estimation of free water in edematous and infiltrated peritumoral regions, using single-shell diffusion MRI data. The method has been extensively investigated on simulated data and healthy dataset. Additionally, it has been applied to clinically acquired data from brain tumor patients to characterize the peritumoral region and improve tractography in it.

Author Correction: The challenge of mapping the human connectome based on diffusion tractography.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The challenge of mapping the human connectome based on diffusion tractography.

Tractography based on non-invasive diffusion imaging is central to the study of human brain connectivity. To date, the approach has not been systematically validated in ground truth studies. Based on a simulated human brain data set with ground truth tracts, we organized an open international tractography challenge, which resulted in 96 distinct submissions from 20 research groups. Here, we report the encouraging finding that most state-of-the-art algorithms produce tractograms containing 90% of the ground truth bundles (to at least some extent). However, the same tractograms contain many more invalid than valid bundles, and half of these invalid bundles occur systematically across research groups. Taken together, our results demonstrate and confirm fundamental ambiguities inherent in tract reconstruction based on orientation information alone, which need to be considered when interpreting tractography and connectivity results. Our approach provides a novel framework for estimating reliability of tractography and encourages innovation to address its current limitations.

Retrograde drilling of talar osteochondritis dissecans lesions: a feasibility and accuracy analysis of a novel electromagnetic navigation method versus a standard fluoroscopic method.

PURPOSE: A novel method using an electromagnetic navigation system (ENS) was developed, and its feasibility and accuracy for retrograde drilling procedures were evaluated and compared with the standard freehand fluoroscopic method in an experimental setting. METHODS: A controlled laboratory study of 16 standard freehand fluoroscopically guided and 16 electromagnetically navigated retrograde drilling procedures was performed on 4 cadaveric human ankle joints. Four artificial cartilage lesions were consecutively set, 2 on the medial and 2 on the lateral talar dome. Drilling accuracy was measured in terms of the distance from the final position of the drill bit to the tip of the probe hook and the distance between the tip of the drill bit and the center of the cartilage lesion on the articular cartilage surface. Intraoperative fluoroscopy exposure times were documented, as were readjustments of drilling directions or complete restarts. All procedures were timed with a stopwatch. RESULTS: Successful retrograde drilling was accomplished in 12 cases with the standard fluoroscopy-guided technique and in all 16 ENS-guided procedures. The overall mean time for the fluoroscopy-guided procedures was 660.00 ± 239.87 seconds and the overall mean time for the ENS method was 308.06 ± 54.03 seconds, providing a mean time benefit of 420.13 seconds. The mean distance from the final position of the drill bit to the tip of the probe hook was 3.25 ± 1.29 mm for the standard method and 2.19 ± 0.54 mm for the ENS method, and the mean distance between the tip of the drill bit and the center of the cartilage lesion on the articular cartilage surface was 2.50 ± 0.97 mm for the standard method and 0.88 ± 0.81 mm for the ENS method. CONCLUSIONS: Compared with the standard fluoroscopic technique, the ENS method used in this study showed higher accuracy and a shorter procedure time and required no X-ray radiation. CLINICAL RELEVANCE: The novel method considerably improves on the standard operating procedure in terms of safety, operation time, and radiation exposure.

Arthroscopically assisted retrograde drilling for osteochondritis dissecans (OCD) lesions of the knee.

PURPOSE: Accurate retrograde drilling for osteochondritis dissecans lesions remains technically challenging. A novel, radiation-free method using an electromagnetic guidance system was developed, and its feasibility and accuracy for retrograde drilling procedures evaluated in an experimental setting. METHODS: Sixteen arthroscopically assisted, electromagnetically guided retrograde drilling procedures were performed in 4 human cadaveric knee joints. Therefore, two artificial cartilage lesions were set consecutively on each condyle. Final drill bit position was documented in two planes using fluoroscopy. Subsequently, drilling accuracy was measured in terms of distance from the final position of the drill bit to the articular cartilage surface (D1), and distance between the tip of the drill bit to the centre of the cartilage lesion on the articular cartilage surface (D2). All procedures were timed using a stopwatch. RESULTS: Successful retrograde drilling was accomplished in all 16 cases. The overall mean time for the retrograde drilling procedures was 361.6 ± 34.7 s. Mean D1 was 2.2 ± 0.5 mm; mean D2 was 0.8 ± 0.7 mm. No complications occurred. CONCLUSIONS: The novel electromagnetic guidance system used in this study showed accurate targeting results, required no radiation, was associated with no complications and demonstrated user-friendliness. LEVEL OF EVIDENCE: II.

p65-Dependent production of interleukin-1ß by osteolytic prostate cancer cells causes an induction of chemokine expression in osteoblasts.

Skeletal metastases are a frequent complication of prostate, breast and lung cancer, and the interactions of tumor cells with bone-forming osteoblasts and bone-resorbing osteoclasts have been suggested to play critical roles in disease progression. We have previously shown that treatment of primary murine osteoblasts with conditioned medium of the human osteolytic prostate cancer cell line PC-3 results in a rapid induction of chemokine expression, thereby providing further evidence for a molecular crosstalk between bone and tumor cells. The aim of our current study was to identify PC-3-derived molecules mediating this effect. Using Affymetrix Gene Chip hybridization followed by qRT-PCR we were able to confirm that the expression of chemokine-encoding genes is markedly induced in human primary osteoblasts following incubation with PC-3-conditioned medium. Since this induction was significantly affected upon alteration of p65-levels in PC-3 cells, we performed a second genome-wide expression analysis to identify p65-regulated cytokines, which were then tested for their ability to induce chemokine expression. Here we observed that interleukin-1ß (IL-1B) did not only increase the expression of chemokines in osteoblasts, but also the phosphorylation of p65 and thereby its own expression. Since immunohistochemistry on bone biopsy sections from prostate cancer metastases demonstrated IL-1B expression in both, tumor cells and osteoblasts, our data suggest that IL-1B is one of the relevant cytokines involved in the skeletal complications of cancer metastases.

Levels of steroidogenic acute regulatory protein and mitochondrial membrane potential in granulosa cells of older poor-responder women.

OBJECTIVE: To compare mitochondrial function in granulosa cells obtained from older (>40 y) low-responder IVF patients with that of young (<35 y) good-responder patients. DESIGN: Prospective laboratory research. SETTING: In vitro fertilization unit in a university hospital. PATIENT(S): Twenty patients undergoing IVF treatment cycles. INTERVENTION(S): Ultrasound guided oocytes pick-up. MAIN OUTCOME MEASURE(S): Mitochondrial function examined by using JC-1 stain for the mitochondrial membrane potential in granulosa cells of both groups and Western blots for assaying and quantification of steroidogenic acute regulatory protein (StAR) and p450scc (side-chain cleavage). RESULT(S): The number of granulosa cells per follicle differed between the two groups, with fewer granulosa cells isolated in the older low-responder women, compared with in the young, normal responders who were the control women. Trypan blue-negative cells showed similar undisturbed mitochondrial membrane potential, and similar ratios of apoptotic granulosa cells were observed in the two groups. In addition, there was no difference in StAR and P450scc protein levels between the two groups. CONCLUSION(S): Our results demonstrate a significant decrease in the number of total aspirated granulosa cells per follicle in older, poor-responder women, which probably explains the reduced hormonal production by those follicles. However, those cells demonstrate normal mitochondrial membrane potential as well as similar levels of StAR, P450scc, and de novo steroid hormone synthesis in the two groups of patients. Our results do not support mitochondrial dysfunction as a main mechanism of reproductive aging.

Three-dimensional isotropic wavelets for post-acquisitional extraction of latent images of atherosclerotic plaque components from micro-computed tomography of human coronary arteries.

RATIONALE AND OBJECTIVES: The capability of wavelet transforms to separate signals into frequency bands is the basis for its use in image compression and storage, data management and transmission, and, recently, extraction of latent images of tissue components from noisy medical images. Analysis of temporal variations of radiofrequency backscatter of intravascular ultrasound with one-dimensional wavelets can detect lipid-laden plaque in coronary arteries with a sensitivity and specificity of >80%. In this study we evaluate the capability of a novel, 3-dimensional isotropic wavelet analysis to perform high resolution, non-directionally biased, statistically reliable, non-invasive discrimination between components of human coronary atherosclerotic plaques in micro-CT. MATERIALS AND METHODS: Coronary artery segments (5-15 mm) were excised at necropsy from 18 individuals with advanced coronary atherosclerosis. Specimens were imaged using a GE Locus SP ex vivo micro-CT scanner and processed for histological correlation (833 sections). The isotropic wavelet constructs were applied to the entire volume of CT data of each arterial segment to distinguish tissue textures of varying scales and intensities. Voxels were classified and plaque characterization achieved by comparing the relative magnitudes of these wavelet constituents to that of several reference plaque tissue components. RESULTS: Processing of micro-CT images via these isotropic wavelet algorithms permitted 3-D, color-coded, high resolution, digital discrimination between lumen, calcific deposits, lipid-rich deposits, and fibromuscular tissue providing detail not possible with conventional thresholding based on Hounsfield intensity units. Using the isotropic wavelets (with histology as the gold standard), lipid-rich pools approaching the size of the filter for the isotropic wavelet algorithm (0.25 mm [250 microns] in length) were identified with 81% sensitivity and 86% specificity. Calcific deposits, fibromuscular tissue, and lumen equal to or larger than the wavelet filter size were detected without error (100% sensitivity and specificity). CONCLUSION: Isotropic wavelet analysis permits high resolution, multi-dimensional identification of coronary atherosclerotic plaque components in micro-CT with sensitivity and specificity similar to that achieved with data obtained invasively (from IVUS in vivo) using one-dimensional wavelets. Further studies are necessary to test the applicability of this technology to clinical, multi-detector scanners.