Preinterventional Third-Molar Assessment Using Robust Machine Learning.

Machine learning (ML) models, especially deep neural networks, are increasingly being used for the analysis of medical images and as a supporting tool for clinical decision-making. In this study, we propose an artificial intelligence system to facilitate dental decision-making for the removal of mandibular third molars (M3M) based on 2-dimensional orthopantograms and the risk assessment of such a procedure. A total of 4,516 panoramic radiographic images collected at the Center of Dental Medicine at the University of Zurich, Switzerland, were used for training the ML model. After image preparation and preprocessing, a spatially dependent U-Net was employed to detect and retrieve the region of the M3M and inferior alveolar nerve (IAN). Image patches identified to contain a M3M were automatically processed by a deep neural network for the classification of M3M superimposition over the IAN (task 1) and M3M root development (task 2). A control evaluation set of 120 images, collected from a different data source than the training data and labeled by 5 dental practitioners, was leveraged to reliably evaluate model performance. By 10-fold cross-validation, we achieved accuracy values of 0.94 and 0.93 for the M3M-IAN superimposition task and the M3M root development task, respectively, and accuracies of 0.9 and 0.87 when evaluated on the control data set, using a ResNet-101 trained in a semisupervised fashion. Matthew's correlation coefficient values of 0.82 and 0.75 for task 1 and task 2, evaluated on the control data set, indicate robust generalization of our model. Depending on the different label combinations of task 1 and task 2, we propose a diagnostic table that suggests whether additional imaging via 3-dimensional cone beam tomography is advisable. Ultimately, computer-aided decision-making tools benefit clinical practice by enabling efficient and risk-reduced decision-making and by supporting less experienced practitioners before the surgical removal of the M3M.

Computer-assisted bone augmentation, implant planning and placement: An in vitro investigation.

AIM: To assess in vitro the workflow for alveolar ridge augmentation with customised 3D printed block grafts and simultaneous computer-assisted implant planning and placement. METHODS: Twenty resin mandible models with an edentulous area and horizontal ridge defect in the region 34-36 were scanned with cone beam computed tomography (CBCT). A block graft for horizontal ridge augmentation in the region 34-36 and an implant in the position 35 were digitally planned. Twenty block grafts were 3D printed out of resin and one template for guided implant placement were stereolithographically produced. The resin block grafts were positioned onto the ridge defects and stabilised with two fixation screws each. Subsequently, one implant was inserted in the position 35 through the corresponding template for guided implant placement. Optical scans of the study models together with the fixated block graft were performed prior to and after implant placement. The scans taken after block grafting were superimposed with the virtual block grafting plan through a best-fit algorithm, and the linear deviation between the planned and the achieved block positions was calculated. The precision of the block fixation was obtained by superimposing the 20 scans taken after grafting and calculating the deviation between the corresponding resin blocks. The superimposition between the scans taken after and prior to implant placement was performed to measure a possible displacement in the block position induced by guided implant placement. The (98-2%)/2 percentile value was determined as a parameter for surface deviation. RESULTS: The mean deviation in the position of the block graft compared to the virtual plan amounted to 0.79 ± 0.13 mm. The mean deviation between the positions of the 20 block grafts measured 0.47 ± 0.2 mm, indicating a clinically acceptable precision. Guided implant placement induced a mean shift of 0.16 ± 0.06 mm in the position of the block graft. CONCLUSIONS: Within the limitations of this in vitro study, it can be concluded that customised block grafts fabricated through CBCT, computer-assisted design and 3D printing allow alveolar ridge augmentation with clinically acceptable predictability and reproducibility. Computer-assisted implant planning and placement can be performed simultaneously with computer-assisted block grafting leading to clinically non-relevant dislocation of block grafts.

Novel prediction models for hyperketonemia using bovine milk Fourier-transform infrared spectroscopy.

Metabolic diseases driven by negative energy balance in dairy cattle contribute to reduced milk production, increased disease incidence, culling, and death. Cow side tests for negative energy balance markers are available but are labor-intensive. Milk sample analysis using Fourier transform infrared spectroscopy (FTIR) allows for sampling numerous cows simultaneously. FTIR prediction models have moderate accuracy for hyperketonemia diagnosis (beta-hydroxybutyrate (BHB) ≥ 1.2 mmol/L). Most research using FTIR has focused on homogenous datasets and conventional prediction models, including partial least squares, linear discriminant analysis, and ElasticNet. Our objective was to evaluate more diverse modeling options, such as deep learning, gradient boosting machine models, and model ensembles for hyperketonemia classification. We compiled a sizable, heterogeneous dataset including milk FTIR and concurrent blood samples. Blood samples were tested for blood BHB, and wavenumber data was obtained from milk FTIR analysis. Using this dataset, we trained conventional prediction models and other options listed above. We demonstrate prediction model performance is similar for convolutional neural networks and ensemble models to simpler algorithm options. Results obtained from this study indicate that deep learning and model ensembles are potential algorithm options for predicting hyperketonemia in dairy cattle. Additionally, our results indicate hyperketonemia prediction models can be developed using heterogeneous datasets.

Influence of pedestal diameter on mode instabilities in Yb/Ce/Al-doped fibers.

In this paper we present numerical and experimental results revealing that the mode instability threshold of highly Yb-doped, Ce/Al co-doped pedestal fibers is affected by the size of the index-increased pedestal structure surrounding the core. An alternative preparation technology for the realization of large mode area fibers with very large Al-doped silica pedestals is introduced. Three different pedestal fiber design iterations characterized by low photodarkening were manufactured and tested in counter-pumped amplifier setups. Up to 1.9 kW continuous-wave output power of near-diffraction-limited beam quality (M2 = 1.26) was achieved with an 18/200/420 µm fiber of very low NA = 0.042, limited only by the occurrence of mode instabilities.

Hormone signaling and fatty liver in females: analysis of estrogen receptor α mutant mice.

BACKGROUND: Treatment with estrogen in early menopausal women protects against development of hepatic steatosis and nonalcoholic fatty liver disease but estrogen has undesirable side effects, which negate its beneficial effects in premenopausal and postmenopausal women. Targeted therapies require better understanding of the target sites and mechanisms by which estrogen signaling exerts its protective effects in women. Estrogen receptor α (ERα) is thought to be the primary mediator for estrogen signaling to protect against hepatic steatosis. ERα has several mechanisms for signal transduction: (1) inducing gene transcription by direct binding to specific DNA sequences, (2) inducing tethered transcription with other DNA-binding factors, and (3) stimulating nongenomic action through membrane-associated ERα. However, it is still unclear which mechanisms mediate ERα-dependent protection against hepatic steatosis. METHODS: To understand the mechanisms of estrogen signaling for protection against hepatic steatosis in females, we analyzed the global ERα knockout mouse (αERKO), ERα DNA-binding domain mutant mouse (KIKO) and liver-specific ERα knockout mouse (LERKO) fed high-fat diets (HFD). The KIKO mouse disrupts the direct DNA-binding transcription activity but retains tethered transcription regulation and nongenomic action. Hepatic steatosis was evaluated by scoring the macrovesicular and microvesicular steatosis as well as serum alanine aminotransferase (ALT) levels. We analyzed serum testosterone to assess its correlation with hepatic steatosis. RESULTS: Liver fat accumulation was far greater in HFD-fed αERKO and KIKO females than in HFD-fed wild-type (WT) controls. Conversely, HFD-fed LERKO females did not accumulate excess liver fat. HFD-fed αERKO and KIKO females showed higher microvesicular steatosis and ALT levels than WT controls that correlated with increased serum testosterone levels. CONCLUSIONS: ERα-mediated direct transcription in non-hepatic tissues is essential for estrogen-mediated protection against hepatic steatosis in HFD-fed females. The balance between non-hepatic estrogen signaling and hepatic or non-hepatic testosterone action may control hepatic steatosis.

[News in osteogenesis imperfecta: from research to clinical management]. / Nouveautés dans l'ostéogenèse imparfaite: de la recherche à la prise en charge multidisciplinaire.

Osteogenesis imperfecta (OI) is a rare genetic disease. Today we are able to propose an adapted and efficient management to the patients with this rare disorder (and their families) thanks to a strong collaboration of clinicians and researchers. Recent knowledge regarding the genetics of OI permits an accurate diagnosis of the specific type of OI and its own molecular mechanism, a genetic counseling for family planning and prenatal diagnosis, and in addition more targeted therapeutic options. A specific support with re-education for patients with OI is necessary and efficient. To optimize patient care, a multidisciplinary consultation is proposed at the CHUV, moreover a web site is available for patients, families and therapists: www.infomaladiesrares.ch

Use of an Additional Diagnostic Work-up Following a Treatment Recommendation from the Preoperative Conference of the Mammography Screening Units.

Objective: If a focus of suspicion is classified as being B 3-5 by a punch biopsy as part of a mammography screening, a recommendation for further action to be taken will be given in the preoperative conference of the screening unit. As part of this investigation, these treatment recommendations were compared with the final therapeutic approach taken at a certified breast centre. Furthermore, it was investigated whether and which additional examinations were performed on patients, depending on compliance with the recommended treatment. Material and Method: The data from 272 breast cancer patients from the years 2007, 2008 and 2009 was analysed. The patients took part in the screening programmes of four screening units in the German mammography screening programme, in one federal state. In addition, the data from each patient from one screening unit was analysed in two further federal states. Results: In total, the most recently conducted intervention deviated from the treatment recommendation from the preoperative conference in the screening unit in 77 out of 272 patients (28.3 %). Of these, there were 50 recommendations for open biopsy which ultimately resulted in breast-conserving surgery, which is not to be evaluated as an error, as the bioptic result was supplemented by the open biopsy. Additional examinations were performed in patients with deviating treatment recommendation in 39 cases (50.6 %) and in patients without deviating treatment recommendation in 66 cases (34.0 %). The additional examinations carried out included additional punch biopsies (most frequent) and MRI scans, but also additional ultrasounds or a mammography. Conclusions: Additional examinations lead to a change in treatment in a higher percentage of patients in comparison with the initial screening including assessment. An exact reexamination of the findings obtained in the screening is therefore preoperatively necessary in order to guarantee optimum treatment.

High-sensitivity dispersive Mach-Zehnder interferometer based on a dissimilar-doping dual-core fiber for sensing applications.

A dual-core fiber in which one of the cores is doped with germanium and the other with phosphorus is used as an in-line Mach-Zehnder dispersive interferometer. By ensuring an equal length but with different dispersion dependencies in the interferometer arms (the two cores), high-sensitivity strain and temperature sensing are achieved. Opposite sensitivities for high and low wavelength peaks were also demonstrated when strain and temperature was applied. To our knowledge this is the first time that such behavior is demonstrated using this type of in-line interferometer based on a dual-core fiber. A sensitivity of (0.102±0.002) nm/µÎµ, between 0 and 800 µÎµ and (-4.2±0.2) nm/°C between 47°C and 62°C is demonstrated.

Effect of pasteurization on selected immune components of donated human breast milk.

OBJECTIVE: Pasteurized, donated milk is increasingly provided to preterm infants in the absence of mother's own milk. The aim of this study was to determine the effect of pasteurization on the concentration of selected components in donated human breast milk. STUDY DESIGN: Donated milk from 34 mothers was pooled into 17 distinct batches (4 mothers per batch). Aliquots of each batch were then Holder pasteurized (62.5 °C for 30 min). Interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70 and IL-13 were measured in a multiplex enzyme-linked immunosorbent assay (ELISA). Granulocyte colony-stimulating factor (G-CSF), heparin-binding epidermal-like growth factor (HB-EGF) and hepatocyte growth factor (HGF) were measured by ELISA. Lipids were assessed by gas chromatography and gangliosides by the resorcinol-HCl reaction. RESULT: IFN-γ, TNF-α, IL-1ß, IL-10 and HGF were significantly reduced by pasteurization (P<0.05). Gangliosides were not affected, but the proportion of medium-chain saturated fats was increased (P<0.05) with a trend towards a decreased proportion of oleic acid (P=0.057). CONCLUSION: Pasteurization significantly reduced the concentration of several immunoactive compounds present in breast milk, but did not have an impact on others.

KIF1A is the primary anterograde motor protein required for the axonal transport of dense-core vesicles in cultured hippocampal neurons.

Dense-core vesicles (DCVs) are responsible for transporting, processing, and secreting neuropeptide cargos that mediate a wide range of biological processes, including neuronal development, survival, and learning and memory. DCVs are synthesized in the cell body and are transported by kinesin motor proteins along microtubules to pre- and postsynaptic release sites. Due to the dependence on kinesin-based transport, we sought to determine if the kinesin-3 family member, KIF1A, transports DCVs in primary cultured hippocampal neurons, as has been described for invertebrate neurons. Two-color, live-cell imaging showed that the DCV markers, chromogranin A-RFP and BDNF-RFP, move together with KIF1A-GFP in both the anterograde and retrograde directions. To demonstrate a functional role for KIF1A in DCV transport, motor protein expression in neurons was reduced using RNA interference (shRNA). Fluorescently tagged DCV markers showed a significant reduction in organelle flux in cells expressing shRNA against KIF1A. The transport of cargo driven by motors other than KIF1A, including mitochondria and the transferrin receptor, was unaffected in KIF1A shRNA expressing cells. Taken together, these data support a primary role for KIF1A in the anterograde transport of DCVs in mammalian neurons, and also provide evidence that KIF1A remains associated with DCVs during retrograde DCV transport.

Newborn frontal horn cysts: cause for concern?

OBJECTIVE: To document the incidence, natural history and compare neurodevelopmental outcome of newborns with and without frontal horn cysts (FHC). STUDY DESIGN: This was a case-control study. Newborns with and without FHC were identified and matched for demographics and worst cranial ultrasound scan (CUS) findings. Neurodevelopmental outcome was assessed at 18 to 24 months. RESULT: A total of 30 FHC cases were identified from medical imaging database. Twenty-five cases occurred in preterm 32 weeks gestation with an incidence of 1% (25 of 2340). The diagnosis was made on the initial CUS in 28 cases. The cyst size and number varied from 1 to 18 mm and 1 to 6 respectively with no change noted on repeat CUS during hospital stay. Neurodevelopmental outcomes were not statistically significantly different between the groups. CONCLUSION: FHC are not uncommon in the newborn period. They appear to be benign with no impact on neurodevelopmental outcome. This information is vital for counseling parents of infants with FHC.

Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family.

BACKGROUND: Mutations in TRPV4, a gene that encodes a Ca(2+) permeable non-selective cation channel, have recently been found in a spectrum of skeletal dysplasias that includes brachyolmia, spondylometaphyseal dysplasia, Kozlowski type (SMDK) and metatropic dysplasia (MD). Only a total of seven missense mutations were detected, however. The full spectrum of TRPV4 mutations and their phenotypes remained unclear. OBJECTIVES AND METHODS: To examine TRPV4 mutation spectrum and phenotype-genotype association, we searched for TRPV4 mutations by PCR-direct sequencing from genomic DNA in 22 MD and 20 SMDK probands. RESULTS: TRPV4 mutations were found in all but one MD subject. In total, 19 different heterozygous mutations were identified in 41 subjects; two were recurrent and 17 were novel. In MD, a recurrent P799L mutation was identified in nine subjects, as well as 10 novel mutations including F471del, the first deletion mutation of TRPV4. In SMDK, a recurrent R594H mutation was identified in 12 subjects and seven novel mutations. An association between the position of mutations and the disease phenotype was also observed. Thus, P799 in exon 15 is a hot codon for MD mutations, as four different amino acid substitutions have been observed at this codon; while R594 in exon 11 is a hotspot for SMDK mutations. CONCLUSION: The TRPV4 mutation spectrum in MD and SMDK, which showed genotype-phenotype correlation and potential functional significance of mutations that are non-randomly distributed over the gene, was presented in this study. The results would help diagnostic laboratories establish efficient screening strategies for genetic diagnosis of the TRPV4 dysplasia family diseases.

Stüve-Wiedemann syndrome: long-term follow-up and genetic heterogeneity.

Stüve-Wiedemann syndrome (SWS, OMIM 601559) is a severe autosomal recessive condition caused by mutations in the leukemia inhibitory receptor (LIFR) gene. The main characteristic features are bowing of the long bones, neonatal respiratory distress, swallowing/sucking difficulties and dysautonomia symptoms including temperature instability often leading to death in the first years of life. We report here four patients with SWS who have survived beyond 36 months of age with no LIFR mutation. These patients have been compared with six unreported SWS survivors carrying null LIFR mutations. We provide evidence of clinical homogeneity of the syndrome in spite of the genetic heterogeneity.

Human milk banking.

It is universally accepted that breast milk is the optimum exclusive source of nutrition for the first six months of life, and may remain part of the healthy infant diet for the first two years of life and beyond. Despite advances in infant formulas, human breast milk provides a bioactive matrix of benefits that cannot be replicated by any other source of nutrition. When the mother's own milk is unavailable for the sick, hospitalized newborn, pasteurized human donor breast milk should be made available as an alternative feeding choice followed by commercial formula. There is a limited supply of donor breast milk in Canada and it should be prioritized to sick, hospitalized neonates who are the most vulnerable and most likely to benefit from exclusive human milk feeding.

The medial periosteal hinge, a key structure in fractures of the proximal humerus: a biomechanical cadaver study of its mechanical properties.

The medial periosteal hinge plays a key role in fractures of the head of the humerus, offering mechanical support during and after reduction and maintaining perfusion of the head by the vessels in the posteromedial periosteum. We have investigated the biomechanical properties of the medial periosteum in fractures of the proximal humerus using a standard model in 20 fresh-frozen cadaver specimens comparable in age, gender and bone mineral density. After creating the fracture, we displaced the humeral head medial or lateral to the shaft with controlled force until complete disruption of the posteromedial periosteum was recorded. As the quality of periosteum might be affected by age and bone quality, the results were correlated with the age and the local bone mineral density of the specimens measured with quantitative CT. Periosteal rupture started at a mean displacement of 2.96 mm (SD 2.92) with a mean load of 100.9 N (SD 47.1). The mean maximum load of 111.4 N (SD 42.5) was reached at a mean displacement of 4.9 mm (SD 4.2). The periosteum was completely ruptured at a mean displacement of 34.4 mm (SD 11.1). There was no significant difference in the mean distance to complete rupture for medial (mean 35.8 mm (SD 13.8)) or lateral (mean 33.0 mm (SD 8.2)) displacement (p = 0.589). The mean bone mineral density was 0.111 g/cm(3) (SD 0.035). A statistically significant but low correlation between bone mineral density and the maximum load uptake (r = 0.475, p = 0.034) was observed. This study showed that the posteromedial hinge is a mechanical structure capable of providing support for percutaneous reduction and stabilisation of a fracture by ligamentotaxis. Periosteal rupture started at a mean of about 3 mm and was completed by a mean displacement of just under 35 mm. The microvascular situation of the rupturing periosteum cannot be investigated with the current model.

Identification of loss-of-function mutations of SLC35D1 in patients with Schneckenbecken dysplasia, but not with other severe spondylodysplastic dysplasias group diseases.

BACKGROUND: Schneckenbecken dysplasia (SBD) is an autosomal recessive lethal skeletal dysplasia that is classified into the severe spondylodysplastic dysplasias (SSDD) group in the international nosology for skeletal dysplasias. The radiological hallmark of SBD is the snail-like configuration of the hypoplastic iliac bone. SLC35D1 (solute carrier-35D1) is a nucleotide-sugar transporter involved in proteoglycan synthesis. Recently, based on human and mouse genetic studies, we showed that loss-of-function mutations of the SLC35D1 gene (SLC35D1) cause SBD. OBJECT: To explore further the range of SLC35D1 mutations in SBD and elucidate whether SLC35D1 mutations cause other skeletal dysplasias that belong to the SSDD group. METHODS AND RESULTS: We searched for SLC35D1 mutations in five families with SBD and 15 patients with other SSDD group diseases, including achodrogenesis type 1A, spondylometaphyseal dysplasia Sedaghatian type and fibrochondrogenesis. We identified four novel mutations, c.319C>T (p.R107X), IVS4+3A>G, a 4959-bp deletion causing the removal of exon 7 (p.R178fsX15), and c.193A>C (p. T65P), in three SBD families. Exon trapping assay showed IVS4+3A>G caused skipping of exon 4 and a frameshift (p.L109fsX18). Yeast complementation assay showed the T65P mutant protein lost the transporter activity of nucleotide sugars. Therefore, all these mutations result in loss of function. No SLC35D1 mutations were identified in all patients with other SSDD group diseases. CONCLUSION: Our findings suggest that SLC35D1 loss-of-function mutations result consistently in SBD and are exclusive to SBD.