Exploring the potential of transfer learning for metamodels of heterogeneous material deformation.

From the nano-scale to the macro-scale, biological tissue is spatially heterogeneous. Even when tissue behavior is well understood, the exact subject specific spatial distribution of material properties is often unknown. And, when developing computational models of biological tissue, it is usually prohibitively computationally expensive to simulate every plausible spatial distribution of material properties for each problem of interest. Therefore, one of the major challenges in developing accurate computational models of biological tissue is capturing the potential effects of this spatial heterogeneity. Recently, machine learning based metamodels have gained popularity as a computationally tractable way to overcome this problem because they can make predictions based on a limited number of direct simulation runs. These metamodels are promising, but they often still require a high number of direct simulations to achieve an acceptable performance. Here we show that transfer learning, a strategy where knowledge gained while solving one problem is transferred to solving a different but related problem, can help overcome this limitation. Critically, transfer learning can be used to leverage both low-fidelity simulation data and simulation data that is the outcome of solving a different but related mechanical problem. In this paper, we extend Mechanical MNIST, our open source benchmark dataset of heterogeneous material undergoing large deformation, to include a selection of low-fidelity simulation results that require ≈ 2 - 4 orders of magnitude less CPU time to run. Then, we show that transferring the knowledge stored in metamodels trained on these low-fidelity simulation results can vastly improve the performance of metamodels used to predict the results of high-fidelity simulations. In the most dramatic examples, metamodels trained on 100 high fidelity simulations but pre-trained on 60,000 low-fidelity simulations achieves nearly the same test error as metamodels trained on 60,000 high-fidelity simulations (1 - 1.5% mean absolute percent error). In addition, we show that transfer learning is an effective method for leveraging data from different load cases, and for leveraging low-fidelity two-dimensional simulations to predict the outcomes of high-fidelity three-dimensional simulations. Looking forward, we anticipate that transfer learning will enable us to better capture the influence of tissue spatial heterogeneity on the mechanical behavior of biological materials across multiple different domains.

Understanding the relationship between cell death and tissue shrinkage via a stochastic agent-based model.

Cell death, a process which can occur both naturally and in response to insult, is both a complex and diverse phenomenon. Under some circumstances, dying cells actively contract and cause their neighbors to rearrange and maintain tissue integrity. Under other circumstances, dying cells leave behind gaps, which results in tissue separation. A better understanding of how the cellular scale features of cell death manifest on the population scale has implications ranging from morphogenesis to tumor response to treatment. However, the mechanistic relationship between cell death and population scale shrinkage is not well understood, and computational methods for studying these relationships are not well established. Here we propose a mechanically robust agent-based cell model designed to capture the implications of cell death on the population scale. In our agent-based model, algorithmic rules applied on the cellular level emerge on the population scale where their effects are quantified. To better quantify model uncertainty and parameter interactions, we implement a recently developed technique for conducting a variance-based sensitivity analysis on the stochastic model. From this analysis and subsequent investigation, we find that cellular scale shrinkage has the largest influence of all model parameters tested, and that by adjusting cellular scale shrinkage population shrinkage varies widely even across simulations which contain the same fraction of dying cells. We anticipate that the methods and results presented here are a starting point for significant future investigation toward quantifying the implications of different mechanisms of cell death on population and tissue scale behavior.

Interval training in men at risk for insulin resistance.

We compared 3 months of eucaloric (12 kcal/kg/wk) steady state aerobic training (AER) to interval training (INT) in men at risk for insulin resistance. Primary outcomes included oral glucose tolerance testing (OGTT) and HOMA-IR 24 h and 72 h after each participants last exercise session. Secondary outcomes were VO2max, anthropometry, and metabolic syndrome expressed as a summed z-score (zMS). We also performed a sub-analysis for participants entering the trial above and below the HOMA-IR study median. Mean (95% CI) AER ( - 12.81 mg/dl; - 24.7, - 1.0) and INT ( - 14.26 mg/dl; - 24.9, - 3.6) significantly improved 24 h OGTT. HOMA-IR did not improve for AER, but did for INT 24 h and 72 h post-exercise. VO2max improved similarly for both groups. Changes in body mass for INT ( - 2.29 kg; - 3.51, - 1.14), AER, ( - 1.32 kg; - 2.62, 0.58)] and percent body fat [INT, - 0.83%; - 1.62, - 0.03), AER ( - 0.17%; - 1.07, 0.06)] were only significant for INT. When examined as a full cohort, zMS improved for both groups. Upon HOMA-IR stratification, only high HOMA-IR AER showed significant improvements, while both low and high INT HOMA-IR participants demonstrated significant reductions (P<0.05). Eucaloric AER and INT appear to affect fasting glucose, OGTT and VO2max similarly, while INT may have a greater impact on HOMA-IR and zMS.

On the connection between RNAi and heterochromatin at centromeres.

RNA interference (RNAi) is a conserved silencing mechanism whereby double-strand RNA induces specific down-regulation of homologous sequences. In the fission yeast Schizosaccharomyces pombe, centromeric heterochromatin assembly is an RNAi-dependent process. Noncoding RNAs transcribed from pericentromeric repeat sequences are processed into short interfering RNAs (siRNAs) that direct the Argonaute-containing RNA-induced transcriptional silencing (RITS) effector complex to homologous nascent transcripts. RITS is required for H3K9 methylation by the histone methyltransferase (HMT) Clr4; conversely, H3K9 methylation can attract RITS to chromatin via binding of the chromodomain protein Chp1. This codependency has hampered dissection of the order of events and mechanisms of cross talk between the RNAi and chromatin modification machineries. To tackle this problem, we have developed systems that reconstitute heterochromatin at a euchromatic locus, using either hairpin triggers or DNA-tethered chromatin-modifying complexes. These systems reveal that RNAi is sufficient to promote heterochromatin assembly in cis and that direct recruitment of the HMT Clr4 can bypass the role of RNAi in heterochromatin assembly. We have also characterized a new pathway component, Stc1, that translates the RNAi signal into chromatin marks. We discuss the implications of these findings for our understanding of the mechanism and function of RNAi-directed heterochromatin assembly at centromeres.

Subchondral tibial bone mineral density predicts future joint space narrowing at the medial femoro-tibial compartment in patients with knee osteoarthritis.

Preliminary studies have shown that dual-energy X-ray absorptiometry (DXA) produces images of sufficient quality for a precise and accurate measurement at density of the subchondral bone. The objective of this study was to investigate the relationship between baseline subchondral tibial bone mineral density (BMD) and joint space narrowing observed after 1 year at the medial femoro-tibial compartment of the knee joint. Fifty-six consecutive patients, from both genders, with knee osteoarthritis diagnosed according to the American College of Rheumatology criteria, were included in the study. Radiographic posteroanterior views were taken, at baseline and after 1 year of follow-up. Minimum joint space width (JSW) measurement, at the medial femoro-tibial joint, was performed with a 0.1-mm graduated magnifying lens. Baseline BMD of the subchondral tibial bone was assessed by DXA. The mean +/- SD age of the patients was 65.3 +/- 8.7 years, with a body mass index of 28.0 +/- 4.9 kg/m(2). The minimum JSW was 3.5 +/- 1.5 mm and the mean BMD of the subchondral bone was 0.848 +/- 0.173 g/cm(2). There was a significant negative correlation between subchondral BMD and 1-year changes in minimum JSW (r = -0.43, p = 0.02). When performing a multiple regression analysis with age, sex, body mass index, and minimum JSW at baseline as concomitant variables, BMD of the subchondral bone as well as JSW at baseline were independent predictors of 1-year changes in JSW (p = 0.02 and p = 0.005, respectively). Patients in the lowest quartile of baseline BMD (<0.73 g/cm(2)) experienced less joint space narrowing than those in the highest BMD quartile (>0.96 g/cm(2)) (+0.61 +/- 0.69 mm versus -0.13 +/- 0.27 mm; p = 0.03). Assessment of BMD of the subchondral tibial bone is significantly correlated with future joint space narrowing and could be used as a predictor of knee osteoarthritis progression.

Influence of daily regimen calcium and vitamin D supplementation on parathyroid hormone secretion.

Calcium and vitamin D supplementation has been shown to reduce secondary hyperparathyroidism and play a role in the management of senile osteoporosis. In order to define the optimal regimen of calcium and vitamin D supplementation to produce the maximal inhibition of parathyroid hormone secretion, we have compared the administration of a similar amount of Ca and vitamin D, either as a single morning dose or split in two doses, taken 6 hours apart. Twelve healthy volunteers were assigned to three investigational procedures, at weekly intervals. After a blank control procedure, when they were not exposed to any drug intake, they received two calcium-vitamin D supplement regimens including either two doses of Orocal D3 (500 mg Ca and 400 IU vitamin D) 6 hours apart or one water-soluble effervescent powder pack of Cacit D3 in a single morning dose (1000 mg Ca and 880 IU vitamin D). During the three procedures (control and the two calcium-vitamin D supplementations), venous blood was drawn every 60 minutes for up to 9 hours, for serum Ca and serum PTH measurements. The order of administration of the two Ca and vitamin D supplementation sequences was allocated by randomization. No significant changes in serum Ca were observed during the study. During the 6 hours following Ca and vitamin D supplementation, a statistically significant decrease in serum PTH was observed with both regimens, compared with baseline and with the control procedure. Over this period of time, no differences were observed between the two treatment regimens. However, between the sixth and the ninth hour, serum PTH levels were still significantly decreased compared with baseline with split dose Orocal D3 administration, while they returned to baseline value with the Cacit D3 preparation. During this period, the percentage decrease in serum PTH compared with baseline was significantly more pronounced with Orocal D3 than with Cacit D3 (P = 0.0021). We therefore conclude that the administration of two doses of 500 mg of calcium and 400 IU of vitamin D3 6 hours apart provides a more prolonged decrease in serum PTH levels than the administration of the same total amount of Ca and vitamin D as a single morning dose in young healthy volunteers. This might have implications in terms of protection of the skeleton against secondary hyperparathyroidism and increased bone resorption and turnover in elderly subjects.

Influence of daily calcium and vitamin D supplementation on parathyroid hormone secretion.

Calcium and vitamin D supplementation have been shown to reduce secondary hyperparathyroidism and play a role in age-related osteoporosis. In order to define the optimal regimen of calcium and vitamin D supplementation to produce the maximal inhibition of parathyroid hormone secretion, we compared the administration of a calcium-vitamin D supplement as a single morning dose with the administration of two divided doses at 6-hour intervals. Twelve healthy male volunteers were assigned to three investigational procedures, which were alternated at weekly intervals. After a 'blank' control procedure, when they were not exposed to any supplements, they received one of two calcium-vitamin D supplement regimens: either two doses of Orocal D3 (500 mg calcium and 400 IU vitamin D3) with a 6-hour interval between doses, or one water-soluble effervescent powder pack of Cacit vitamin D3, taken in the morning (1000 mg calcium and 880 IU vitamin D3). During the three procedures (control and the two calcium-vitamin D supplementation protocols), veinous blood was drawn every 60 minutes for up to 9 hours, for serum calcium and parathyroid hormone measurements. The order of administration of the two calcium and vitamin D supplementation regimens was allocated by randomization. No significant changes in serum calcium were observed during the study. During the first 6 hours following calcium-vitamin D supplementation, a statistically significant decrease in serum parathyroid hormone was observed with both regimens, compared with baseline and the control procedure. During this first period, no differences were observed between the two treatment regimens. However, between the 6th and the 9th hour, serum parathyroid hormone levels remained significantly decreased compared to baseline with the twice-daily Orocal D3 administration, while they returned to baseline values with the once-daily Cacit D3 preparation. During this period, the percentage decrease in serum parathyroid hormone relative to baseline was significantly greater with Orocal D3 than Cacit D3 (p = 0.0021). We therefore conclude that the twice-daily administration of 500 mg calcium and 400 IU vitamin D3 at 6-hour intervals provides a more prolonged decrease in serum parathyroid hormone levels than the administration of the same total amount of calcium and vitamin D, as a single morning dose in young healthy.

Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial.

BACKGROUND: Treatment of osteoarthritis is usually limited to short-term symptom control. We assessed the effects of the specific drug glucosamine sulphate on the long-term progression of osteoarthritis joint structure changes and symptoms. METHODS: We did a randomised, double-blind placebo controlled trial, in which 212 patients with knee osteoarthritis were randomly assigned 1500 mg sulphate oral glucosamine or placebo once daily for 3 years. Weightbearing, anteroposterior radiographs of each knee in full extension were taken at enrolment and after 1 and 3 years. Mean joint-space width of the medial compartment of the tibiofemoral joint was assessed by digital image analysis, whereas minimum joint-space width--ie, at the narrowest point--was measured by visual inspection with a magnifying lens. Symptoms were scored by the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index. FINDINGS: The 106 patients on placebo had a progressive joint-space narrowing, with a mean joint-space loss after 3 years of -0.31 mm (95% CI -0.48 to -0.13). There was no significant joint-space loss in the 106 patients on glucosamine sulphate: -0.06 mm (-0.22 to 0.09). Similar results were reported with minimum joint-space narrowing. As assessed by WOMAC scores, symptoms worsened slightly in patients on placebo compared with the improvement observed after treatment with glucosamine sulphate. There were no differences in safety or reasons for early withdrawal between the treatment and placebo groups. INTERPRETATION: The long-term combined structure-modifying and symptom-modifying effects of gluosamine sulphate suggest that it could be a disease modifying agent in osteoarthritis.

Cerebrospinal fluid dynamics in the tardive cauda equina syndrome of ankylosing spondylitis.

Typical cauda equina syndrome secondary to long-standing ankylosing spondylitis is reported in a 63-year-old man. Radionuclide cisternography demonstrated a resorption defect of cerebrospinal fluid in the enlarged lumbosacral dural sac. After transient symptomatic improvement with acetazolamide, a lumboperitoneal shunt was placed. The rate of cerebrospinal fluid, isotope resorption became normal. In the 5 years of follow-up, partial remission has been observed.

[Spinal osteoblastoma. Report of 8 cases]. / L'ostéoblastome rachidien. A propos de huit observations.

The authors studied the special features of the vertebral location of this benign tumour of osteoblastic origin in eight cases of spinal osteoblastoma. Clinically, neurological complications are frequently present and scolioses may arise and persist after treatment; radiologically, new imaging techniques enable the limits of the tumour to be assessed with greater accuracy with respect to the neighbouring bone and their relationship to the components of the vertebral canal; surgically, there are difficulties specific to this location raised by the proximity of nervous components, and also by the vertebral destabilization entailed by the considerable bone involvement. Anatomicopathological diagnosis remains difficult, particularly in the case of osteoid osteoma.

Compared effects of isoxicam and indomethacin on the urinary excretion of prostaglandins in degenerative articular diseases.

The effects of a 7 day-treatment with isoxicam (200 mg/24 h) on the urinary excretion of prostaglandins (PG) were compared to those of indomethacin (150 mg/24 h) in a double-blind randomized study conducted in 18 patients with degenerative arthritic disease and normal renal function. Indomethacin decreased the urinary excretion of PGF2 alpha by about 70% and 6-keto-PGF1 alpha and thromboxane (Tx)B2, the stable break-down products of prostacyclin and TxA2 respectively, by about 40%. Isoxicam effects on urinary PG did not significantly differ from those of indomethacin. During both treatments, urinary gamma-glutamyl transferase and N- acetyl-glucosaminidase remained stable and none of the changes in the urinary excretion of PGs could be related to either plasma or urinary drug concentrations. In conclusion, chronic administration of isoxicam inhibited the renal PG biosynthesis to a similar extent than indomethacin which suggests that non steroidal anti-inflammatory drugs of the oxicam group ought also be used cautiously in patients with renal impairment.

[Candida spondylodiscitis. Report of 2 personal cases and 28 cases from the literature]. / Spondylodiscites à Candida. A propos de 2 observations personnelles et de 28 observations de la littérature.

Vertebral osteomyelitis caused by Candida spp. has recently been described and seems to be rare since only 30 cases have been published so far. Its clinical, laboratory and radiological features are identical with those on non-tuberculous bacterial spondylitis. It develops in subjects with poor general condition who underwent multiple surgical operations or received prolonged antibiotic therapy. The finding of Candida at needle biopsy of the since clinches the diagnosis. Serological tests might provide an earlier diagnosis and, above all, enable therapeutic effectiveness to be evaluated. In 27 of the 30 cases reported here, cure was obtained by prolonged infusions of antifungal drugs, chiefly amphotericin B and/or 5-fluorocytosine.

The rheumatoid heel: its relationship to other disorders in the rheumatoid foot.

Four-hundred and eight rheumatoid feet are studied. The percentage of talalgia is 3.7%; for inferior exostosis it is 29.6%, and 30.8% for posterior exostosis. Posterior demineralisation is present in 12%, whereas for bony erosion it is 8.1%. Plantar spurs are very closely associated to flattened feet (p less than 0.0001). Likewise a very noticeable statistical association is noted between postero-superior calcaneitis and tarsal arthritis (p less than 0.0001), and calcaneitis was more frequent among marked valgus (p less than 0.001). These results are compared with findings of other works. Therapeutic consequences are evoked.

[Enlarged transfacial approach in the surgery of tumors of the ethmoid]. / La voie trans-faciale élargie dans la chirurgie des tumeurs de l'ethmoïde.

Cancers and tumours of the ethmoid bone are characterized by the possibility of extension towards the lamina cribrosa and within the cranium. Removal via a combined neurosurgical and paralateronasal route would appear to provide a more favourable prognosis for the patient. It is, however, a particularly cumbersome approach, and the neurosurgical follow up may be difficult. This is why we recommend a direct approach to both the ethmoid bone and the anterior part of the base of the cranium via a transfacial route, thus permitting complete removal of the tumour and of any intracranial extension through the lamina cribrosa. A number of points of technique are important: the line of the skin incision and the flap of cranial periosteum, operative examination and exploration of the upper part of the tumour, the reconstruction of the meningeal barrier and, if necessary the base of the cranium. The price to be paid for this approach route is the scar which is, however, always of minimum size and well tolerated by patients. Operative follow up is simple--which is the major advantage of the technique--and the carcinological prognosis appears to be as satisfactory as for the combined route.

Deformation of the adult rheumatoid rearfoot. A radiographic study.

Three hundred ninety-seven adult rheumatoid feet were examined. Those in whom pain had been present since the onset of the disease were compared radiographically with the painless feet in standing position: examination of the talar angle and of the internal arch showed flattening on the affected feet. The calcaneal angle, on the other hand, showed no difference between the two groups, but this latter parameter is little affected by the valgus pronation deformity of the hindfoot most often seen in patients who had experienced foot pain.