Implementing a fracture liaison service open model of care utilizing a cloud-based tool.

PURPOSE: Although half of women and one-quarter of men aged 50 and older will sustain an acute low-trauma fracture, less than a quarter receive appropriate secondary fracture prevention. The goal of this quality improvement demonstration project was to implement a Fracture Liaison Service (FLS) focused on secondary prevention of an osteoporotic fracture in three open health care systems aided by a cloud-based tool. METHODS: The pre-post study design examined the proportion of men and women over age 50 who received appropriate assessment (bone mineral density, vitamin D levels) and treatment (calcium/vitamin D, pharmacologic therapy) in the six months following a recently diagnosed fracture. The pre-study (Pre FLS) included a retrospective chart review for baseline data (N = 344 patients) within each health care system. In the post-evaluation (Post FLS, N = 148 patients), the FLS coordinator from each health care system examined these parameters following enrollment and for 6 months following the recently diagnosed fracture. Data were managed in the cloud-based FLS application tool. RESULTS: Ninety-three participants completed the program. The FLS program increased the percentage of patients receiving bone mineral density testing from 21% at baseline to 93% (p < 0.001) Post FLS implementation. Assessments of vitamin D levels increased from 25 to 84% (p < 0.001). Patients prescribed calcium/vitamin D increased from 36% at baseline to 93% (p < 0.001) and those prescribed pharmacologic treatment for osteoporosis increased on average from 20 to 54% (p < 0.001) Post FLS. CONCLUSIONS: We conclude that the FLS model of care in an open health care system, assisted by a cloud-based tool, significantly improved assessment and/or treatment of patients with a recently diagnosed osteoporotic fracture. Future studies are necessary to determine if this model of care is scalable and if such programs result in prevention of fractures. Mini-Abstract: The goal was to implement a Fracture Liaison Service (FLS) focused on secondary prevention of an osteoporotic fracture in open health care systems aided by a cloud-based tool. This model significantly improved assessment and/or treatment of patients with a recently diagnosed fracture.

Development of a cloud-based application for the Fracture Liaison Service model of care.

UNLABELLED: The aims of this study are to develop a cloud-based application of the Fracture Liaison Service for practitioners to coordinate the care of osteoporotic patients after suffering primary fractures and provide a performance feedback portal for practitioners to determine quality of care. The application provides continuity of care, improved patient outcomes, and reduced medical costs. INTRODUCTION: The purpose of this study is to describe the content development and functionality of a cloud-based application to broadly deploy the Fracture Liaison Service (FLS) to coordinate post-fracture care for osteoporotic patients. METHODS: The Bone Health Collaborative developed the FLS application in 2013 to support practitioners' access to information and management of patients and provide a feedback portal for practitioners to track their performance in providing quality care. A five-step protocol (identify, inform, initiate, investigate, and iterate) organized osteoporotic post-fracture care-related tasks and timelines for the application. A range of descriptive data about the patient, their medical condition, therapies and care, and current providers can be collected. Seven quality of care measures from the National Quality Forum, The Joint Commission, and the Centers for Medicare and Medicaid Services can be tracked through the application. RESULTS: There are five functional areas including home, tasks, measures, improvement, and data. The home, tasks, and data pages are used to enter patient information and coordinate care using the five-step protocol. Measures and improvement pages are used to enter quality measures and provide practitioners with continuous performance feedback. The application resides within a portal, running on a multitenant, private cloud-based Avedis enterprise registry platform. All data are encrypted in transit and users access the application using a password from any common web browser. CONCLUSION: The application could spread the FLS model of care across the US health care system, provide continuity of care, effectively manage osteoporotic patients, improve outcomes, and reduce medical costs.

Use of Arotinolol Pharmacotherapy to Treat Drug-induced Tremor: A Report of Three Cases.

OBJECTIVE: The aim of the present study is to demonstrate the effect of arotinolol on drug-induced tremor in psychiatric patients. METHODS: This is a case study of three psychiatric patients with the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) diagnosis of major depressive disorder who were treated in inpatient or outpatient psychiatric settings with antidepressant or antipsychotics. Patients developed tremor. Arotinolol was started to treat the tremor. RESULTS: Drug-induced tremor almost resolved completely. No adverse effects were observed. CONCLUSION: We have presented a case series of drug-induced tremors that responded well to treatment with arotinolol, which appears to be a safe and well-tolerated drug in the dose ranges used. The possible utility of arotinolol to treat drug-induced tremor deserves attention and further investigation.

Investigation of Werner protein as an early DNA damage response in actinic keratosis, Bowen disease and squamous cell carcinoma.

BACKGROUND: Werner protein (WRN) has DNA helicase activity and participates in recombination, replication and repair of DNA. Loss-of-function mutations in WRN gives rise to genetic instability and diseases such as premature ageing and cancer. Upregulation of WRN promotes proliferation and survival of cancer cells. AIM: To evaluate the expression pattern of WRN in closely related skin cancers and their correlation with age, sex and UV exposure. METHODS: Immunohistochemistry was used to investigate expression of WRN in formalin-fixed, paraffin wax-embedded tissue specimens of 9 squamous cell carcinoma (SCC), 15 actinic keratosis (AK), 11 Bowen disease (BD) and 11 normal-appearing peripheral tissue samples, obtained from patients during surgical resections. RESULTS: WRN expression was significantly increased in BD, AK and SCC compared with normal controls, with the mean WRN staining score being highest in BD, followed by AK and SCC. However, age, sex and sun exposure were not associated with WRN expression. CONCLUSIONS: To our knowledge, this is the first report to date investigating the expression of WRN in skin cancers. The overtly high expression of WRN in premalignant lesions and in in situ cancer, with relatively low WRN expression in SCC, may indicate that WRN contributes as a checkpoint for early DNA damage response in skin tumorigenesis.

Super-resolution of magnetic systems using deep learning.

We construct a deep neural network to enhance the resolution of spin structure images formed by spontaneous symmetry breaking in the magnetic systems. Through the deep neural network, an image is expanded to a super-resolution image and reduced to the original image size to be fitted with the input feed image. The network does not require ground truth images in the training process. Therefore, it can be applied when low-resolution images are provided as training datasets, while high-resolution images are not obtainable due to the intrinsic limitation of microscope techniques. To show the usefulness of the network, we train the network with two types of simulated magnetic structure images; one is from self-organized maze patterns made of chiral magnetic structures, and the other is from magnetic domains separated by walls that are topological defects of the system. The network successfully generates high-resolution images highly correlated with the exact solutions in both cases. To investigate the effectiveness and the differences between datasets, we study the network's noise tolerance and compare the networks' reliabilities. The network is applied with experimental data obtained by magneto-optical Kerr effect microscopy and spin-polarized low-energy electron microscopy.

Topological magnetic structure generation using VAE-GAN hybrid model and discriminator-driven latent sampling.

Recently, deep generative models using machine intelligence are widely utilized to investigate scientific systems by generating scientific data. In this study, we experiment with a hybrid model of a variational autoencoder (VAE) and a generative adversarial network (GAN) to generate a variety of plausible two-dimensional magnetic topological structure data. Due to the topological properties in the system, numerous and diverse metastable magnetic structures exist, and energy and topological barriers separate them. Thus, generating a variety of plausible spin structures avoiding those barrier states is a challenging problem. The VAE-GAN hybrid model can present an effective approach to this problem because it brings the advantages of both VAE's diversity and GAN's fidelity. It allows one to perform various applications including searching a desired sample from a variety of valid samples. Additionally, we perform a discriminator-driven latent sampling (DDLS) using our hybrid model to improve the quality of generated samples. We confirm that DDLS generates various plausible data with large coverage, following the topological rules of the target system.

Optimization of physical quantities in the autoencoder latent space.

We propose a strategy for optimizing physical quantities based on exploring in the latent space of a variational autoencoder (VAE). We train a VAE model using various spin configurations formed on a two-dimensional chiral magnetic system. Three optimization algorithms are used to explore the latent space of the trained VAE. The first algorithm, the single-code modification algorithm, is designed for improving the local energetic stability of spin configurations to generate physically plausible spin states. The other two algorithms, the genetic algorithm and the stochastic algorithm, aim to optimize the global physical quantities, such as topological index, magnetization, energy, and directional correlation. The advantage of our method is that various optimization algorithms can be applied in the latent space containing the abstracted representation constructed by the trained VAE model. Our method based on latent space exploration is utilized for efficient physical quantity optimization.

Searching for the ground state of complex spin-ice systems using deep learning techniques.

Searching for the ground state of a given system is one of the most fundamental and classical questions in scientific research fields. However, when the system is complex and large, it often becomes an intractable problem; there is essentially no possibility of finding a global energy minimum state with reasonable computational resources. Recently, a novel method based on deep learning techniques was devised as an innovative optimization method to estimate the ground state. We apply this method to one of the most complicated spin-ice systems, aperiodic Penrose P3 patterns. From the results, we discover new configurations of topologically induced emergent frustrated spins, different from those previously known. Additionally, a candidate of the ground state for a still unexplored type of Penrose P3 spin-ice system is first proposed through this study. We anticipate that the capabilities of the deep learning techniques will not only improve our understanding on the physical properties of artificial spin-ice systems, but also bring about significant advances in a wide range of scientific research fields requiring computational approaches for optimization.

Estimating the effective fields of spin configurations using a deep learning technique.

The properties of complicated magnetic domain structures induced by various spin-spin interactions in magnetic systems have been extensively investigated in recent years. To understand the statistical and dynamic properties of complex magnetic structures, it is crucial to obtain information on the effective field distribution over the structure, which is not directly provided by magnetization. In this study, we use a deep learning technique to estimate the effective fields of spin configurations. We construct a deep neural network and train it with spin configuration datasets generated by Monte Carlo simulation. We show that the trained network can successfully estimate the magnetic effective field even though we do not offer explicit Hamiltonian parameter values. The estimated effective field information is highly applicable; it is utilized to reduce noise, correct defects in the magnetization data, generate spin configurations, estimate external field responses, and interpret experimental images.

Unanticipated stimulatory action of glucocorticoids on epithelial calcium absorption. Effect of dexamethasone on rat distal colon.

UNLABELLED: We studied the action of a glucocorticoid (GC, dexamethasone) and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on transepithelial calcium (Ca) transport in rat distal colon. GC 1.2 mg or 1,25(OH)2D3 270 ng were given daily for 4 d and Ca fluxes were measured in vitro in the absence of electrochemical gradients (Ussing technique). RESULTS: (a) Both 1,25(OH)2D3 and GC increased Ca absorptive flux from 24 +/- 3 (SEM) to 50 +/- 1 and from 23 +/- 1 to 38 +/- 4 nmol/cm2 per h, respectively (in each case n = 9, P less than 0.01); both steroid hormones had no effect on Ca secretory flux. (b) GC, but not 1,25(OH)2D3 increased the short-circuit current Isc) from 30 +/- 5; to 111 +/- 13 microA/cm2 (P less than 0.01), reflecting stimulation of electrogenic sodium (Na) transport. Choline replacement of Na in the bathing buffer abolished both the Isc and the active Ca transport induced by GC, but has no effect on the 1,25(OH)2D3-stimulated active Ca absorption. (c) When the buffer Ca concentration ([Ca]) on both sides of the epithelium was reduced from 1.25 to 1.25 X 10(-2) mM, the GC-induced, but not the 1,25(OH)2D3-induced, stimulation in Ca absorption was abolished. This suggests that the GC-stimulated Ca absorption may require a "threshold" Ca gradient across the luminal membrane through which Ca influx occurs. Thus, contrary to the current consensus, this study demonstrates that GC stimulates active Ca transport and that this action is mediated through a mechanism dependent on the presence of Na and a critical [Ca] in the ambient medium.

Calcium and inorganic phosphate transport in rat colon: dissociated response to 1,25-dihydroxyvitamin D3.

In the small intestine, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] stimulates both calcium (Ca) and inorganic phosphate (Pi) absorption. This is mediated through an increase in mucosal-to-serosal flux (Jms) whereas the serosal-to-mucosal flux (Jsm) remains unchanged. We now report that in rat proximal colon, 1,25(OH)(2)D(3) produces active Ca absorption without affecting Pi transport, and that this induced active Ca absorption is associated with alterations in kinetics of both Jms and Jsm so that both processes demonstrate saturable components. Vitamin D-deficient rats were given daily injections of solvent (-D) or 270 ng 1,25(OH)(2)D(3) (+D) for 3 d. (45)Ca and [(32)P]phosphate fluxes were measured employing the Ussing technique using a modified Krebs-Ringer-HCO(3) buffer ([Ca] 1.25, [Pi] 1.18, [glucose] 11 mM). In -D rats there was no net flux (Jnet) of either Ca or Pi. In +D rats net active Ca absorption was observed (-D = 3.3 nmol/cm(2) per h +/-3.4 (SEM); +D = 27.3 +/-3.8, n = 11, P < 0.001) whereas Pi transport was unchanged, i.e., still no Jnet. Pi Jms was not different from Pi Jsm measured at the following buffer [Pi]: 0.0118, 0.118, 1.18, and 2.36 mM. Ca saturation kinetics were estimated using buffer [Ca] from 0.0125 to 5.0 mM. Saturable processes were demonstrated for both Jms and Jsm. Jnet for Ca across colon from +D rats exhibited saturation at [Ca] > 3 mM, with an estimated V(max) of 44.0 nmol/cm(2) per h and a K(m) of 0.9 mM. This colonic model may provide a useful system for studying 1,25(OH)(2)D(3)-induced molecular events related to Ca but not Pi transport. The apparent action of 1,25(OH)(2)D(3) on Ca secretory process may furnish new insights into the mechanism of action of vitamin D.

Analysis of segmental phosphate absorption in intact rats. A compartmental analysis approach.

Available information supports the dominance of the proximal intestine in inorganic phosphate (Pi) absorption. However, there is no strategy for analyzing segmental Pi absorption from a spontaneously propelled meal in an intact animal. We propose a solution using compartmental analysis. After intragastric administration of a 32P-labeled Pi liquid meal containing a nonabsorbable marker, [14C]polyethylene glycol (PEG), rats were killed at 2, 10, 20, 30, 60, 120, and 240 min. The gastrointestinal tract was removed and divided into seven segments, from which 32P and [14C]PEG were recovered. Data was expressed as a percentage of the dose fed, i.e., (32P[in segment] divided by 32P[fed]) and [14C]PEG[in segment] divided by [14C]PEG[fed]), respectively. A compartmental model was constructed and the rate constants for intersegmental transit and segmental absorption were estimated. The "goodness of fit" between the simulated model and the actual data indicates the estimated rate constants reflect in vivo events. The duodenum, with the highest transit and absorption rates, accounted for a third of the total absorption. However, the terminal ileum, with a lower absorption rate but a longer transit time, absorbed an equal amount of Pi. This approach allows the analysis of the mechanism and the regulation of Pi absorption under more authentic in vivo conditions.

Acetylation polymorphism and prevalence of colorectal adenomas.

Polymorphic N-acetyltransferase (NAT2), an enzyme present in the colon, may effect incidence of colon cancer. Individuals with NAT2 fast acetylator genotypes may have higher colon cancer risks due to faster conversion of certain carcinogens to mutagens. We determined NAT2 genotypes in 447 subjects with distal colon adenomas and in 487 controls. No significant increase in adenoma prevalence among fast acetylators was observed. However, there was a suggestion of ethnic differences in NAT2 effects. For example, white fast acetylators potentially had slightly increased risks for adenomas (odds ratio, 1.29; 95% confidence interval, 0.90-1.84), whereas fast acetylation was potentially protective among blacks (odds ratio, 0.64; 95% confidence interval, 0.32-1.28). The apparent difference between blacks and whites may simply reflect random variation around an overall null effect, or it could represent a real difference. There was preliminary evidence for a possible interaction between NAT2 and the glutathione transferase M1 null genotype. Smokers' adenoma prevalence was 10-fold higher for fast acetylators with the null genotype compared to slow acetylators without the null genotype. Large, multiethnic populations and analysis of combinations of genes for carcinogen metabolism may be needed to further assess the role of NAT2 in colorectal tumorigenesis.

Glutathione transferase (GSTM1) null genotype, smoking, and prevalence of colorectal adenomas.

Colorectal cancer is caused by environmental exposures and genetic predisposition. However, little is known of hereditary factors that influence development of common, non-Mendelian forms of this cancer. Interactions among carcinogen exposure, hereditary variants of enzymes involved in carcinogen metabolism, and other host factors may play a role. Genetic polymorphisms of carcinogen metabolism, such as the glutathione transferase M1 (GSTM1) null genotype, are thus possibly related to cancer risk. The GSTM1 enzyme detoxifies mutagens formed from polycyclic aromatic hydrocarbons which are found in tobacco smoke. We analyzed GSTM1 genotypes and smoking among 488 controls and 446 individuals with a first time diagnosis of colorectal adenomas which are precursors to cancer. Subjects were from two Kaiser Permanente sigmoidoscopy clinics in southern California. We observed no overall effect of the GSTM1 null genotype on the risk for colorectal adenomas (odds ratio, 0.85; 95% confidence interval = 0.65-1.10). The odds ratio for smokers with the null genotype was 2.07 (95% confidence interval = 1.14-3.77) when compared to "never smokers" without the null genotype. Using this same reference group, the odds ratio for smokers without the null genotype was 1.73 (95% confidence interval = 1.03-2.90). These two odds ratios were not significantly different (P = 0.30).

Isolation and characterization of Neurospora mutants affected in invertase synthesis.

We have outlined a procedure that allows the large-scale screening of mutagenized Neurospora crassa populations for invertaseless mutants. We have isolated and characterized three mutations, inv(DBL1), inv(DBL9) and inv(DBL14), which have been mapped at or near the invertase structural gene. One of these, inv(DBL1), is particularly interesting. Our experiments indicate that the reduced level of invertase activity in the inv(DBL1)-containing cell can be explained as the result of a reduced number of normal enzyme molecules. We also show that wild-type Neurospora is able to respond rapidly to a change of medium and can dramatically increase its production of invertase within 20 min after a transfer to a carbon-free medium.

Neurospora trehalase and its structural gene.

We have isolated Neurospora trehalaseless mutants and mapped the trehalase structural gene to linkage group I. The structural gene mutations not only affect thermostability and other characteristics of the enzyme but also affect the production of an inhibitor of the wild-type trehalase. The inhibitor appears to be the mutant trehalase. We suggest that the mutant subunits act as inhibitors by entering into the multimeric forms of the enzyme and altering the ability of the normal wild-type subunits to catalyze the cleavage of trehalose.--Wild type trehalase has been purified to near homogeneity, and its characteristics have been studied. It was purified as a tetramer, with each subunit having a molecular weight of 88,000.--We have studied the regulation of trehalase and found the production of trehalase to be glucose repressible. Cells begin to produce trehalase 60 min after being transferred to glucose-free medium.

Development of a lesion resembling diabetic nephropathy in a renal homograft.

One month following a cadaver renal transplant for obstructive uropathy, a 27-year-old man developed diabetes mellitus. Two years later, marked proteinuria and decreased renal function were detected. Eight months later, a second decline in function occurred. Light microscopy of graft biopsy specimens obtained after each decline in renal function showed increased mesangial cells and matrix, thickening of Bowman capsule, and tubular atrophy with basement membrane thickening. Vascular changes, interstitial infiltrate, and fibrosis were not prominent. Electron microscopic studies of the second biopsy specimen confirmed the light microscopic changes; subepithelial dense deposits were also detected. Immunofluorescent studies of both biopsy specimens demonstrated linear staining of glomerular and tubular basement membranes and Bowman capsule for IgG and albumin. Antikidney antibodies were not detected in the patient's serum. These observations suggest development of the diffuse form of diabetic nephropathy in a renal homograft following steroid-induced diabetes mellitus.

Calciphylaxis in man. A syndrome of tissue necrosis and vascular calcification in 11 patients with chronic renal failure.

Eleven patients with chronic renal failure and presumed secondary hyperparathyroidism developed a syndrome of medial calcinosis of the arteries and painful ischemic ulcers of the fingers, legs, or thighs, or any combination of the three. Five patients required maintenance hemodialysis; six had functioning renal homografts. Severe hyperphosphatemia had existed in each; seven showed roentgenographic evidence of subperiosteal resorption. Similarities are evident between the lesions and experimentally produced calciphylaxix. The lesions demonstrated a relentless, progressive course, with serious morbidity and mortality. Hyperplastic or adenomatours parathyroid tissue was removed from ten of 11 patients unergoing surgical procedures; healing followed in seven patients. Treatment with phosphate-binding antacids to lower serum phosphorus levels may prevent this syndrome. Total or subtotal parathyroidectomy should be considered when ischemic skin lesions appear in uremic patients or in renal transplant recipients.

Cyclosporin A-induced hyperreninemic hypoaldosteronism. A model of adrenal resistance to angiotensin II.

We studied the effects of cyclosporin A on the renin-aldosterone axis in Sprague-Dawley rats. Two weeks of intragastric administration of cyclosporin A (5 mg/kg/day or or 20 mg/kg/day) resulted in large increases in plasma renin concentration (23 +/- 5, 70 +/- 12, and 79 +/- 11 ng/ml/hr in control rats and rats receiving 5 mg and 20 mg of cyclosporin A, respectively), with no parallel increments in plasma aldosterone. In vitro angiotensin II (ANG II)-stimulated aldosterone secretion by zona glomerulosa cells obtained from cyclosporin A-treated rats was also reduced (4.8 +/- 0.5, 1.5 +/- 0.2, and 0.2 +/- 0.2 ng/10(5) cells in control rats and rats receiving 5 mg and 20 mg of cyclosporin A, respectively). In contrast, in vitro aldosterone response to graded increments of potassium (3.7-10.7 mmol/L) or adrenocorticotropic hormone (ACTH) (10(-11)-10(-8) M) was preserved in cyclosporin A-treated rats. When added in vitro to zona glomerulosa cells from untreated rats, cyclosporin A also attenuated ANG II-stimulated aldosterone secretion, but did not affect potassium or ACTH-mediated aldosterone production. Thus, cyclosporin A-induced hyperreninemic hypoaldosteronism in the rat depends on opposing renal and adrenal effects, with a direct or feedback stimulation of renin secretion and a specific blockade of ANG II-mediated aldosterone production.