Miracle-dz/UniFAR-FTUs huggingface dataset:
A Model of Glucose-Insulin-Pramlintide Pharmacokinetics and Pharmacodynamics in Type I Diabetes

Background: Type 1 diabetes mellitus (T1DM) complications are significantly reduced when normoglycemic levels are maintained via intensive therapy. The artificial pancreas is designed for intensive glycemic control; however, large postprandial excursions after a meal result in poor glucose regulation. Pramlintide, a synthetic analog of the hormone amylin, reduces the severity of postprandial excursions by reducing appetite, suppressing glucagon release, and slowing the rate of gastric emptying. The goal of this study is to create a glucose-insulin-pramlintide physiological model that can be employed into a controller to improve current control approaches used in the artificial pancreas. Methods: A model of subcutaneous (SC) pramlintide pharmacokinetics (PK) was developed by revising an intravenous (IV) pramlintide PK model and adapting SC insulin PK from a glucose-insulin model. Gray-box modeling and least squares optimization were used to obtain parameter estimates. Pharmacodynamics (PD) were obtained by choosing parameters most applicable to pramlintide mechanisms and then testing using a proportional PD effect using least squares optimization. Results: The model was fit and validated using 27 data sets, which included placebo, PK, and PD data. SC pramlintide PK root mean square error values range from 1.98 to 10.66 pmol/L. Pramlintide PD RMSE values range from 10.48 to 42.76 mg/dL. Conclusions: A new in silico model of the glucose-insulin-pramlintide regulatory system is presented. This model can be used as a platform to optimize dosing of both pramlintide and insulin as a combined therapy for glycemic regulation, and in the development of an artificial pancreas as the kernel for a model-based controller.
Patient-Centered Medical Home Implementation and Primary Care Provider Turnover

Background:The Veterans Health Administration (VHA) began implementing a patient-centered medical home (PCMH) model of care delivery in April 2010 through its Patient Aligned Care Team (PACT) initiative. PACT represents a substantial system reengineering of VHA primary care and its potential effect on primary care provider (PCP) turnover is an important but unexplored relationship. This study examined the association between a system-wide PCMH implementation and PCP turnover. Methods:This was a retrospective, longitudinal study of VHA-employed PCPs spanning 29 calendar quarters before PACT and eight quarters of PACT implementation. PCP employment periods were identified from administrative data and turnover was defined by an indicator on the last quarter of each uncensored period. An interrupted time series model was used to estimate the association between PACT and turnover, adjusting for secular trend and seasonality, provider and job characteristics, and local unemployment. We calculated average marginal effects (AME), which reflected the change in turnover probability associated with PACT implementation. Results:The quarterly rate of PCP turnover was 3.06% before PACT and 3.38% after initiation of PACT. In adjusted analysis, PACT was associated with a modest increase in turnover (AME=4.0 additional PCPs per 1000 PCPs per quarter, P=0.004). Models with interaction terms suggested that the PACT-related change in turnover was increasing in provider age and experience. Conclusions:PACT was associated with a modest increase in PCP turnover, concentrated among older and more experienced providers, during initial implementation. Our findings suggest that policymakers should evaluate potential workforce effects when implementing PCMH.
Edoxaban administration following enoxaparin: A pharmacodynamic, pharmacokinetic, and tolerability assessment in human subjects

Summary Edoxaban is an oral direct factor (F)Xa inhibitor in advanced stages of clinical development. The primary objective of the present study was to assess the pharmacodynamics (PD) and safety of enoxaparin 1 mg/kg followed 12 hours (h) post-dose by edoxaban 60 mg, which is the regimen being used in the phase III study of edoxaban for the treatment of venous thromboembolism (Hokusai-VTE). This was a phase I, open-label, randomised, four-period, four-treatment cross-over study. Treatments were edoxaban alone (EDOX), enoxaparin alone (ENOX), edoxaban plus enoxaparin (EDOX+ENOX), and enoxaparin followed by edox aban 12 h later (ENOX12-EDOX). Serial blood samples were collected for PD (thrombin generation, anti-FXa) and pharmacokinetic (PK) variables (edoxaban and its principal metabolite M4 by LC-MS/MS, and anti-FIIa as a surrogate of enoxaparin). The highest effect on thrombin AUC (endogenous thrombin potential, or ETP), thrombin (peak), thrombin generation lag time, and velocity index was observed for EDOX+ENOX, followed by ENOX, ENOX12-EDOX, and EDOX. The greatest effect on anti-FXa activity was observed for EDOX+ENOX, followed by ENOX12-EDOX. As expected, neither edoxaban nor enoxaparin significantly altered the PK of the other drug. There were no serious adverse events during the study. It is concluded that a 60-mg dose of edoxaban can be safely administered 12 h following enoxaparin 1 mg/ kg.
he role of apoptosis in MCLR-induced developmental toxicity in ebrafish embryos

We previously demonstrated that cyanobacteria-derived microcystin–leucine–arginine (MCLR) is able to induce developing toxicity, such as malformation, growth delay and also decreased heart rates in zebrafish embryos. However, the molecular mechanisms by which MCLR induces its toxicity during the development of zebrafish remain largely unknown. Here, we evaluate the role of apoptosis in MCLRinduced developmental toxicity. Zebrafish embryos were exposed to various concentrations of MCLR (0, 0.2, 0.5, 2, and 5.0 mg L−1) for 96 h, at which time reactive oxygen species (ROS) was significantly induced in the 2 and 5.0 mg L−1 MCLR exposure groups. Acridine orange (AO) staining and terminal deoxynucleotide transferase-mediated deoxy-UTP nick end labelling (TUNEL) assay showed that MCLR exposure
Design and analysis of the control and stability of a Blended Wing Body aircraft

Future aircraft generations are required to provide higher performance and capacity with minimum cost and environmental impact. This fact calls for the design of revolutionary unconventional configurations, such as the Blended Wing Body (BWB), a tailless aircraft which integrates wing and fuselage into a single lifting surface with efficient and promising results. In this paper, a BWB aircraft baseline was designed and its aerodynamic behaviour and performance were analyzed with a special emphasis on its challenging stability and control features. This problem was approached by enhancing the CEASIOM software for conventional aircraft design by implementing DLR's CPACS, as an unified and more versatile software framework. This improvement enables the design and analysis of future unconventional aircraft configurations. A Vortex Lattice Method (VLM) and a 3D panel method were employed for the aerodynamic analysis and both showed a close agreement. The allocation and sizing of the control surfaces were then iterated to find the optimum winglet size for minimum drag and radar detectability conditions. A global 12% reduction of the control surfaces area was achieved, which implies lower weight and drag. All in all, the satisfactory performance of the BWB concept was confirmed and a new tool for unconventional aircraft design was obtained.
Binding of Candida albicans yeast cells to mouse popliteal lymph node tissue is mediated by macrophages

We previously reported that Candida albicans yeast cells adhere to the macrophage-rich medullary and subcapsular sinus areas of mouse lymph node tissue. To determine whether the yeast cell-lymph node interaction is mediated by macrophages, the effect of specific elimination of macrophages on yeast cell binding was studied, and yeast cell adherence was correlated with the ingestion of India ink by lymph node cells. Macrophage elimination was done by use of liposome-containing dichloromethylene diphosphonate (L-Cl2MDP). Mice were injected in the hind footpads with the L-Cl2MDP preparation, popliteal lymph nodes were removed 5 days later, and yeast cell adherence was determined by an ex vivo binding assay. As controls, lymph nodes from mice that received footpad injections of either phosphate-buffered saline (PBS) alone or liposome-containing PBS were used. Use of macrophage- and neutrophil-specific monoclonal antibodies in tissue immunostaining showed that the L-Cl2MDP treatment eliminated macrophages but not neutrophils from the medullary and subcapsular sinus areas of the popliteal lymph nodes. A striking reduction of yeast cell adherence occurred with lymph nodes from L-Cl2MDP-treated mice compared with lymph nodes from control animals. The lymph node-yeast cell binding patterns of L-Cl2MDP-treated and control mice were the same regardless of mouse strain, sex, or T-cell competency. Results of India ink experiments, in which India ink was injected into footpads of mice and was rapidly taken up by popliteal lymph node macrophages, showed a strong correlation between yeast adherence and India ink staining of cells. In addition, the interaction of yeast cells with lymph node tissue from normal mice was not significantly affected by the addition of two extracellular matrix proteins, fibronectin and laminin, during the ex vivo adherence assay. These data indicate that medullary and subcapsular sinus lymph node macrophages express an adhesion system similar to that described for mouse splenic marginal zone macrophages.
Neurogenesis in the Hippocampus of an Adult Marsupial

In the adult eutherian brain, stem cells in the dentate gyrus continually divide throughout adult life and into old age producing new granule cells. However, it was not known whether this is also the case for marsupials. Previously, in fact, it was thought that marsupials did not have continued neurogenesis in the mature brain. Here we examined neurogenesis in the adult brain of a small marsupial, the fat-tailed dunnart, using 3H-thymidine to label newly generated cells. We showed that neurogenesis takes place in the adult dentate gyrus along its inner margin, as seen in eutherian mammals. Control animals had similar numbers of labeled cells 24 h and 1 month after 3H-thymidine injection. An enriched environment resulted in similar numbers of cells being generated as controls. However, there was a significant decline in the number of labeled cells one month later. Stress and old age resulted in significantly lower numbers of new cells being generated. In immunohistochemically treated control brains, 3H-thymidine-labeled cells at the early stage were sometimes GFAP positive, were not calbindin positive at either stage examined and at the later stage were PSA-NCAM positive. We hypothesize that, as seen in eutherian mammals, the new cells progressed from being GFAP positive at stem cell stage to PSA-NCAM positive during outgrowth of mossy fibers 1 month later, to calbindin positive when mature. It is possible that maturity of these cells was not reached by 1 month as marsupials have a slower metabolic rate and this species also undergoes daily periods of torpor.
Early versus delayed stabilization of femoral fractures.

To The Editor: I am writing a somewhat belated Letter to the Editor regarding the article by Bone et al. entitled "Early versus Delayed Stabilization of Femoral Fractures. A Prospective Randomized Study" (1989;71:336-40). That prospective, randomized study on the effects of early versus delayed stabilization of femoral fractures represented an immense amount of clinical work on the part of the authors. The results of the study seem to support the hypothesis that early stabilization of femoral shaft fractures decreases pulmonary morbidity in patients with polytrauma. However, in recent years, the validity of this work has been called into question. This is most striking when one realizes that the Eastern Association for the Surgery of Trauma (EAST) has developed a series of "trauma practice guidelines" that are based on evidence-based recommendations resulting from …
Functional specialization of β-arrestin interactions revealed by proteomic analysis

β-arrestins are cytosolic proteins that form complexes with seven-transmembrane receptors after agonist stimulation and phosphorylation by the G protein-coupled receptor kinases. They play an essential role in receptor desensitization and endocytosis, and they also serve as receptor-regulated signaling scaffolds and adaptors. Moreover, in the past decade, a growing list of protein–protein interactions of β-arrestins pertinent to these functions has been documented. The discovery of several novel functions of β-arrestins stimulated us to perform a global proteomics analysis of β-arrestin-interacting proteins (interactome) as modulated by a model seven-transmembrane receptor, the angiotensin II type 1a receptor, in an attempt to assess the full range of functions of these versatile molecules. As determined by LC tandem MS, 71 proteins interacted with β-arrestin 1, 164 interacted with β-arrestin 2, and 102 interacted with both β-arrestins. Some proteins bound only after agonist stimulation, whereas others dissociated. Bioinformatics analysis of the data indicates that proteins involved in cellular signaling, organization, and nucleic acid binding are the most highly represented in the β-arrestin interactome. Surprisingly, both S-arrestin (visual arrestin) and X-arrestin (cone arrestin) were also found in heteromeric complex with β-arrestins. The β-arrestin interactors distribute not only in the cytoplasm, but also in the nucleus as well as other subcellular compartments. The binding of 16 randomly selected newly identified β-arrestin partners was validated by coimmunoprecipitation assays in HEK293 cells. This study provides a comprehensive analysis of proteins that bind β-arrestin isoforms and underscores their potentially broad regulatory roles in mammalian cellular physiology.
Childhood Facial Recognition Predicts Adolescent Symptom Severity in Autism Spectrum Disorder

Limited accuracy and speed in facial recognition (FR) and in the identification of facial emotions (IFE) have been shown in autism spectrum disorders (ASD). This study aimed at evaluating the predictive value of atypicalities in FR and IFE for future symptom severity in children with ASD. Therefore we performed a seven‐year follow‐up study in 87 children with ASD. FR and IFE were assessed in childhood (T1: age 6–12) using the Amsterdam Neuropsychological Tasks (ANT). Symptom severity was assessed using the Autism Diagnostic Observation Schedule (ADOS) in childhood and again seven years later during adolescence (T2: age 12–19). Multiple regression analyses were performed to investigate whether FR and IFE in childhood predicted ASD symptom severity in adolescence, while controlling for ASD symptom severity in childhood. We found that more accurate FR significantly predicted lower adolescent ASD symptom severity scores (ΔR2 = .09), even when controlling for childhood ASD symptom severity. IFE was not a significant predictor of ASD symptom severity in adolescence. From these results it can be concluded, that in children with ASD the accuracy of FR in childhood is a relevant predictor of ASD symptom severity in adolescence. Test results on FR in children with ASD may have prognostic value regarding later symptom severity. Autism Res 2015, 8: 261–271. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
Differences between patients with or without the need for intensive care due to severe odontogenic infections.

PURPOSE Despite greatly improved dental health in industrialized countries, severe odontogenic infections still occasionally lead to hospitalization. The aim of the present study was to determine whether what symptoms, signs, or laboratory parameters on hospital admission were associated with the need for treatment in the intensive care unit (ICU). PATIENTS AND METHODS Over an 18-month period, 100 consecutive patients (59 male, 41 female) were included in the study. Twenty percent of the patients required ICU treatment because of cardiorespiratory problems or severe complications of their infection. Both ICU and non-ICU patients were examined clinically and blood samples were taken and studied in respect to several parameters associated with infection, including C-reactive protein (CRP) levels. The findings were analyzed statistically for differences between the groups. RESULTS No particular anamnestic background variable was associated with the need for intensive care. However, a particularly high CRP level on admission was found to be associated with a more severe course of the infection. CONCLUSIONS This study showed that determination of CRP levels may be useful in clinical decision-making in patients with severe odontogenic infections.
Massive vitamin A intoxication with ascites and pleural effusion.

Vitamin A intoxication was diagnosed in a 14-year-old girl who presented with massive exudative ascites and right pleural effusion, impaired liver enzymes, and hypertriglyceridemia. Electron microscopy of liver biopsy material demonstrated numerous perisinusoidal lipid-filled Ito cells. The patient had taken 100-200,000 I.U. vitamin A per day for 15 months. Serum vitamin A level remained elevated for 4 months after vitamin discontinuation. The unusual severity of portal hypertension was documented by a high wedged hepatic vein pressure level. The ascites occurred 2 months after vitamin A had been discontinued, probably owing to particularly slow mobilization of large hepatic stores of vitamin A. Portal hypertension disappeared after a 6-month low vitamin A diet, but the liver biopsy failed to demonstrate any decrease in number or size of Ito cells, suggesting that lipid venous obstruction is unlikely to be the only mechanism responsible for portal hypertension in vitamin A-induced liver disease.
Temporarily Divide to Conquer: Centralized, Decentralized, and Reintegrated Organizational Approaches to Exploration and Adaptation

To create a competitive advantage, firms need to find activity configurations that are not only internally consistent, but also appropriate given the firm's current environment. This challenge is particularly acute after firms have experienced an environmental change that has shifted the existing competitive landscape and created new, high-performing sets of activity choices. How should firms organize to explore and search such an altered performance landscape? While it has been noted that adaptive entities need to maintain a balance of exploration and exploitation, little is known about how different organizational structures moderate this balance. With the help of an agentbased simulation model, we study the value of three different organizational structures: a centralized organization, in which decisions are made only at the level of the firm as a whole; a decentralized organization, in which decisions are made independently in two divisions; and a temporarily decentralized firm, which starts out with a decentralized structure and later reintegrates.We find that if interactions among a firm's activities are pervasive, neither the centralized nor the permanently decentralized organizational structure leads to high performance. In this case, temporary decentralization--an organizational structure that has not found much attention in the literature--yields the highest long-term performance. This organizational structure allows the firm both to avoid low-performing activity configurations and to eventually coordinate across its divisions. Thus, even if the decision problem a . rm faces is not fully decomposable, a temporary bifurcation can lead to a higher long-term performance outcome. Initial decentralized exploration is, however, costly in the short run, as compared to centralized exploration. As a result, a tradeoff exists between the short-term costs of decentralized exploration and the longterm benefits of reaching higher performance. As interactions across and within divisions increase, the optimal length of decentralized exploration tends to grow.Paralleling our first result, we further show that even if a decision problem is decomposable, that is, can be perfectly modularized, it can be beneficial to create a temporary decision allocation that creates "unnecessary" interdependencies across the subsystems. This benefit arises in particular when the modules are complex by themselves. In both cases, an initial phase of exploration, enabled by an appropriate organizational structure, followed by refinement and coordination, enabled by a different structure, leads to high performance. To illustrate our general model, we focus on incumbent firms' responses to the Internet and discuss implications for the product design process.
Negative feedback in the bone morphogenetic protein 4 (BMP4) synexpression group governs its dynamic signaling range and canalizes development

What makes embryogenesis a robust and canalized process is an important question in developmental biology. A bone morphogenetic protein (BMP) morphogen gradient plays a key role in embryonic development, and we are beginning to understand how the self-regulating properties of its signaling circuitry ensure robust embryonic patterning. An unexplored question is why the BMP signaling circuit is organized as a modular synexpression group, with a prevalence of feedback inhibitors. Here, we provide evidence from direct experimentation and mathematical modeling that the synexpressed feedback inhibitors BAMBI, SMAD6, and SMAD7 (i) expand the dynamic BMP signaling range essential for proper embryonic patterning and (ii) reduce interindividual phenotypic and molecular variability in Xenopus embryos. Thereby, negative feedback linearizes signaling responses and confers robust patterning, thus promoting canalized development. The presence of negative feedback inhibitors in other growth factor synexpression groups suggests that these properties may constitute a general principle.
CPAP pressure requirements for obstructive sleep apnea patients at varying altitudes.

STUDY OBJECTIVES This study was performed to determine whether the obstructive sleep apnea patient who requires a certain CPAP pressure at one altitude requires the same or a different CPAP pressure at a different altitude. PARTICIPANTS 7 mountain residents with OSA, comfortably using CPAP and planning to travel to lower altitude. DESIGN AND SETTING Participants used a ResMed Autoset autotitrating CPAP unit for at least 3 days at their home and at each of their lower travel destinations. MEASUREMENTS Nightly CPAP 95th percentile pressure, median CPAP pressure and AHI were recorded. RESULTS At high altitude, 7400 ft. to 10,100 ft (2255 m to 3080 m), average CPAP 95th percentile pressure was 9.43 (+/- 0.12) cm H2O. At low altitude, sea level to 2800 ft. (0-853m), average CPAP 95th percentile pressure was 9.54 (+/- 0.13) cm H2O, P = 0.18. At high altitude, median CPAP pressure was 7.00 (+/- 0.10) cm H2O vs. 7.21 (+/- 0.14) cm. H20 at low altitude, P = 0.54. Three patients had a slight decrease in required pressure at low elevation, 4 had a slight increase. INTERVENTIONS N/A. CONCLUSIONS For obstructive sleep apnea patients living at altitude, changes in elevation between 10,100 ft (3075 m) and sea level do not significantly alter absolute CPAP pressure requirements.