Single Image Video Prediction with Auto-Regressive GANs.

In this paper, we introduce an approach for future frames prediction based on a single input image. Our method is able to generate an entire video sequence based on the information contained in the input frame. We adopt an autoregressive approach in our generation process, i.e., the output from each time step is fed as the input to the next step. Unlike other video prediction methods that use "one shot" generation, our method is able to preserve much more details from the input image, while also capturing the critical pixel-level changes between the frames. We overcome the problem of generation quality degradation by introducing a "complementary mask" module in our architecture, and we show that this allows the model to only focus on the generation of the pixels that need to be changed, and to reuse those that should remain static from its previous frame. We empirically validate our methods against various video prediction models on the UT Dallas Dataset, and show that our approach is able to generate high quality realistic video sequences from one static input image. In addition, we also validate the robustness of our method by testing a pre-trained model on the unseen ADFES facial expression dataset. We also provide qualitative results of our model tested on a human action dataset: The Weizmann Action database.

Optimal Placement of Cerebral Oximeter Monitors to Avoid the Frontal Sinus as Determined by Computed Tomography.

OBJECTIVE: To determine the optimal location to place cerebral oximeter optodes to avoid the frontal sinus, using the orbit of the skull as a landmark. DESIGN: Retrospective observational study. SETTING: Academic hospital. PARTICIPANTS: Fifty adult patients with previously acquired computed tomography angiography scans of the head. INTERVENTIONS: The distance between the superior orbit of the skull and the most superior edge of the frontal sinus was measured using imaging software. MEASUREMENTS AND MAIN RESULTS: The mean (SD) frontal sinus height was 16.4 (7.2) mm. There was a nonsignificant trend toward larger frontal sinus height in men compared with women (p = 0.12). Age, height, and body surface area did not correlate with frontal sinus height. Head circumference was positively correlated (r = 0.32; p = 0.03) to frontal sinus height, with a low level of predictability based on linear regression (R(2) = 0.10; p = 0.02). CONCLUSIONS: Placing cerebral oximeter optodes>3 cm from the superior rim of the orbit will avoid the frontal sinus in>98% of patients. Predicting the frontal sinus height based on common patient variables is difficult. Additional studies are required to evaluate the recommended height in pediatric populations and patients of various ethnic backgrounds. The clinical relevance of avoiding the frontal sinus also needs to be further elucidated.

Ultrasound assessment of gastric volume in the fasted pediatric patient undergoing upper gastrointestinal endoscopy: development of a predictive model using endoscopically suctioned volumes.

BACKGROUND: Aspiration of gastric contents can be a serious anesthetic-related complication. Gastric antral sonography prior to anesthesia may have a role in identifying pediatric patients at risk of aspiration. We examined the relationship between sonographic antral area and endoscopically suctioned gastric volumes, and whether a 3-point qualitative grading system is applicable in pediatric patients. METHODS: Fasted patients presenting to a pediatric hospital for upper gastrointestinal endoscopy were included in the study. Sonographic measurement of the antral cross-sectional area (CSA) in supine (supine CSA) and right lateral decubitus (RLD CSA) position was completed, and the antrum was designated as empty or nonempty. Gastric contents were endoscopically suctioned and measured. Multiple regression analysis was used to fit a mathematical model to estimate gastric volume. RESULTS: One hundred patients (aged 11-216 months) were included. The gastric antrum was measured in 94% and 99% of patients in the supine and RLD positions, respectively. Gastric antral CSA correlated with total gastric volume in both supine (ρ = 0.63) and RLD (ρ = 0.67) positions. A mathematical model incorporating RLD CSA and age (R(2)  = 0.60) was determined as the best-fit model to predict gastric volumes. Increasing gastric antral grade (0-2) was associated with increasing gastric fluid volume. CONCLUSION: The results suggest that sonographic assessment of the gastric antrum provides useful information regarding gastric content (empty versus nonempty) and volume (ml·kg(-1) ) in pediatric patients. Results suggest that the three-point grading system may be a valuable tool to assess gastric 'fullness' based on a qualitative exam of the antrum.

Local Ancestry-Informed Candidate Pathway Analysis of Warfarin Stable Dose in Latino Populations.

Accuracy of warfarin dose prediction algorithms may be improved by including data from diverse populations in genetic studies of dose variability. Here, we surveyed single nucleotide polymorphisms in vitamin K-related genetic pathways for association with warfarin dose requirements in two admixed Latino populations in standard-principal component adjusted and contemporary-local ancestry adjusted regression models. A total of five variants from vitamin K-related genes/pathways were associated with warfarin dose in both cohorts (P < 0.0125) in standard models. Local ancestry-adjusted analysis unveiled 35 associated variants with absolute effects ranging from ß = 9.04 ( ±2.23) to 39.18 ( ±10.89) per ancestral allele in the discovery cohort and ß = 6.47 (± 2.02) to 17.82 (± 6.83) in the replication cohort. Importantly, we demonstrate the technical validity of the Tractor model in cohorts with admixed ancestry from three founder populations and bring attention to the technical hurdles obstructing the inclusion of diverse, especially admixed, populations in pharmacogenomic research.

Multi-site Investigation of Genetic Determinants of Warfarin Dose Variability in Latinos.

We conducted a multi-site investigation of genetic determinants of warfarin dose variability in Latinos from the U.S. and Brazil. Patients from four institutions in the United States (n = 411) and Brazil (n = 663) were genotyped for VKORC1 c.-1639G> A, common CYP2C9 variants, CYP4F2*3, and NQO1*2. Multiple regression analysis was used in the U.S. cohort to test the association between warfarin dose and genotype, adjusting for clinical factors, with further testing in an independent cohort of Brazilians. In the U.S. cohort, VKORC1 and CYP2C9 variants were associated with lower warfarin dose (ß = -0.29, P < 2.0 × 10-16 ; ß = -0.21, P = 4.7 × 10-7 , respectively) whereas CYP4F2 and NQO1 variants were associated with higher dose (ß = 0.10, P = 2 × 10-4 ; ß = 0.10, P = 0.01, respectively). Associations with VKORC1 (ß = -0.14, P = 2.0 × 10-16 ), CYP2C9 (ß = -0.07, P = 5.6 × 10-10 ), and CYP4F2 (ß = 0.03, P = 3 × 10-3 ), but not NQO1*2 (ß = 0.01, P = 0.30), were replicated in the Brazilians, explaining 43-46% of warfarin dose variability among the cohorts from the U.S. and Brazil, respectively. We identified genetic associations with warfarin dose requirements in the largest cohort of ancestrally diverse, warfarin-treated Latinos from the United States and Brazil to date. We confirmed the association of variants in VKORC1, CYP2C9, and CYP4F2 with warfarin dose in Latinos from the United States and Brazil.

Anaphylaxis and cardiac surgery for hypertrophic obstructive cardiomyopathy: a case report and review of anaesthetic management.

BACKGROUND: The aim of this paper is to describe clinical management in a situation where patient has experienced anaphylaxis while undergoing surgical septal myectomy for hypertrophic obstructive cardiomyopathy (HOCM). CASE REPORT: A 40-yr-old female was scheduled to undergo surgical septal myectomy for the treatment of HOCM. After induction, the patient developed refractory hypotension that did not respond to escalating doses of vasopressors and volume therapy. Although a clinical examination led to the diagnosis of anaphylaxis, epinephrine, which is the usual treatment of choice, failed to improve the patient's haemodynamics. A transesophageal echocardiography revealed a worsening of left ventricular outflow tract obstruction (LVOTO) after epinephrine administration. In the end, the rapid institution of a cardiopulmonary bypass was required as a rescue therapy instead of to save a patient. CONCLUSION: The anaesthetic goals in a patient in HOCM are to maintain preload and afterload and to avoid stimulation of inotropy and chronotropy to leading to left ventricular outflow obstruction. In a patient with anaphylaxis, maintaining these haemodynamic goals becomes much more difficult since the pathophysiology and usual treatment of choice will worsen LVOTO. Special consideration for the need to have extracorporeal life support to treat refractory hypotension in surgical patients with HOCM may be warranted.

The Effect of Hemoglobin Levels on Mortality in Pediatric Patients with Severe Traumatic Brain Injury.

Objective. There is increasing evidence of adverse outcomes associated with blood transfusions for adult traumatic brain injury patients. However, current evidence suggests that pediatric traumatic brain injury patients may respond to blood transfusions differently on a vascular level. This study examined the influence of blood transfusions and anemia on the outcome of pediatric traumatic brain injury patients. Design. A retrospective cohort analysis of severe pediatric traumatic brain injury (TBI) patients was undertaken to investigate the association between blood transfusions and anemia on patient outcomes. Measurements and Main Results. One hundred and twenty patients with severe traumatic brain injury were identified and included in the analysis. The median Glasgow Coma Scale (GCS) was 6 and the mean hemoglobin (Hgb) on admission was 115.8 g/L. Forty-three percent of patients (43%) received at least one blood transfusion and the mean hemoglobin before transfusion was 80.1 g/L. Multivariable regression analysis revealed that anemia and the administration of packed red blood cells were not associated with adverse outcomes. Factors that were significantly associated with mortality were presence of abusive head trauma, increasing PRISM score, and low GCS after admission. Conclusion. In this single centre retrospective cohort study, there was no association found between anemia, blood transfusions, and hospital mortality in a pediatric traumatic brain injury patient population.

Cancers of the gallbladder and biliary ducts.

Neoplasms of the biliary tract tree are uncommon and have a poor overall prognosis. Although numerous risk factors have been identified, little is known about the pathogenesis of these tumors, and no effective screening technique is available for early detection. Surgery remains the principal treatment modality and the only potential cure, with laparoscopy playing an increasingly important role in determining the resectability of these tumors. The role of postoperative adjuvant chemotherapy and radiation remains controversial. The efficacy of chemotherapy for advanced disease is relatively limited, with response rates of less than 10% for single-agent fluorouracil. Of the newer agents, gemcitabine (Gemzar) holds the most promise in the treatment of these difficult malignancies.

The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin.

AML remains a difficult disease to treat. Despite response to induction chemotherapy, most patients ultimately relapse. Further, among elderly patients, aggressive therapy options are often limited due to other medical conditions and decreased tolerance of these patients to conventional chemotherapy. Internal tandem duplications (ITD) of the FLT3 juxtamembrane domain occur in 20-30% of AML patients and predict poor outcome. First clinical data with the FLT3 inhibitor tandutinib demonstrated antileukemic activity in approximately half of the patients--predominantly with FLT3 ITD positive AML. But the data also show that optimal use of tandutinib will require combination therapy with cytotoxic agents. Notably, single agent tandutinib has not been associated with myelosuppression, mucositis or cardiac toxicity--the dose limiting toxicities of AML chemotherapy. We determined the feasibility of combining tandutinib with the standard "3 + 7" induction regimen in AML and show that, in contrast to other structurally unrelated FLT3 inhibitors recently evaluated in clinical trials, the use of tandutinib displayed application sequence independent synergistic antileukemic effects in combination with cytarabine and daunorubicin. Strong synergistic antiproliferative and proapoptotic effects were thereby predominantly seen on FLT3 ITD positive blasts. Further we demonstrate, that addition of tandutinib may allow dose reduction of chemotherapy without loss of overall antileukemic activity--resulting in a potential decrease of side effects. This approach might be an interesting novel strategy especially in the treatment of elderly/comorbid patients. Our data provide a rationale for combining tandutinib with induction chemotherapy in intensified as well as in dose reduction protocols for FLT3 ITD positive AML.

Electronic health records: which practices have them, and how are clinicians using them?

BACKGROUND: Limited data exist to estimate the use of electronic health records (EHRs) in ambulatory care practices in the United States. METHODS: We surveyed a stratified random sample of 1829 office practices in Massachusetts in 2005. The one-page survey measured use of health information technology, plans for EHR adoption and perceived barriers to adoption. RESULTS: A total of 847 surveys were returned, for a response rate of 46%. Overall, 18% of office practices reported having an EHR. Primary-care-only and mixed practices reported similar adoption rates (23% and 25%, respectively, P = 0.70). The adoption rate in specialty practices (14%) was lower compared with both primary-care-only (P < 0.01) and mixed (P < 0.05) practices. The number of clinicians in the practice strongly correlated with EHR adoption (P < 0.001), with fewer small practices adopting EHRs. Among practices that have EHRs with laboratory and radiology result retrieval capabilities, at least 87% of practices report that a majority of their clinicians actively use these functionalities, while 74% of practices with electronic decision support report that the majority of clinicians actively use it. Among the practices without an EHR, 13% plan to implement one within the next 12 months, 24% within the next 1-2 years, 11% within the next 3-5 years, and 52% reported having no plans to implement an EHR in the foreseeable future. The most frequently reported barrier to implementation was lack of adequate funding (42%). CONCLUSIONS: Overall, fewer than 1 in 5 medical practices in Massachusetts have an EHR. Even among adopters, though, doctor usage of EHR functions varied considerably by functionality and across practices. Many clinicians are not actively using functionalities that are necessary to improve health care quality and patient safety. Furthermore, among practices that do not have EHRs, more than half have no plan for adoption. Inadequate funding remains an important barrier to EHR adoption in ambulatory care practices in the United States.

Tricyclic quinoxalines as potent kinase inhibitors of PDGFR kinase, Flt3 and Kit.

Here we report on novel quinoxalines as highly potent and selective inhibitors of the type III receptor tyrosine kinases PDGFR, FLT3, and KIT. These compounds, tricyclic quinoxalines, were generated in order to improve bioavailability over the highly hydrophobic bicyclic quinoxalines. Four of the highly active compounds were characterized in detail and are shown to inhibit PDGFR kinase activity of the isolated receptor as well as in intact cells in the sub-micromolar concentration range. We show that the most active inhibitor (compound 13, AGL 2043) is approximately 15-20 times more potent than its isomer (compound 14, AGL 2044). We therefore compared the three dimensional structures of the two compounds by X-ray crystallography. These compounds are also highly effective in blocking the kinase activity of FLT3, KIT, and the oncogenic protein Tel-PDGFR in intact cells. These compounds are potent inhibitors of the proliferation of pig heart smooth muscle cells. They fully arrest the growth of these cells and the effect is fully reversible. The chemical, biochemical and cellular properties of these compounds as well as the solubility properties make them suitable for development as anti-restenosis and anti-cancer agents.

Synergistic effect of SU11248 with cytarabine or daunorubicin on FLT3 ITD-positive leukemic cells.

Fetal liver tyrosine kinase 3 internal tandem duplication (FLT3 ITD) mutations are the most common molecular abnormality associated with adult acute myeloid leukemia (AML). To exploit this molecular target, a number of potent and specific FLT3 kinase inhibitors have been developed and are currently being tested in early phase clinical trials of patients with refractory AML. To explore the efficacy of combining a FLT3 inhibitor with standard AML chemotherapy drugs, we tested the effect of combining the FLT3 inhibitor SU11248 with cytarabine or daunorubicin on the proliferation and survival of cell lines expressing either mutant (FLT3 ITD or FLT3 D835V) or wild-type (WT) FLT3. SU11248 had additive-to-synergistic inhibitory effects on FLT3-dependent leukemic cell proliferation when combined with cytarabine or daunorubicin. The synergistic interaction of SU11248 and the traditional antileukemic agents was more pronounced for induction of apoptosis. SU11248 inhibited the proliferation of primary AML myeloblasts expressing mutant FLT3 ITD but not WT FLT3 protein. Combining SU11248 and cytarabine synergistically inhibited the proliferation of primary AML myeloblasts expressing FLT3 ITD but not WT FLT3 protein. These data suggest that the addition of potent FLT3 inhibitors such as SU11248 to AML chemotherapy regimens could result in improved treatment results.

Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970.

Oncogenic mutations of the receptor tyrosine kinase KIT occur in gastrointestinal stromal tumors (GISTs), some cases of acute myelogenous leukemia (AML), and systemic mastocytosis (SM). GISTs commonly contain mutations of the KIT juxtamembrane region while SM and AML harbor active site KIT mutations. Imatinib, which potently inhibits juxtamembrane mutants, is effective for the treatment of GISTs but has no activity against active site mutants. We analyzed the inhibitory potential of 2 small molecule inhibitors, MLN518 and PD180970, against different classes of KIT mutants. Both compounds inhibit the growth of cell lines expressing juxtamembrane mutant KIT. MLN518 additionally targets active site mutant cell lines, inhibiting cell proliferation, KIT, and signal transducer and activator of transcription-3 (Stat3) phosphorylation and inducing apoptosis at concentrations that may be clinically achievable. As phase 1 clinical trials of MLN518 in AML have shown little toxicity, our data suggest MLN518 is a promising candidate for the treatment of SM or AML with KIT mutations.

SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase.

Internal tandem duplication (ITD) in the juxtamembrane portion of Fms-like tyrosine kinase 3 (FLT3), a type III receptor tyrosine kinase (RTK), is the most common molecular defect associated with acute myeloid leukemia (AML). The high prevalence of this activating mutation makes it a potential target for molecularly based therapy. Indolinone tyrosine kinase inhibitors have known activity against KIT, another member of the type III RTK family. Given the conserved homology between members of this family, we postulated that the activity of some KIT inhibitors would extend to FLT3. We used various leukemic cell lines (BaF3, MV 4-11, RS 4;11) to test the activity of indolinone compounds against the FLT3 kinase activity of both wild-type (WT) and ITD isoforms. Both SU5416 and SU5614 were capable of inhibiting autophosphorylation of ITD and WT FLT3 (SU5416 concentration that inhibits 50% [IC(50)], 100 nM; and SU5614 IC(50) 10 nM). FLT3-dependent activation of the downstream signaling proteins mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 5 (STAT5) was also inhibited by treatment in the same concentration ranges. FLT3 inhibition by SU5416 and SU5614 resulted in reduced proliferation (IC(50), 250 nM and 100 nM, respectively) and induction of apoptosis of FLT3 ITD-positive leukemic cell lines. Treatment of these cells with an alternative growth factor (granulocyte-macrophage colony-stimulating factor [GM-CSF]) restored MAPK signaling and cellular proliferation, demonstrating specificity of the observed inhibitory effects. We conclude that SU5416 and SU5614 are potent inhibitors of FLT3. Our finding that inhibition of FLT3 induces apoptosis of leukemic cells supports the feasibility of targeting FLT3 as a novel treatment strategy for AML.

SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo.

FLT3 (fms-related tyrosine kinase/Flk2/Stk-2) is a receptor tyrosine kinase (RTK) primarily expressed on hematopoietic cells. In blasts from acute myelogenous leukemia (AML) patients, 2 classes of FLT3 activating mutations have been identified: internal tandem duplication (ITD) mutations in the juxtamembrane domain (25%-30% of patients) and point mutations in the kinase domain activation loop (7%-8% of patients). FLT3-ITD mutations are the most common molecular defect identified in AML and have been shown to be an independent prognostic factor for decreased survival. FLT3-ITD is therefore an attractive molecular target for therapy. SU11248 is a recently described selective inhibitor with selectivity for split kinase domain RTKs, including platelet-derived growth factor receptors, vascular endothelial growth factor receptors, and KIT. We show that SU11248 also has potent activity against wild-type FLT3 (FLT3-WT), FLT3-ITD, and FLT3 activation loop (FLT3-Asp835) mutants in phosphorylation assays. SU11248 inhibits FLT3-driven phosphorylation and induces apoptosis in vitro. In addition, SU11248 inhibits FLT3-induced VEGF production. The in vivo efficacy of SU11248 was investigated in 2 FLT3-ITD models: a subcutaneous tumor xenograft model and a bone marrow engraftment model. We show that SU11248 (20 mg/kg/d) dramatically regresses FLT3-ITD tumors in the subcutaneous tumor xenograft model and prolongs survival in the bone marrow engraftment model. Pharmacokinetic and pharmacodynamic analysis in subcutaneous tumors showed that a single administration of an efficacious drug dose potently inhibits FLT3-ITD phosphorylation for up to 16 hours following a single dose. These results suggest that further exploration of SU11248 activity in AML patients is warranted.