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Purpose:PIK3CA mutations are common in breast cancer and promote tumor progression and treatment resistance. We conducted a phase I/II trial of alpelisib (α-specific PI3K inhibitor) plus nab-paclitaxel in patients with HER2-negative metastatic breast cancer (MBC).Patients and Methods:Eligible patients had HER2-negative MBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of alpelisib (250, 300, and 350 mg) daily plus nab-paclitaxel 100 mg/m2 administered on days 1, 8, and 15 every 28 days. Phase II was according to Simon's two-stage design. PIK3CA mutations in tumor/circulating tumor DNA (ctDNA) were assessed. Primary endpoints were recommended phase II dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, pharmacokinetics, progression-free survival (PFS), and association of PIK3CA mutation with outcomes.Results:A total of 43 patients were enrolled (phase I, n = 13 and phase II, n = 30). A total of 84% had visceral disease and 84% had prior taxane. No dose-limiting toxicities occurred in phase I. RP2D was alpelisib 350 mg daily plus nab-paclitaxel 100 mg/m2 on days 1, 8, and 15. Hyperglycemia (grade 3, 26% and grade 4, 0%), neutropenia (grade 3, 23% and grade 4, 7%), diarrhea (grade 3, 5% and grade 4, 0%), and rash (grade 3, 7% and grade 4, 0%) were the most common adverse events. Among 42 evaluable patients, ORR was 59% (complete response, 7% and partial response, 52%), 21% of whom had response lasting >12 months; median PFS was 8.7 months. A total of 40% of patients demonstrated tumor and/or ctDNA PIK3CA mutation; patients with tumor/ctDNA mutation demonstrated better PFS compared with those without mutation (11.9 vs. 7.5 months; HR, 0.44; P = 0.027). Patients with normal metabolic status had longer PFS compared with prediabetic/diabetic patients (12 vs. 7.5 months; P = 0.014). No pharmacokinetics interactions were detected.Conclusions:The alpelisib plus nab-paclitaxel combination was well tolerated and shows encouraging efficacy, especially in patients with PIK3CA-mutated tumor/ctDNA. The impact of metabolic status on response to this combination merits further investigation.

Kaplan-Meier estimates of progression-free survival by baseline metabolic status

Gene expression signatures by PIK3CA mutation status

Kaplan-Meier estimates of overall survival

Ciclopirox (CPX) is an FDA-approved topical antifungal agent that has demonstrated preclinical anticancer activity in a number of solid and hematologic malignancies. Its clinical utility as an oral anticancer agent, however, is limited by poor oral bioavailability and gastrointestinal toxicity. Fosciclopirox, the phosphoryloxymethyl ester of CPX (Ciclopirox Prodrug, CPX-POM), selectively delivers the active metabolite, CPX, to the entire urinary tract following parenteral administration. We characterized the activity of CPX-POM and its major metabolites in in vitro and in vivo preclinical models of high-grade urothelial cancer. CPX inhibited cell proliferation, clonogenicity and spheroid formation, and increased cell cycle arrest at S and G0/G1 phases. Mechanistically, CPX suppressed activation of Notch signaling. Molecular modeling and cellular thermal shift assays demonstrated CPX binding to γ-secretase complex proteins Presenilin 1 and Nicastrin, which are essential for Notch activation. To establish in vivo preclinical proof of principle, we tested fosciclopirox in the validated N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) mouse bladder cancer model. Once-daily intraperitoneal administration of CPX-POM for four weeks at doses of 235 mg/kg and 470 mg/kg significantly decreased bladder weight, a surrogate for tumor volume, and resulted in a migration to lower stage tumors in CPX-POM treated animals. This was coupled with a reduction in the proliferation index. Additionally, there was a reduction in Presenilin 1 and Hes-1 expression in the bladder tissues of CPX-POM treated animals. Following the completion of the first-in-human Phase 1 trial (NCT03348514), the pharmacologic activity of fosciclopirox is currently being characterized in a Phase 1 expansion cohort study of muscle-invasive bladder cancer patients scheduled for cystectomy (NCT04608045) as well as a Phase 2 trial of newly diagnosed and recurrent urothelial cancer patients scheduled for transurethral resection of bladder tumors (NCT04525131).

Polyphase permanent magnet synchronous motors exhibit outstanding advantages over the traditional three-phase traction motors in electrified transportation applications. This article introduces a novel direct torque model predictive control technique aiming at developing a highly reliable, loss-minimizing, and energy-efficient five-phase permanent magnet synchronous motor drive. Leveraging the underlying constrained optimization process, the direct torque model predictive control approach optimizes the torque delivery and speed regulation quality, improves the flux and torque ripples, reduces higher order current harmonics, minimizes motor drive losses, and boosts power efficiency of the electric powertrain. dSPACE DS1104 hardware-in-the-loop and computer simulation studies are jointly utilized to verify the effectiveness and robustness of the proposed direct torque model predictive control approach in polyphase permanent magnet synchronous motor drive applications.

Recently, a major challenge in the adoption of wide bandgap semiconductors for power electronic applications is the need to trade device performance for device safety. In this article, methods for predicting gate voltage overshoot in normally-OFF gallium nitride (GAN) high electron mobility transistors (HEMTs) are derived in order to deliver optimal device performance. Two models are proposed; a simple, yet less accurate second order model and a complex, yet more accurate fourth order model. These models allow for the calculation of gate resistances necessary for a desired amount of gate voltage overshoot. The nonlinear capacitances of the device are considered in the analysis. The models are validated with an experimental double-pulse tester. These newly developed models allow design engineers to extract the best possible performance of commercially available GaN devices while keeping the devices in their safe-operating region.

Brinker, Amanda/0000-0003-1134-0572; Weir, Scott/0000-0002-8020-434X WOS:000477702600002 PubMed: 31113837 Pharmacokinetic studies in rats and dogs were performed to characterize the in vivo performance of a novel prodrug, fosciclopirox. Ciclopirox olamine (CPX-O) is a marketed topical antifungal agent with demonstrated in vitro and in vivo preclinical anticancer activity in several solid tumor and hematologic malignancies. The oral route of administration for CPX-O is not feasible due to low bioavailability and dose-limiting gastrointestinal toxicities. To enable parenteral administration, the phosphoryl-oxymethyl ester of ciclopirox (CPX), fosciclopirox (CPX-POM), was synthesized and formulated as an injectable drug product. In rats and dogs, intravenous CPX-POM is rapidly and completely metabolized to its active metabolite, CPX. The bioavailability of the active metabolite is complete following CPX-POM administration. CPX and its inactive metabolite, ciclopirox glucuronide (CPX-G), are excreted in urine, resulting in delivery of drug to the entire urinary tract. The absolute bioavailability of CPX following subcutaneous administration of CPX-POM is excellent in rats and dogs, demonstrating the feasibility of this route of administration. These studies confirmed the oral bioavailability of CPX-O is quite low in rats and dogs compared with intravenous CPX-POM. Given its broad-spectrum anticancer activity in several solid tumor and hematologic cancers and renal elimination, CPX-POM is being developed for the treatment of urothelial cancer. The safety, dose tolerance, pharmacokinetics, and pharmacodynamics of intravenous CPX-POM are currently being characterized in a United States multicenter first-in-human Phase 1 clinical trial in patients with advanced solid tumors. National Institutes of Health National Cancer Institute Cancer Center Support Grant [P30 CA168524]; NATIONAL CANCER INSTITUTEUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA168524, R01CA190291] Funding Source: NIH RePORTER Research reported in this presentation was supported by the National Institutes of Health National Cancer Institute Cancer Center Support Grant [Grant P30 CA168524] and by a public-private partnership between The Institute for Advancing Medical Innovation at the University of Kansas Medical Center and CicloMed LLC, Kansas City, MO.

Purpose:PIK3CA mutations are common in breast cancer and promote tumor progression and treatment resistance. We conducted a phase I/II trial of alpelisib (α-specific PI3K inhibitor) plus nab-paclitaxel in patients with HER2-negative metastatic breast cancer (MBC).Patients and Methods:Eligible patients had HER2-negative MBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of alpelisib (250, 300, and 350 mg) daily plus nab-paclitaxel 100 mg/m2 administered on days 1, 8, and 15 every 28 days. Phase II was according to Simon's two-stage design. PIK3CA mutations in tumor/circulating tumor DNA (ctDNA) were assessed. Primary endpoints were recommended phase II dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, pharmacokinetics, progression-free survival (PFS), and association of PIK3CA mutation with outcomes.Results:A total of 43 patients were enrolled (phase I, n = 13 and phase II, n = 30). A total of 84% had visceral disease and 84% had prior taxane. No dose-limiting toxicities occurred in phase I. RP2D was alpelisib 350 mg daily plus nab-paclitaxel 100 mg/m2 on days 1, 8, and 15. Hyperglycemia (grade 3, 26% and grade 4, 0%), neutropenia (grade 3, 23% and grade 4, 7%), diarrhea (grade 3, 5% and grade 4, 0%), and rash (grade 3, 7% and grade 4, 0%) were the most common adverse events. Among 42 evaluable patients, ORR was 59% (complete response, 7% and partial response, 52%), 21% of whom had response lasting >12 months; median PFS was 8.7 months. A total of 40% of patients demonstrated tumor and/or ctDNA PIK3CA mutation; patients with tumor/ctDNA mutation demonstrated better PFS compared with those without mutation (11.9 vs. 7.5 months; HR, 0.44; P = 0.027). Patients with normal metabolic status had longer PFS compared with prediabetic/diabetic patients (12 vs. 7.5 months; P = 0.014). No pharmacokinetics interactions were detected.Conclusions:The alpelisib plus nab-paclitaxel combination was well tolerated and shows encouraging efficacy, especially in patients with PIK3CA-mutated tumor/ctDNA. The impact of metabolic status on response to this combination merits further investigation.

Quasi-static time-series (QSTS) simulation is used to simulate the behavior of distribution systems over long periods of time (typically hours to years). The technique involves repeatedly solving the load-flow problem for a distribution system model and is useful for distributed energy resource planning. When a QSTS simulation has a small time step and a long duration, the computational burden of the simulation can be a barrier to integration into utility workflows. One way to relieve the computational burden is to simplify the system model. The segment substitution method of simplifying distribution system models introduced in this paper offers model bus reduction of up to 98% with a simplification error as low as 0.2% (0.002 p.u. voltage). In contrast to existing methods of distribution system model simplification, which rely on topological inspection and linearization, the segment substitution method uses black-box segment data and an assumed simplified topology.

Although energy resource sustainability has been researched extensively, the understanding of how we use and interact with electricity sustainably is less understood. New electrical designs, like microgrids, provide opportunities to better address the immediate needs of electrical sustainability and urban development. This paper analyzes the role of microgrids in urban development and examines how greater systemic thinking between infrastructure planning and energy policymaking can increase a city’s resilience.

We investigated habitat use of bobcats (Lynx rufus) across spatial scales in New Hampshire, USA, by integrating independent sources of information into one statewide model of habitat suitability. First, statewide distribution of bobcats (second-order selection) was estimated using observations of bobcats solicited from the public. Probability functions indicated that areas where bobcats were not detected (no sightings) were characterized by high elevations and deep snow during winter. That pattern was corrob-orated by camera traps that were distributed among high and low-elevation landscapes. Second, bobcats equipped with GPS collars in two study areas were used to determine habitat use within established home ranges (third-order selection). Resource-selection probability functions developed from locations of marked bobcats indicated they selected forests, shrub/scrub, and wetlands, and avoided developed areas, agricultural areas, and open water relative to availability. Bobcats also avoided areas with high road densities and selected areas close to forest edges, and preferred rugged south-facing slopes. Finally, these measures of bobcat distribution were combined to obtain fine-scale estimates of bobcat habitat suitability across New Hampshire. A comparison of models of habitat suitability to an index of bobcat abundance (effort-corrected detections of bobcats by hunter) indicated that the hierarchical model (second-order multiplied by third-order of selection) provided a better description of statewide bobcat habitat than either single-scale analyses. As a result, we recommend caution when extrapolating information on the distribution of a species obtained at a limited spatial scale.

Efforts to retain ecological connectivity have become a conservation priority to permit animal movements within home ranges, allow dispersal between populations and provide opportunities for animals to respond to climate change. We used expert-opinion and empirically derived models to investigate landscape connectivity at two spatial scales among bobcats Lynx rufus in New Hampshire, USA. Paths of marked bobcats were compared to random movements in the context of program CircuitScape. At the local scale (within home ranges), the empirical model (based on observations and telemetry locations) performed better than the expert-opinion model. At the regional scale (state of New Hampshire), both models identified urban development as a potential barrier; however, the models differed in predicting how specific natural features (e.g. mountains and large water bodies) and some roads affected bobcat movements. When compared with bobcat population structure based on genetic information, the expert-opinion model overestimated the influence of roads. Alternatively, the empirical model overestimated the influence of snow. Our findings indicate that the empirically based resistance model was better at describing landscape-scale effects, whereas the expert-opinion model provided a good understanding of gene flow at a regional scale. As such, both models may be considered complementary. Bobcats were sensitive to disruptions imposed by habitat fragmentation and thus may be a suitable focal species for evaluating the consequences of land-use changes on the regional suite of mesocarnivores.

1076 Background: Histone deacetylase inhibitors (HDACi) upregulate genes involved in antigen presentation machinery and increase expression of natural killer group 2, member D ligands (NKG2DL), thus resulting in enhanced tumor cell recognition and response to PD-1/CTLA-4 blockade. Cisplatin and HDACi combination synergistically induces cytotoxicity, apoptosis, and DNA damage. This phase I-II trial investigated combination of romidepsin (HDACi) plus cisplatin and nivolumab (PD-1 inhibitor) in mTNBC. Patients and Methods: Eligible patients had mTNBC with any number of prior chemotherapies. Phase I was 3+3 dose-escalation design with three dose levels of romidepsin (8, 10, 12mg/m2, D2, 9) plus cisplatin 75mg/m2 D 1 every 21 days. Phase II treatment included romidepsin plus cisplatin plus nivolumab 360mg every 21 days and was designed according to Simon’s two stage minimax design. Primary endpoints were recommended phase 2 dose (RP2D) and objective response rate (ORR). Additional endpoints included safety, PFS, and pharmacokinetics. Results: 51 patients were enrolled (N=13 phase I, N=38 phase II) between 2015-2020. 69% had received ≥1 prior metastatic chemotherapy, 47% had prior platinum, 53% had liver metastasis, 12% had BRCA1/2 mutation, and 11% had PD-L1 positive disease. There were no dose limiting toxicities in phase I. The RP2D was romidepsin 12mg/m2 D2,9 + cisplatin 75mg/m2 D1 + nivolumab 360mg D1 every 21 days. Thrombocytopenia (G3:27%, G4:0%), neutropenia (G3:25%, G4:0%), anemia (G3:22%, G4:0%), nausea (G3:22%, G4:0%), and vomiting (G3:20%, G4:0%) were the most common grade 3/4 adverse events. 21% of patients had immune AEs (G3-4:8%). Among 34 evaluable phase II patients, ORR was 44% (Table), median PFS was 4.4 months, and 1-year PFS was 23%. Median OS was 10.3 months and 1-year OS was 43%. No pharmacokinetic interactions were detected with co-administration of romidepsin-cisplatin-nivolumab. Conclusions: The triplet combination of romidepsin plus cisplatin and nivolumab was well tolerated and shows encouraging efficacy in pretreated mTNBC, including in patients with PD-L1 negative disease and in those with liver metastasis. Correlative biomarker work is ongoing. This combination warrants further evaluation in larger studies. Clinical trial information: NCT02393794 .[Table: see text]

This paper addresses the protection of a high voltage direct current (HVDC) transmission system, utilizing the modular multilevel converter (MMC) topology in addition to incorporating a hybrid transmission corridor (transmission line including overhead line and cable sections). A solution is proposed for identifying the section within which a dc fault is located for the purpose of maintaining power delivery. A detailed model of the MMC-HVDC system is simulated using PSCAD and an in depth fault analysis is performed. A characteristic signal is discovered and then implemented into a novel solution. The end result is a fault section identification protection algorithm, implementing protective relay coordination to protect the system from false circuit breaker reclose as well as enabling fast system restart for nonpermanent faults. This restart protection algorithm is implemented without the use of a communications channel between converter stations, introducing novelty and quick restart response.

This paper presents a new method of constructing a transformerless voltage-sourced medium-voltage multilevel converter using existing discrete power semiconductor devices and printed circuit board technology. While the approach is general, it is particularly well suited for medium-voltage converters and motor drives in the 4.16 kV 500–1000 kW range. A novel way of visualizing the power stage topology is developed, which allows simplified mechanical layouts, while managing the commutation paths. Using so many discrete devices typically drives cost and complexity of the gate-drive system including its control and isolation; a gate-drive circuit is presented to address this problem. As with most multilevel topologies, the dc-link voltages must be balanced during operation. This is accomplished using an auxiliary circuit made up of the same power stage and an associated control algorithm. Experimental results are presented for a 4.16-kV 746-kW five-level power converter prototype.

Microgrids have been introduced to integrate more renewable resources onto the utility grid. Bidirectionality and low fault current levels are issues that cause fault detection problems for microgrids in both grid-connected and islanded modes of operation. During an upstream fault condition the desired reaction for the microgrid is to island itself. This allows certain loads, such as critical loads, to remain uninterrupted during an outage on the main grid. Therefore, the maintenance crew can be safely dispatched to alleviate the problem without fear of back-feed from the microgrid side. Hence, a critical problem that still needs adequate solutions developed is the detection of upstream faults in the grid connected mode without the reliance on communication systems. A protection method to detect upstream faults through second order harmonic magnitudes is proposed in this paper. The protection solution detects faults based on voltage and current second harmonic magnitudes during a fault transient period. A microgrid system was built in computer simulation and validated against an actual operational microgrid. The effectiveness of the proposed solution was demonstrated against multiple case studies in the PSCAD/EMTDC simulation environment.

In this paper, the idea of operating parallel inverters to mimic the dynamic stability of a synchronous generator (SG) is investigated when the inertia and damping constants are differed. These inverters are virtual synchronous machines (VSM) due to the replication of the inertial dynamics inherent to the SGs. Instead of using a conventional Phase-Lock Loop (PLL) in order to synchronize distributed generation (DG) to the grid frequency, the swing equation inherent to SG dynamics implemented. Parallel VSM controlled inverters can have behaviors based on the constants of their individual swing equation. This can cause the phase angles to differ beyond IEEE synchronization limits. The proposed algorithm is implemented to correct the phase angle and return parallel VSMs to acceptable operating ranges. Simulation results are performed in PSCAD-EMTDC simulation environment.

Pancreatic cancer is among the most lethal cancers with poorly tolerated treatments. There is increasing interest in using high-dose intravenous ascorbate (IVC) in treating this disease partially because of its low toxicity. IVC bypasses bioavailability barriers of oral ingestion, provides pharmacological concentrations in tissues, and exhibits selective cytotoxic effects in cancer cells through peroxide formation. Here, we further revealed its anti-pancreatic cancer mechanisms and conducted a phase I/IIa study to investigate pharmacokinetic interaction between IVC and gemcitabine. Pharmacological ascorbate induced cell death in pancreatic cancer cells with diverse mutational backgrounds. Pharmacological ascorbate depleted cellular NAD+ preferentially in cancer cells versus normal cells, leading to depletion of ATP and robustly increased α-tubulin acetylation in cancer cells. While ATP depletion led to cell death, over-acetylated tubulin led to inhibition of motility and mitosis. Collagen was increased, and cancer cell epithelial-mesenchymal transition (EMT) was inhibited, accompanied with inhibition in metastasis. IVC was safe in patients and showed the possibility to prolong patient survival. There was no interference to gemcitabine pharmacokinetics by IVC administration. Taken together, these data revealed a multi-targeting mechanism of pharmacological ascorbate’s anti-cancer action, with minimal toxicity, and provided guidance to design larger definitive trials testing efficacy of IVC in treating advanced pancreatic cancer.

With the increasingly high demand for well-trained power systems engineers, the University of Pittsburgh has partnered with Eaton in the creation of the new Electric Power Systems Laboratory at the Swanson School of Engineering. This laboratory demands the capability to perform a wide variety of experimental procedures while providing students and researchers with a seamless working environment. To accomplish that goal, a novel lab workbench was developed. This lab workbench integrates the load banks necessary for laboratory procedures with advanced metering, controls and safety features, and contains them within a work station ideally suited for the laboratory space. This paper details the development of those lab workbenches, from concept, to design, to prototype construction, to testing. Additionally, this work describes planned classroom experiments utilizing the developed bench. Ultimately the realized workbench demonstrates its capability to be reconfigured to suit the demands of both education as well as new research projects for undergraduate and graduate studies.

Microgrids are a key component in the evolution of the power grid. Microgrids are required to operate in both grid connected and standalone island mode using local sources of power. A major challenge in implementing microgrids is the communications and control to support transition from grid connected mode and operation in island mode. Here, we propose a secure communication architecture to support microgrid operation and control. A security model, including network, data, and attack models, is defined and a security protocol to address the real-time communication needs of microgrids is proposed. The implementation of the proposed security scheme is discussed and its performance evaluated using theoretical and co-simulation analysis, which shows it to be superior to existing protocols.

This multicenter, open-label, dose-escalating, phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary tumor response of a nanoparticulate formulation of paclitaxel (Nanotax®) administered intraperitoneally for multiple treatment cycles in patients with solid tumors predominantly confined to the peritoneal cavity for whom no other curative systemic therapy treatment options were available.Twenty-one patients with peritoneal malignancies received Nanotax® in a modified dose-escalation approach utilizing an accelerated titration method. All patients enrolled had previously received chemotherapeutics and undergone surgical procedures, including 33 % with optimal debulking. Six doses (50-275 mg/m(2)) of Cremophor-free Nanotax® were administered intraperitoneally for one to six cycles (every 28 days).Intraperitoneal (IP) administration of Nanotax® did not lead to increases in toxicity over that typically associated with intravenous (IV) paclitaxel. No patient reported ≥Grade 2 neutropenia and/or ≥Grade 3 neurologic toxicities. Grade 3 thrombocytopenia unlikely related to study medication occurred in one patient. The peritoneal concentration-time profile of paclitaxel rose during the 2 days after dosing to peritoneal fluid concentrations 450-2900 times greater than peak plasma drug concentrations and remained elevated through the entire dose cycle. Best response assessments were made in 16/21 patients: Four patients were assessed as stable or had no response and twelve patients had increasing disease. Five of 21 patients with advanced cancers survived longer than 400 days after initiation of Nanotax® IP treatment.Compared to IV paclitaxel administration, Cremophor-free IP administration of Nanotax® provides higher and prolonged peritoneal paclitaxel levels with minimal systemic exposure and reduced toxicity.

When comparing alternative courses of action, modern military decision makers often must consider both the military effectiveness and the ethical consequences of the available alternatives. The basis, design, calibration, and performance of a principles-based computational model of ethical considerations in military decision making are reported in this article. The relative ethical violation (REV) model comparatively evaluates alternative military actions based upon the degree to which they violate contextually relevant ethical principles. It is based on a set of specific ethical principles deemed by philosophers and ethicists to be relevant to military courses of action. A survey of expert and non-expert human decision makers regarding the relative ethical violation of alternative actions for a set of specially designed calibration scenarios was conducted to collect data that was used to calibrate the REV model. Perhaps unsurprisingly, the survey showed that people, even experts, disagreed greatly amongst themselves regarding the scenarios’ ethical considerations. Despite this disagreement, two significant results emerged. First, after calibration the REV model performed very well in terms of replicating the ethical assessments of human experts for the calibration scenarios. The REV model outperformed an earlier model that was based on tangible consequences rather than ethical principles, that earlier model performed comparably to human experts, the experts outperformed human non-experts, and the non-experts outperformed random selection of actions. All of these performance comparisons were measured quantitatively and confirmed with suitable statistical tests. Second, although humans tended to value some principles over others, none of the ethical principles involved—even the principle of not harming civilians—completely overshadowed all of the other principles.

Our clinical experience with low dose loxapine (5-15 mg/day) suggests promising efficacy and safety for irritability in autism spectrum disorders (ASD). We studied low dose loxapine prospectively in adolescents and adults with ASD and irritability. Additionally, we measured loxapine and metabolite concentrations, and brain-derived neurotrophic factor (BDNF) as a biomarker of neuromodulation.We performed a 12 week open trial of add-on loxapine in subjects, ages 13-65 years, diagnosed with ASD, and Aberrant Behavior Checklist-Irritability (ABC-I) subscale scores14. Loxapine was dosed flexibly up to 15 mg daily, starting with 5 mg on alternate days. From weeks 1 to 6, other psychoactive medications were tapered if possible; from weeks 6 to 12, all medication doses were held stable. The primary outcome was the Clinical Global Impressions-Improvement subscale (CGI-I), ratings of Much Improved or Very Much Improved. Secondary outcomes were the ABC-I, Repetitive Behavior Scale-Revised, and Schalock Quality of Life scale. Serum BDNF and loxapine and metabolite concentrations were assayed. BDNF rs6265 was genotyped.Sixteen subjects were enrolled; 12 completed all visits. Median age was 18 years (range 13-39). Median final loxapine dose was 7.5 mg/day (2.5-15). All 14 subjects (100%) with data at week 12 were rated as Much Improved on CGI-I at 12 weeks. Mean change on ABC-I at 12 weeks was -31%, p=0.01. Mean body mass index (BMI)-Z decreased between weeks 6 and 12, p=0.03. Side effects were minimal, and prolactin elevation occurred in only one subject. BDNF concentrations measured in 11 subjects increased significantly (p=0.04). Subjects with AG genotype for BDNF rs6265 required a lower dose of loxapine at study end, but had similar behavioral and BDNF concentration changes as the GG genotype.Low dose loxapine shows promise as a repurposed drug for irritability in ASD. Loxapine effects on BDNF warrant further study.

Earlier work has shown how to perform system impact studies of distributed generation interconnections using lengthy model development and analysis. In order to reduce the analysis time, hosting capacity methods have been developed to determine, in advance, distributed generation interconnections that can be accepted at certain locations up to certain sizes, without detailed study. Hosting capacity studies also require lengthy model development and analysis steps. Using databases and geographic information systems, we report on a method that reliably and automatically builds a detailed circuit model. A web-based simulator executes scripted analysis tasks that focus on results needed for the interconnection study. Using these automated methods, it's possible to reduce the analysis time for a project's impact study to one day.

This paper presents an analytical framework, supplemented with experimental validation, for optimizing the value of the external gate resistance employed in power conversion circuits using EPC enhancement-mode GaN transistors. A second order analytical model of the GaN device is utilized to determine a function that relates the external gate resistance to the peak gate voltage during turn-on. The results obtained from the analytical model were experimentally validated in a double pulse-test. The derived model allows for optimal selection of gate resistances such that GaN HFETs can be switched as rapidly as possible while keeping them in their safe operating region.

This paper proposes a DC-DC Modular Multilevel Converter (MMC) as an alternative to traditional isolated and non-isolated converter topologies for the purpose of achieving high voltage and power density in Anode Discharge Power Modules (ADPMs) for Solar Electric Propulsion (SEP) systems. The paper presents the background for the use of GaN HFETs in multilevel topologies at high frequency and makes the case for GaN HFETs in spacecraft power systems. It then presents an analytical model, simulation results, and initial hardware evaluation of the proposed topology. The result is a 2 kW converter system operating at 600 V output at a power density of 110 W/in3, achieving 83% full load efficiency at 1 MHz. The proposed topology is scalable to higher voltage and power ratings.

To understand large scale animal – habitat associations, biologists often rely on intensive home-range based studies, where a large number of locations are obtained from relatively few individuals equipped with radio transmitters and then extrapolate patterns of habitat use to much larger areas. Alternatively, extensive methods (e.g. incidental observations) that provide few observations per individual can be eff ectively used to sample large areas. Both methods have advantages, limitations, and potential sources of bias. We used these diff erent approaches in an eff ort to identify habitat features that may be important to expanding populations of bobcats Lynx rufus in New Hampshire, USA. Twelve adult bobcats with GPS-equipped transmitters provided detailed summaries of movement patterns within a 2300-km 2 study area. We also solicited incidental observations from citizens throughout the state (24 200 km 2 ). Using locations from both methods, we developed logistic models based on a comparison of home range composition to study area composition (second-order habitat selection). We also explored an approach to reduce potential bias associated with incidental observations (overrepresentation of human population centers) by applying a weighing factor. Th e telemetry and uncorrected observation-based models overlapped substantially with eight common covariates. Th e telemetry-based model indicated that bobcats preferred areas with few roads, limited human development, high stream densities, and steep topography. In contrast, the adjusted (to reduce bias) observation-based model indicated bobcats preferred areas with an abundance of roads and development with few streams and limited topographic variation. Because of these diff erences, we recommend caution when using sightings to model habitat associations unless biases associated with such information can be identifi ed and overcome. Although public sightings had limited application for describing bobcat habitat, they were useful in documenting a recent range expansion and revealing novel prey use by bobcats.

We examined the effects of two over-the-counter H1-antihistamines on the progression of fatty liver disease in male C57Bl/6 wild-type and apolipoprotein E (ApoE)−/− mice. Mice were fed a high-fat diet (HFD) for 3 mo, together with administration of either cetirizine (4 mg/kg body wt) or fexofenadine (40 mg/kg body wt) in drinking water. Antihistamine treatments increased body weight gain, gonadal fat deposition, liver weight, and hepatic steatosis in wild-type mice but not in ApoE−/− mice. Lobular inflammation, acute inflammation, and necrosis were not affected by H1-antihistamines in either genotype. Serum biomarkers of liver injury tended to increase in antihistamine-treated wild-type mice. Serum level of glucose was increased by fexofenadine, whereas lipase was increased by cetirizine. H1-antihistamines reduced the mRNA expression of ApoE and carbohydrate response element-binding protein in wild-type mice, without altering the mRNA expression of sterol regulatory element-binding protein 1c, fatty acid synthase, or ApoB100, in either genotype. Fexofenadine increased both triglycerides and cholesterol ester, whereas cetirizine increased only cholesterol ester in liver, with a concomitant decrease in serum triglycerides by both antihistamines in wild-type mice. Antihistamines increased hepatic levels of conjugated bile acids in wild-type mice, with the effect being significant in fexofenadine-treated animals. The increase was associated with changes in the expression of organic anion transport polypeptide 1b2 and bile salt export pump. These results suggest that H1-antihistamines increase the progression of fatty liver disease in wild-type mice, and there seems to be an association between the severity of disease, presence of ApoE, and increase in hepatic bile acid levels.

Power electronic conversion units will serve as a key enabling technology for assisting in the continued growth of grid-scale energy storage. This paper presents existing and future power electronic conversion systems and components that aid the interconnection of grid-scale energy storage or utilize storage to minimize grid disruption at all voltage classes including transmission, distribution, and future grid architectures such as the microgrid. New R&D solutions to aid the interconnection process including efforts in bidirectional charger design and potentially solid-state transformers (SSTs) are emphasized. The role of energy storage to support microgrid research and growth, while highlighting power electronic behavior within this environment, is considered. Last, an example that bridges the microgrid and energy storage theme is given through the design and operation of a direct current (dc) electric vehicle (battery) charging station. When appropriate, manufacturer solutions and success stories of utilizing latest battery technologies interfaced via power electronic solutions at the utility scale are provided.

This paper proposes a compact configuration of aircraft flows at intersections. The goal is to achieve a higher capacity of the airspace, allowing more aircraft to safely fly through a fixed region. Intersections of aircraft flows can be considered as basic building blocks for air traffic networks, and traffic networks can be designed through finding optimal arrangements of intersections whose conflict zones do not overlap. A conflict zone is defined as a minimal circular area centered at the intersection of two flows, which allows aircraft approaching the intersections to resolve conflict completely within the conflict zone. This paper derives the relationship between the size of a conflict zone and the intersection angle of the two flows. Such a relationship guides the choice of the most compact configuration for intersecting aircraft flows. An example involving multiple converging flows of aircraft demonstrates the efficiency of the proposed configuration of intersections. The result of conflict resolution shows a greatly reduced traffic complexity. Therefore, our study provides a potential solution to increase airspace capacity.

The antimycotic ciclopirox olamine is an intracellular iron chelator that has anticancer activity in vitro and in vivo. We developed an oral formulation of ciclopirox olamine and conducted the first-in-human phase I study of this drug in patients with relapsed or refractory hematologic malignancies (Trial registration ID: NCT00990587). Patients were treated with 5-80 mg/m² oral ciclopirox olamine once daily for five days in 21-day treatment cycles. Pharmacokinetic and pharmacodynamic companion studies were performed in a subset of patients. Following definition of the half-life of ciclopirox olamine, an additional cohort was enrolled and treated with 80 mg/m² ciclopirox olamine four times daily. Adverse events and clinical response were monitored throughout the trial. Twenty-three patients received study treatment. Ciclopirox was rapidly absorbed and cleared with a short half-life. Plasma concentrations of an inactive ciclopirox glucuronide metabolite were greater than those of ciclopirox. Repression of survivin expression was observed in peripheral blood cells isolated from patients treated once daily with ciclopirox olamine at doses greater than 10 mg/m², demonstrating biological activity of the drug. Dose-limiting gastrointestinal toxicities were observed in patients receiving 80 mg/m² four times daily, and no dose limiting toxicity was observed at 40 mg/m² once daily. Hematologic improvement was observed in two patients. Once-daily dosing of oral ciclopirox olamine was well tolerated in patients with relapsed or refractory hematologic malignancies, and further optimization of dosing regimens is warranted in this patient population.

This paper proposes an adaptive control architecture for maximum power point tracking (MPPT) in photovoltaic systems. MPPT technologies have been used in photovoltaic systems to deliver the maximum available power to the load under changes of the solar insolation and ambient temperature. To improve the performance of MPPT, this paper develops a two-level adaptive control architecture that can reduce complexity in system control and effectively handle the uncertainties and perturbations in the photovoltaic systems and the environment. The first level of control is ripple correlation control (RCC), and the second level is model reference adaptive control (MRAC). By decoupling these two control algorithms, the system achieves MPPT with overall system stability. This paper focuses mostly on the design of the MRAC algorithm, which compensates the underdamped characteristics of the power conversion system. The original transfer function of the power conversion system has time-varying parameters, and its step response contains oscillatory transients that vanish slowly. Using the Lyapunov approach, an adaption law of the controller is derived for the MRAC system to eliminate the underdamped modes in power conversion. It is shown that the proposed control algorithm enables the system to converge to the maximum power point in milliseconds.