Crossover Phase Research Articles

FASTENER Feature Selection for Inference from Earth Observation Data.

In this paper, a novel feature selection algorithm for inference from high-dimensional data (FASTENER) is presented. With its multi-objective approach, the algorithm tries to maximize the accuracy of a machine learning algorithm with as few features as possible. The algorithm exploits entropy-based measures, such as mutual information in the crossover phase of the iterative genetic approach. FASTENER converges to a (near) optimal subset of features faster than other multi-objective wrapper methods, such as POSS, DT-forward and FS-SDS, and achieves better classification accuracy than similarity and information theory-based methods currently utilized in earth observation scenarios. The approach was primarily evaluated using the earth observation data set for land-cover classification from ESA’s Sentinel-2 mission, the digital elevation model and the ground truth data of the Land Parcel Identification System from Slovenia. For land cover classification, the algorithm gives state-of-the-art results. Additionally, FASTENER was tested on open feature selection data sets and compared to the state-of-the-art methods. With fewer model evaluations, the algorithm yields comparable results to DT-forward and is superior to FS-SDS. FASTENER can be used in any supervised machine learning scenario.

Microscopic pairing theory of a binary Bose mixture with interspecies attractions: Bosonic BEC-BCS crossover and ultradilute low-dimensional quantum droplets

Ultradilute quantum droplets are intriguing new state of matter, in which the attractive mean-field force can be balanced by the repulsive force from quantum fluctuations to avoid collapse. Here, we present a microscopic theory of ultradilute quantum droplets in three-, one- and two-dimensional two-component Bose-Bose mixtures, by generalizing the conventional Bogoliubov theory to include the bosonic pairing arising from the interspecies attraction. Our pairing theory is fully equivalent to a variational approach and hence gives an upper bound for the energy of quantum droplets. In three dimensions, we predict the existence of a strongly interacting Bose droplet at the crossover from Bose-Einstein condensates (BEC) to Bardeen--Cooper--Schrieffer (BCS) superfluids and map out the bosonic BEC-BCS crossover phase diagram. In one dimension, we find that the energy of the one-dimensional Bose droplet calculated by the pairing theory is in an excellent agreement with the latest diffusion Monte Carlo simulation {[}Phys. Rev. Lett. \textbf{122}, 105302 (2019){]}, for nearly all the interaction strengths at which quantum droplets exist. In two dimensions, we show that Bose droplets disappear and may turn into a soliton-like many-body bound state, when the interspecies attraction exceeds a critical value. Below the threshold, the pairing theory predicts more or less the same results as the Bogoliubov theory derived by Petrov and Astrakharchik {[}Phys. Rev. Lett. \textbf{117}, 100401 (2016){]}. The predicted energies from both theories are higher than the diffusion Monte Carlo results, due to the weak interspecies attraction and the increasingly important role played by the beyond-Bogoliubov-approximation effect in two dimensions.

Frequency frame approach on tuning FOPI controller for TOPTD thermal processes

The frequency frame is used to tune fractional order proportional–integral​ controllers for stability, performance and robustness of third order plus time delay plants. Such plants are frequently used in describing thermal processes such as an air heater or a fired boiler. The aim is to tune the controller to meet some frequency domain properties. As robustness is an indispensable issue for thermal processes, main inspiration of the paper comes from flattening the phase curve in the Bode plot to provide improved robustness for the system. In spite of some existing studies, flattening is not realized by equalizing the phase derivative to zero at a given frequency value. Firstly, gain and phase crossover frequency points are enclosed with a rectangular frame. Then, lengths of the edges of this frame are changed to tune phase and gain margins. Curves inside the frame can be flattened by proper tuning of the edges. This will enhance the robustness and also ensure the iso-damping property. Equations to obtain the controller are given with two theorems. Demonstrations are made on two different thermal plants which are a novel electrical air heater and a bagasse fired boiler and the results are given on detailed illustrations. The results proved that preferred gain and phase properties are successfully obtained and improved performance and robustness are provided for related systems.

Quark-hadron phase transition in DGP including BD brane * * T. G. has been supported financially by Vice Chancellorship of Research and Technology, University of Kurdistan under research Project (98/11/2724). A. M. has been supported financially by Vice Chancellorship of Research and Technology, University of Kurdistan under research Project (98/10/34704)

A Dvali–Gabadadze–Porrati (DGP) brane-world model with perfect fluid brane matter including a Brans-Dicke (BD) scalar field on brane was utilized to investigate the problem of the quark-hadron phase (QHP) transition in early evolution of the Universe. The presence of the BD scalar field arises with several modified terms in the Friedmann equation. Because the behavior of the phase transition strongly depends on the basic evolution equations, even a small change in these relations might lead to interesting results about the time of transition. The phase transition is investigated in two scenarios, namely the first-order phase transition and smooth crossover phase transition. For the first-order scenario, which is used for the intermediate temperature regime, the evolution of the physical quantities, such as temperature and scale factor, are investigated before, during, and after the phase transition. The results show that the transition occurs in about a micro-second. In the following part, the phenomenon is studied by assuming a smooth crossover transition, where the lattice QCD data is utilized to obtain a realistic equation for the state of the matter. The investigation for this part is performed in the high and low-temperature regimes. Using the trace anomaly in the high-temperature regime specifies a simple equation of state, which states that the quark-gluon behaves like radiation. However, in the low-temperature regime, the trace anomaly is affected by discretization effects, and the hadron resonance gas model is utilized instead. Using this model, a more realistic equation of state is found in the low-temperature regime. The crossover phase transition in both regimes is considered. The results determine that the transition lasts around a few micro-seconds. Further, the transition in the low-temperature regime occurs after the transition in the high-temperature regime.

Tuning of fractional complex‐order direct current motor controller using frequency domain analysis

For the speed control of direct current motor, a fractional complex‐order controller (FCOC) is proposed in this paper. The FCOC is an extension of the fractional‐order controller. It is known that fractional‐order controllers exhibit strong robustness to open‐loop gain variations. However, in actual situations, due to external interference, the phase angle and gain of the system may change at the same time. The FCOC proposed in this paper adds an additional parameter, which makes the system show strong robustness when the phase angle and gain change simultaneously. Existing methods for parameter tuning of FCOCs only consider the preset gain crossover frequency and the expected phase margin. This may not allow the system to exhibit good dynamic and stable performance. In this paper, based on the frequency domain analysis, the parameters of the FCOC are tuned by integrating the gain crossover frequency, cutoff frequency, phase margin, and amplitude margin. The optimal solution satisfying a set of constraint equations is obtained by optimization algorithm. Finally, the simulation results are compared with those of the fractional‐order controller and the integer‐order controller. At the same time, the robustness of the system under disturbance is analyzed. The results show that the complex fractional‐order control presented in this paper has better dynamic performance and robustness.

Fractional order proportional derivative control for time delay plant of the second order: The frequency frame

This paper intends to tune fractional order proportional derivative controller for the performance, stability and robustness of second order plus time delay plant. The tuning method is based on the previously proposed “frequency frame” which is a rectangular frame enclosing gain and phase margins limited with gain and phase crossover frequencies in the Bode plot. Edges of the frame are tuned to achieve desired crossover frequencies and margins. By shaping the curves of the Bode plot, improvements are observed in the performance and robustness of the second order plus time delay system controlled by a fractional order proportional derivative controller. Generalized equations to obtain the parameters of the fractional order proportional derivative controller for second order plus time delay plant are given. In contrast to existing studies, this method reduces mathematical complexity when providing desired properties. Three examples are considered and effectiveness of the frequency frame is shown.

Therapeutic Equivalence of a New Preparation of Liquid Levothyroxine with Tablets in Patients with Overt Primary Hypothyroidism

Background: A new liquid levothyroxine (LT4) dissolved in glycerol and water has recently been developed by a Greek pharmaceutical company (Uni-Pharma, Athens, Greece). Objectives: To evaluate the therapeutic equivalence of this new liquid LT4 preparation versus the already existing tablet formulation of the same manufacturer, in order to obtain approval by the Greek National Organization for Medicines. Methods: This was a prospective, randomized, cross-over phase III study. The study included 50 patients (9 men and 41 non-pregnant women, with a mean age of 42.5 ± 12.5 years), with documented overt primary hypothyroidism. All subjects were well controlled on substitution therapy with various LT4 formulations. None of the patients had known LT4 malabsorption. The patients were randomized into 2 groups (A and B). The individuals of group A initially received T4® tablets for 10 ± 2 weeks and subsequently switched to T4® drops (100 μg/mL solution) at the same dose for another 10 ± 2 weeks. In group B, the reverse procedure was followed. Total T3 (T3), free T4 (fT4), and TSH were measured in all participants at enrollment and at the end of each 10 ± 2-week trial period. Results: Out of the 50 recruited patients, 6 were lost to follow-up and 5 were excluded due to non-compliance with the study protocol. In the 39 patients who completed the study, the serum TSH levels after 10 ± 2 weeks of treatment either with T4® tablets or with T4® drops did not differ (1.759 ± 1.104 vs. 2.076 ± 1.334 mIU/L, mean ± SD). Conclusions: In hypothyroid patients, the new liquid LT4 preparation (T4® drops) is therapeutically equivalent to the tablet form (T4® tablets).

Quantum phase crossover in the spherical mean-field plus quadrupole–quadrupole and pairing model with two j-orbits

The shape phase crossover in the mean-field plus the geometric quadrupole–quadrupole and pairing model within two [Formula: see text]-orbits is analyzed, for which a simple description of [Formula: see text]Sn confined in the lowest [Formula: see text] and [Formula: see text] orbits above the [Formula: see text]Sn core is demonstrated to reveal the crossover behavior of the model. It is shown that [Formula: see text], [Formula: see text] and [Formula: see text], [Formula: see text] in this case may serve as effective order parameters for even–even and odd-A systems, respectively, from which the shape phase crossover from the rotation-like phase to the superconducting-like phase can be observed with variation of the number of valence neutrons.

Tuning Method of Resonant Current Controller With DC Elimination for PWM Rectifiers in Electric Multiple Units

Current control in electric multiple unit (EMU) pulsewidth-modulated (PWM) rectifiers is crucial for the system's stable operation and fast transient response. It should not only regulate the sinusoidal current under very low switching frequency but also eliminate dc current avoiding transformer core saturation. Therefore, proportional integral (PI) plus vector proportional integral with phase compensation (VPIc) controller is chosen for the current control in such single-phase rectifiers. However, the gains of PI and VPIc are coupled and determine the system performance together, invalidating the traditional gain tuning method. Therefore, a gain tuning method for PI + VPIc based on Nichols chart is proposed in this article, which decouples the two gains and simplifies the gain tuning into the tuning of gain margin and phase crossover frequency, while settling time and overshoot are considered for the optimal gain tuning. The designed system has good transient responses, stability, and robustness. The experimental results validate the theoretical analysis of the tuning method on a laboratory prototype and the effectiveness of the current control on the EMU PWM rectifiers.

Bioequivalence of macitentan and tadalafil given as fixed-dose combination or single-component tablets in healthy subjects.

AimsTo demonstrate the bioequivalence of macitentan/tadalafil fixed‐dose combination (FDC) tablets with single‐component tablets of macitentan and tadalafil in healthy subjects.MethodsStudies AC‐077‐101 and AC‐077‐103 were single‐centre, open‐label, single‐dose, 2‐period, randomized, crossover Phase 1 studies conducted in healthy subjects. Two FDCs were investigated: FDC‐1 and FDC‐2 in Study AC‐077‐101 and FDC‐2 in Study AC‐077‐103. Both FDCs contained 10 mg/40 mg of macitentan/tadalafil and differed in excipients and coating materials used. In both studies, pharmacokinetic sampling over 216 hours was conducted, and pharmacokinetic parameters were derived using noncompartmental methods.ResultsBioequivalence of macitentan, its active metabolite ACT‐132577, and tadalafil was established for FDC‐2 in both studies AC‐077‐101 and AC‐077‐103 in which tadalafil as a single component was sourced from the USA and EU, respectively, to fulfil regional regulatory requirements. The area under the plasma concentration–time curve and maximum plasma concentration with 90% confidence intervals of all components were entirely within the bioequivalence limits (0.8000–1.2500). No subject died and no serious adverse events were reported in either studies.ConclusionThe FDC‐2 tablet containing 10 mg/40 mg of macitentan/tadalafil was bioequivalent to the free combination of 10 mg macitentan and 40 mg tadalafil (both US and EU sourced). Macitentan and tadalafil were well tolerated when administered as FDC or as a free combination.

Results of crossover phase II component of randomized placebo-controlled trial evaluating oral THC/cannabis extract for refractory chemotherapy-induced nausea and vomiting (CINV).

12008 Background: The aim of this multi-centre, randomised, double-blinded, placebo-controlled, phase 2/3 trial is to determine efficacy of addition of oral cannabis in adults with any malignancy of any stage, experiencing CINV during moderate-highly emetogenic intravenous chemotherapy, despite guideline-consistent anti-emetic prophylaxis, requiring ≥ 2 chemotherapy cycles. Here we report the crossover phase 2 component results. Methods: Treatment consisted of 1 cycle of oral THC 2.5mg/CBD 2.5mg (TN-TC11M) capsules tds days -1 to 5 and 1 cycle matching placebo in a crossover design, then blinded patient preference for a 3rd cycle. Primary end-point is difference in proportion of patients with ‘complete response’ (no emesis & no use of rescue medications) during 0-120 hours from chemotherapy between cycles. 80 patients provides 80% power with 2p of 0.1 to detect a 20% difference. Results: 81 patients recruited (2016-9). 72 completing 2 cycles are included in efficacy analyses. 78 not withdrawing consent are included in safety analyses. Median age was 55 years (range 29-80), 78% were female, 42% report historic cannabis use, 55% were treated with curative intent. Most common regimens were AC (26%), FOLFOX (17%). All received steroids & 5-HT3 antagonist, 79% received NK-1 antagonist, 4% received olanzapine. Efficacy is shown in table. 83% preferred cannabis to placebo. Most common bothersome cannabinoid-related adverse events (cannabis, placebo) were sedation (19%,4%), dizziness (10%,1%), disorientation (3%,0%). No SAEs were attributed to THC/CBD. Conclusions: Addition of oral THC/CBD to standard anti-emetics was associated with less nausea & vomiting but additional side effects. Most preferred THC/CBD to placebo. Based on these positive results, the definitive parallel phase 3 trial component continues (additional n=170). Acknowledgements: Trial participants, investigators, research staff. Funding from NSW Government Dept of Health. Clinical trial information: ACTRN12616001036404 . [Table: see text]

Quality of life (QOL) for the treatment sequence of abiraterone acetate plus prednisone (AAP) followed by enzalutamide (ENZ) versus the opposite sequence for metastatic castration-resistant prostate cancer (mCRPC): Results from a phase II randomized clinical trial.

5578 Background: A randomized cross-over phase II trial (Lancet Oncol 20(12):1730, 2019) showed the sequence of AAP followed by ENZ is associated with a better time to PSA progression compared with the opposite sequence and superior 2nd line activity of ENZ. It is unknown whether one treatment sequence is associated with better QOL than the other. Methods: 202 Patients were randomized (1:1) to receive either AAP followed by ENZ at PSA progression (arm A) or the opposite sequence of ENZ followed by AAP (arm B). FACT-P questionnaires were completed at baseline, cross-over and every 4 weeks on treatment. Time to QOL deterioration (TTQOLD) for the treatment sequence was determined from start of 1st line treatment to first questionnaire with a clinically meaningful decrease from baseline and compared between arms using the log-rank test. TTQOLD was also determined for 1st line and 2nd line separately. The proportion of patients with QOL deterioration for total FACT-P score and FACT-P subscores from baseline to week 12 of 1st and 2nd line treatment was compared between arms using X2 test. Results: Median follow-up for 1st and 2nd line and whole sequence were 9.3, 6.6 and 22.0 months (mos) respectively and questionnaire completion rate was 81%. TTQOLD for total FACT-P score for the whole sequence for arm A vs B was 10.5 mo (95% CI 5.0-15.5) vs 10.8 mo (5.5-13.1), p = 0.74. For 1st-line AAP vs ENZ, median TTQOLD was 15.5 mo (5.5-21.2) vs 11.0 (5.5-13.3) respectively (p = 0.23). For 2nd line ENZ vs ABI, median TTQOLD was 3.7 mo (2.0-5.4) vs 5.8 (2.8-12.1), p = 0.13. There was a higher rate of deterioration in physical well-being (PWB) for 1st line ENZ (arm B) and 2nd line ENZ (arm A) (Table). Conclusions: There was no difference in TTQOLD between the two treatment sequences of AAP and ENZ. Although treatment with second line ENZ has been associated with greater anti-cancer effects, ENZ was associated worse PWB QOL scores. Clinical trial information: NCT02125357 . [Table: see text]

S193. EFFICACY AND SAFETY OF TRANSCRANIAL DIRECT CURRENT STIMULATION FOR TREATING NEGATIVE SYMPTOMS IN SCHIZOPHRENIA: THE FOLLOW-UP PHASE

BackgroundSchizophrenia is a severe mental illness presenting a substantial, increasing burden. Its negative symptoms include flattened affect, loss of interest, and emo- tional withdrawal and are associated with poor functional outcomes. Most antipsychotic drugs are not effective for such symptoms and present important adverse effects3 and low tolerability. v Nonpharmacological interventions are also limited. Transcranial direct current stimulation (tDCS) is a noninvasive neuromodulatory technique that presents low costs, portability, ease of use, and no serious adverse effects. The technique injects weak, direct currents via scalp electrodes. A current fraction penetrates the brain, increasing or decreasing the neuronal excitability of regions near the anode or the cathode, respectively. Mimicking rTMS studies, tDCS trials have used anodal stimulation over the left PFC aiming to ameliorate negative symptoms. In a seminal study, Brunelin et al used a frontotemporoparietal montage in 30 patients with schizophrenia and demonstrated large effect sizes for improvement of negative symptoms and auditory hallucinations (AHs). Recently, we confirmed that active tDCS is more effective than sham tDCS for the negative symptoms of schizophrenia in a randomized, sham-controlled clinical trial with 100 patients. However, the studies showed tDCS efficacy only during the acute phase of the treatment of the negative symptoms of schizophrenia. In fact, as to understand tDCS’ role in the therapeutic arsenal of schizophrenia, it is crucial to assess its efficacy during the continuation treatment. We performed a 24- week follow-up study to assess the relapse of patients presenting a clinical response after acute tDCS treatment. We also explored whether baseline clinical and demographic characteristics were predictors of relapse. Finally, we report the results of patients from the open-label, crossover phase of the study.MethodsThe follow-up phase was the open-label in which all responders (>20% negative PANSS improvement or negative PANSS < 20) who had previously received active-tDCS were enrolled to a 24-week, follow-up phase in which a maximum of 9 tDCS sessions were performed – every other week for 3 months and, thereafter, once a month for the subsequent 3 months – sessions would be interrupted earlier whether the subject relapsed. TDCS was applied at 2mA/30-min, with the anode over the left dorsolateral prefrontal cortex and the cathode over the tempoparietal junction. Relapse was the outcome measure.ResultsWe had 20 responder in the clinical trial to tDCS and more 12 out 29 in the cross-over phase (who were sham and entered in an open-label exactly as the original clinical trial). Of this 32, 27 accepted to participate in the follow-up phase. The survival rate per Kaplan–Meier analysis was 61%. Patients with treatment ultra-resistant presented lower 24-week survival rate as compared to nonrefractory patients (58% vs. 67%), but without statistical difference between groups(P < .5).Equivalents dosages use of haloperidol, clozapine use, number of hospitalizations or length of the schizophrenia were a predictor of relapse. TDCS was well tolerated and with few side effectsDiscussionPatients after using tDCS for negative symptoms of schizophrenia presents a low rate of relapse when compared the use of tDCS for major depression. tDCS can be an alternative to the treatment of negative symptoms of schizophrenia at long-term.

From microcanonical ensemble to canonical ensemble: phase transitions of a spin chain with a long-range interaction

A long-range interacting spin chain placed in a staggered magnetic field can exhibit either first order phase transition or second order phase transition depending on the magnetic field intensity. The first order phase transition of this model is known to be accompanied with the temperature jump phenomenon in the microcanonical ensemble, while this anomalous temperature jump phenomenon can not be observed in the canonical ensemble. We obtain the crossover phase transition properties passing from a microcanonical to a canonical ensemble, by placing this previously isolated spin chain model in contact with a two-level system that acts as a thermal reservoir. The magnitude of the temperature jump monotonically decreases with the increase of the size of the thermal reservoir. And the microcanonical phase diagram can gradually turn into the canonical phase diagram by increasing the number of particles of the reservoir.

Final results from IMPROVE: a randomized, controlled, open-label, two-arm, cross-over phase IV study to determine patients\u2019 preference for everolimus in combination with exemestane or capecitabine in combination with bevacizumab in advanced HR-positive, HER2-negative breast cancer

BackgroundThe objective of the IMPROVE study was patients’ preference for either endocrine-based therapy or combined chemo- and anti-angiogenic therapy in advanced HR-positive/HER2-negative breast cancer.MethodsIn this randomized, cross-over phase IV study, 77 patients were recruited in 26 sites in Germany. Patients were randomized 1:1 to receive either capecitabine plus bevacizumab (Cap+Bev) as first-line therapy followed by cross-over to everolimus plus exemestane (Eve+Exe) as second-line therapy (Arm A) or the reverse sequence (Arm B). The primary endpoint was patients’ preference for either regimen, assessed by the Patient Preference Questionnaire 12 weeks after cross-over. Key secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and quality of life (QoL).Results61.5% of patients preferred Cap+Bev (p = 0.1653), whereas 15.4% preferred Eve+Exe and 23.1% were indecisive. Physicians showed a similar tendency towards Cap+Bev (58.1%) as the preferred regimen versus Eve+Exe (32.3%). Median first-line PFS was longer for Cap+Bev than for Eve+Exe (11.1 months versus 3.5 months). Median second-line PFS was similar between Cap+Bev and Eve+Exe (3.6 months versus 3.7 months). Median OS was comparable between Arm A (28.8 months) and Arm B (24.7 months). 73.0% and 52.6% (first−/second-line, Cap+Bev) and 54.1% and 52.9% (first−/second-line, Eve+Exe) of patients experienced grade 3/4 TEAEs. No treatment-related deaths occurred. QoL and treatment satisfaction were not significantly different between arms or treatment lines.ConclusionsPatients tended to favor Cap+Bev over Eve+Exe, which was in line with physicians’ preference. Cap+Bev showed superior first-line PFS, while QoL was similar in both arms. No new safety signals were reported.Trial registrationEudraCT No: 2013–005329-22. Registered on 19 August 20

One-dimensional few-electron effective Wigner crystal in quantum and classical regimes

A system of confined charged electrons interacting via the long-range Coulomb force can form a Wigner crystal due to their mutual repulsion. This happens when the potential energy of the system dominates over its kinetic energy, i.e., at low temperatures for a classical system and at low densities for a quantum one. At $T=0$, the system is governed by quantum mechanics, and hence, the spatial density peaks associated with crystalline charge localization are sharpened for a lower average density. Conversely, in the classical limit of high temperatures, the crystalline spatial density peaks are suppressed (recovered) at a lower (higher) average density. In this paper, we study those two limits separately using an exact diagonalization of small one-dimensional (1D) systems containing few ($<10$) electrons and propose an approximate method to connect them into a unified effective phase diagram for Wigner few-electron crystallization. The result is a qualitative quantum-classical crossover phase diagram of an effective 1D Wigner crystal. We show that the spatial density peaks associated with the quasi-crystallization should be experimentally observable in a few-electron 1D system. We find that the effective crystalline structure slowly disappears with both the crossover average density and crossover temperature for crystallization decreasing with increasing particle number, consistent with the absence of any true long-range 1D order. In fact, one peculiar aspect of the effective finite-size nature of 1D Wigner crystallization we find is that even a short-range interaction would lead to a finite-size 1D crystal, except that the crystalline order vanishes much faster with increasing system size in the short-range interacting system compared with the long-range interacting one.

Termal Sistemler için Oransal-Integral Denetleyici Tasarımı

This study proposes to tune proportional integral (PI) controllers for the stability and performance of thermal processes described by first order plus time delay (FOPTD) and second order plus time delay (SOPTD) plants. In addition to stability, parameters of the controllers are tuned to meet the desired gain crossover frequency and phase margin for each system. Design schemes of the controllers are clearly given and the results are applied on some plants provided from the literature. Illustrative examples are given to prove the method.

Pharmacokinetics and Safety of Two Voriconazole Formulations after Intravenous Infusion in Healthy Korean Volunteers.

BackgroundVoriconazole, a triazole antifungal agent exhibits broad-spectrum antifungal activity. It is used to treat severe, invasive fungal infections, including invasive aspergillosis and candidemia. The aim of this study was to assess the pharmacokinetic equivalence of a test formulation (Vorico® Injection) and reference formulation (Vfend® IV) of voriconazole.Materials and MethodsThis was a randomized, open-label, single-dose, three-group, two-treatment, two-sequence, two-period, crossover phase I trial with 7-day washout periods (ClinicalTrials.gov identifier NCT02631954). Twenty-four healthy Korean male subjects were recruited. In each group, eight subjects were randomized in a 1:1 manner to receive a single dose of 200 mg test or reference formulation intravenously over 1.5 h. Blood samples were collected over 24 h post-dose, and plasma drug concentrations were determined by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were determined using a non-compartmental analysis, and safety was evaluated.ResultsTwenty-three subjects completed the study. The geometric mean ratio (90% confidence interval) of the test formulation to reference formulation was 0.9570 (0.8178 – 1.1199) for the maximum plasma concentration (Cmax) and 1.0720 (1.0262 – 1.1198) for the area under the concentration–time curve from dosing to the last quantifiable concentration (AUClast). The mean plasma concentration–time profiles, pharmacokinetic parameters, and safety were comparable between the two formulations.ConclusionEquivalent pharmacokinetic characteristics that satisfied the criteria of bioequivalence and similar safety profiles were observed for both test and reference formulations of voriconazole.

The FAFA Trial: A Phase 2 Randomized Clinical Trial on the Effect of a Fan Blowing Air on the Face to Relieve Dyspnea in Filipino Patients with Terminal Cancer

Abstract Introduction Fan therapy has been suggested by some studies as one of the nonpharmacological supportive interventions to alleviate breathlessness for dyspneic patients with terminal cancer. Unfortunately, data among Asians are limited and there are currently no published data showing that this intervention works among Filipinos—thus this study. Study Design This study was an open-label, randomized, placebo-controlled, crossover Phase 2 trial. The experimental group had a fan blowing air directly to the patient’s face for 5 minutes, and the control group had a fan blowing air to the patient’s legs. Treatment crossover was done after a washout period of 1 hour. The primary outcome, which is dyspnea, was measured subjectively using the Modified Borg Scale (MBS). Differences in the patient’s respiratory rate (RR) and oxygen saturation were also measured. Results A total of 48 patients were enrolled in this trial. The mean age of the patients enrolled was 51 years, and the most common primary tumor was lung cancer (21%). In the control group, results showed that the mean difference before and after intervention in the MBS was 0.15, and the mean difference in RR was 0.25. On the other hand, the intervention group showed a statistically significant decrease in the patient’s dyspnea as evidenced by a mean MBS decrease of 2.79 (p &lt; 0.0001), and a mean RR decrease of 1.88 (p &lt; 0.0001). Conclusion The results of this study reveal that fan on face (FAFA) therapy in terminally ill Filipino cancer patients in addition to the prescribed standard of care can significantly alleviate their level of dyspnea. Thus, FAFA therapy should be considered as an adjunct to standard of care for these patients.

Deep brain stimulation in treatment resistant schizophrenia: A pilot randomized cross-over clinical trial.

BackgroundUp to 30% of patients with schizophrenia are resistant to antipsychotic drug treatment, with 60% of such cases also failing to respond to clozapine. Deep brain stimulation (DBS) has been used in treatment resistant patients with other psychiatric disorders, but there is a lack of trials in schizophrenia, partly due to uncertainties over where to site the electrodes. This trial aimed to examine the effectiveness of nucleus accumbens (NAcc) and subgenual anterior cingulate cortex (subgenual ACC) targeted DBS; the primary outcome measure was PANSS total score, as assessed fortnightly.MethodsEight patients with schizophrenia, who met criteria for treatment resistance and were also resistant to/intolerant of clozapine, were randomly assigned using central allocation to receive DBS in the NAcc or subgenual ACC. An open stabilization phase lasting at least six months was followed by a randomized double-blind crossover phase lasting 24 weeks in those who met symptomatic improvement criteria. The primary end-point was a 25% improvement in PANSS total score. (ClinicalTrials.gov Identifier: NCT02377505; trial completed).FindingsOne implanted patient did not receive DBS due to complications of surgery. Of the remaining 7 patients, 2/3 with NAcc and 2/4 with subgenual ACC electrode placements met the symptomatic improvement criteria (58% and 86%, and 37% and 68% improvement in PANSS total score, respectively). Three of these patients entered the crossover phase and all showed worsening when the stimulation was discontinued. The fourth patient worsened after the current was switched off accidentally without her or the investigators’ knowledge. Physical adverse events were uncommon, but two patients developed persistent psychiatric adverse effects (negative symptoms/apathy and mood instability, respectively).InterpretationThese preliminary findings point to the possibility of DBS having therapeutic effects in patients with schizophrenia who do not respond to any other treatment. Larger trials with careful attention to blinding will be necessary to establish the extent of the benefits and whether these can be achieved without psychiatric side-effects.