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Artemisinin-hydroxychloroquine sulfate tablets (AH) are relatively inexpensive and a novel combination therapy for the treatment of all forms of malaria, especially aminoquinine drug-resistant strains of P. falciparum. Our aim was to assess the pharmacokinetics (PK) and toxicokinetics (TK) of AH following oral administration in Sprague Dawley rats and Beagle dogs by using the liquid chromatography tandem mass spectrometry methods (LC-MS/MS). The PK studies were carried out in eighteen rats at three doses and six dogs at three rounds of three doses after a single oral administration of AH. The TK studies in rats and dogs were accompanied by the 14-day repeated dosing studies. The PK results revealed that artemisinin was absorbed and cleared rapidly in rats with obvious gender difference and interindividual variability, and the systemic exposure with regard to AUC was positively correlated with the dosage in female rats. However, the kinetics parameters of artemisinin in dogs were not obtained because the plasma concentration was undetectable. The absorption and elimination of hydroxychloroquine in dogs and rats were relatively slow, and no gender difference was observed. The AUC of hydroxychloroquine showed a linear correlation with the dosage, but Cmax varied significantly among individuals. After 14-day repeated oral administration of AH, hydroxychloroquine shows an increase in systemic exposure and accumulation in rats and dogs, whereas the AUC and Cmax of artemisinin remarkably decreased in female rats due to its autoinduction metabolism. The TK results were basically consistent with the dose- and time-dependent toxic reaction in 14-day repeated dosing studies of AH in rats and dogs. The information from our studies could be helpful for further pharmacological and toxicological research and clinical application of AH.

Selection by progressive refinement allows the accurate acquisition of targets with small visual sizes while keeping the required precision of the task low. Using the eyes as a means to perform 3D selections is naturally hindered by the low accuracy of eye movements. To account for this low accuracy, we propose to use the concept of progressive refinement to allow accurate 3D selection. We designed a novel eye tracking selection technique with progressive refinement–Eye-controlled Sphere-casting refined by QUAD-menu (EyeSQUAD). We propose an approximation method to stabilize the calculated point-of-regard and a space partitioning method to improve computation. We evaluated the performance of EyeSQUAD in comparison to two previous selection techniques–ray-casting and SQUAD–under different target size and distractor density conditions. Results show that EyeSQUAD outperforms previous eye tracking-based selection techniques, is more accurate and can achieve similar selection speed as ray-casting, and is less accurate and slower than SQUAD. We discuss implications of designing eye tracking-based progressive refinement interaction techniques and provide a potential solution for multimodal user interfaces with eye tracking.

IntroductionIn clinical practice, the ideal time at which to perform a Frozen–thawed Embryo Transfer (FET) after a failed In-vitro Fertilization-embryo Transfer (IVF-ET) is still unclear to most practicing physicians. In addition, physicians often delay the introduction of FET due to concerns on the possible residual effects of ovarian hyperstimulation, which may interfere with the regular menstrual cycle. Moreover, given that most of the published studies on the topic are retrospective with contradictory findings, it is crucial to provide evidence-based randomized control guides for clinical practice.Methods/analysisThe study is a randomized, non-inferiority, parallel-group, controlled trial that will enroll a total of 732 women undergoing their first FET after a failed fresh embryo transfer (ET) cycle. The participants will then be randomized into two groups based on a computer-generated randomized list. The two groups include: (i) an immediate group were FET will be carried out during the first menstrual cycle after a failed fresh ET cycle and (ii) a delayed group where FET will be carried out during the second menstrual cycle after a failed fresh ET cycle. Primary outcomes will be defined as viable pregnancies with fetal heartbeats, diagnosed through pelvic ultrasonography after twelve weeks of gestation.Ethics and disseminationThe study was approved by the Ethics Committee of the Assisted Reproductive Medicine at the Affiliated Hospital of Shandong University of Traditional Chinese Medicine (SDTCM/E-2020.2.01). In addition, written informed consent will be obtained from all the participants before the study. The results of this trial will be disseminated in a peer-reviewed journal.DiscussionCurrently, there is no consensus with regard to the duration after which the effects of ovarian stimulation are observed after a failed fresh ET and the optimal time required to begin FET. Moreover, no randomized controlled trial exists that compares the ongoing pregnancy rates after immediate versus delayed FET following a failed fresh ET cycle. Therefore, it is important to conduct a well-designed randomized trial to determine whether it is necessary to delay FET for at least one menstrual cycle after the failure of fresh ET.Clinical Trial RegistrationChiCTR2000033313 (http://www.chictr.org.cn/enIndex.aspx).

High-frequency trading (HFT) has continuously evolved and dominated trading in the past decades. However, HFT trading marker prediction is a rarely investigated problem in Fintech literature. In this study, we first propose a novel manifold learning based HFT trading marker prediction model: M-SCAN to handle this challenge. Our study takes advantage of manifold embeddings of HFT data and seeks potential markers among the outliers in density-based clustering. We further propose HFT trading marker evaluation algorithms to validate the prediction effectiveness besides unveiling trading marker discovery via visualization. Our results demonstrate locally linear embedding (LLE) outperforms its peers in capturing trading markers in terms of accuracy and complexity for its local data structure keeping mechanism in embedding though different stocks may demonstrate their model preference under M-SCAN. Our studies also propose novel entropy and variance concentration ratios (VCR) to quantify HFT data and show that a high-entropy dataset is more likely to have better trading marker prediction than a low-entropy one. To the best of our knowledge, it is the first study in HFT trading marker prediction and will inspire coming studies in this area.

Background: Moyamoya disease (MMD) is a type of chronic cerebrovascular disease. Currently, revascularization surgery including direct/indirect procedure is recommended for symptomatic patients. However, some patients still respond poorly to the treatment or develop secondary symptoms. Case report: We report the first case of an MMD patient treated with deep brain stimulation (DBS) and thalamotomy. Symptoms of dystonia due to hemorrhage in the thalamus responded poorly to revascularization surgery, but were considerably alleviated by stereotactic neurosurgery. Discussion: Our case report provides a potential strategy for management of refractory symptomatic MMD patients with dystonia and also supports the combined efficacy of DBS with thalamotomies. Highlights: Approximately 30% of patients with Moyamoya disease (MMD) presenting movement symptoms do not respond well to revascularization surgery. We reported an MMD patient treated with deep brain stimulation (DBS) and thalamotomy with significant dystonia and dystonic tremor symptom amelioration. It indicates that DBS or stereotactic lesioning might be a potential treatment for the refractory movement symptoms of MMD.

Background Acute intermittent porphyria is an inherited disease that is rarely diagnosed in prepubertal children. It can affect the autonomic, peripheral, and central nervous system. Posterior reversible encephalopathy syndrome is a clinicoradiological entity characterized by headache, seizures, altered consciousness, and visual disorder associated with potentially reversible neuroradiological abnormalities predominantly in the parieto-occipital lobes. We report a child with acute intermittent porphyria who presented with radiological manifestations suggestive of posterior reversible encephalopathy syndrome. Patient A 9-year-old girl underwent an appendectomy after developing abdominal pain. She subsequently developed bilateral visual disturbance, confusion, seizures, hypertension, tachycardia, nausea, vomiting, constipation, dark tea-colored urine, and recurrent abdominal pain. Results Initial brain magnetic resonance imaging revealed hyperintense gyriform lesions on T 2 -weighted images and hypointense to isointense lesions on T 1 -weighted images in both parieto-occipital lobes with mild enhancement. The diagnosis of acute intermittent porphyria was confirmed by increased urinary excretion of porphyrin precursors. Her clinical signs gradually improved after intravenous high-dose glucose treatment and symptomatic therapies. A repeat magnetic resonance imaging confirmed complete resolution of the parieto-occipital lesions, suggesting with posterior reversible encephalopathy syndrome. Conclusions The association of abdominal pain, mental status changes, and autonomic dysfunction should arouse the suspicion of acute intermittent porphyria. Acute intermittent porphyria can be associated with posterior reversible encephalopathy syndrome.

Multi-user MIMO (MU-MIMO) employing Tomlinson Harashima Precoding (THP) is a powerful technique to enhance the system capacity in multi-user mobile communications systems. However, MU-MIMO has an inherent drawback in the degradation of the transmission performance due to the time variant fading channels which are caused by the mobility of the mobile station (MS). Considering that MU-MIMO is mainly applied to mobile communications systems, the performance degradation due to this terminal mobility has to be solved. This paper proposes a novel MU-MIMO THP transmission scheme for the sake of alleviating the performance degradation due to the terminal mobility. The feature of the proposed approach is to incorporate the concept of time division multiplexing (TDM) into MU-MIMO THP system, which enables the transmission of high mobility user to take precedence over that of the lower mobility user. Thanks to the use of TDM, the proposed scheme exploits the space diversity benefit because TDM decreases the number of MSs within a time slot. The effectiveness of the proposed scheme is demonstrated in comparison with the traditional MU-MIMO THP scheme by means of computer simulations.