Search

Dominique Milea,1 See-Hwee Yeo,1 Yein Nam,2 Aldo Amador Navarro Rojas,1 Sumitra Shantakumar,1 Janine Beale,3 Brett Marett,3 Robert P Young,4 Raewyn J Scott,4 Barry Gribben5 1Value Evidence and Outcomes, GlaxoSmithKline plc., Greater China and Intercontinental, 139234, Singapore; 2Real World Evidence & Epidemiology, Adelphi Real World, Macclesfield, Cheshire, UK; 3Medical Affairs, GlaxoSmithKline plc., Auckland, New Zealand; 4Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; 5Public Sector Surveying, CBG Health Research Limited, Auckland, New ZealandCorrespondence: Dominique MileaValue Evidence and Outcomes, GlaxoSmithKline plc., Greater China and Intercontinental, 23 Rochester Park, 139234, SingaporeTel +65 9830 7891Email dominique.x.milea@gsk.comPurpose: Long-acting bronchodilator (LABD) use is the mainstay of pharmacologic treatment for chronic obstructive pulmonary disease (COPD). Few studies describe evolving patterns of LABD use in the setting of changing inhaler availability and updated clinical guidelines.Methods: A retrospective cohort study in New Zealand using the HealthStat general practice database (01/2014 to 04/2018). Eligible patients (aged ≥ 40 years) had COPD and ≥ 1 LABD prescription (long-acting muscarinic antagonist [LAMA] and/or long-acting β2-agonist [LABA]) during the index period (05/2015 to 04/2016). Demographics and clinical characteristics of all LABD users (overall/by treatment) were described at baseline. Patients starting LABD treatment during the index period, termed “new” users, were also described, as was their treatment evolution over 24 months of follow-up. Yearly LABD initiation rates were assessed from 2015 to 2017, covering changes to Pharmaceutical Management Agency criteria and clinical guidelines.Results: Across 2140 eligible patients, the most common index treatments were inhaled corticosteroid (ICS)/LABA (59.0%) and open triple therapy (LAMA+LABA+ICS; 26.7%). ICS/LABA therapy was highest in younger patients, with open triple therapy highest in older patients. Prior yearly exacerbation rates were lowest in those receiving monotherapy (LABA: 0.9/year; LAMA: 1.1/year) versus dual therapy (all 1.4/year) and open triple therapy (2.2/year). Of 312 new LABD users, ICS/LABA was the most common index treatment (69.6%), followed by LAMA monotherapy (16.0%). Continuous use with index treatment was 31.1% at 12 months and 13.5% at 24 months; mean time to treatment change was 175.5 and 244.1 days, respectively. Among patients modifying treatment at 24 months, 23.0% augmented, 7.0% switched, 45.6% re-started, and 24.4% discontinued/stepped down. Among patients initiating LABD each year from 2015 to 2017, LAMA prescription increased (17% to 46%) while ICS prescription remained stable (approximately 20%).Conclusion: Predominant use of ICS/LABA (05/2015 to 04/2016) reflects available LABDs and previous restrictions on LAMA use in New Zealand.Keywords: bronchodilator therapy, chronic obstructive pulmonary disease, long-acting muscarinic antagonist, long-acting β2-agonist, inhaled corticosteroid, New Zealand

We investigated olfactory function and its relation to cardiac 123I-metaiodobenzylguanidine (MIBG) uptake in 15 patients with drug induced parkinsonism (DIP). The mean Cross Cultural Smell Identification (CCSI) score was significantly greater in patients with DIP than in those with Parkinson's disease (PD: 6.9 (1.6) vs 4.4 (2.2); p<0.001); however, the mean CCSI score in patients with DIP was not significantly different from controls. One patient with DIP, whose CCSI score was significantly reduced, also exhibited decreased cardiac MIBG uptake. DIP patients with CCSI scores within the normal range had normal cardiac MIBG uptake. Our study suggests that an olfactory function test may be a useful tool for detecting DIP unrelated to PD and for identifying patients with DIP who have subclinical PD. [ABSTRACT FROM AUTHOR]

Introduction: Limited evidence is available on real-world management of atopic dermatitis (AD) among Asian adults. This cross-sectional study aimed to assess current approaches in AD diagnosis and management in Asia., Methods: Practising dermatologists regularly treating patients with moderate-to-severe AD were recruited from eight Asia-Pacific territories, namely Mainland China, Hong Kong, India, Japan, Singapore, South Korea, Taiwan, and Thailand. A survey was administered to eligible dermatologists after screening and taking informed consent. Data from fully completed submissions were analysed using descriptive statistics. The study was reviewed by the institutional review board in each territory., Results: Data from 271 dermatologists were included for analysis. About one-third (31.7%) reported that they referred to the Hanifin and Rajka criteria during diagnosis. The majority of dermatologists used clinical impression when assessing AD severity and treatment response. Reduction of eczema and pruritus was the primary treatment objective when managing both acute (98.1%) and chronic (69.1%) AD. More than half of dermatologists preferred adding systemic anti-inflammatory medication for patients who did not respond to maximized topical treatment, while 43.6% would switch to another systemic medication for those failing to respond to maximized systemic treatment. Topical corticosteroids were frequently selected by dermatologists. For systemic therapies, oral corticosteroids were most frequently used, followed by cyclosporin and dupilumab. Narrow-band ultraviolet B was the most common phototherapy reported (84.9%). There was considerable variation in estimated average and maximum durations of therapies used to treat AD., Conclusion: This study has provided insights on the real-world management of moderate-to-severe AD in the Asia-Pacific region. The diverse approaches in diagnosis and treatment highlight the multifactorial nature of AD, reliance on clinical judgement, and importance of personalized care. To improve outcomes in patients with AD, it will be crucial to develop biomarkers for diagnosis, reduce subjectivity in assessment, as well as promote access to newer and effective therapies., (© 2024. The Author(s).)

Introduction: The burden of atopic dermatitis (AD) is significant, with a substantial impact on quality of life (QoL). This cross-sectional study aimed to ascertain the burden of AD, its impact on QoL, and associated costs., Methods: Patients with moderate-to-severe AD were enrolled from eight territories, namely Hong Kong, India, Japan, Mainland China, Singapore, South Korea, Taiwan, and Thailand. After screening was performed and informed consent was obtained, eligible participants were asked to provide responses on their AD symptoms, severity, treatment, and out-of-pocket costs via an online survey. QoL was assessed using EQ-5D-5L and Dermatology Life Quality Index (DLQI), while productivity loss was quantified using the Work Productivity and Activity Impairment (WPAI) questionnaire. Data from completed submissions were analyzed using descriptive statistics. The study was reviewed by the institutional review board in each territory., Results: Median age of enrolled patients (N = 1103) was 41.0 years (interquartile range, IQR 16.0). The majority of patients reported that their head/neck, trunk, upper limbs, and lower limbs were affected during a flare. Topical (74.2%) and oral steroids (58.7%) were frequently prescribed to manage AD. Common atopic comorbidities were allergic urticaria (64.2%), allergic rhinitis (61.8%), and allergic conjunctivitis (51.5%). Median DLQI score was 13.0 (IQR 11.0), while median EQ-5D-5L (based on China value set) score was 0.8 (IQR 0.4); 87.2% and 77.2% of patients reported pain/discomfort and anxiety/depression on the EQ-5D-5L domains, respectively. Median total annual costs associated with AD were USD 10,128.52 (IQR 12,963.26) per patient, with indirect costs being the largest component. Findings from WPAI indicated that presenteeism is a major contributor to productivity loss., Conclusion: This multinational survey study showed that AD is associated with substantial QoL impairment and economic burden among Asian adult patients with moderate-to-severe AD. To alleviate burden of AD, clinicians should be more proactive in managing other concomitant conditions including psychological issues, and advocate for increased reimbursement for AD treatments., (© 2024. The Author(s).)

Introduction: It remains unclear how patients with atopic dermatitis (AD) and clinicians perceive the level of patient-clinician communication and if there could be potential lapses. This cross-sectional study aims to compare perspectives between patients with AD and dermatologists regarding communication and treatment expectations in Asia., Methods: Moderate-to-severe patients with AD and practicing dermatologists were recruited from eight Asia-Pacific territories, including Mainland China, Hong Kong, India, Japan, Singapore, South Korea, Taiwan, and Thailand. Patients and dermatologists completed separate surveys designed to elicit their expectations regarding AD management, and their perceived level of patient-clinician communication. Patients were also asked about their treatment satisfaction and whether they prefer additional treatment beyond what was prescribed. Demographic information and responses were analyzed using descriptive statistics. The study was reviewed by the institutional review board in each territory, and all participants provided informed consent., Results: A total of 1103 patients and 271 dermatologists completed the surveys. Both patients and dermatologists were largely aligned in their top treatment goals in AD management. However, greater proportions of patients prioritized the prevention of exacerbation (78.0% versus 47.2%), minimization of treatment adverse effects (46.4% versus 9.1%), and improvement in mental health (16.0% versus 4.9%), compared with dermatologists. Although patient-clinician communication was observed to be generally good, 10.9% of patients reported dissatisfaction with communication in AD management. The majority of patients were either "very satisfied" or "satisfied" with their latest acute AD treatment, but 65.5% of patients still desired additional treatment., Conclusions: This multinational study has provided insights on the perspectives of Asian patients and dermatologists in treatment goals, AD management, and communication. In general, both patients and dermatologists were aligned in treatment goals and there was satisfactory patient-clinician communication in most aspects. However, potential areas of improvement have been identified to further enhance patient-centered care., (© 2024. The Author(s).)

Mirror therapy has become an effective and recommended intervention for a range of conditions affecting the upper limb (e.g. hemiparesis following stroke). However, little is known about how mirror feedback affects the control of bimanual movements (as performed during mirror therapy). In this study, in preparation for future clinical investigations, we examined the kinematics of bimanual circle drawing in unimpaired participants both with (Experiment 1) and without (Experiment 2) a visual template to guide movement. In both experiments, 15 unimpaired right-handed participants performed self-paced continuous bimanual circle-drawing movements with a mirror/symmetrical coordination pattern. For the mirror condition, vision was directed towards the mirror in order to monitor the reflected limb. In the no mirror condition, the direction of vision was unchanged, but the mirror was replaced with an opaque screen. Movements of both hands were recorded using motion capture apparatus. In both experiments, the most striking feature of movements was that the hand behind the mirror drifted spatially during the course of individual trials. Participants appeared to be largely unaware of this marked positional change of their unseen hand, which was most pronounced when a template to guide movement was visible (Experiment 1). Temporal asynchrony between the limbs was also affected by mirror feedback in both experiments; in the mirror condition, illusory vision of the unseen hand led to a relative phase lead for that limb. Our data highlight the remarkable impact that the introduction of a simple mirror can have on bimanual coordination. Modulation of spatial and temporal features is consistent with the mirror inducing a rapid and powerful visual illusion, the latter appearing to override proprioceptive signals., Competing Interests: Declaration of competing interest On behalf of all authors, the corresponding author states that there is no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Acetic acid bacteria (AAB) are major contributors to the production of fermented vinegar, offering various cultural, culinary, and health benefits. Although the residual unpasteurized AAB after vinegar production are not pathogens, these are necessary and require safety evaluations, including antibiotic resistance, before use as a starter. In this research, we investigated the antibiotic resistance profiles of 26 AAB strains, including various species of Komagataeibacter and Acetobacter , against 10 different antibiotics using the E-test method. All strains exhibited resistance to aztreonam and clindamycin. Komagataeibacter species demonstrated a 50% resistance rate to ciprofloxacin, analogous to Acetobacter species, but showed twice the resistance rates to chloramphenicol and erythromycin. Genomic analysis of K. saccharivorans CV1 identified intrinsic resistance mechanisms, such as multidrug efflux pumps, thereby enhancing our understanding of antibiotic resistance in acetic acid-producing bacteria. These findings enhance understanding of antibiotic resistance in AAB for food safety and new antimicrobial strategies, suggesting the need for standardized testing methods and molecular genetic study.

Reproduction is safeguarded by multiple, often cooperative, regulatory networks. Kisspeptin signaling, via KISS1R, plays a fundamental role in reproductive control, primarily by regulation of hypothalamic GnRH neurons. We disclose herein a pathway for direct kisspeptin actions in astrocytes that contributes to central reproductive modulation. Protein-protein interaction and ontology analyses of hypothalamic proteomic profiles after kisspeptin stimulation revealed that glial/astrocyte markers are regulated by kisspeptin in mice. This glial-kisspeptin pathway was validated by the demonstrated expression of Kiss1r in mouse astrocytes in vivo and astrocyte cultures from humans, rats, and mice, where kisspeptin activated canonical intracellular signaling-pathways. Cellular coexpression of Kiss1r with the astrocyte markers GFAP and S100-β occurred in different brain regions, with higher percentage in Kiss1- and GnRH-enriched areas. Conditional ablation of Kiss1r in GFAP-positive cells in the G-KiR-KO mouse altered gene expression of key factors in PGE2 synthesis in astrocytes and perturbed astrocyte-GnRH neuronal appositions, as well as LH responses to kisspeptin and LH pulsatility, as surrogate marker of GnRH secretion. G-KiR-KO mice also displayed changes in reproductive responses to metabolic stress induced by high-fat diet, affecting female pubertal onset, estrous cyclicity, and LH-secretory profiles. Our data unveil a nonneuronal pathway for kisspeptin actions in astrocytes, which cooperates in fine-tuning the reproductive axis and its responses to metabolic stress.

Purpose: To develop models to predict programmed death ligand 1 (PD-L1) expression in pulmonary squamous cell carcinoma (SCC) using CT., Materials and Methods: A total of 97 patients diagnosed with SCC who underwent PD-L1 expression assay were included in this study. We performed a CT analysis of the tumors using pretreatment CT images. Multiple logistic regression models were constructed to predict PD-L1 positivity in the total patient group and in the 40 advanced-stage (≥ stage IIIB) patients. The area under the receiver operating characteristic curve (AUC) was calculated for each model., Results: For the total patient group, the AUC of the 'total significant features model' (tumor stage, tumor size, pleural nodularity, and lung metastasis) was 0.652, and that of the 'selected feature model' (pleural nodularity) was 0.556. For advanced-stage patients, the AUC of the 'selected feature model' (tumor size, pleural nodularity, pulmonary oligometastases, and absence of interstitial lung disease) was 0.897. Among these factors, pleural nodularity and pulmonary oligometastases had the highest odds ratios (8.78 and 16.35, respectively)., Conclusion: Our model could predict PD-L1 expression in patients with lung SCC, and pleural nodularity and pulmonary oligometastases were notable predictive CT features of PD-L1., Competing Interests: Conflicts of Interest: The authors have no potential conflicts of interest to disclose., (Copyrights © 2024 The Korean Society of Radiology.)

Optical markerless hand-tracking systems incorporated into virtual reality (VR) headsets are transforming the ability to assess fine motor skills in VR. This promises to have far-reaching implications for the increased applicability of VR across scientific, industrial, and clinical settings. However, so far, there are little data regarding the accuracy, delay, and overall performance of these types of hand-tracking systems. Here we present a novel methodological framework based on a fixed grid of targets, which can be easily applied to measure these systems' absolute positional error and delay. We also demonstrate a method to assess finger joint-angle accuracy. We used this framework to evaluate the Meta Quest 2 hand-tracking system. Our results showed an average fingertip positional error of 1.1cm, an average finger joint angle error of 9.6 ∘ and an average temporal delay of 45.0 ms. This methodological framework provides a powerful tool to ensure the reliability and validity of data originating from VR-based, markerless hand-tracking systems., (© 2023. The Author(s).)

Highly enantiomerically enriched dihydrohydroquinolines were prepared in two steps from quinoline. Addition of aryllithiums to quinoline with tert-butoxycarbonyl (Boc) protection gave N-Boc-2-aryl-1,2-dihydroquinolines. These were treated with n-butyllithium and electrophilic trapping occurred exclusively at C-4 of the dihydroquinoline, a result supported by DFT studies. Variable temperature NMR spectroscopy gave kinetic data for the barrier to rotation of the carbonyl group (ΔG ≠ ≈49 kJ mol -1 , 195 K). Lithiation using the diamine sparteine allowed kinetic resolutions with high enantioselectivities (enantiomer ratio up to 99 : 1). The enantioenriched 1,2-dihydroquinolines could be converted to 1,4-dihydroquinolines with retention of stereochemistry. Further functionalisation led to trisubstituted products. Reduction provided enantioenriched tetrahydroquinolines, whereas acid-promoted removal of Boc led to quinolines, and this was applied to a synthesis of the antimalarial compound M5717., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Traditional yeast ( Saccharomyces cerevisiae ) has been used for its benefits in various fermentation processes; the benefits of non- Saccharomyces yeast as a material for food, feed, and pharmaceuticals have been studied recently. This study evaluated the anti-inflammatory activity and extracellular functional characteristics of wild-type yeasts isolated from traditional fermented foods ( doenjang (common name: soybean paste) and nuruk ) in Korea. The viability of the yeast and lipopolysaccharide (LPS)-stimulated RAWBlue™ cells was improved, similar to unstimulated RAWBlue™ cells, and the isolates demonstrated NF-κB inhibitory activity. Yeast suppressed the nitric oxide production in LPS-stimulated RAWBlue™ cells, which was attributed to the inhibition of iNOS or COX-2 mRNA expression depending on the strain. Although there were differences depending on the strain, the production of anti-inflammatory cytokines was reduced in the yeast and LPS-stimulated RAWBlue™ cells, some of which were demonstrated at the mRNA level. In addition, the isolates exhibited high antioxidant and antihypertensive activities (similar to the positive control), which varied depending on the strain. This suggests that yeast can be used for fermentation with enhanced antioxidant and antihypertensive activities. Furthermore, the isolates inhibited the growth of pathogenic Gram-negative bacteria, indicating that yeast can inhibit food spoilage and the growth of pathogenic bacteria during fermentation. Consequently, utilizing raw materials to cultivate yeast strains could be a promising avenue for developing functional foods to prevent and treat inflammatory reactions; such foods may exhibit antioxidant, antihypertensive, and antibacterial properties.

Despite the importance of the mouse in biomedical research, the levels of circulating gonadal steroids across the estrous cycle are not established with any temporal precision. Using liquid chromatography-mass spectrometry, now considered the gold standard for steroid hormone analysis, we aimed to generate a detailed profile of gonadal steroid levels across the estrous cycle of C57BL/6J mice. For reference, luteinizing hormone (LH) and prolactin concentrations were measured in the same samples by sandwich enzyme-linked immunosorbent assay. Terminal blood samples were collected at 8-hour intervals (10 Am, 6 Pm, 2 Am) throughout the 4 stages of the estrous cycle. As expected, the LH surge was detected at 6 Pm on proestrus with a mean (±SEM) concentration of 11 ± 3 ng/mL and occurred coincident with the peak in progesterone levels (22 ± 4 ng/mL). Surprisingly, estradiol concentrations peaked at 10 Am on diestrus (51 ± 8 pg/mL), with levels on proestrus 6 Pm reaching only two-thirds of this value (31 ± 5 pg/mL). We also observed a proestrus peak in prolactin concentrations (132.5 ± 17 ng/mL) that occurred earlier than expected at 2 Am. Estrone and androstenedione levels were often close to the limit of detection (LOD) and showed no consistent changes across the estrous cycle. Testosterone levels were rarely above the LOD (0.01 ng/mL). These observations provide the first detailed assessment of fluctuating gonadal steroid and reproductive hormone levels across the mouse estrous cycle and indicate that species differences exist between mice and other spontaneously ovulating species., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

With continued advancements in portable eye-tracker technology liberating experimenters from the restraints of artificial laboratory designs, research can now collect gaze data from real-world, natural navigation. However, the field lacks a robust method for achieving this, as past approaches relied upon the time-consuming manual annotation of eye-tracking data, while previous attempts at automation lack the necessary versatility for in-the-wild navigation trials consisting of complex and dynamic scenes. Here, we propose a system capable of informing researchers of where and what a user's gaze is focused upon at any one time. The system achieves this by first running footage recorded on a head-mounted camera through a deep-learning-based object detection algorithm called Masked Region-based Convolutional Neural Network (Mask R-CNN). The algorithm's output is combined with frame-by-frame gaze coordinates measured by an eye-tracking device synchronized with the head-mounted camera to detect and annotate, without any manual intervention, what a user looked at for each frame of the provided footage. The effectiveness of the presented methodology was legitimized by a comparison between the system output and that of manual coders. High levels of agreement between the two validated the system as a preferable data collection technique as it was capable of processing data at a significantly faster rate than its human counterpart. Support for the system's practicality was then further demonstrated via a case study exploring the mediatory effects of gaze behaviors on an environment-driven attentional bias., (© 2022. The Author(s).)

Objective: Tracking skeletal muscle architecture using B-mode ultrasound is a widely used method in the field of human movement science and biomechanics. Sequential methods based on optical flow algorithms allow for smooth and coherent muscle tracking but are known to drift over time. Non-sequential feature detection methods on the other hand, do not suffer from drift, but are limited to tracking only lower-dimensional features. They are also known to be sensitive to image noise, and therefore often result in highly irregular tracking patterns. Building on the complimentary nature of both approaches, we present a novel automated hybrid muscle tracking approach that combines a sequential feature-point tracking method and a non-sequential method based on Hough transform., Methods: Tibialis anterior fascicle pennation angle and length, and central aponeurosis displacement, were measured in five healthy individuals during isometric contractions at five different ankle angles., Results: Our hybrid method was demonstrated to significantly (p < 0.001) reduce drift compared to two sequential methods, and curve irregularity was significantly (p < 0.001) decreased compared to a non-sequential method., Conclusion: These findings suggest that the proposed hybrid approach can uniquely mitigate drift and irregularity limitation of individual methods used for tracking skeletal muscle architecture., Significance: Automated muscle tracking allows for convenient analysis of large datasets, whereas automatic drift correction opens the door for tracking muscle architecture in long ultrasound recordings during common movements, such as walking, running, and jumping without the need for manual intervention.

Hill-type muscle models are highly preferred as phenomenological models for musculoskeletal simulation studies despite their introduction almost a century ago. The use of simple Hill-type models in simulations, instead of more recent cross-bridge models, is well justified since computationally 'light-weight'-although less accurate-Hill-type models have great value for large-scale simulations. However, this article aims to invite discussion on numerical instability issues of Hill-type muscle models in simulation studies, which can lead to computational failures and, therefore, cannot be simply dismissed as an inevitable but acceptable consequence of simplification. We will first revisit the basic premises and assumptions on the force-length and force-velocity relationships that Hill-type models are based upon, and their often overlooked but major theoretical limitations. We will then use several simple conceptual simulation studies to discuss how these numerical instability issues can manifest as practical computational problems. Lastly, we will review how such numerical instability issues are dealt with, mostly in an ad hoc fashion, in two main areas of application: musculoskeletal biomechanics and computer animation.

Although synchrony between the limbs is an often-cited feature of bimanual coordination, recent studies have also highlighted the small asynchronies that can occur. The visuo-motor demands of any bimanual task are considered central to the emergence of asynchrony, but the relationship between the two remains largely unexplored. This study aimed to address this issue. Hand and eye movements were measured in 19 participants, while they made either unimanual or bimanual reach-to-point (aiming) movements to targets presented on a touchscreen. Bimanual movements were either congruent (same-sized targets) or incongruent (different-sized targets). Resulting hand data showed many of the typical patterns of movement previously reported. While temporal coupling between the limbs remained largely evident for bimanual movements, small between-limb asynchronies were apparent and demonstrated clear associations with the competing precision requirements of the targets and related visual attention. Participants mainly directed their gaze towards the more difficult target with corresponding reaching movements demonstrating greater precision than for the easier target. Additionally, there was a reliable tendency for the hand reaching towards the more difficult target to lead. Importantly, it was the competing visuo-motor demands of individual movements rather than overall difficulty that resulted in greater between-limb asynchrony; accordingly, where both targets were small (i.e., the most difficult condition), asynchrony was significantly less pronounced than for incongruent bimanual conditions. The results show how the visuo-motor system balances its apparent drive for synchrony in coordinating bimanual movements with the competing demands that characterise the constituent unimanual movements., (© 2023. The Author(s).)

The mechanism by which arcuate nucleus kisspeptin (ARN KISS ) neurons co-expressing glutamate, neurokinin B, and dynorphin intermittently synchronize their activity to generate pulsatile hormone secretion remains unknown. An acute brain slice preparation maintaining synchronized ARN KISS neuron burst firing was used alongside in vivo GCaMP GRIN lens microendoscope and fiber photometry imaging coupled with intra-ARN microinfusion. Studies in intact and gonadectomized male mice revealed that ARN KISS neuron synchronizations result from near-random emergent network activity within the population and that this was critically dependent on local glutamate-AMPA signaling. Whereas neurokinin B operated to potentiate glutamate-generated synchronizations, dynorphin-kappa opioid tone within the network served as a gate for synchronization initiation. These observations force a departure from the existing "KNDy hypothesis" for ARN KISS neuron synchronization. A "glutamate two-transition" mechanism is proposed to underlie synchronizations in this key hypothalamic central pattern generator driving mammalian fertility., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The SingHealth-Duke-GlaxoSmithKline COPD and Asthma Real-world Evidence (SDG-CARE) collaboration was formed to accelerate the use of Singaporean real-world evidence in research and clinical care. A centerpiece of the collaboration was to develop a near real-time database from clinical and operational data sources to inform healthcare decision making and research studies on asthma and chronic obstructive pulmonary disease (COPD)., Methods: Our multidisciplinary team, including clinicians, epidemiologists, data scientists, medical informaticians and IT engineers, adopted the hybrid waterfall-agile project management methodology to develop the SingHealth COPD and Asthma Data Mart (SCDM). The SCDM was developed within the organizational data warehouse. It pulls and maps data from various information systems using extract, transform and load (ETL) pipelines. Robust user testing and data verification was also performed to ensure that the business requirements were met and that the ETL pipelines were valid., Results: The SCDM includes 199 data elements relevant to asthma and COPD. Data verification was performed and found the SCDM to be reliable. As of December 31, 2019, the SCDM contained 36,407 unique patients with asthma and COPD across the spectrum from primary to tertiary care in our healthcare system. The database updates weekly to add new data of existing patients and to include new patients who fulfil the inclusion criteria., Conclusions: The SCDM was systematically developed and tested to support the use RWD for clinical and health services research in asthma and COPD. This can serve as a platform to provide research and operational insights to improve the care delivered to our patients., (© 2023. The Author(s).)

Skeletal muscles have inertia that leads to inertial forces acting around joints. Although these inertial muscle forces contribute to joint kinetics, they are not typically accounted for in musculoskeletal models used for human movement biomechanics research. Ignoring inertial forces can lead to errors in joint kinetics, but how large these errors are in inverse dynamics calculations of common movements is yet unclear. We, therefore, examined the role of shank muscle inertia on ankle joint moments during the swing phase of running at different speeds. A custom musculoskeletal modelling and simulation platform was used to perform inverse dynamics with a model that either combined muscle mass in the total shank mass, or considered the gastrocnemius lateralis/medialis, soleus, and tibialis anterior muscles as separate masses from the shank. Ankle moments were considerably affected when muscles were modelled as separate masses, with a general shift towards reduced dorsiflexion and higher plantarflexion moments. Differences between both modelling conditions increased with running speed and ranged between 0.8 and 1.6 Nm (ankle moment profile root mean square error), 8-18 % (peak dorsiflexion moment difference) and 24-42 % (peak plantarflexion moment difference). Moreover, we observed a complex combination of inertial forces, especially those due to rotation and translation of the shank, in which the direction of inertial force changed during the swing phase. These results show that ignoring muscle inertia in musculoskeletal models can lead to under- or overestimations of structure-specific loads and thus erroneous study conclusions. Our results suggest that muscle inertial forces should be carefully considered when using musculoskeletal models., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The fermentation of traditional vinegar is a spontaneous and complex process that involves interactions among various microorganisms. Here, we used a microbiome approach to determine the effects of networks, such as fermentation temperature, location, physicochemical and sensory characteristics, and bacterial profile, within traditional grain vinegar samples collected from various regions of Korea. Acetic acid and lactic acid were identified as the major metabolites of grain vinegar, and sourness and umami were determined as taste fingerprints that could distinguish between vinegar samples. Acetobacter ghanensis and Lactobacillus acetotolerans were the predominant bacterial species, and the functional composition of the microbiota revealed that the nucleotide biosynthesis pathway was the most enriched. These results reveal that vinegar samples fermented outdoors are more similar to each other than vinegar samples fermented at 30 °C, when comparing the distance matrix for comprehending bacterial networks among samples. This study may help obtain high-quality vinegar through optimized fermentation conditions by suggesting differences in sensory characteristics according to the fermentation environment.

Background and Objective: As a novel non-invasive human brain stimulation method, transcranial focused ultrasound (tFUS) is receiving growing attention due to its superior spatial specificity and depth penetrability. Since the focal point of tFUS needs to be fixated precisely to the target brain region during stimulation, a critical issue is to identify and maintain the accurate position and orientation of the tFUS transducer relative to the subject's head. This study aims to propose the entire framework of tFUS stimulation integrating the methods previously proposed by the authors for tFUS transducer configuration optimization and a subject-specific 3D-printed helmet, and to validate this complete setup in a human behavioral neuromodulation study., Methods: To find the optimal configuration of the tFUS transducer, a numerical method based on subject-specific tFUS beamlines simulation was used. Then, the subject-specific 3D-printed helmet has been applied to effectively secure the transducer at the estimated optimal configuration. To validate this tFUS framework, a common behavioral neuromodulation paradigm was chosen; the effect of the dorsolateral prefrontal cortex (DLPFC) stimulation on anti-saccade (AS) behavior. While human participants (n=2) were performing AS tasks, tFUS stimulations were randomly applied to the left DLPFC right after the fixation target disappeared., Results: The neuromodulation result strongly suggests that the cortical stimulation using the proposed tFUS setup is effective in significantly reducing the error rates of anti-saccades (about -10 %p for S1 and -16 %p for S2), whereas no significant effect was observed on their latencies. These observed behavioral effects are consistent with the previous results based on conventional brain stimulation or lesion studies., Conclusions: The proposed subject-specific tFUS framework has been effectively used in human neuromodulation study. The result suggests that the tFUS stimulation targeted to the DLPFC can generate a neuromodulatory effect on AS behavior., Competing Interests: Conflict of Interest NOne, (Copyright © 2022. Published by Elsevier B.V.)

Objective: To investigate preferences of pregnant women for the characteristics of prenatal testing, and to quantify their willingness-to-pay (WTP) for non-invasive prenatal testing (NIPT) as first-line screening for Down Syndrome., Method: A cross-sectional discrete choice experiment survey including five testing attributes was administered to 192 pregnant women (≤14 weeks' gestation) who were aged ≥21 years in Singapore. We calculated marginal WTP for improvements in testing characteristics and NIPT., Results: We identified two groups of women with distinct preferences for prenatal testing. Women aged ≥35 years, with at least a university education, and with intention to terminate pregnancy of an affected fetus were more likely to be in the group with higher WTP for improvements in test characteristics. While participants valued increased detection rate and lower screen positive rate associated with NIPT, they also valued no risk of test failure and ability to test for birth defects using standard testing. The participants, on average, were not willing to pay for NIPT over the standard testing as a first-line screening test., Conclusions: As a first-line screening, NIPT was not preferred over standard testing. The prenatal consultations should focus on each testing characteristic equally as our findings show diverse preferences for testing characteristics., (© 2022 John Wiley & Sons Ltd.)

Background: Multiple inhaler triple therapy (MITT), comprising inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA), has been used as an escalation treatment for patients with chronic obstructive pulmonary disease (COPD). However, real-world use of MITT has not been investigated in Asia, including South Korea. This study reports baseline characteristics of patients with COPD initiated on MITT in South Korea, and their treatment patterns. Healthcare resource utilization (HRU) and costs associated with COPD exacerbations following MITT initiation were also assessed., Methods: This was a retrospective cohort study using the South Korea National Health Insurance database (2014-2018). Included patients were ≥ 40 years, had a COPD diagnosis, were newly initiated on MITT and had ≥ 12 months' data both before (baseline) and after index date (the first day with overlapping supply of all MITT components). Treatment immediately before initiation and immediately following discontinuation of MITT were identified, and proportion of days covered (PDC) by MITT was calculated. HRU and costs (per person per year [PPPY]) associated with exacerbations were identified following MITT initiation; costs were calculated using the average 2020 exchange rate (0.0008 USD/KRW)., Results: Among 37,400 patients, the mean age was 69 (SD 10) years and 73% were males; 56% had ≥ 1 COPD exacerbation during the baseline period, with a mean of 2 (SD 5) events/year. ICS/LABA was the most frequent regimen prescribed immediately before initiation (37%) and immediately following discontinuation (41% of 34,264 patients) of MITT. At 3, 6, and 12 months from treatment initiation, mean PDC was 81%, 63% and 49%, respectively; median treatment duration was 102 days. The mean (95% confidence interval [CI]) number of total visits for severe COPD exacerbations was 0.77 PPPY (0.75-0.78); mean PPPY total healthcare costs were 2093 USD., Conclusions: Patients with COPD in South Korea experienced frequent exacerbations prior to MITT, and PDC by MITT was low. Patients may benefit from early optimization of COPD therapy, and greater emphasis on adherence to inhaled COPD therapy. Severe exacerbations were found to incur substantial costs; treatment alternatives that can reduce the rate of severe exacerbations are likely to minimize healthcare costs., (© 2022. The Author(s).)

The production of good Meju soybean paste primarily depends on the selection of raw materials and fermenting microorganisms, which together influence its characteristic metabolites, taste, and aroma. In this study, we analyzed the relationship between properties and metabolites in Meju samples fermented by Aspergillus oryzae alone or with Bacillus velezensis . We developed fast-stable processing techniques to obtain Meju from A. oryzae and B. velezensis using the inoculation method, thereby ensuring safety in the production of soybean paste. The amino-type nitrogen content increased from an initial 180-228 mg% to a final 226-776 mg% during fermentation and was higher in Meju inoculated separately with the fungi and bacteria (C group) than in Meju co-inoculated with both the starters concurrently (D group). The levels of metabolites such as glucose, myo-inositol, glycerol, and fatty acids (palmitic, stearic, oleic, and linoleic acids) in Meju fermented by A. oryzae with B. velezensis were higher than those in Meju fermented by A. oryzae alone. Fungal growth was affected by the inoculated bacteria, which often occurs during the fermentation of co-inoculated Meju .

Weissella cibaria is one of the bacteria in charge of the initial fermentation of kimchi and has beneficial effects such as immune-modulating, antagonistic, and antioxidant activities. In our study, we aimed to estimate the safety of W. cibaria JW15 for the use of probiotics according to international standards based on phenotypic (antibiotic resistance, hemolysis, and toxic metabolite production) and genotypic analysis (virulence genes including antibiotic resistance genes). The results of the safety assessment on W. cibaria JW15 were as follows; (1) antibiotic resistance genes (ARGs) (kanamycin and vancomycin etc.) were intrinsic characteristics; (2) There were no acquired virulence genes including Cytolysin ( cylA ), aggregation substance ( asa1 ), Hyaluronidase ( hyl ), and Gelatinase ( gelE ); (3) this strain also lacked β-hemolysis and the production of toxic metabolites (D-lactate and bile salt deconjugation). Consequently, W. cibaria JW15 is expected to be applied as a functional food ingredient in the food market.

The roles GABAergic and glutamatergic inputs in regulating the activity of the gonadotrophin-releasing hormone (GnRH) neurons at the time of the preovulatory surge remain unclear. We used expansion microscopy to compare the density of GABAergic and glutamatergic synapses on the GnRH neuron cell body and proximal dendrite in dioestrous and pro-oestrous female mice. An evaluation of all synapses immunoreactive for synaptophysin revealed that the highest density of inputs to rostral preoptic area GnRH neurons occurred within the first 45 µm of the primary dendrite (approximately 0.19 synapses µm -1 ) with relatively few synapses on the GnRH neuron soma or beyond 45 µm of the dendrite (0.05-0.08 synapses µm -1 ). Triple immunofluorescence labelling demonstrated a predominance of glutamatergic signalling with twice as many vesicular glutamate transporter 2 synapses detected compared to vesicular GABA transporter. Co-labelling with the GABA A receptor scaffold protein gephyrin and the glutamate receptor postsynaptic density marker Homer1 confirmed these observations, as well as the different spatial distribution of GABA and glutamate inputs along the dendrite. Quantitative assessments revealed no differences in synaptophysin, GABA or glutamate synapses at the proximal dendrite and soma of GnRH neurons between dioestrous and pro-oestrous mice. Taken together, these studies demonstrate that the GnRH neuron receives twice as many glutamatergic synapses compared to GABAergic synapses and that these inputs preferentially target the first 45 µm of the GnRH neuron proximal dendrite. These inputs appear to be structurally stable before the onset of pro-oestrous GnRH surge., (© 2021 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Primitive-based models of motor learning suggest that adaptation occurs by tuning the responses of motor primitives. Based on this idea, we consider motor learning as an information encoding procedure, that is, a procedure of encoding a motor skill into primitives. The capacity of encoding is determined by the number of recruited primitives, which depends on how many primitives are "visited" by the movement, and this leads to a rather counterintuitive prediction that faster movement, where a larger number of motor primitives are involved, allows learning more complicated motor skills. Here, we provide a set of experimental results that support this hypothesis. First, we show that learning occurs only with movement, that is, only with nonzero encoding capacity. When participants were asked to counteract a rotating force applied to a robotic handle, they were unable to do so when maintaining a static posture but were able to adapt when making small circular movements. Our second experiment further investigated how adaptation is affected by movement speed. When adapting to a simple (low-information-content) force field, fast (high-capacity) movement did not have an advantage over slow (low-capacity) movement. However, for a complex (high-information-content) force field, the fast movement showed a significant advantage over slow movement. Our final experiment confirmed that the observed benefit of high-speed movement is only weakly affected by mechanical factors. Taken together, our results suggest that the encoding capacity is a genuine limiting factor of human motor adaptation. NEW & NOTEWORTHY We propose a novel concept called "encoding capacity" of motor adaptation, which describes an inherent limiting-factor of our brain's ability to learn new motor skills, just like any other storage system. By reinterpreting the existing primitive-based models of motor learning, we hypothesize that the encoding capacity is determined by the size of the movement, and present a set of experimental evidence suggesting that such limiting effect of encoding capacity does exist in human motor adaptation.

The necessity and functional significance of neurotransmitter co-transmission remains unclear. The glutamatergic 'KNDy' neurons co-express kisspeptin, neurokinin B (NKB), and dynorphin and exhibit a highly stereotyped synchronized behavior that reads out to the gonadotropin-releasing hormone (GnRH) neuron dendrons to drive episodic hormone secretion. Using expansion microscopy, we show that KNDy neurons make abundant close, non-synaptic appositions with the GnRH neuron dendron. Electrophysiology and confocal GCaMP6 imaging demonstrated that, despite all three neuropeptides being released from KNDy terminals, only kisspeptin was able to activate the GnRH neuron dendron. Mice with a selective deletion of kisspeptin from KNDy neurons failed to exhibit pulsatile hormone secretion but maintained synchronized episodic KNDy neuron behavior that is thought to depend on recurrent NKB and dynorphin transmission. This indicates that KNDy neurons drive episodic hormone secretion through highly redundant neuropeptide co-transmission orchestrated by differential post-synaptic neuropeptide receptor expression at the GnRH neuron dendron and KNDy neuron., Competing Interests: XL, SY, HM, MH, SH, IC, RP, AH No competing interests declared, (© 2021, Liu et al.)

Objective: The importance of continuous monitoring of fasting blood sugar (FBS) levels of diabetic patients has been established., Materials and Methods: An observational prospective study was conducted. Our analysis included 1,700,796 individuals from the nationwide South Korean National Health Insurance System cohort. FBS variability was measured by standard deviation (SD)., Results: Kaplan-Meier curves demonstrated elevated disease probability in the higher FBS fluctuation group compared with the lower FBS fluctuation group. After adjusting for confounding variables, Cox proportional hazards analysis showed that the hazard ratios of 411 individuals in the highest quartile of SD variation of FBS were 1.77 (95% confidence interval 1.37-2.28, p<0.001) compared with the lowest quartile of SD variation of FBS. The impact of FBS fluctuation on the risk of cardiovascular diseases (CVDs), cerebrovascular diseases, CVD mortality and all-cause mortality in the highest quartiles of diabetic and non-diabetic individuals was statistically significant., Conclusions: Visit-to-visit FBS variability has prognostic value for predicting micro- and macrovascular disease, cardiovascular mortality, and all-cause mortality.

Previous studies have suggested that vinegar intake can help to reduce body fat and hyperglycemia. Therefore, this study aimed to evaluate the anti-obesity efficacy of vinegar fermented using Cudrania tricuspidata fruits (CTFV) and its main phenolic constituents and to analyze its molecular mechanism and changes in obesity-related metabolizing enzymatic activities. We found that HFD significantly caused hepatic steatosis; increases in body fats, feed efficiency, liver mass, lipids, insulin, oxidative parameters, cardiovascular-associated risk indices, lipase and α-amylase activities, whereas CTFV efficaciously attenuated HFD-induced oxidant stress, fat accumulation, obesity-related enzymatic activity, and the activation or reduction of obesity-related molecular reactions via improving metabolic parameters including phosphorylated insulin receptor substrate 1, protein tyrosine phosphatase 1B, phosphorylated phosphoinositide 3-kinase/protein kinase B, phosphorylated mitogen-activated protein kinases, sterol regulatory element-binding protein 1c, CCAAT/enhancer-binding protein, and fatty acid synthase; and decreases in adiponectin receptor 1, leptin receptor, adenosine monophosphate-activated protein kinase, acetyl-CoA carboxylase, and peroxisome proliferator-activated receptor, subsequently ameliorating HFD-induced obesity. Therefore, CTFV might provide a functional food resource or nutraceutical product for reducing body fat accumulation.

Vinegar has been found to have in vitro improvement effect on inflammatory biomarkers, and clinically used to improve inflammation and obesity-related diseases. This study was designed to analyze in vitro anti-inflammatory effects of Cudrania tricuspidata fruits vinegar (CTFV) in a co-culture system with macrophages and adipocytes. We analyzed the physicochemical properties and polyphenolic ingredients of CTFV, and investigated in vitro anti-inflammatory effects of CTFV in a co-culture system with macrophages and adipocytes. The cells were cultured in the presence of CTFV for 24 h in contact with each other, then, harvested. The levels of monocyte chemoattractant protein (MCP)-1, tumour necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS), nitric oxide (NO), and interleukin (IL)-6 were evaluated by using the Griess reagent, western blot, or enzyme-linked immunosorbent assay assays. We found that increasing levels for NO, iNOS, TNF-α, IL-6 and MCP-1 were caused by LPS treatment and co-culture using the contact method, whereas CTFV efficaciously attenuated inflammatory response by improving inflammatory parameters including NO, iNOS, TNF-α, IL-6 and MCP-1. The present study indicates that CTFV might provide a nutraceutical product or functional food resource for improving inflammation processed via the interaction of adipocytes and macrophages.

Fermented vinegar is prepared from grains and medicinal plants. Here, we produced vinegar from peeled and unpeeled roots of bellflowers ( Platycodon grandiflorum ) using Acetobacter pasteurianus A11-2 and analyzed bellflower vinegar (BV) samples using gas chromatography-mass spectrometry and quadrupole time-of-flight mass spectrometry over 15 days of fermentation to assess the quality. We also evaluated their antibacterial and immunoenhancing effects using RAW 264.7 macrophage cells. The major metabolites in BV are organic acids, with the main volatile compounds being ethyl acetate, isoamyl acetate, 1-pentanol, hydroxypropanoic acid, and malonic acid. When we fermented BV from unpeeled roots for 10 days with a starter culture, we observed significant antibacterial and immunoenhancing effects in macrophages. Therefore, we could determine the metabolite and functional differences in vinegar obtained from bellflower roots and proposed that bellflower roots with peel are an effective substrate for developing vinegar and healthy food products.

This study aims to bridge the gap between the discrepant views of existing studies in different modalities on the cognitive effect of video game play. To this end, we conducted a set of tests with different modalities within each participant: (1) Self-Reports Analyses (SRA) consisting of five popular self-report surveys, and (2) a standard Behavioral Experiment (BE) using pro- and antisaccade paradigms, and analyzed how their results vary between Video Game Player (VGP) and Non-Video Game Player (NVGP) participant groups. Our result showed that (1) VGP scored significantly lower in Behavioral Inhibition System (BIS) than NVGP ( p = 0.023), and (2) VGP showed significantly higher antisaccade error rate than NVGP ( p = 0.005), suggesting that results of both SRA and BE support the existing view that video game play has a maleficent impact on the cognition by increasing impulsivity. However, the following correlation analysis on the results across individual participants found no significant correlation between SRA and BE, indicating a complex nature of the cognitive effect of video game play.

Purpose: This retrospective cohort study aims to examine adherence to secondary stroke preventive medications and their association with risk of stroke recurrence and mortality in patients after first-ever ischemic stroke., Methods: Using data from the National Healthcare Group and Singapore Stroke Registry, patients with first-ever ischemic stroke between 2010 and 2014 were included, and categorized based on antithrombotic or statin adherence using the proportion of days covered: high (≥75%), intermediate (50%-74%), low (25%-49%), and very low (<25%). The primary outcome was first recurrent ischemic stroke within a year after hospital discharge, while the secondary composite outcomes were (a) stroke recurrence and all-cause mortality and (b) stroke recurrence and cardiovascular mortality. The Cox proportional hazard model was used to examine the association between medication adherence and outcomes. Adjusted hazard ratios (aHRs) and the corresponding 95% confidence intervals (CIs) were reported., Results: Among ischemic stroke patients prescribed with antithrombotics (n = 1139) or statins (n = 1160) at hospital discharge, about one-third were highly adherent to their medications. Patients with lower medication adherence tended to be younger, were admitted to private ward classes, and were without hypertension. Compared with the patients with high medication adherence, the risk of stroke recurrence was higher in patients with very low antithrombotic (aHR = 4.65; 95% CI: 1.45-14.89) or statin (aHR = 3.44; 95% CI: 0.93-12.74) adherence. Similar findings were observed for the secondary outcomes., Conclusions: Poor adherence to antithrombotic and statin treatment increases the risk of recurrent stroke and mortality in patients after first-ever ischemic stroke. Further measures are needed to improve medication adherence among stroke survivors., (© 2020 John Wiley & Sons Ltd.)

A Gram-stain-negative, obligately aerobic bacterium, designated strain B6 T , was isolated from rice wine vinegar in the Republic of Korea. Cells were non-motile and oval short rods showing catalase-positive and oxidase-negative activities. Growth was observed at 15-45 °C (optimum, 30 °C) and pH 3.5-8.0 (optimum, pH 5.5-6.5). Strain B6 T contained summed feature 8 (comprising C 18 : 1 ω7 c and/or C 18 : 1 ω 6 c ), and C 16 : 0 as major fatty acids and ubiquinone-9 was identified as the sole isoprenoid quinone. The G+C content of the genomic DNA calculated from the whole genome was 53.1 mol%. Strain B6 T was most closely related to Acetobacter pasteurianus LMG 1262 T with very high 16S rRNA gene sequence similarity (100 %) and the strains formed a very close phylogenetic lineage together in phylogenetic trees based on 16S rRNA gene sequences. However, relatedness analyses based on concatenated amino acid sequences of 354 core genes and whole-cell MALDI-TOF profiles showed that strain B6 T may form a distinct phyletic lineage from Acetobacter species. In addition, average nucleotide identity and in silico DNA-DNA hybridization values between strain B6 T and the type strains of Acetobacter species were less than 93.3 and 51.4 %, respectively. The genomic features of strain B6 T were also differentiated from those of closely related Acetobacter type strains. Based on the phenotypic, chemotaxonomic and genomic features, strain B6 T clearly represents a novel species of the genus Acetobacter , for which the name Acetobacter oryzoeni sp. nov. is proposed. The type strain is B6 T (=KACC 21201 T =JCM 33371 T ).

Introduction: Data on drug utilisation among stroke patients of Asian ethnicities are lacking. The objectives of the study were to examine the temporal trends and patient characteristics associated with prescription of thrombolytic, antithrombotic and statin medications among patients with first-ever stroke., Materials and Methods: First-ever ischaemic and haemorrhagic stroke patients admitted to 2 Singapore tertiary hospitals between 2010‒2014 were included. Data were extracted from the National Healthcare Group Chronic Disease Management System. Association between drug utilisation and admission year, as well as characteristics associated with drug use, were explored using multivariable logistic regression., Results: There was an increasing trend in the combined use of all 3 guideline medications in ischaemic stroke patients ( P <0.001)-specifically thrombolytic agents ( P <0.001), oral antithrombotics ( P = 0.002) and statins ( P = 0.003) at discharge. Among antithrombotics, the use of clopidogrel ( P <0.001) and aspirin-clopidogrel ( P <0.001) had increased, whereas prescription of dipyridamole ( P <0.001) and aspirin-dipyridamole ( P <0.001) had declined. For statins, the increase in atorvastatin prescription ( P <0.001) was accompanied by decreasing use of simvastatin ( P <0.001). Age, ethnicity and certain comorbidities (hyperlipidaemia, atrial fibrillation and chronic kidney disease) were associated with the combined use of all 3 guideline medications ( P <0.05). In haemorrhagic stroke, prescription of statins at discharge were comparatively lower., Conclusion: This study reveals changes in prescription behaviour over time in a multiethnic Asian population with first-ever stroke. Patient characteristics including younger age, Malay ethnicity and certain comorbidities (i.e. hyperlipidaemia, atrial fibrillation) were associated with the combined use of all 3 guideline medications among ischaemic stroke patients.

Kiss1 neurons of the arcuate (ARC) nucleus form an interconnected network of cells that communicate via neurokinin B (encoded by Tac2) and its receptor (encoded by Tacr3) and play key roles in the control of the reproductive axis through sex hormone-regulated synthesis and release of kisspeptin peptides (Kp, encoded by Kiss1). The aim of this study was to determine whether the Kiss1 cell population of the ARC already displays sexually dimorphic features at embryonic age E16.5 in mice. At this time of development, Kiss1-GFP- and Kp-immunoreactive cell bodies were restricted to the ARC and not found in the pre-optic area (POA). The Kiss1-GFP cell population was identical in size between sexes but had significantly lower Kiss1, Tac2, and Tacr3 mRNA levels and lower Kp-ir fiber density in the POA in male compared to female fetuses. Receptors for androgen (Ar) and estrogen (Esr1, Esr2, Gpr30) and the Cyp19a1 gene (encoding the estradiol-producing enzyme aromatase) transcripts were also detected in fetal ARC Kiss1-GFP cells with significant sex differences for Ar (higher in males) and Esr1 (higher in females). Functional studies on primary cultures of sorted fetal Kiss1-GFP cells revealed a significant negative effect of estradiol treatment on neurite outgrowth on the fourth day of culture in the female group specifically. We conclude that the ARC Kiss1 cell population is already sexually differentiated at E16.5 and that its morphogenetic development may be particularly vulnerable to estradiol exposure at this early developmental time.

The purpose of the present study was to investigate whether several phytophenolic ingredients isolated from Maclura tricuspidata (Carr.) Bur fruits inhibit the activity of obesity-related enzymes including pancreatic lipase, α-amylase, β-glucosidase, phosphodiesterase IV, alkaline phosphatase, and citrate synthase, and the compounds play as an inhibitor against the target enzymes in kinetic studies. The enzyme assays indicated that the fruit extract and its phytophenolic compounds inhibited significantly the enzymatic activity of the five target enzymes. The kinetic studies demonstrated that the inhibitory properties of p-hydroxybenzoic acid (4-HA), protocatechuic acid (PA), and isovanillic acid (IA) against pancreatic lipase, β-glucosidase, citrate synthase, or alkaline phosphatase. Our results suggested that the compounds detected from Maclura tricuspidata (Carr.) Bur fruit extract may regulate carbohydrate/lipid/energy metabolism by obesity-related enzymes' inhibition. PRACTICAL APPLICATIONS: The obesity-related metabolizing enzymes affect (in)directly the metabolites absorption on carbohydrate/lipid/energy metabolism. Accordingly, it is an important strategy to treat obesity through target pathways and enzymes which include the reduction in energy intake and consumption. In our results, Maclura tricuspidata (Carr.) Bur fruit extract and its phytophenolic compounds inhibited significantly the enzymatic activity of the five target enzymes, in particular, 4-HA, PA, and IA have each specific inhibition type on pancreatic lipase, β-glucosidase, citrate synthase, and alkaline phosphatase. Therefore, M. tricuspidata (Carr.) Bur fruit may be a strong candidate as a food material or therapeutic agent for obesity improvement., (© 2019 Wiley Periodicals, Inc.)

Purpose: The aim of this study was to examine the association between selective serotonin reuptake inhibitor (SSRI) therapy and rehabilitation outcomes, specifically disability and quality of life (QOL), in a real-world setting of multi-ethnic Asian patients with first-ever stroke., Methods: In this prospective observational pilot cohort study, we included patients with first-ever stroke admitted to two inpatient rehabilitation centres in Singapore between January and July 2018. Outcomes were measured using Functional Independence Measure (FIM)-motor scale, modified Barthel Index (MBI) and the Stroke and Aphasia Quality of Life Scale-39 generic (SAQOL-39g) questionnaire. Linear regression was used to assess the association between SSRI therapy and outcomes. Regression coefficients and 95% confidence intervals (CIs) were reported., Results: Among 57 patients included for analyses, 38.6% received SSRIs. Although SSRI therapy was significantly associated with gains in MBI (coefficient 11.35; 95% CI 0.21-22.50) and SAQOL-39g overall score (coefficient 0.45; 95% CI 0.05-0.85) based on simple linear regression, no significant association between SSRI therapy and any of the investigated outcomes was found after adjustment for confounders. However, an increase in the mean number of physiotherapy and occupational therapy (PT/OT) sessions per day significantly improved FIM-motor (coefficient 16.86; 95% CI 2.64-31.07) and MBI (coefficient 22.79; 95% CI 2.35-43.23) scores., Conclusion: SSRI therapy did not improve disability and QOL in multi-ethnic Asian patients with first-ever stroke undergoing rehabilitation.

Under a vibrating ultrasonic horn device, intense cavitation occurs but is restricted to a small volume due to strong attenuation effects. In this study, milli-scale channels were introduced under the horn. The effect of this on the cavitation development and intensity within the channels were explored. High speed videography of up to 100,000 fps and acoustic signal acquisition through hydrophone were conducted. Cavitation intensity was observed to increase within the channels as compared to free field condition. Bubble density increased with a decrease in channel diameter and a rise in ultrasonic amplitude. Furthermore, an intriguing phenomenon of large bubble cluster formation near the channel exit (20 mm away from the horn surface) was detected. The oscillation behaviour of these clusters is dependent on both channel diameter and ultrasonic amplitude. At the maximum ultrasonic amplitude, the clusters reached maximum radiuses exceeding 3 mm and collapsed violently. Repetitive transient collapses near the exit region suggest that the introduction of milli-scale channels could extend the effective cavitation zone length and enhance the overall cavitation intensity under an ultrasonic horn., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Transdermal drug delivery is widely investigated as an alternative drug administration route to oral delivery and hypodermic injections. Owing to the availability of human skin samples, in vitro tests are used to predict the in vivo delivery of transdermal drugs. The most widely used validation method is skin permeation using diffusion cells. Traditional diffusion cells, however, are capacious and often require large amounts of skin sample and drugs, which is undesirable, given the scarcity of new drug entities and the limitation of skin sample supply. In this study, we fabricated miniaturized multichannel devices (MCDs) by 3D printing, to minimize the use of skin and drug samples. The MCDs were compared with conventional static diffusion cells and achieved comparable drug permeation profiles. The finite element method-based simulation revealed the efficient carry-off of permeated ingredients by the multichannel devices, and a critical role of distance between the buffer stream and skin sample in determining the flow velocity inside the chamber. The results support these devices as qualified alternatives to Franz cells for in vitro permeation studies using biomembranes, with reduced use of skin and drug samples., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Introduction: Drug utilization and outcomes research in multi-ethnic Asian stroke populations is lacking., Objectives: Our objective was to examine temporal trends and predictors of drug utilization and outcomes in a multi-ethnic Asian stroke population., Methods: This registry-based study included ischemic and hemorrhagic first-ever stroke patients hospitalized between 2009 and 2016. Utilization of medications included in-hospital thrombolytic agents, early antithrombotics (antiplatelets, anticoagulants) within 48 h of admission, and antithrombotics and statins at discharge. Outcomes analyzed were in-hospital all-cause mortality; 28-day, 90-day, and 1-year case fatality (CF); and discharge destination., Results: Of the 36,615 included patients, 81.6% had ischemic stroke and 18.4% had hemorrhagic stroke (15.5% intracerebral hemorrhage [ICH] and 2.8% subarachnoid hemorrhage [SAH]). For ischemic stroke, the combined use of all three guideline medications (in-hospital thrombolytic therapy, as well as antithrombotics and statins at discharge) increased (P = 0.006). Being on the stroke pathway was associated with prescription of all three guideline medications in ischemic stroke. Decreasing trends for in-hospital mortality, 28-day, 90-day, and 1-year CF and proportion of patients discharged home without rehabilitation appointment were observed in ischemic stroke (P < 0.05) but not in ICH or SAH (apart from 28-day CF). Ischemic stroke patients who received guideline medications were less likely to die or be discharged to nursing homes and chronic sick hospitals. Hemorrhagic stroke patients prescribed statins at discharge were less likely to have 28-day and 1-year CF., Conclusions: Prescription of secondary stroke preventive medications (particularly in ischemic stroke) was associated with more favorable outcomes, highlighting the importance of physician adherence to evidence-based pharmacotherapy.

The normal function of the mammalian reproductive axis is strongly influenced by physiological, metabolic and environmental factors. Kisspeptin neuropeptides, encoded by the Kiss1 gene, are potent regulators of the mammalian reproductive axis by stimulating gonadodropin releasing hormone secretion from the hypothalamus. To understand how the reproductive axis is modulated by higher order neuronal inputs we have mapped the afferent circuits into arcuate (ARC) Kiss1 neurons. We used a transgenic mouse that expresses the CRE recombinase in Kiss1 neurons for conditional viral tracing with genetically modified viruses. CRE-mediated activation of these viruses in Kiss1 neurons allows the virus to move transynaptically to label neurons with primary or secondary afferent inputs into the Kiss1 neurons. Several regions of the brain showed synaptic connectivity to arcuate Kiss1 neurons including proopiomelanocortin neurons in the ARC itself, kisspeptin neurons in the anteroventral periventricular nucleus, vasopressin neurons in the supraoptic and suprachiasmatic nuclei, thyrotropin releasing neurons in the paraventricular nucleus and unidentified neurons in other regions including the subfornical organ, amygdala, interpeduncular nucleus, ventral premammilary nucleus, basal nucleus of stria terminalis and the visual, somatosensory and piriform regions of the cortex. These data provide an insight into how the activity of Kiss1 neurons may be regulated by metabolic signals and provide a detailed neuroanatomical map for future functional studies., Competing Interests: The authors have declared that no competing interests exist.