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Polyphenols have been well-established to exert sedative-hypnotic effects in psychopharmacology. Lime (Citrus aurantifolia) peel is rich in biologically active polyphenols; however, the effects of lime peel extract on sleep have not yet been demonstrated. A comparison was conducted in mice, between the sleep-promoting effects of a standardized lime peel supplement (SLPS) and a well-known hypnotic drug, zolpidem, and its hypnotic mechanism was investigated using in vivo and in vitro assays. The effects of SLPS on sleep were assessed using a pentobarbital-induced sleep test and sleep architecture analysis based on recording electroencephalograms and electromyograms. Additionally, a GABA A receptor binding assay, electrophysiological measurements, and in vivo animal models were used to elucidate the hypnotic mechanism. SLPS (200 and 400 mg/kg) was found to significantly decrease sleep latency and increase the amount of non-rapid eye movement sleep without altering delta activity. The hypnotic effects of SLPS were attributed to its flavonoid-rich ethyl acetate fraction. SLPS had a binding affinity to the GABA-binding site of the GABA A receptor and directly activated the GABA A receptors. The hypnotic effects and GABA A receptor activity of SLPS were completely blocked by bicuculline, a competitive antagonist of the GABA A receptor, in both in vitro and in vivo assays. To the best of our knowledge, this study is the first to demonstrate the hypnotic effects of SLPS, which acts via the GABA-binding site of the GABA A receptor. Our results suggest that lime peel, a by-product abundantly generated during juice processing, can potentially be used as a novel sedative-hypnotic., 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 © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Shape-morphing displays alter their surface geometry to convey information through three-dimensional shapes. However, rapid transformation into seamless shapes with multimodal tactile sensations poses challenges. Here, we introduce a versatile soft shape-morphing and tactile display, using a novel actuator that combines a PVC gel composite, dielectric liquid, and an electrode array. Proposed device facilitates on-demand liquid flow control through electrohydraulic actuation. Liquid channels within the device can be dynamically reconfigured using localized electrostatic zipping, enabling swift shape morphing and reconfiguration into diverse seamless 3D shapes. Our device achieves a large deformation and high output force, in a slim and lightweight framework. It also offers various haptic feedback, including dynamic tactile patterns and vibrations for localizable surface textures on the morphed shape. Additionally, its potential in robotics was demonstrated through high-speed object manipulation, leveraging liquid flow-induced inertia. In summary, our innovative soft shape-morphing tactile display could open new ways that we interact with technology, offering a more immersive and intuitive experience.

Maintaining extracellular potassium (K + ) within narrow limits, critical for membrane potential and excitability, is accomplished through the internal redistribution of K + between extracellular fluid (ECF) and intracellular fluid (ICF) in concert with the regulation of renal K + output to balance K + intake. Here we present evidence from high-precision analyses of stable K + isotopes in rats maintained on a control diet that the tissues and organs involved in the internal redistribution of K + differ in their speed of K + exchange with ECF and can be grouped into those that exchange K + with ECF either rapidly or more slowly ("fast" and "slow" pools). After 10 days of K + restriction, a compartmental analysis indicates that the sizes of the ICF K + pools decreased but that this decrease in ICF K + pools was not homogeneous, rather occurring only in the slow pool (15% decrease, p < 0.01), representing skeletal muscles, not in the fast pool. Furthermore, we find that the dietary K + restriction is associated with a decline in the rate constants for K + effluxes from both the "fast" and "slow" ICF pools ( p < 0.05 for both). These results suggest that changes in unidentified transport pathways responsible for K + efflux from ICF to ECF play an important role in buffering the internal redistribution of K + between ICF and ECF during K + restriction. Thus, the present study introduces novel stable isotope approaches to separately characterize heterogenous ICF K + pools in vivo and assess K + uptake by individual tissues, methods that provide key new tools to elucidate K + homeostatic mechanisms in vivo.

Background: Computerized cognitive training (CCT) has been proposed as a potential therapy for cognitive decline. One of the benefits of CCT is a transfer effect, but its mechanism on the memory domain is unclear. This study aimed to investigate the transfer effect of non-memory multidomain CCT on the memory domain and its neural basis in patients with mild cognitive impairment (MCI) through a randomized controlled trial., Methods: Patients with MCI recruited from memory clinics were randomly assigned to either the CCT or the control group. The CCT group received multidomain CCT training excluding memory training, while the control group read educational books with learning-based quizzes twice a week for 8 weeks. Participants underwent memory tests yielding a composite score, other cognitive domain tests, non-cognitive scales, and resting-state functional magnetic resonance imaging (rsfMRI), at baseline and after intervention. Within- and between-group comparisons, group × time interactions, and seed-to-voxel analyses in memory-involving brain networks were performed., Results: The CCT group showed improvement over the control group in memory domain (Group × time, F = 5.87, P = 0.03, η 2  = 0.31), which was related with the increased connectivity in the hippocampal-frontal and fusiform-occipital network. No other cognitive and non-cognitive symptoms differed between groups after adjusting for covariates., Conclusion: Eight weeks of multidomain CCT without memory training improved memory function and restored functional network in the hippocampal and medial temporal region in MCI patients. These results can provide evidence for the transferring ability of CCT on memory functioning with its neural basis., (© 2024 The Author(s). Psychogeriatrics published by John Wiley & Sons Australia, Ltd on behalf of Japanese Psychogeriatric Society.)

Hypertriglyceridemia is a risk factor for type 2 diabetes and cardiovascular disease (CVD). Plasma triglycerides (TGs) are a key factor for assessing the risk of diabetes or CVD. However, previous lipidomics studies have demonstrated that not all TG molecules behave the same way. Individual TGs with different fatty acid compositions are regulated differentially under various conditions. In addition, distinct groups of TGs were identified to be associated with increased diabetes risk (TGs with lower carbon number [C#] and double-bond number [DB#]), or with decreased risk (TGs with higher C# and DB#). In this study, we examined the effects of high-fat feeding in rats on plasma lipid profiles with special attention to TG profiles. Wistar rats were maintained on either a low-fat (control) or high-fat diet (HFD) for 2 weeks. Plasma samples were obtained before and 2.5 h after a meal ( n = 10 each) and subjected to lipidomics analyses. High-fat feeding significantly impacted circulating lipid profiles, with the most significant effects observed on TG profile. The effects of an HFD on individual TG species depended on DB# in their fatty acid chains; an HFD increased TGs with low DB#, associated with increased diabetes risk, but decreased TGs with high DB#, associated with decreased risk. These changes in TGs with an HFD were associated with decreased indices of hepatic stearoyl-CoA desaturase (SCD) activity, assessed from hepatic fatty acid profiles. Decreased SCD activity would reduce the conversion of saturated to monounsaturated fatty acids, contributing to the increases in saturated TGs or TGs with low DB#. In addition, an HFD selectively depleted ω-3 polyunsaturated fatty acids (PUFAs), contributing to the decreases in TGs with high DB#. Thus, an HFD had profound impacts on circulating TG profiles. Some of these changes were at least partly explained by decreased hepatic SCD activity and depleted ω-3 PUFA.

In recent years, soft robotic grippers have emerged as a promising solution for versatile and safe manipulation of objects in various fields. However, precise force control is critical, especially when handling delicate or fragile objects, to avoid excessive grip force application or to prevent object slippage. Herein, we propose a novel three-degree-of-freedom force sensor incorporated within a soft robotic gripper to realize stable grasping with force feedback. The proposed optical sensor employs lightweight and compact optical fibers, thereby allowing for cost-effective fabrication, and a robust sensing system that is immune to electromagnetic fields. By innervating the soft gripper with optical fibers, a durable system is achieved with the fibers functioning as a strengthening layer, thereby eliminating the need for embedding an external stiffening structure for efficient bending actuation. The innovative contact-based light loss sensing mechanism allows for a robust and stable sensing mechanism with low drift (<0.1% over 9000 cycles) that can be applied to soft pneumatic bending grippers. We used the developed sensor-incorporated soft gripper to grasp various objects, including magnetic materials, and achieved slip detection along with grip force feedback without any signal interference. Overall, this study proposes a robust measuring multi-degree-of-freedom force sensor that can be incorporated into grippers for improved grasping stability.

Microgrippers that incorporate soft actuators are appropriate for micromanipulation or microsurgery owing to their ability to grasp objects without causing damage. However, developing a microgripper with a large gripping range that can produce a large force with high speed remains challenging in soft actuation mechanisms. Herein, we introduce a compliant microgripper driven by a soft dielectric elastomer actuator (DEA) called a spiral flexure cone DEA (SFCDEA). The submillimeter-scale SFCDEA exhibited a controllable linear displacement over a high bandwidth and the capability of lifting 100.9 g, which was 670 times higher than its mass. Subsequently, we developed a compliant microgripper based on the SFCDEA using smart composite microstructure technology to fabricate three-dimensional gripper linkages. We demonstrated that the microgripper was able to grasp various millimeter-scale objects with different shapes, sizes, and weights without a complex feedback control owing to its compliance. We proved the versatility of our gripper in robotic manipulation by demonstrating adaptive grasping and releasing of small objects using vibrations owing to its high bandwidth.

Brillouin Optical Time-Domain Analysis (BOTDA) is a widely-used distributed optical fiber sensing technology employing pulse-modulated pump waves for local information retrieval of the Brillouin gain or loss spectra. The spatial resolution of BOTDA systems is intrinsically linked to pulse duration, so high-resolution measurements demand high electronic bandwidths inversely proportional to the resolution. This paper introduces Brillouin Expanded Time-Domain Analysis (BETDA) as a modified BOTDA system, simultaneously achieving high spatial resolution and low detection bandwidth. Utilizing two optical frequency combs (OFCs) with different frequency intervals as pump and probe, local Brillouin gain spectra are recorded by their spectral beating traces in an expanded time domain. A 2-cm-long hotspot located in a 230 m single-mode fiber is successfully measured in the time domain with a detection bandwidth of less than 100 kHz using dual OFCs with tailored spectral phase, line spacing, and bandwidth., (© 2024. The Author(s).)

The shape of flexible endoscopic surgical robot should be obtained to increase control accuracy and prevent unwanted tissue damage. To estimate the shape of flexible manipulator, space efficiency, cost-effectiveness, system complexity, and ease of calibration should be considered to integrate sensors into the manipulator. In this article, we propose a real-time method to estimate the shape of a hyper-redundant manipulator having embedded coiled fiber sensors. The main advantage of this method is guaranteeing shape recognition even when the manipulator is subjected to an external load. The fiber sensors are highly flexible, compact, and inexpensive, as well as they can functionally measure both compressive and tensile strain of hyper-redundant manipulator. The sensor design was optimized to achieve durability and sensitivity. The numbers of sensor and the placements were determined by the analysis of the kinematics and moment distribution of the manipulator. The accuracy of shape estimation was validated experimentally under both free-loading and loading conditions. The proposed method achieved real-time estimating capability with a mean maximum error of each joint position smaller than 3.54% in free-loading condition and 5.47% in loading condition.

Reconfigurable tactile displays are being used to provide refreshable Braille information; however, the delivered information is currently limited to an alternative of Braille because of difficulties in controlling the deformation height. Herein, we present a photothermally activated polymer-bilayer-based morphable tactile display that can programmably generate tangible three-dimensional topologies with varying textures on a thin film surface. The morphable tactile display was composed of a heterogeneous polymer structure that integrated a stiffness-tunable polymer into a light-absorbing elastomer, near-infra-red light-emitting diode (NIR-LED) array, and small pneumatic chamber. Topological expression was enabled by producing localized out-of-plane deformation that was reversible, height-adjustable, and latchable in response to light-triggered stiffness modulation at each target area under switching of stationary pneumatic pressure. Notably, the tactile display could express a spatial softness map of the latched topology upon re-exposing the target areas to modulated light from the NIR-LED array. We expect the developed tactile display to open a pathway for generating high-dimensional tactile information on electronic devices and enable realistic interaction in augmented and virtual environments., (© 2024. The Author(s).)

Background: Clinical guidelines commonly recommend preventative treatments for people above a risk threshold. Therefore, decision-makers must have faith in risk prediction tools and model-based cost-effectiveness analyses for people at different levels of risk. Two problems that arise are inadequate handling of competing risks of death and failing to account for direct treatment disutility (i.e. the hassle of taking treatments). We explored these issues using two case studies: primary prevention of cardiovascular disease using statins and osteoporotic fracture using bisphosphonates., Objectives: Externally validate three risk prediction tools [QRISK®3, QRISK®-Lifetime, QFracture-2012 (ClinRisk Ltd, Leeds, UK)]; derive and internally validate new risk prediction tools for cardiovascular disease [competing mortality risk model with Charlson Comorbidity Index (CRISK-CCI)] and fracture (CFracture), accounting for competing-cause death; quantify direct treatment disutility for statins and bisphosphonates; and examine the effect of competing risks and direct treatment disutility on the cost-effectiveness of preventative treatments., Design, Participants, Main Outcome Measures, Data Sources: Discrimination and calibration of risk prediction models (Clinical Practice Research Datalink participants: aged 25-84 years for cardiovascular disease and aged 30-99 years for fractures); direct treatment disutility was elicited in online stated-preference surveys (people with/people without experience of statins/bisphosphonates); costs and quality-adjusted life-years were determined from decision-analytic modelling (updated models used in National Institute for Health and Care Excellence decision-making)., Results: CRISK-CCI has excellent discrimination, similar to that of QRISK3 (Harrell's c = 0.864 vs. 0.865, respectively, for women; and 0.819 vs. 0.834, respectively, for men). CRISK-CCI has systematically better calibration, although both models overpredict in high-risk subgroups. People recommended for treatment (10-year risk of ≥ 10%) are younger when using QRISK-Lifetime than when using QRISK3, and have fewer observed events in a 10-year follow-up (4.0% vs. 11.9%, respectively, for women; and 4.3% vs. 10.8%, respectively, for men). QFracture-2012 underpredicts fractures, owing to under-ascertainment of events in its derivation. However, there is major overprediction among people aged 85-99 years and/or with multiple long-term conditions. CFracture is better calibrated, although it also overpredicts among older people. In a time trade-off exercise ( n = 879), statins exhibited direct treatment disutility of 0.034; for bisphosphonates, it was greater, at 0.067. Inconvenience also influenced preferences in best-worst scaling ( n = 631). Updated cost-effectiveness analysis generates more quality-adjusted life-years among people with below-average cardiovascular risk and fewer among people with above-average risk. If people experience disutility when taking statins, the cardiovascular risk threshold at which benefits outweigh harms rises with age (≥ 8% 10-year risk at 40 years of age; ≥ 38% 10-year risk at 80 years of age). Assuming that everyone experiences population-average direct treatment disutility with oral bisphosphonates, treatment is net harmful at all levels of risk., Limitations: Treating data as missing at random is a strong assumption in risk prediction model derivation. Disentangling the effect of statins from secular trends in cardiovascular disease in the previous two decades is challenging. Validating lifetime risk prediction is impossible without using very historical data. Respondents to our stated-preference survey may not be representative of the population. There is no consensus on which direct treatment disutilities should be used for cost-effectiveness analyses. Not all the inputs to the cost-effectiveness models could be updated., Conclusions: Ignoring competing mortality in risk prediction overestimates the risk of cardiovascular events and fracture, especially among older people and those with multimorbidity. Adjustment for competing risk does not meaningfully alter cost-effectiveness of these preventative interventions, but direct treatment disutility is measurable and has the potential to alter the balance of benefits and harms. We argue that this is best addressed in individual-level shared decision-making., Study Registration: This study is registered as PROSPERO CRD42021249959., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 15/12/22) and is published in full in Health and Social Care Delivery Research ; Vol. 12, No. 4. See the NIHR Funding and Awards website for further award information.

A practical method for C(sp 3 )-B bond activation was developed. Using a combination of alkyl trifluoroborates and N -iodosuccinimide (NIS), various C(sp 3 )-heteroatom bonds were readily generated in an efficient manner. Mechanistic studies revealed the bifunctional ability of NIS: mediating the formation of reactive halogenated intermediates and activating them via halogen bonding. This electrophilic activation of the reaction center enables the utilization of general heteroatom nucleophiles, which are used in a limited capacity in traditional 1,2-metalate rearrangements.

Soluble epoxide hydrolase (sEH) is an important enzyme for metabolic and cardiovascular health. sEH converts FFA epoxides (EpFAs), many of which are regulators of various cellular processes, to biologically less active diols. In human studies, diol (sEH product) to EpFA (sEH substrate) ratios in plasma or serum have been used as indices of sEH activity. We previously showed these ratios profoundly decreased in rats during acute feeding, possibly reflecting decreases in tissue sEH activities. The present study was designed to test which tissue(s) these measurements in the blood represent and if factors other than sEH activity, such as renal excretion or dietary intake of EpFAs and diols, significantly alter plasma EpFAs, diols, and/or their ratios. The results show that postprandial changes in EpFAs and diols and their ratios in plasma were very similar to those observed in the liver but not in other tissues, suggesting that the liver is largely responsible for these changes in plasma levels. EpFAs and diols were excreted into the urine, but their levels were not significantly altered by feeding, suggesting that renal excretion of EpFAs and diols may not play a major role in postprandial changes in circulating EpFAs, diols, or their ratios. Diet intake had significant impacts on circulating EpFA and diol levels but not on diol-to-EpFA (D-to-E) ratios, suggesting that these ratios, reflecting sEH activities, may not be significantly affected by the availability of sEH substrates (i.e., EpFAs). In conclusion, changes in FFA D-to-E ratios in plasma may reflect those in the liver, which may in turn represent sEH activities in the liver, and they may not be significantly affected by renal excretion or the dietary intake of EpFAs and diols.

Computer modeling and simulation (CM&S) technology is widely used in the medical device industry due to its advantages such as reducing testing time and costs. However, the developer's parameter settings during the modeling and simulation process can have a significant impact on the results. This study developed a test model for the rotational shear strength of dental implants and the constraint force of total knee replacements based on CM&S technology and proposes ideal parameters to ensure reliability. For dental implants, the load area and sliding contact conditions were considered, and for total knee replacements, the friction coefficient, medial-lateral displacement, valgus-varus rotation, and elastic modulus were considered. By comparing the simulation results and mechanical tests, boundary conditions with an error rate of less than 1.5% were selected. When a jig (gripper and collector) was applied with the same boundary conditions, an error rate of 48~22% occurred; otherwise, it was confirmed that the error rate was within 10~0.2%. The FE model was verified with an error of 2.49 to 3% compared to the mechanical test. The friction coefficient variable had the greatest influence on the results, accounting for 10 to 13%, and it was confirmed that valgus-varus rotation had a greater influence on the results than medial-lateral displacement. Relatively, the elastic modulus of the insert had the least effect on the results. These research results are expected to make CM&S techniques useful as a medical device digital development tool (M3DT) in the development of total knee replacements and dental implants.

Context: Shoulder disorders impair the ability to work. In most cases, the primary symptoms caused by shoulder disorders consist of pain and limitations in the range of motion., Objectives: This study aimed to investigate the efficacy of motion style acupuncture treatment (MSAT), a conservative treatment modality for shoulder disorders., Design: prospective observational study SETTING: A Korean Medicine hospital PATIENTS: Eighty outpatients with shoulder disorders INTERVENTION: Either MSAT with integrative Korean medicine treatment (MSAT group; n = 40) or integrative Korean medicine treatment only (control group; n = 40)., Outcome Measures: The primary outcome was the shoulder range of motion (ROM), and the secondary outcomes were the numeric rating scale (NRS), visual analog scale (VAS), shoulder pain and disability index (SPADI), and 5-level EuroQol 5-dimension (EQ-5D-5L) scores., Results: At the primary endpoint (2 weeks from the start of the treatment), the MSAT group showed statistically significantly larger ROM for all motions, except adduction ROM, compared to the control group [Flexion ROM (165.10±4.14 vs. 150.49±4.06; P<0.001), extension ROM (43.24±1.55 vs. 40.56±1.51; P<0.05), abduction ROM (160.92±5.68 vs. 134.95±5.54; P<0.001), internal rotation ROM (73.38±2.96 vs. 65.00±2.89; P<0.001), and external rotation ROM (73.78±3.61 vs. 65.88±3.50; P<0.01)]. Additionally, the MSAT group showed significantly lower NRS, SPADI scores at week 2 than the control group; this trend was maintained until the 3-month follow-up., (Copyright © 2023. Published by Elsevier Inc.)

Research on coronavirus disease 2019 vaccination in immune-deficient/disordered people (IDP) has focused on cancer and organ transplantation populations. In a prospective cohort of 195 IDP and 35 healthy volunteers (HV), antispike immunoglobulin G (IgG) was detected in 88% of IDP after dose 2, increasing to 93% by 6 months after dose 3. Despite high seroconversion, median IgG levels for IDP never surpassed one-third that of HV. IgG binding to Omicron BA.1 was lowest among variants. Angiotensin-converting enzyme 2 pseudo-neutralization only modestly correlated with antispike IgG concentration. IgG levels were not significantly altered by receipt of different messenger RNA-based vaccines, immunomodulating treatments, and prior severe acute respiratory syndrome coronavirus 2 infections. While our data show that three doses of coronavirus disease 2019 vaccinations induce antispike IgG in most IDP, additional doses are needed to increase protection. Because of the notably reduced IgG response to Omicron BA.1, the efficacy of additional vaccinations, including bivalent vaccines, should be studied in this population.

Background: Direct treatment disutility (DTD) represents an individual's disutility associated with the inconvenience of taking medicine over a long period of time., Objectives: The main aim of this study was to elicit DTD values for taking a statin or a bisphosphonate for primary prevention. A secondary aim was to understand factors which influence DTD values., Methods: Design: We used a cross-sectional study consisting of time-trade off exercises embedded within online surveys. Respondents were asked to compare a one-off pill ('Medicine A') assumed to have no inconvenience and a daily pill ('Medicine B') over 10 years (statins) or 5 years (bisphosphonates). Setting: Individuals from National Health Service (NHS) primary care and the general population were surveyed using an online panel company. Participants: Two types of participants were recruited. First, a purposive sample of patients with experience of taking a statin (n=260) or bisphosphonate (n=100) were recruited from an NHS sampling frame. Patients needed to be aged over 30, have experience of taking the medicine of interest and have no diagnosis of dementia or of using dementia drugs. Second, a demographically balanced sample of members of the public were recruited for statins (n=376) and bisphosphonates (n=359). Primary and secondary outcome measures: Primary outcome was mean DTD. Regression analysis explored factors which could influence DTD values., Results: A total of 879 respondents were included for analysis (514 for statins and 365 for bisphosphonates). The majority of respondents reported a disutility associated with medicine use. Mean DTD for statins was 0.034 and for bisphosphonates 0.067, respectively. Respondent characteristics including age and sex did not influence DTD. Experience of bisphosphonate-use reduced reported disutilities., Conclusions: Statins and bisphosphonates have a quantifiable DTD. The size of estimated disutilities suggest they are likely to be important for cost-effectiveness, particularly in individuals at low-risk when treated for primary prevention., Competing Interests: Competing interests: DM reports that he is supported by a Wellcome Trust Clinical Research Fellowship (214588/Z/18/Z) and is a member of the European Medicines Agency Pharmacovigilance Risk Assessment Committee. No other authors report any conflicts of interest directly relevant to the content of this article., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

High error rates of viral RNA-dependent RNA polymerases lead to diverse intra-host viral populations during infection. Errors made during replication that are not strongly deleterious to the virus can lead to the generation of minority variants. However, accurate detection of minority variants in viral sequence data is complicated by errors introduced during sample preparation and data analysis. We used synthetic RNA controls and simulated data to test seven variant-calling tools across a range of allele frequencies and simulated coverages. We show that choice of variant caller and use of replicate sequencing have the most significant impact on single-nucleotide variant (SNV) discovery and demonstrate how both allele frequency and coverage thresholds impact both false discovery and false-negative rates. When replicates are not available, using a combination of multiple callers with more stringent cutoffs is recommended. We use these parameters to find minority variants in sequencing data from SARS-CoV-2 clinical specimens and provide guidance for studies of intra-host viral diversity using either single replicate data or data from technical replicates. Our study provides a framework for rigorous assessment of technical factors that impact SNV identification in viral samples and establishes heuristics that will inform and improve future studies of intra-host variation, viral diversity, and viral evolution. IMPORTANCE When viruses replicate inside a host cell, the virus replication machinery makes mistakes. Over time, these mistakes create mutations that result in a diverse population of viruses inside the host. Mutations that are neither lethal to the virus nor strongly beneficial can lead to minority variants that are minor members of the virus population. However, preparing samples for sequencing can also introduce errors that resemble minority variants, resulting in the inclusion of false-positive data if not filtered correctly. In this study, we aimed to determine the best methods for identification and quantification of these minority variants by testing the performance of seven commonly used variant-calling tools. We used simulated and synthetic data to test their performance against a true set of variants and then used these studies to inform variant identification in data from SARS-CoV-2 clinical specimens. Together, analyses of our data provide extensive guidance for future studies of viral diversity and evolution., Competing Interests: The authors declare no conflict of interest.

Background/aims: Among several methods used to prevent endoscopic submucosal dissection (ESD) bleeding, the recently developed hemostatic powder (HP) has few technical limitations and is relatively easy-to-use. This study aimed to analyze the hemostatic effects and mechanisms of two HPs using a porcine upper gastrointestinal hemorrhage model., Methods: We evaluated HPs (Endospray and epidermal growth factor [EGF]-endospray) for adhesion, waterproofing ability, permeability, and absorption in vitro . ESD was performed to induce bleeding ulcers in the porcine stomachs. In a total of three pigs, three bleeding ulcers per animal were generated. Hemostasis and rebleeding were evaluated endoscopically. After 72 hours, the animals were sacrificed, and histologically analyzed., Results: The water absorption of HPs was over 20 times the initial value within 30 minutes. The gelated HPs completely blocked water penetration into the applied site within 5 minutes and strongly adhered to the Petri-dish surface for up to 6 hours. The initial hemostasis rates within 5 minutes were 33.3%, 100.0%, and 66.7%, and the rebleeding rates at 6 to 72 hours after HP application were 33.3%, 16.7%, and 33.3% (control, Endospray, and EGF-endospray groups, respectively). Histological analysis revealed the thickness of the regenerated mucosa (522.1, 514.5, and 680.3 μm) and the submucosal layer (1,510.3, 2,848.2, and 3,062.3 μm) and the number of newly formed blood vessels (15.3, 17.9, and 20.5) in the control, Endospray, and EGF-endospray groups, respectively., Conclusions: The endoscopic HPs demonstrated the ability to elicit effective initial hemostasis and the histological ulcer-healing effect of EGF in an animal model of hemorrhagic gastric ulcers.

Three types of DNA methyl modifications have been detected in bacterial genomes, and mechanistic studies have demonstrated roles for DNA methylation in physiological functions ranging from phage defense to transcriptional control of virulence and host-pathogen interactions. Despite the ubiquity of methyltransferases and the immense variety of possible methylation patterns, epigenomic diversity remains unexplored for most bacterial species. Members of the Bacteroides fragilis group (BFG) reside in the human gastrointestinal tract as key players in symbiotic communities but also can establish anaerobic infections that are increasingly multi-drug resistant. In this work, we utilize long-read sequencing technologies to perform pangenomic (n = 383) and panepigenomic (n = 268) analysis of clinical BFG isolates cultured from infections seen at the NIH Clinical Center over four decades. Our analysis reveals that single BFG species harbor hundreds of DNA methylation motifs, with most individual motif combinations occurring uniquely in single isolates, implying immense unsampled methylation diversity within BFG epigenomes. Mining of BFG genomes identified more than 6000 methyltransferase genes, approximately 1000 of which were associated with intact prophages. Network analysis revealed substantial gene flow among disparate phage genomes, implying a role for genetic exchange between BFG phages as one of the ultimate sources driving BFG epigenome diversity., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Oxylipins, oxidation products of unsaturated free fatty acids (FFAs), are involved in various cellular signaling systems. Among these oxylipins, FFA epoxides are associated with beneficial effects in metabolic and cardiovascular health. FFA epoxides are metabolized to diols, which are usually biologically less active, by soluble epoxide hydrolase (sEH). Plasma epoxide-diol ratios have been used as indirect measures of sEH activity. This study was designed to examine the effects of acute elevation of individual plasma FFAs on a variety of oxylipins, particularly epoxides, diols, and their ratios. We tested if FFA epoxide-diol ratios are altered by circulating FFA levels (i.e., substrate availability) independent of sEH activity. Wistar rats received a constant intravenous infusion of olive (70% oleic acid (OA)), safflower seed (72% linoleic acid (LA)), and fish oils (rich in ω-3 FFAs) as emulsions to selectively raise OA, LA, and ω-3 FFAs (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)), respectively. As expected, olive, safflower seed, and fish oil infusions selectively raised plasma OA (57%), LA (87%), EPA (70%), and DHA (54%), respectively ( p < 0.05 for all). Raising plasma FFAs exerted substrate effects to increase hepatic and plasma epoxide and diol levels. These increases in epoxides and diols occurred to similar extents, resulting in no significant changes in epoxide-diol ratios. These data suggest that epoxide-diol ratios, often used as indices of sEH activity, are not affected by substrate availability or altered plasma FFA levels and that epoxide-diol ratios may be used to compare sEH activity between conditions of different circulating FFA levels.

Frequency-modulated continuous wave (FMCW) radar system synchronization using external clock signals can cause repeated Range-Doppler (R-D) map corruption when clock signal asynchronization problems occur between the transmitter and receiver. In this paper, we propose a signal processing method for the reconstruction of the corrupted R-D map owing to the FMCW radar's asynchronization. After calculating the image entropy for each R-D map, the corrupted ones are extracted and reconstructed using the normal R-D maps acquired before and after the individual maps. To verify the effectiveness of the proposed method, three target detection experiments were conducted: a human target detection in an indoor environment and a wide place and a moving bike-rider target detection in an outdoor environment. The corrupted R-D map sequence of observed targets in each case was reconstructed properly and showed the validity by comparing the map-by-map range and speed changes in the detected target with the ground-truth information of the target.

The Streptococcus bovis group (previously group D streptococci) consists of seven distinct species and subspecies. Definitive identification within the group is important, as certain organisms have been associated with gastrointestinal carcinoma, bacteremia, infective endocarditis, meningitis, biliary tract disease, and carcinoma, among others. Definitive identification, however, remains elusive due to limitations and inconsistencies across commonly used identification platforms in the United States. Here, we compared the performance of standard biochemical (Trek Gram-positive identification [GPID] plate, Vitek 2 GPID), sequencing (16S rDNA, sodA ) databases (NCBI, RDP, CDC MicrobeNet), and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) platforms (Vitek MS, Bruker Biotyper MS) using a set of eight type strains representing all seven strains within the S. bovis group. Despite the evaluation of contemporary methods, no single platform was able to definitively identify all type strains within the S. bovis group. Vitek MS (85.7%, 7/8) provided the most accurate definitive identifications, followed by sodA sequencing (75%, 6/8). Vitek 2 and Bruker Biotyper RUO platforms performed the next best (62.5%, 5/8). All remaining platforms failed to adequately differentiate type strains within the S. bovis group (range, 0 to 37.5%). Laboratorians and clinicians should be aware of the identification limitations of routine testing algorithms and incorporate reflex testing, when appropriate, to platforms such as Vitek MS and/or sodA sequencing that are more able to definitively identify S. bovis group organisms. Further clinical evaluation was conducted using 65 clinical isolates from three geographically distinct U.S. institutions. Future improvements in identification platforms may reveal new clinical and epidemiological trends for members of the S. bovis group.

Coronavirus disease 2019 (COVID-19) has been a global health problem since December 2019. Vaccination has been widely considered the best way to prevent COVID-19 pandemic, but public concerns about the safety of vaccines remain. There have been many studies reporting adverse events in the vaccinated. However, to date, no meta-analysis of the association of COVID-19 vaccination with psychiatric adverse events has been conducted yet. In this meta-analysis, studies on depression, anxiety and distress after COVID-19 vaccination were searched in the PubMed, Cochrane and Embase from January 2020 to April 2022. The OR of depression in four studies with a total sample size of 462,406 is obtained as 0.88 (95% CI; 0.75, 1.03), and the OR of anxiety as 0.86 (95% CI; 0.71, 1.05). However, there were no statistically significant differences between the groups. The mean difference of distress in two studies was −0.04 (95%CI; −0.05, −0.02; p < 0.0001). As a result of the moderator analysis, married people experienced less depression and anxiety after vaccination, and in White people, depression after vaccination was lower than others. We also found that people with a history of COVID-19 infection were more depressed and anxious after vaccination. We suggest that COVID-19 vaccination was not associated with a worsening of depression and anxiety.

The walkability of a neighborhood impacts public health and leads to economic and environmental benefits. The condition of sidewalks is a significant indicator of a walkable neighborhood as it supports and encourages pedestrian travel and physical activity. However, common sidewalk assessment practices are subjective, inefficient, and ineffective. Current alternate methods for objective and automated assessment of sidewalk surfaces do not consider pedestrians' physiological responses. We developed a novel classification framework for the detection of irregular walking surfaces that uses a machine learning approach to analyze gait parameters extracted from a single wearable accelerometer. We also identified the most suitable location for sensor placement. Experiments were conducted on 12 subjects walking on good and irregular walking surfaces with sensors attached at three different locations: right ankle, lower back, and back of the head. The most suitable location for sensor placement was at the ankle. Among the five classifiers trained with gait features from the ankle sensor, Support Vector Machine (SVM) was found to be the most effective model since it was the most robust to subject differences. The model's performance was improved with post-processing. This demonstrates that the SVM model trained with accelerometer-based gait features can be used as an objective tool for the assessment of sidewalk walking surface conditions.

Purpose: This prospective, single-center, open-label, therapeutic confirmatory, randomized clinical trial aimed to assess the alleviation of anal pain by applying structured anal skin care including skin protectants in rectal cancer patients with low anterior resection syndrome (LARS) combined with anal pain., Methods: From December 2017 to May 2020, 42 patients with LARS (scores of ≥21) and anal pain (visual analogue scale [VAS] score of ≥3) were randomly assigned and observed for 4 weeks. The conventional treatment consisted of dietary management, sitz baths, prohibition of anal scrubbing, loperamide, and dioctahedral smectite. In the anal care group, cleanser, barrier cream, and barrier spray were applied to the anal skin after defecation following the conventional treatment. The primary outcome was analgesic effect on anal pain after 2 weeks of structured treatment (anal care group) or conventional (control group). The cutoff for analgesic effect was a decrease in the anal pain score (VAS score of ≥2 or ≥30% reduction)., Results: As a primary outcome, the analgesic effect was significantly higher in the anal care group (P = 0.034). The incontinence-associated dermatitis skin condition score was significantly improved in the anal care group than control group after 4 weeks (P = 0.023). There were no significant differences in LARS scores and quality of life scores between 2 groups., Conclusion: Structured anal skin care has a significant analgesic effect in reducing anal pain and improving anal skin conditions in patients with LARS after rectal cancer surgery., Competing Interests: Conflict of Interest: Although this study was conducted with medical supplies provided by Coloplast Korea, the study design, patient enrollment, data analysis, and manuscript writing were completely and independently performed by the researchers., (Copyright © 2022, the Korean Surgical Society.)

Hypermutation due to DNA mismatch repair (MMR) deficiencies can accelerate the development of antibiotic resistance in Pseudomonas aeruginosa. Whether hypermutators generate resistance through predominantly similar molecular mechanisms to wild-type (WT) strains is not fully understood. Here, we show that MMR-deficient P. aeruginosa can evolve resistance to important broad-spectrum cephalosporin/beta-lactamase inhibitor combination antibiotics through novel mechanisms not commonly observed in WT lineages. Using whole-genome sequencing (WGS) and transcriptional profiling of isolates that underwent in vitro adaptation to ceftazidime/avibactam (CZA), we characterized the detailed sequence of mutational and transcriptional changes underlying the development of resistance. Surprisingly, MMR-deficient lineages rapidly developed high-level resistance (>256 μg/mL) largely without corresponding fixed mutations or transcriptional changes in well-established resistance genes. Further investigation revealed that these isolates had paradoxically generated an early inactivating mutation in the mexB gene of the MexAB-OprM efflux pump, a primary mediator of CZA resistance in P. aeruginosa, potentially driving an evolutionary search for alternative resistance mechanisms. In addition to alterations in a number of genes not known to be associated with resistance, 2 mutations were observed in the operon encoding the RND efflux pump MexVW. These mutations resulted in a 4- to 6-fold increase in resistance to ceftazidime, CZA, cefepime, and ceftolozane-tazobactam when engineered into a WT strain, demonstrating a potentially important and previously unappreciated mechanism of resistance to these antibiotics in P. aeruginosa. Our results suggest that MMR-deficient isolates may rapidly evolve novel resistance mechanisms, sometimes with complex dynamics that reflect gene inactivation that occurs with hypermutation. The apparent ease with which hypermutators may switch to alternative resistance mechanisms for which antibiotics have not been developed may carry important clinical implications., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RAB reports grants from Entasis, Merck, Wockhardt, Shionogi, and Venatorx. None of these entities were involved in any part of this study in any way. The other authors declare no conflicts of interest., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

The purpose of this study was to evaluate the performance of biodegradable polymer sirolimus and ascorbic acid eluting stent systems with four commercially available drug-eluting stents (DES). We investigated the characterization of mechanical properties by dimension, foreshortening, recoil, radial force, crossing profile, folding shape, trackability, and dislodgement force. Additionally, we identify the safety and efficacy evaluation through registry experiments. Each foreshortening and recoil of D + Storm® DES is 1.3 and 3.70%, which has better performance than other products. A post-marketing clinical study to evaluate the performance and safety of D + Storm® DES is ongoing in real-world clinical settings. Two hundred one patients were enrolled in this study and have now completed follow-up for up to 1 month. No major adverse cardiovascular event (MACE) occurred in any subjects, confirming the safety of D + Storm® DES in the clinical setting. An additional approximately 100 subjects will be enrolled in the study and the final safety profile will be assessed in 300 patients. In conclusion, this study reported the objective evaluation of DES performance and compared the mechanical responses of four types of DES available in the market. There is little difference between the four cardiovascular stents in terms of mechanical features, and it can help choose the most suitable stent in a specific clinical situation if those features are understood. Graphical abstract., (© 2022. The Author(s).)

As the most abundant cation in archaeal, bacterial, and eukaryotic cells, potassium (K + ) is an essential element for life. While much is known about the machinery of transcellular and paracellular K transport-channels, pumps, co-transporters, and tight-junction proteins-many quantitative aspects of K homeostasis in biological systems remain poorly constrained. Here we present measurements of the stable isotope ratios of potassium ( 41 K/ 39 K) in three biological systems (algae, fish, and mammals). When considered in the context of our current understanding of plausible mechanisms of K isotope fractionation and K + transport in these biological systems, our results provide evidence that the fractionation of K isotopes depends on transport pathway and transmembrane transport machinery. Specifically, we find that passive transport of K + down its electrochemical potential through channels and pores in tight-junctions at favors 39 K, a result which we attribute to a kinetic isotope effect associated with dehydration and/or size selectivity at the channel/pore entrance. In contrast, we find that transport of K + against its electrochemical gradient via pumps and co-transporters is associated with less/no isotopic fractionation, a result that we attribute to small equilibrium isotope effects that are expressed in pumps/co-transporters due to their slower turnover rate and the relatively long residence time of K + in the ion pocket. These results indicate that stable K isotopes may be able to provide quantitative constraints on transporter-specific K + fluxes (e.g., the fraction of K efflux from a tissue by channels vs. co-transporters) and how these fluxes change in different physiological states. In addition, precise determination of K isotope effects associated with K + transport via channels, pumps, and co-transporters may provide unique constraints on the mechanisms of K transport that could be tested with steered molecular dynamic simulations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Higgins, Ramos, Gili, Spetea, Kanoski, Ha, McDonough and Youn.)

The present study aimed to evaluate whether the cerebrospinal fluid (CSF) neurofilament light chain (NfL) is a potential prognostic marker for patients with leptomeningeal metastasis (LM). NfL levels were measured in CSF using a single-molecule array assay. A total of 42 patients with LM who were treated with ventriculo-lumbar perfusion (VLP) chemotherapy and had available stored CSF samples from the lumbar subarachnoid space before VLP chemotherapy were included in the present study, in order to investigate the prognostic value of CSF NfL. The median CSF NfL level in patients with LM was 8.15 ng/ml; 30% of patients who had died at the time of analysis had CSF NfL levels higher than the calculated overall prognostic cut-off value (11 ng/ml). The median overall survival after initiation of VLP chemotherapy was significantly longer in patients with LM and low CSF NfL levels compared with in patients with LM and high CSF NfL levels (P<0.001). The statistical significance remained after adjusting for other known prognostic factors and in a subgroup analysis according to age. In conclusion, CSF NfL could be considered a putative prognostic marker in patients with LM treated with VLP chemotherapy., Competing Interests: Kim Y, Kim KH, Park EY, Youn JH, Yoo H, Gwak HS report no conflict of interest. Hyun JW has received a grant from the National Cancer Center and the National Research Foundation of Korea. Kim SH has lectured, consulted, and received honoraria from Bayer Schering Pharma, Biogen, Genzyme, Merck Serono, and UCB and received a grant from the National Research Foundation of Korea. Kim HJ received a grant from the National Research Foundation of Korea and research support from Aprilbio and Eisai; received consultancy/speaker fees from Alexion, Aprilbio, Biogen, Celltrion, Daewoong, Eisai, GC Pharma, HanAll BioPharma, MDimune, Merck Serono, Novartis, Roche, Sanofi Genzyme, Teva-Handok, UCB, and Viela Bio; and is a co-editor for the Multiple Sclerosis Journal and an associated editor for the Journal of Clinical Neurology., (Copyright © 2022, Spandidos Publications.)

Mycoplasma orale is a rare cause of invasive infection in immunodeficient hosts. Phosphatidylinositol 3-kinase, regulatory subunit 1 ( PI3KR1 ) mutations predispose patients to sinopulmonary infections, alongside bronchiectasis autoimmunity and lymphoproliferation. We report 2 cases of PI3KR1 deficiency with invasive M orale and effective treatment options., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

Introduction: Randomized controlled trials (RCTs) comparing triple therapies (inhaled corticosteroid [ICS], long-acting β 2 -agonist [LABA], and long-acting muscarinic antagonist [LAMA]) for the treatment of chronic obstructive pulmonary disease (COPD) are limited. This network meta-analysis (NMA) investigated the comparative efficacy of single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus any triple (ICS/LABA/LAMA) combinations and dual therapies in patients with COPD., Methods: This NMA was conducted on the basis of a systematic literature review (SLR), which identified RCTs in adults aged at least 40 years with COPD. The RCTs compared different ICS/LABA/LAMA combinations or an ICS/LABA/LAMA combination with any dual therapy (ICS/LABA or LAMA/LABA). Outcomes of interest included forced expiratory volume in 1 s (FEV 1 ), annualized rate of combined moderate and severe exacerbations, St George's Respiratory Questionnaire (SGRQ) total score and SGRQ responders, transition dyspnea index focal score, and rescue medication use (RMU). Analyses were conducted at 24 weeks (primary endpoint), and 12 and 52 weeks (if feasible)., Results: The NMA was informed by five trials reporting FEV 1 at 24 weeks. FF/UMEC/VI was statistically significantly more effective at increasing trough FEV 1 (based on change from baseline) than all triple comparators in the network apart from UMEC + FF/VI. The NMA was informed by 17 trials reporting moderate or severe exacerbation endpoints. FF/UMEC/VI demonstrated statistically significant improvements in annualized rate of combined moderate or severe exacerbations versus single-inhaler budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR). At 24 weeks, the NMA was informed by five trials. FF/UMEC/VI showed statistically significant improvements in annualized rate of combined moderate or severe exacerbations versus UMEC + FF/VI and BUD/GLY/FOR. FF/UMEC/VI also demonstrated improvements in mean SGRQ score versus other triple therapy comparators at 24 weeks, and a significant reduction in RMU compared with BUD/GLY/FOR (160/18/9.6)., Conclusion: The findings of this NMA suggest favorable efficacy with single-inhaler triple therapy comprising FF/UMEC/VI. Further analysis is required as additional evidence becomes available., (© 2022. The Author(s).)

Objective: This study is an investigator-initiated, prospective, randomized, controlled study to evaluate the efficacy and safety of the combined use of recombinant human BMP-2 (rhBMP-2) and a hydroxyapatite (HA) carrier in multilevel fusion in patients with adult spinal deformity (ASD)., Methods: Thirty patients underwent posterolateral fusion for lumbar spinal deformities at 3 to 5 segments between L1 and S1. The patients received rhBMP-2+HA or HA on the left or right side of the transverse processes. They were followed up regularly at 1, 3, 6, and 12 months postoperatively. Fusion was defined according to the bone bridging on computed tomography scans. The fusion rate per segment was subanalyzed. Function and quality of life as well as pain in the lower back and lower extremities were evaluated., Results: The union rate for the rhBMP-2+HA group was 100% at 6 and 12 months. The union rate for the HA group was 77.8% (21 of 27) at 6 months and 88.0% (22 of 25) at 12 months (p = 0.014 at 6 months; not significant at 12 months). All segments were fused at 6 and 12 months in the rhBMP-2+HA group (p < 0.001). In the HA group, 108 of 115 segments (93.5%) were fused at 6 months and 105 of 109 segments (96.3%) at 12 months. Other clinical parameters (visual analogue scale, 36-item Short Form Health Survey, and Scoliosis Research Society-22 scores) improved compared to baseline., Conclusion: Combining rhBMP-2 and an HA carrier is a safe and effective method to achieve multilevel fusion in patients with ASD.

Due to a ship's extreme motion, there is a risk of injuries and accidents as people may become unbalanced and be injured or fall from the ship. Thus, individuals must adjust their movements when walking in an unstable environment to avoid falling or losing balance. A person's ability to control their center of mass (COM) during lateral motion is critical to maintaining balance when walking. Dynamic balancing is also crucial to maintain stability while walking. The margin of stability (MOS) is used to define this dynamic balancing. This study aimed to develop a model for predicting balance control and stability in walking on ships by estimating the peak COM excursion and MOS variability using accelerometers. We recruited 30 healthy individuals for this study. During the experiment, participants walked for two minutes at self-selected speeds, and we used a computer-assisted rehabilitation environment (CAREN) system to simulate the roll motion. The proposed prediction models in this study successfully predicted the peak COM excursion and MOS variability. This study may be used to protect and save seafarers or passengers by assessing the risk of balance loss.

Salicylic acid (SA) plays an important role in plant immune response, including resistance to pathogens and systemic acquired resistance. Two major components, NONEXPRESSOR OF PATHOGENESIS-RELATED GENES (NPRs) and TGACG motif-binding transcription factors (TGAs), are known to mediate SA signaling, which might also be orchestrated by other hormonal and environmental changes. Nevertheless, the molecular and functional interactions between SA signaling components and other cellular signaling pathways remain poorly understood. Here we showed that the steroid plant hormone brassinosteroid (BR) promotes SA responses by inactivating BR-INSENSITIVE 2 (BIN2), which inhibits the redox-sensitive clade I TGAs in Arabidopsis. We found that both BR and the BIN2 inhibitor bikinin synergistically increase SA-mediated physiological responses, such as resistance to Pst DC3000. Our genetic and biochemical analyses indicated that BIN2 functionally interacts with TGA1 and TGA4, but not with other TGAs. We further demonstrated that BIN2 phosphorylates Ser-202 of TGA4, resulting in the suppression of the redox-dependent interaction between TGA4 and NPR1 as well as destabilization of TGA4. Consistently, transgenic Arabidopsis overexpressing TGA4-YFP with a S202A mutation displayed enhanced SA responses compared to the wild-type TGA4-YFP plants. Taken together, these results suggest a novel crosstalk mechanism by which BR signaling coordinates the SA responses mediated by redox-sensitive clade I TGAs., (Copyright © 2022 The Author. Published by Elsevier Inc. All rights reserved.)

Recently, light-emitting diode (LED)-based devices have emerged as effective and safe tools for the treatment of photoaged skin. However, few studies have been conducted to elucidate the underlying mechanism behind the effect on photoageing of LED light. In this study, we induced photoageing of human dermal fibroblasts (HDFs) with Ultraviolet B (UVB) irradiation and evaluated the ability of 590-nm LED radiation to induce recovery from oxidative stress, restore collagen formation and regulate inflammatory changes. Photoageing was induced in cultured human dermal fibroblasts (HDFs) using UVB irradiation of 50 mJ/cm 2 . Then, the photoaged HDFs were irradiated with LED using a custom-built 590-nm LED device which emits light with an intensity of 38 mW/cm 2 (irradiated for 900 s with 34.2 J/cm 2 of total energy). LED irradiation significantly attenuated UVB-induced reactive oxygen species generation and UVB-induced phosphorylation of JNK, c-Fos and c-Jun. In addition, the procollagen levels were recovered significantly, and MMP-9 levels were significantly suppressed after LED irradiation. The UVB-induced phosphorylation levels of NF-κB and pro-inflammatory enzyme COX-2 also significantly decreased. Our results suggest that 590-nm yellow light irradiation may be an effective and safe anti-oxidative and anti-inflammatory treatment modality for photoaged skin., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hundreds of leucine-rich repeat receptor kinases (LRR-RKs) have evolved to control diverse processes of growth, development and immunity in plants, but the mechanisms that link LRR-RKs to distinct cellular responses are not understood. Here we show that two LRR-RKs, the brassinosteroid hormone receptor BRASSINOSTEROID INSENSITIVE 1 (BRI1) and the flagellin receptor FLAGELLIN SENSING 2 (FLS2), regulate downstream glycogen synthase kinase 3 (GSK3) and mitogen-activated protein (MAP) kinases, respectively, through phosphocoding of the BRI1-SUPPRESSOR1 (BSU1) phosphatase. BSU1 was previously identified as a component that inactivates GSK3s in the BRI1 pathway. We surprisingly found that the loss of the BSU1 family phosphatases activates effector-triggered immunity and impairs flagellin-triggered MAP kinase activation and immunity. The flagellin-activated BOTRYTIS-INDUCED KINASE 1 (BIK1) phosphorylates BSU1 at serine 251. Mutation of serine 251 reduces BSU1's ability to mediate flagellin-induced MAP kinase activation and immunity, but not its abilities to suppress effector-triggered immunity and interact with GSK3, which is enhanced through the phosphorylation of BSU1 at serine 764 upon brassinosteroid signalling. These results demonstrate that BSU1 plays an essential role in immunity and transduces brassinosteroid-BRI1 and flagellin-FLS2 signals using different phosphorylation sites. Our study illustrates that phosphocoding in shared downstream components provides signalling specificities for diverse plant receptor kinases., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Based on systematic electrochemical analysis, an integrated synthetic platform of C(sp 3 )-based organoboron compounds was established for the introduction of heteroatoms. The electrochemically mediated bond-forming strategy was shown to be highly effective for the functionalization of sp 3 -hybridized carbon atoms with significant steric hindrance. Moreover, virtually all the nonmetallic heteroatoms could be utilized as reaction partners using one unified protocol. The observed reactivity stems from the two consecutive single-electron oxidations of the substrate, which eventually generates an extremely reactive carbocation as the key intermediate. The detailed reaction profile could be elucidated through multifaceted electrochemical studies. Ultimately, a new dimension in the activation strategies for organoboron compounds was accomplished through the electrochemically driven reaction development.

B-cell-depleting therapies may lead to prolonged disease and viral shedding in individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and this viral persistence raises concern for viral evolution. We report sequencing of early and late samples from a 335-day infection in an immunocompromised patient. The virus accumulated a unique deletion in the amino-terminal domain of the spike protein, and complete deletion of ORF7b and ORF8, the first report of its kind in an immunocompromised patient. Unique viral mutations found in this study highlight the importance of analyzing viral evolution in protracted SARS-CoV-2 infection, especially in immunosuppressed hosts., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Extracellular potassium (K + ) homeostasis is achieved by a concerted effort of multiple organs and tissues. A limitation in studies of K + homeostasis is inadequate techniques to quantify K + fluxes into and out of organs and tissues in vivo. The goal of the present study was to test the feasibility of a novel approach to estimate K + distribution and fluxes in vivo using stable K + isotopes. 41 K was infused as KCl into rats consuming control or K + -deficient chow ( n = 4 each), 41 K-to- 39 K ratios in plasma and red blood cells (RBCs) were measured by inductively coupled plasma mass spectrometry, and results were subjected to compartmental modeling. The plasma 41 K/ 39 K increased during 41 K infusion and decreased upon infusion cessation, without altering plasma total K + concentration ([K + ], i.e., 41 K + 39 K). The time course of changes was analyzed with a two-compartmental model of K + distribution and elimination. Model parameters, representing transport into and out of the intracellular pool and renal excretion, were identified in each rat, accurately predicting decreased renal K + excretion in rats fed K + -deficient vs. control diet ( P < 0.05). To estimate rate constants of K + transport into and out of RBCs, 41 K/ 39 K were subjected to a simple model, indicating no effects of the K + -deficient diet. The findings support the feasibility of the novel stable isotope approach to quantify K + fluxes in vivo and sets a foundation for experimental protocols using more complex models to identify heterogeneous intracellular K + pools and to answer questions pertaining to K + homeostatic mechanisms in vivo.

Background and Purpose: Verbal and nonverbal fluency tests are the conventional methods for examining executive function in the elderly population. However, differences in impairments result in fluency tests in patients with mild cognitive impairments (MCIs) and Alzheimer's disease (AD) and in neural correlates underlying the tests still necessitate concrete evidence., Methods: We compared the test performances in 27 normal controls, 28 patients with MCI, and 20 with AD, and investigated morphological changes in association with the test performances using structural magnetic imaging., Results: Patients with AD performed poorly across all the fluency tests, and a receiver operating characteristics curve analysis revealed that only category fluency test discriminated all the 3 groups. Association, category, and design fluency tests involved temporal and frontal regions, while letter fluency involved the cerebellum and caudate., Conclusions: Category fluency is a reliable measure for screening patients with AD and MCI, and this efficacy might be related to morphological correlates that underlie semantic and executive processing., Competing Interests: Conflict of Interest: The authors have no financial conflicts of interest., (© 2022 Korean Dementia Association.)

Background and Objectives: This clinical trial was conducted to evaluate the safety and efficacy of D+Storm™ drug-eluting stent (DES) and BioMatrix Flex™ DES., Methods: This study was a multicenter, subject-single-blind, randomized, and confirmed comparative clinical trial. According to the inclusion criteria, those diagnosed with stable angina, unstable angina, silent ischemia, or non-ST-segment myocardial infarction were selected among patients with coronary artery stenosis as subjects. Among the subjects with 50% stenosis on coronary angiography, the experiment was performed on those who had a lesion with reference vessel 2.5-4.0 mm in diameter and ≤40 mm in length. The primary endpoint was an in-segment late loss and the secondary endpoints were in-stent late lumen loss, stent malapposition, the incidence of mortality, myocardial infarction, reoperation, and stent thrombosis at 36 weeks., Results: 57 patients in the D+Storm™ DES group and 55 patients in the BioMatrix Flex™ DES group were enrolled in the study. Fifty-seven patients in the D+Storm™ DES group and Fifty-five patients in the BioMatrix Flex™ DES group were enrolled in the study. An average of in-segment late lumen loss was 0.08±0.13 mm in the D+Storm™ DES group and 0.14±0.32 mm in the BioMatrix Flex™ DES group with no significant difference between the 2 groups (p=0.879). In addition, there was no significant difference in adverse events between D+Storm™ DES and BioMatrix Flex™ DES., Conclusions: This study demonstrated the clinical effectiveness and safety of D+Storm™ DES implantation in patients with coronary artery disease over a 36-week follow-up period., Competing Interests: Jun-kyu Park and Ji Hyun Youn are researchers at CG Bio, a manufacturer of D+Storm DES. This clinical trial was funded by CG Bio. The other authors report no conflicts., (Copyright © 2021. The Korean Society of Cardiology.)

The exposure risk to the highly infectious hepatitis B virus (HBV) is an established and recognizable hazard to healthcare professionals (HCPs). In the United States, implementing preemptive vaccination programs and safety procedures resulted in drastic reductions in HBV infections among HCPs; however, many HCPs remain unprotected and risk of exposure persists, especially among those first entering a healthcare system and undergoing professional training. First-generation HBV vaccines require completion of a 3-dose schedule over a 6-month interval for maximum immunogenicity. By comparison, HepB-CpG (HEPLISAV-B®) is a 2-dose HBV vaccine licensed in the United States in 2017, inducing rapid seroprotection over a 1-month interval and may represent a more effective strategy for combating HBV infection in US healthcare systems. In this modeling study, the health and economic impact of implementing an HBV vaccination strategy with HepB-CpG versus the 3-dose HBV vaccine (Engerix-B®) was evaluated among HCPs newly entering a healthcare system. The model used effective seroprotection rate, a real-world metric accounting for HCP vaccine compliance and seroprotection rates for different dosing regimens and considered current pricing for postexposure prophylaxis treatment. Compared with the 3-dose vaccine, HepB-CpG was anticipated to provide faster, increased protection against HBV infection among newly entered HCPs. In protecting a greater percentage of HCPs, HepB-CpG was also projected to substantially reduce the risk of HBV exposure. Accordingly, an economic analysis showed HepB-CpG vaccination would reduce costs of postexposure prophylaxis treatment compared with the 3-dose vaccine. Overall, HepB-CpG represents an effective therapeutic strategy against HBV infection for US healthcare systems.

The Timed Up and Go (TUG) test has been frequently used to assess the risk of falls in older adults because it is an easy, fast, and simple method of examining functional mobility and balance without special equipment. The purpose of this study is to develop a model that predicts the TUG test using three-dimensional acceleration data collected from wearable sensors during normal walking. We recruited 37 older adults for an outdoor walking task, and seven inertial measurement unit (IMU)-based sensors were attached to each participant. The elastic net and ridge regression methods were used to reduce gait feature sets and build a predictive model. The proposed predictive model reliably estimated the participants' TUG scores with a small margin of prediction errors. Although the prediction accuracies with two foot-sensors were slightly better than those of other configurations (e.g., MAPE: foot (0.865 s) > foot and pelvis (0.918 s) > pelvis (0.921 s)), we recommend the use of a single IMU sensor at the pelvis since it would provide wearing comfort while avoiding the disturbance of daily activities. The proposed predictive model can enable clinicians to assess older adults' fall risks remotely through the evaluation of the TUG score during their daily walking.

Aspergillus flavus is one of the most important agents of invasive and non-invasive aspergillosis, especially in tropical and subtropical regions of the world, including Iran. Aspergillus oryzae is closely related to A. flavus , and it is known for its economic importance in traditional fermentation industries. Reports of infection due to A. oryzae are scarce. Several studies reported that differentiating these two species in clinical laboratories is not possible using MALDI-TOF or by targeting fungal barcode genes, such as Internal Transcribed Spacer (ITS) and β-tubulin ( benA ). The species-level identification of causative agents and the determination of antifungal susceptibility patterns can play significant roles in the outcome of aspergillosis. Here, we aimed to investigate the discriminatory potential of cyp51A PCR-sequencing versus that of the ITS, benA and calmodulin ( CaM ) genes for the differentiation of A. flavus from A. oryzae . In a prospective study investigating the molecular epidemiology of A. flavus in Iran between 2008 and 2018, out of 200 clinical isolates of A. flavus , 10 isolates showed >99% similarity to both A. flavus and A. oryzae . Overall, the ITS, β-tubulin and CaM genes did not fulfil the criteria for differentiating these 10 isolates. However, the cyp51A gene showed promising results, which warrants further studies using a larger set of isolates from more diverse epidemiological regions of the world.

Clinically relevant members of the Scedosporium / Pseudallescheria species complex and Lomentospora prolificans are generally resistant against currently available systemic antifungal agents in vitro , and infection due to these species is difficult to treat. We studied the in vivo efficacy of a new fungicidal agent, olorofim (formerly F901318), against scedosporiosis and lomentosporiosis in neutropenic animals. Cyclophosphamide-immunosuppressed CD-1 mice infected by Scedosporium apiospermum, Pseudallescheria boydii (Scedosporium boydii), and Lomentospora prolificans were treated by intraperitoneal administration of olorofim (15 mg/kg of body weight every 8 h for 9 days). The efficacy of olorofim treatment was assessed by the survival rate at 10 days postinfection, levels of serum (1-3)-β-d-glucan (BG), histopathology, and fungal burdens of kidneys 3 days postinfection. Olorofim therapy significantly improved survival compared to that of the untreated controls; 80%, 100%, and 100% of treated mice survived infection by Scedosporium apiospermum, Pseudallescheria boydii, and Lomentospora prolificans, respectively, while less than 20% of the control mice (phosphate-buffered saline [PBS] treated) survived at 10 days postinfection. In the olorofim-treated neutropenic CD-1 mice infected with any of the three species, serum BG levels were significantly suppressed and fungal DNA detected in the target organs was significantly lower than in controls. Furthermore, histopathology of kidneys revealed no or only a few lesions with hyphal elements in the olorofim-treated mice, while numerous fungal hyphae were present in control mice. These results indicate olorofim to be a promising therapeutic agent for systemic scedosporiosis/lomentosporiosis, devastating emerging fungal infections that are difficult to treat with currently available antifungals.