Telemedicine Research Trends in 2001-2022 and Research Cooperation Between China and Other Countries Before and After the COVID-19 Pandemic: Bibliometric Analysis.

BACKGROUND: Advancements in technology have overcome geographical barriers, making telemedicine, which offers remote emergency services, healthcare, and medication guidance, increasingly popular. COVID-19 restrictions amplified its global importance by bridging distances. OBJECTIVE: This study aimed to analyze Chinese and global literature data, present new global telemedicine research trends, and clarify the development potential, collaborations, and deficiencies in China's telemedicine research. METHODS: We conducted bibliometrics and network analyses on relevant documents from the Web of Science database from 2001 to 2022. Data collection was completed on October 30, 2023. Considering COVID-19's impact, 2020 was used as a baseline, dividing the data into 2 periods: 2001-2019 and 2020-2022. The development potential was determined based on publication trends. An international coauthorship network analysis identified collaboration statuses and potential. Co-occurrence analysis was conducted for China and the world. RESULTS: We identified 25,333 telemedicine-related research papers published between 2001 and 2022, with a substantial increase during the COVID-19 period (2020-2022), particularly in China (1.93-fold increase), moving its global publication rank from tenth to sixth. The United States, the United Kingdom, and Australia contributed 62.96% of the literature, far ahead of China's 3.90%. Globally, telemedicine research increased significantly post-2020. Between 2001 and 2019, the United States and Australia were central in coauthor networks; post-2020, the United States remained the largest node. Network hubs included the United States, the United Kingdom, Australia, and Canada. Keyword co-occurrence analysis revealed 5 global clusters from 2001 to 2019 (system technology, health care applications, mobile health, mental health, and electronic health) and 2020 to 2022 (COVID-19, children's mental health, artificial intelligence, digital health, and rehabilitation of middle-aged and older adults). In China, the research trends aligned with global patterns, with rapid growth post-2020. From 2001 to 2019, China cooperated closely with Indonesia, India, Japan, Taiwan, and South Korea. From 2020 to 2022, cooperation expanded to Japan, Singapore, Malaysia, and South Korea, as well as Saudi Arabia, Egypt, South Africa, Ghana, Lebanon, and other African and Middle Eastern countries. Chinese keyword co-occurrence analysis showed focus areas in system technology, health care applications, mobile health, big data analysis, and electronic health (2001-2019) and COVID-19, artificial intelligence, digital health, and mental health (2020-2022). Although psychology research increased, studies on children's mental health and middle-aged and older adults' rehabilitation were limited. CONCLUSIONS: We identified the latest trends in telemedicine research, demonstrating its significant potential in China and providing directions for future development and collaborations in telemedicine research.

Approach to Establishment of Control Strategy for Oral Solid Dosage Forms Using Continuous Manufacturing.

As a result of the research activities of the Japan Agency for Medical Research and Development (AMED), this document aims to show an approach to establishing control strategy for continuous manufacturing of oral solid dosage forms. The methods of drug development, technology transfer, process control, and quality control used in the current commercial batch manufacturing would be effective also in continuous manufacturing, while there are differences in the process development using continuous manufacturing and batch manufacturing. This document introduces an example of the way of thinking for establishing a control strategy for continuous manufacturing processes.

Analysis and Usage: Subject-to-subject Linear Domain Adaptation in sEMG Classification.

Before the operation of a biosignal-based application, long-duration calibration is required to adjust the pre-trained classifier to a new user data (target data). For reducing such time-consuming step, linear domain adaptation (DA) transfer learning approaches, which transfer pooled data (source data) related to the target data, are highlighted. In the last decade, they have been applied to surface electromyogram (sEMG) data with the implicit assumption that sEMG data are linear. However, sEMGs typically have non-linear characteristics, and due to the discrepancy between the assumption and actual characteristics, linear DA approaches would cause a negative transfer. This study investigated how the correlation between the source and target data affects an 8-class forearm movement classification after applying linear DA approaches. As a result, we found significant positive correlations between the classification accuracy and the source-target correlation. Additionally, the source-target correlation depended on the motion class. Therefore, our results suggest that we should choose a non-linear DA approach when the source-target correlation among subjects or motion classes is low.

A Method to Study Adaptation to Left-Right Reversed Audition.

An unusual sensory space is one of the effective tools to uncover the mechanism of adaptability of humans to a novel environment. Although most of the previous studies have used special spectacles with prisms to achieve unusual spaces in the visual domain, a methodology for studying the adaptation to unusual auditory spaces has yet to be fully established. This study proposes a new protocol to set-up, validate, and use a left-right reversed stereophonic system using only wearable devices, and to study the adaptation to left-right reversed audition with the help of neuroimaging. Although individual acoustic characteristics are not yet implemented, and slight spillover of unreversed sounds is relatively uncontrollable, the constructed apparatus shows high performance in a 360° sound source localization coupled with hearing characteristics with little delay. Moreover, it looks like a mobile music player and enables a participant to focus on daily life without arousing curiosity or drawing attention of other individuals. Since the effects of adaptation were successfully detected at the perceptual, behavioral, and neural levels, it is concluded that this protocol provides a promising methodology for studying adaptation to left-right reversed audition, and is an effective tool for uncovering the adaptability of humans to a novel environments in the auditory domain.

Parasympathetic activation enhanced by slow respiration modulates early auditory sensory gating.

Sensory gating is a preattentional mechanism to filter irrelevant information from the environment. It is typically reflected as a suppression of the event-related P50 component for successive sounds in the auditory modality. Although stress-induced sympathetic activation has been reported to disrupt P50 suppression, little is known about the modulatory effect of parasympathetic activation on early auditory sensory gating. We determined the parasympathetic effect on the magnetic P50 (P50m) suppression by controlling the respiratory rhythm and recording data simultaneously with magnetoencephalography and electrocardiography, using three successive click sounds as stimulus and ten normal individuals as study participants. The respiratory rhythm was guided by visual cues and set at 0.3, 0.25, or 0.2 Hz for distinct auditory stimulus sequence blocks. Heart rate variability analysis showed that slow respiration leads to significantly large high-frequency power, which is known as the parasympathetic index, whereas low-frequency/high-frequency ratio, known as the sympathetic index, did not differ with the respiratory rhythm. Although P50m suppression was observed in the left and right primary auditory areas for every respiratory condition, the left P50m intensity for the first sound was significantly decreased in the case of slow respiration, thereby indicating disruption of the left P50m suppression. Since background alpha oscillatory power, reflecting the arousal level, was similar for every respiratory rhythm, it is concluded that parasympathetic activation enhanced by slow respiration modulates P50m gating by reducing the initial neural sensitivity for an auditory input. Not only sympathetic but also parasympathetic effects should be considered in the evaluation of P50/P50m biomarkers.

1α-Hydroxy derivatives of 7-dehydrocholesterol are selective liver X receptor modulators.

The nuclear receptors liver X receptor (LXR) α and LXRß are involved in the regulation of lipid metabolism, inflammation, immunity, cellular proliferation, and apoptosis. Oxysterols are endogenous LXR ligands, and also interact with other nuclear and membrane receptors. We previously reported that a phytosterol derivative with a 1α-hydroxy group acts as a potent LXR agonist with intestine-selective action and that 25-hydroxy and 26/27-hydroxy metabolites of 7-dehydrocholesterol (7-DHC) exhibit partial LXR agonism. In this study, we report that 1α-hydroxy derivatives of 7-DHC, 1α-OH-7-DHC and 1,25-(OH)2-7-DHC, act as LXR modulators. Luciferase reporter gene assays showed that 1α-OH-7-DHC activates LXRα and LXRß and that 1,25-(OH)2-7-DHC activates both LXRs and vitamin D receptor. Examination of cofactor peptide association showed that the 1α-hydroxy derivatives, specifically 1,25-(OH)2-7-DHC, induce association of coactivator/corepressor peptide in a different manner from the agonist T0901317. Docking modeling and alanine mutational analysis of LXRα demonstrated that 1,25-(OH)2-7-DHC interacts with LXRα residues in a manner distinct from potent agonists, such as T0901317 and 24(S),25-epoxycholesterol. 1α-OH-7-DHC and 1,25-(OH)2-7-DHC induced expression of LXR target genes in a cell type- and gene-selective manner. 1,25-(OH)2-7-DHC effectively suppressed lipopolysaccharide-stimulated proinflammatory gene expression in an LXR-dependent manner. Therefore, 1α-hydroxy derivatives, such as 1,25-(OH)2-7-DHC, are unique LXR modulators with selective agonistic activity and potent transrepression function. These oxysterols have potential as LXR-targeted therapeutics for inflammatory disease.

A wearable system for adaptation to left-right reversed audition tested in combination with magnetoencephalography.

Exposure of humans to unusual spaces is effective to observe the adaptive strategy for an environment. Though adaptation to such spaces has been typically tested with vision, little has been examined about adaptation to left-right reversed audition, partially due to the apparatus for adaptation. Thus, it is unclear if the adaptive effects reach early auditory processing. Here, we constructed a left-right reversed stereophonic system using only wearable devices and asked two participants to wear it for 4 weeks. Every week, the magnetoencephalographic responses were measured under the selective reaction time task, where they immediately distinguished between sounds delivered to either the left or the right ear with the index finger on the compatible or incompatible side. The constructed system showed high performance in sound localization and achieved gradual reduction of a feeling of strangeness. The N1m intensities for the response-compatible sounds tended to be larger than those for the response-incompatible sounds until the third week but decreased on the fourth week, which correlated with the initially shorter and longer reaction times for the compatible and incompatible conditions, respectively. In the second week, disruption of the auditory-motor connectivity was observed with the largest N1m intensities and the longest reaction times, irrespective of compatibility. In conclusion, we successfully produced a high-quality space of left-right reversed audition using our system. The results suggest that a 4-week exposure to the reversed audition causes optimization of the auditory-motor coordination according to the new rule, which eventually results in the modulation of early auditory processing.

Styrylphenylphthalimides as Novel Transrepression-Selective Liver X Receptor (LXR) Modulators.

Anti-inflammatory effects of liver X receptor (LXR) ligands are thought to be largely due to LXR-mediated transrepression, whereas side effects are caused by activation of LXR-responsive gene expression (transactivation). Therefore, selective LXR modulators that preferentially exhibit transrepression activity should exhibit anti-inflammatory properties with fewer side effects. Here, we synthesized a series of styrylphenylphthalimide analogues and evaluated their structure-activity relationships focusing on LXRs-transactivating-agonistic/antagonistic activities and transrepressional activity. Among the compounds examined, 17l showed potent LXR-transrepressional activity with high selectivity over transactivating activity and did not show characteristic side effects of LXR-transactivating agonists in cells. This representative compound, 17l, was confirmed to have LXR-dependent transrepressional activity and to bind directly to LXRß. Compound 17l should be useful not only as a chemical tool for studying the biological functions of LXRs transrepression but also as a candidate for a safer agent to treat inflammatory diseases.

Early auditory change detection implicitly facilitated by ignored concurrent visual change during a Braille reading task.

Unconscious monitoring of multimodal stimulus changes enables humans to effectively sense the external environment. Such automatic change detection is thought to be reflected in auditory and visual mismatch negativity (MMN) and mismatch negativity fields (MMFs). These are event-related potentials and magnetic fields, respectively, evoked by deviant stimuli within a sequence of standard stimuli, and both are typically studied during irrelevant visual tasks that cause the stimuli to be ignored. Due to the sensitivity of MMN/MMF to potential effects of explicit attention to vision, however, it is unclear whether multisensory co-occurring changes can purely facilitate early sensory change detection reciprocally across modalities. We adopted a tactile task involving the reading of Braille patterns as a neutral ignore condition, while measuring magnetoencephalographic responses to concurrent audiovisual stimuli that were infrequently deviated either in auditory, visual, or audiovisual dimensions; 1000-Hz standard tones were switched to 1050-Hz deviant tones and/or two-by-two standard check patterns displayed on both sides of visual fields were switched to deviant reversed patterns. The check patterns were set to be faint enough so that the reversals could be easily ignored even during Braille reading. While visual MMFs were virtually undetectable even for visual and audiovisual deviants, significant auditory MMFs were observed for auditory and audiovisual deviants, originating from bilateral supratemporal auditory areas. Notably, auditory MMFs were significantly enhanced for audiovisual deviants from about 100 ms post-stimulus, as compared with the summation responses for auditory and visual deviants or for each of the unisensory deviants recorded in separate sessions. Evidenced by high tactile task performance with unawareness of visual changes, we conclude that Braille reading can successfully suppress explicit attention and that simultaneous multisensory changes can implicitly strengthen automatic change detection from an early stage in a cross-sensory manner, at least in the vision to audition direction.

Design, synthesis, and biological evaluation of novel transrepression-selective liver X receptor (LXR) ligands with 5,11-dihydro-5-methyl-11-methylene-6H-dibenz[b,e]azepin-6-one skeleton.

To obtain novel transrepression-selective liver X receptor (LXR) ligands, we adopted a strategy of reducing the transactivational agonistic activity of the 5,11-dihydro-5-methyl-11-methylene-6H-dibenz[b,e]azepin-6-one derivative 10, which exhibits LXR-mediated transrepressional and transactivational activity. Structural modification of 10 based on the reported X-ray crystal structure of the LXR ligand-binding domain led to a series of compounds, of which almost all exhibited transrepressional activity at 1 or 10 µM but showed no transactivational activity even at 30 µM. Among the compounds obtained, 18 and 22 were confirmed to have LXR-dependent transrepressional activity by using peritoneal macrophages from wild-type and LXR-null mice. A newly developed fluorescence polarization assay indicated that they bind directly to LXRα. Next, further structural modification was performed with the guidance of docking simulations with LXRα, focusing on enhancing the binding of the ligands with LXRα through the introduction of substituents or heteroatom(s). Among the compounds synthesized, compound 48, bearing a hydroxyl group, showed potent, selective, and dose-dependent transrepressional activity.

Visual mismatch response evoked by a perceptually indistinguishable oddball.

Mismatch field (MMF) is an early magnetoencephalographic response evoked by deviant stimuli within a sequence of standard stimuli. Although auditory MMF is reported to be an automatic response, the automaticity of visual MMF has not been clearly demonstrated, partly because of the difficulty in designing an ignore condition. Our modified oddball paradigm had a masking stimulus inserted between briefly presented standard and deviant stimuli (vertical gratings with different spatial frequencies). Perceptual discrimination between masked standard and deviant stimuli was difficult, but the early magnetoencephalographic response for the deviant was significantly larger than that for the standard, when the former had a higher spatial frequency than the latter. Our findings strongly support the hypothesis that visual MMF is evoked automatically.

Fused heterocyclic amido compounds as anti-hepatitis C virus agents.

We identified a fused heteroaromatic amido structure based on the phenanthridine skeleton as a superior scaffold for candidate drugs with potent anti-HCV activity. Among the compounds synthesized, a phenanthridine analogue with a 1,3-dioxolyl group (24) possessed the most potent anti-HCV activity (EC(50) value: 50 nM), with acceptable cytotoxicity. The structural development and structure-activity relationships of these compounds are described.

Design and synthesis of phthalimide-based fluorescent liver x receptor antagonists.

Based on our structure-activity relationship study of liver X receptor (LXR) ligands, we designed and synthesized fluorescent LXR antagonists containing an unsubstituted or substituted amino group on a phthalimide unit.

Structural development studies of anti-hepatitis C virus agents with a phenanthridinone skeleton.

A phenanthridinone skeleton was derived from our previous researches on thalidomide and retinoids as a multi-template for generation of anti-viral lead compounds. Structural development studies focusing on anti-hepatitis C virus activity afforded 5-butyl-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenanthridin-6(5H)-one (10) and 5-butylbenzo[b]phenanthridin-6(5H)-one (39), which showed EC(50) values of approximately 3.7 and 3.2microM, respectively.

[Design and synthesis of peroxisome proliferator-activated receptor (PPAR) delta agonists and its implication to the driving force to elicit PPAR delta selectivity].

A series of 3-(4-alkoxypheny)propanoic acid derivatives was prepared as candidate peroxisome proliferator-activated receptor (PPAR) delta-selective agonists, based on our previously discovered potent human PPARalpha/delta dual agonist TIPP-401 as a lead compound. Structure-activity relationship studies clearly indicated the importance of the chain length of the alkoxy group at the 4-position, and the n-butoxy compound exhibited the most potent PPARdelta transactivation activity and highest PPARdelta selectivity. The (S)-enantiomer of a representative compound (TIPP-204) exhibited extremely potent PPARdelta transactivation activity, comparable to that of the known PPARdelta-selective agonist GW-501516. To understand why TIPP-204 shows high selectivity for hPPARdelta among hPPAR subtypes, and why TIPP-401, a structurally related compound, is a hPPARalpha/delta dual agonist, computational docking of TIPP-401 to the ligand binding domains of hPPARalpha and hPPARdelta and X-ray structure analysis of TIPP-204-hPPARdelta ligand binding domain were carried out. The results allowed identification of certain amino acids as putative determinants of the hPPARdelta selectivity of TIPP-204. To confirm the significance of these amino acids, GAL4-fusion proteins of mutated hPPARdeltas and hPPARalphas were prepared, and the transactivation activity of TIPP-204 toward the mutants was evaluated. The amino acid(s) that predominantly influence the potency and selectivity of TIPP-204 are different from that of the well-known PPARdelta-selective agonist GW-501516, which belongs to a different chemical class. The significance of these amino acids was confirmed by the examination of the complex structure between TIPP-204 and hPPARdelta. The results revealed several interactions relevant to the hPPARdelta-selectivity of the two ligands and will be useful for logical hPPARdelta ligand design.

Co-existence of alpha-glucosidase-inhibitory and liver X receptor-regulatory activities and their separation by structural development.

Liver X receptors (LXR), which were originally reported as oxysterol-activated nuclear receptors, were recently found to recognize glucose as a physiological ligand. On this basis, we have already developed novel LXR antagonists based upon alpha-glucosidase inhibitors derived from thalidomide. Here, to clarify the relationship between alpha-glucosidase inhibition and LXR modulation, we investigate the alpha-glucosidase-inhibitory activity of typical LXR ligands and the LXR-modulating activity of typical alpha-glucosidase inhibitors. Although there were some exceptions, co-existence of LXR-regulatory and alpha-glucosidase-inhibitory activities seemed to be rather general among the examined compounds. The LXR ligands were found to be non-competitive alpha-glucosidase inhibitors, suggesting that it might be possible to separate the two activities. To test this idea, we focused on riccardin C, a naturally occurring LXR ligand, which we found here to be a potent alpha-glucosidase inhibitor as well. Structural development of riccardin C afforded novel LXR antagonists lacking alpha-glucosidase-inhibitory activity, 19c and 19f, and a LXRalpha-selective antagonist, 22.

Structural development of liver X receptor (LXR) antagonists derived from thalidomide-related glucosidase inhibitors.

Following our previous discovery of LXR antagonistic activity of 2'-substituted phenylphthalimides derived from thalidomide-related glucosidase inhibitors, structure-activity studies and further structural development led to 5-chloro-N-2'-n-pentylphenyl-1,3-dithiophthalimide (5CPPSS-50), with IC50 values of about 10 and 13 microM for LXRalpha and LXRbeta, respectively.

Predictive and sensory integration begins at an early stage of visual processing.

Brain activity was measured by magnetoencephalography to investigate the spatiotemporal stage of visual processing at which predictive and sensory integration begins. We examined the consequences of a visual mismatch between preliminary prediction and incoming stimulus. Following auditory cues (1000- and 1250-Hz tones) for prediction, congruent and incongruent images, pictures of two musical keys, were presented to volunteers. When they predicted visual inputs on the basis of preceding auditory cues, we detected a mismatch signal for predictive-sensory incongruities in the striate and extrastriate areas for 100-200 ms after image presentation. As this signal reflects a compatibility analysis, we propose that the integration process begins in these areas approximately 100 ms after image presentation.

Design, synthesis, and evaluation of potent, structurally novel peroxisome proliferator-activated receptor (PPAR) delta-selective agonists.

A series of 3-(4-alkoxyphenyl)propanoic acid derivatives was prepared as candidate peroxisome proliferator-activated receptor (PPAR) delta-selective agonists, based on our previously discovered potent human PPARalpha/delta dual agonist TIPP-401 as a lead compound. Structure-activity relationship studies clearly indicated the importance of the chain length of the alkoxy group at the 4-position, and the n-butoxy compound exhibited the most potent PPARdelta transactivation activity and highest PPARdelta selectivity. The (S)-enantiomer of a representative compound exhibited extremely potent PPARdelta transactivation activity, comparable with or somewhat superior to that of the known PPARdelta-selective agonist, GW-501516. The representative compound regulated the expression of genes involved in lipid and glucose homeostasis, and should be useful not only as a chemical tool to study PPARdelta function, but also as a candidate drug for the treatment of metabolic syndrome.

Liver X receptor antagonists with a phthalimide skeleton derived from thalidomide-related glucosidase inhibitors.

Alpha-glucosidase inhibitors with a chlorinated phthalimide or a thiophthalimide skeleton, derived from thalidomide, were found to possess liver X receptor (LXR) antagonistic activity. Novel LXR antagonists with a 2'-substituted phenylphthalimide skeleton were obtained by structural development of glucosidase inhibitors derived from thalidomide.