LRRTM3 regulates activity-dependent synchronization of synapse properties in topographically connected hippocampal neural circuits.

Synaptic cell-adhesion molecules (CAMs) organize the architecture and properties of neural circuits. However, whether synaptic CAMs are involved in activity-dependent remodeling of specific neural circuits is incompletely understood. Leucine-rich repeat transmembrane protein 3 (LRRTM3) is required for the excitatory synapse development of hippocampal dentate gyrus (DG) granule neurons. Here, we report that Lrrtm3-deficient mice exhibit selective reductions in excitatory synapse density and synaptic strength in projections involving the medial entorhinal cortex (MEC) and DG granule neurons, accompanied by increased neurotransmitter release and decreased excitability of granule neurons. LRRTM3 deletion significantly reduced excitatory synaptic innervation of hippocampal mossy fibers (Mf) of DG granule neurons onto thorny excrescences in hippocampal CA3 neurons. Moreover, LRRTM3 loss in DG neurons significantly decreased mossy fiber long-term potentiation (Mf-LTP). Remarkably, silencing MEC-DG circuits protected against the decrease in the excitatory synaptic inputs onto DG and CA3 neurons, excitability of DG granule neurons, and Mf-LTP in Lrrtm3-deficient mice. These results suggest that LRRTM3 may be a critical factor in activity-dependent synchronization of the topography of MEC-DG-CA3 excitatory synaptic connections. Collectively, our data propose that LRRTM3 shapes the target-specific structural and functional properties of specific hippocampal circuits.

STING recognition of viral dsDNA by nociceptors mediates pain in mice.

Pain is often one of the initial indicators of a viral infection, yet our understanding of how viruses induce pain is limited. Immune cells typically recognize viral nucleic acids, which activate viral receptors and signaling, leading to immunity. Interestingly, these viral receptors and signals are also present in nociceptors and are associated with pain. Here, we investigate the response of nociceptors to nucleic acids during viral infections, specifically focusing on the role of the viral signal, Stimulator of Interferon Genes (STING). Our research shows that cytosolic double-stranded DNA (dsDNA) from viruses, like herpes simplex virus 1 (HSV-1), triggers pain responses through STING expression in nociceptors. In addition, STING agonists alone can elicit pain responses. Notably, these responses involve the direct activation of STING in nociceptors through TRPV1. We also provided a proof-of-concept showing that STING and TRPV1 significantly contribute to the mechanical hypersensitivity induced by HSV-1 infection. These findings suggest that STING could be a potential therapeutic target for relieving pain during viral infections.

Mapping the semi-nested community structure of 3D chromosome contact networks.

Mammalian DNA folds into 3D structures that facilitate and regulate genetic processes such as transcription, DNA repair, and epigenetics. Several insights derive from chromosome capture methods, such as Hi-C, which allow researchers to construct contact maps depicting 3D interactions among all DNA segment pairs. These maps show a complex cross-scale organization spanning megabase-pair compartments to short-ranged DNA loops. To better understand the organizing principles, several groups analyzed Hi-C data assuming a Russian-doll-like nested hierarchy where DNA regions of similar sizes merge into larger and larger structures. Apart from being a simple and appealing description, this model explains, e.g., the omnipresent chequerboard pattern seen in Hi-C maps, known as A/B compartments, and foreshadows the co-localization of some functionally similar DNA regions. However, while successful, this model is incompatible with the two competing mechanisms that seem to shape a significant part of the chromosomes' 3D organization: loop extrusion and phase separation. This paper aims to map out the chromosome's actual folding hierarchy from empirical data. To this end, we take advantage of Hi-C experiments and treat the measured DNA-DNA interactions as a weighted network. From such a network, we extract 3D communities using the generalized Louvain algorithm. This algorithm has a resolution parameter that allows us to scan seamlessly through the community size spectrum, from A/B compartments to topologically associated domains (TADs). By constructing a hierarchical tree connecting these communities, we find that chromosomes are more complex than a perfect hierarchy. Analyzing how communities nest relative to a simple folding model, we found that chromosomes exhibit a significant portion of nested and non-nested community pairs alongside considerable randomness. In addition, by examining nesting and chromatin types, we discovered that nested parts are often associated with active chromatin. These results highlight that cross-scale relationships will be essential components in models aiming to reach a deep understanding of the causal mechanisms of chromosome folding.

Improving Pediatric Procedural Skills for EMS Clinicians: A Longitudinal Simulation-Based Curriculum with Novel, Remote, First-Person-View Video-Based Outcome Measurement.

OBJECTIVE: Emergency medical services (EMS) clinicians are expected to provide expert care to all patients, but face obstacles in maintaining skillsets required in the care of critically ill or injured children. The objectives of this study were to describe and assess the effectiveness of a pediatric-focused, simulation-based, procedural training program for EMS clinicians, delivered on-site by a pediatric simulation education team. We also describe a novel, remote, asynchronous performance outcome measurement system using first-person-view video review. METHODS: This was a prospective study of simulation-based training and procedural outcomes. The study population involved EMS clinicians at three fire-based EMS agencies stratified as urban, suburban, and rural sites. The primary outcome was performance of intraosseous catheterization (IO), bag-valve-mask ventilation (BVM), and supraglottic device placement (SGD), measured across three time points. Secondary outcomes were identification of differences across EMS agencies and participant survey responses. RESULTS: We obtained video data from 122 clinicians, totaling 561 videos, with survey response rates of 89.0-91.3%. Pre-intervention scores were high: least-square means (95% confident-intervals) 9.5 (8.9, 10.2) for IO; 9.6 (9.3, 9.9) for BVM; and 11.6 (10.9, 12.2) for SGD. There was significant improvement post-intervention: 11.5 (10.7, 12.3) for IO; 11.0 (10.7, 11.4) for BVM; and 13.6 (12.8, 14.4) for SGD. Improvement was maintained at follow-up after a median of 9.5 months: 10.5 (9.8, 11.2) for IO; 10.2 (9.9, 10.6) for BVM; and 12.4 (11.7, 13.1) for SGD. There were no statistical differences between sites. Of survey respondents, half had not cared for a critically ill or injured child in at least a year, the vast majority had not had hands-on pediatric training in over 6 months, and the majority felt that training should occur at least every 6 months. CONCLUSIONS: Our pediatric-focused, simulation-based procedural training program was associated with improvement and maintenance of high-baseline procedural performance for EMS clinicians over the study period. Findings were consistent across sites. Remote assessment was feasible. Participant surveys emphasized a desire for more pediatric-focused training and highlighted the low frequency of clinical exposure to procedures potentially needed in the care of critically ill or injured pediatric patients.

Clinical Characteristics and Treatment Outcomes of Pulmonary Diseases Caused by Coinfections With Multiple Nontuberculous Mycobacterial Species.

BACKGROUND: Coinfections with multiple nontuberculous mycobacterial (NTM) species have not been widely studied. We aimed to evaluate the clinical characteristics and treatment outcomes in patients with NTM-pulmonary disease (PD) caused by coinfection with multiple NTM species. METHODS: We retrospectively reviewed patients with NTM-PD at a tertiary referral hospital in Korea between March 2012 and December 2018. Coinfection was defined as two or more species of NTM pathogens isolated from the same respiratory specimen or different specimens within three months. RESULTS: Among 1,009 patients with NTM-PD, 147 (14.6%) NTM coinfections were observed (average age 64.7 years, 69.4% women). NTM species were identified more frequently (median 6 vs. 3 times, P < 0.001) in the coinfection group than in the single species group, and follow-up duration was also longer in the coinfection group (median 44.9 vs. 27.1 months, P < 0.001). Mycobacterium avium complex (MAC) and M. abscessus and M. massiliense (MAB) were the dominant combinations (n = 71, 48.3%). For patients treated for over six months in the MAC plus MAB group (n = 31), sputum culture conversion and microbiological cure were achieved in 67.7% and 41.9% of patients, respectively. We divided the MAC plus MAB coinfection group into three subgroups according to the target mycobacteria; however, no statistical differences were found in the treatment outcomes. CONCLUSION: In NTM-PD cases, a significant number of multiple NTM species coinfections occurred. Proper identification of all cultured NTM species through follow-up is necessary to detect multispecies coinfections. Further research is needed to understand the nature of NTM-PD in such cases.

Risk Factors for Unfavorable Outcomes of Tuberculosis in Korea: Implications for Patient-Centered Care in Tuberculosis Treatment.

BACKGROUND: The treatment success rate for tuberculosis (TB) has stagnated at 80-81% in South Korea, indicating unsatisfactory outcomes. Enhancing treatment success rate necessitates the development of individualized treatment approaches for each patient. This study aimed to identify the risk factors associated with unfavorable treatment outcomes to facilitate tailored TB care. METHODS: We retrospectively analyzed the data of patients with active TB between January 2019 and December 2020 at a single tertiary referral center. We classified unfavorable treatment outcomes according to the 2021 World Health Organization guidelines as follows: "lost to follow-up" (LTFU), "not evaluated" (NE), "death," and "treatment failure" (TF). Moreover, we analyzed risk factors for each unfavorable outcome using Cox proportional hazard regression analysis. RESULTS: A total of 659 patients (median age 62 years; male 54.3%) were included in the study. The total unfavorable outcomes were 28.1%: 4.6% LTFU, 9.6% NE, 9.1% deaths, and 4.9% TF. Multivariate analysis showed that a culture-confirmed diagnosis of TB was associated with a lower risk of LTFU (adjusted hazard ratio [aHR], 0.25; 95% confidence interval [CI], 0.10-0.63), whereas the occurrence of adverse drug reactions (ADRs) significantly increased the risk of LTFU (aHR, 6.63; 95% CI, 2.63-16.69). Patients living far from the hospital (aHR, 4.47; 95% CI, 2.50-7.97) and those with chronic kidney disease (aHR, 3.21; 95% CI, 1.33-7.75) were at higher risk of being transferred out to other health institutions (NE). Higher mortality was associated with older age (aHR, 1.06; 95% CI, 1.04-1.09) and comorbidities. The ADRs that occurred during TB treatment were a risk factor for TF (aHR, 6.88; 95% CI, 2.24-21.13). CONCLUSION: Unfavorable outcomes of patients with TB were substantial at a tertiary referral center, and the risk factors for each unfavorable outcome varied. To improve treatment outcomes, close monitoring and the provision of tailored care for patients with TB are necessary.

Controlled Bipolar Doping of One-Dimensional van der Waals Nb2Pd3Se8.

Tailoring the electrical properties of one-dimensional (1D) van der Waals (vdW) materials is desirable for their applications toward electronic devices by exploiting their unique characteristics. However, 1D vdW materials have not been extensively investigated for modulation of their electrical properties. Here we control doping levels and types of 1D vdW Nb2Pd3Se8 over a wide energy range by immersion in AuCl3 or ß-nicotinamide adenine dinucleotide (NADH) solutions, respectively. Through spectroscopic analyses and electrical characterizations, we confirm that the charges were effectively transferred to Nb2Pd3Se8, and the dopant concentration was adjusted to the immersion time. Furthermore, we make the axial p-n junction of 1D Nb2Pd3Se8 by a selective area p-doping using the AuCl3 solution, which exhibits rectifying behavior with an Iforward/Ireverse of 81 and an ideality factor of 1.2. Our findings could pave the way to more practical and functional electronic devices based on 1D vdW materials.

The Anti-Inflammatory Agent Bindarit Attenuates the Impairment of Neural Development through Suppression of Microglial Activation in a Neonatal Hydrocephalus Mouse Model.

Neonatal hydrocephalus presents with various degrees of neuroinflammation and long-term neurologic deficits in surgically treated patients, provoking a need for additional medical treatment. We previously reported elevated neuroinflammation and severe periventricular white matter damage in the progressive hydrocephalus (prh) mutant which contains a point mutation in the Ccdc39 gene, causing loss of cilia-mediated unidirectional CSF flow. In this study, we identified cortical neuropil maturation defects such as impaired excitatory synapse maturation and loss of homeostatic microglia, and swimming locomotor defects in early postnatal prh mutant mice. Strikingly, systemic application of the anti-inflammatory small molecule bindarit significantly supports healthy postnatal cerebral cortical development in the prh mutant. While bindarit only mildly reduced the ventricular volume, it significantly improved the edematous appearance and myelination of the corpus callosum. Moreover, the treatment attenuated thinning in cortical Layers II-IV, excitatory synapse formation, and interneuron morphogenesis, by supporting the ramified-shaped homeostatic microglia from excessive cell death. Also, the therapeutic effect led to the alleviation of a spastic locomotor phenotype of the mutant. We found that microglia, but not peripheral monocytes, contribute to amoeboid-shaped activated myeloid cells in prh mutants' corpus callosum and the proinflammatory cytokines expression. Bindarit blocks nuclear factor (NF)-kB activation and its downstream proinflammatory cytokines, including monocyte chemoattractant protein-1, in the prh mutant. Collectively, we revealed that amelioration of neuroinflammation is crucial for white matter and neuronal maturation in neonatal hydrocephalus. Future studies of bindarit treatment combined with CSF diversion surgery may provide long-term benefits supporting neuronal development in neonatal hydrocephalus.SIGNIFICANCE STATEMENT In neonatal hydrocephalus, little is known about the signaling cascades of neuroinflammation or the impact of such inflammatory insults on neural cell development within the perinatal cerebral cortex. Here, we report that proinflammatory activation of myeloid cells, the majority of which are derived from microglia, impairs periventricular myelination and cortical neuronal maturation using the mouse prh genetic model of neonatal hydrocephalus. Administration of bindarit, an anti-inflammatory small molecule that blocks nuclear factor (NF)-kB activation, restored the cortical thinning and synaptic maturation defects in the prh mutant brain through suppression of microglial activation. These data indicate the potential therapeutic use of anti-inflammatory reagents targeting neuroinflammation in the treatment of neonatal hydrocephalus.

Intersite Coulomb Interactions in Charge-Ordered Systems.

Using ab initio approaches for extended Hubbard interactions coupled to phonons, we reveal that the intersite Coulomb interaction plays important roles in determining various distinctive phases of the paradigmatic charge-ordered materials of Ba_{1-x}K_{x}AO_{3} (A=Bi and Sb). We demonstrated that all their salient doping dependent experiment features such as breathing instabilities, anomalous phonon dispersions, and transition between charge-density wave and superconducting states can be accounted for very well if self-consistently obtained nearest neighbor Hubbard interactions are included, thus establishing a minimal criterion for reliable descriptions of spontaneous charge orders in solids.

Deep learning-based clinical decision support system for gastric neoplasms in real-time endoscopy: development and validation study.

BACKGROUND : Deep learning models have previously been established to predict the histopathology and invasion depth of gastric lesions using endoscopic images. This study aimed to establish and validate a deep learning-based clinical decision support system (CDSS) for the automated detection and classification (diagnosis and invasion depth prediction) of gastric neoplasms in real-time endoscopy. METHODS : The same 5017 endoscopic images that were employed to establish previous models were used for the training data. The primary outcomes were: (i) the lesion detection rate for the detection model, and (ii) the lesion classification accuracy for the classification model. For performance validation of the lesion detection model, 2524 real-time procedures were tested in a randomized pilot study. Consecutive patients were allocated either to CDSS-assisted or conventional screening endoscopy. The lesion detection rate was compared between the groups. For performance validation of the lesion classification model, a prospective multicenter external test was conducted using 3976 novel images from five institutions. RESULTS : The lesion detection rate was 95.6 % (internal test). On performance validation, CDSS-assisted endoscopy showed a higher lesion detection rate than conventional screening endoscopy, although statistically not significant (2.0 % vs. 1.3 %; P = 0.21) (randomized study). The lesion classification rate was 89.7 % in the four-class classification (advanced gastric cancer, early gastric cancer, dysplasia, and non-neoplastic) and 89.2 % in the invasion depth prediction (mucosa confined or submucosa invaded; internal test). On performance validation, the CDSS reached 81.5 % accuracy in the four-class classification and 86.4 % accuracy in the binary classification (prospective multicenter external test). CONCLUSIONS : The CDSS demonstrated its potential for real-life clinical application and high performance in terms of lesion detection and classification of detected lesions in the stomach.

Ulnar neuropathy at the elbow: associations of pre-operative DTI parameters with clinical outcomes after cubital tunnel decompression.

OBJECTIVES: To evaluate whether DTI parameters of the ulnar nerve at the elbow are associated with clinical outcomes in patients receiving cubital tunnel decompression (CTD) surgery for ulnar neuropathy. METHODS: This retrospective study included 21 patients with cubital tunnel syndrome who received CTD surgery between January 2019 and November 2020. All patients underwent pre-operative elbow MRI, including DTI. Region-of-interest analysis was performed on the ulnar nerve at three levels around the elbow: above (level 1), cubital tunnel (level 2), and below (level 3). Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were calculated on three sections at each level. Clinical data on symptom improvement in respect to pain and tingling sensation after CTD were recorded. Logistic regression analysis was used to compare DTI parameters of the nerve at three levels and the entire nerve course between patients with and without symptom improvement after CTD. RESULTS: After CTD, 16 patients showed improvement in symptoms, but five did not. ROC analysis of DTI parameters showed that AUCs of FA, AD, and MD were higher at level 1 than at levels 2 and 3, with FA showing the highest AUC (level 1: FA, 0.7104 [95% CI, 0.5206-0.9002] vs AD, 0.6521 [95% CI, 0.4900-0.8142] vs MD, 0.6153 [95% CI, 0.4187-0.8119]). CONCLUSION: In patients who underwent CTD surgery for ulnar neuropathy at the elbow, the DTI parameters of FA, AD, and MD above the cubital tunnel level were associated with clinical outcomes, with FA showing the strongest associations. KEY POINTS: • After CTD surgery for ulnar neuropathy at the elbow, persistent symptoms may be observed, depending on symptom severity. • DTI parameters of the ulnar nerve at the elbow showed differences in their capacity for discriminating between patients with and without symptom improvement following CTD surgery, with this capacity depending on the nerve level at the elbow. • FA, AD, and MD measured above the cubital tunnel on pre-operative DTI may be associated with surgical outcomes, with FA showing the strongest association (AUC at level 1, 0.7104 [95% CI, 0.5206-0.9002]).

When MRI would be useful in patients without evidence of sacroiliitis on radiographs?

We aimed to identify when magnetic resonance imaging (MRI) would be useful to diagnose patients with suspected axial spondyloarthropathy (AxSpA) without evidence of sacroiliitis on radiographs. We retrospectively reviewed electronic medical records of patients who underwent pelvis MRI after radiographs at the rheumatology clinic in a single tertiary center in Korea. Patients underwent imaging from January 2020 to July 2022. We collected data including complete blood count, erythrocyte sedimentation rate, C-reactive protein (CRP), human leukocyte antigen (HLA)-B27, history of acute anterior uveitis (AAU), peripheral arthritis, dactylitis, inflammatory bowel disease (IBD), enthesopathy, and psoriasis. A total of 105 patients who showed no evidence of sacroiliitis on radiographs were included. The median age of patients was 41.0 years, and 44.8% were male. Of them, 34 showed sacroiliitis on MRI (group 1), and 71 showed no evidence of sacroiliitis even on MRI (group 2). Known AxSpA-related clinical features including AAU, peripheral arthritis, dactylitis, IBD, enthesopathy, and psoriasis were not different between the two groups. HLA-B27 positivity (79.4% vs. 40.0%, p < 0.001), median white blood cell count (7700 vs. 6300, p = 0.007), mean platelet count (307.7 ± 69.7 vs. 265.3 ± 68.9 × 103/µL, p = 0.005), and median CRP level (0.38 vs. 0.10, p = 0.001) showed significant differences between the two groups. In a multivariate analysis, HLA-B27 positivity and platelet count were significantly associated with sacroiliitis on MRI. In our cohort, sacroiliitis was observed on MRI in one-third of patients without radiographic evidence. MRI could be recommended to evaluate sacroiliitis in patients with positive HLA-B27 and a high platelet count.

Changes of regional cerebral blood flow after repeated transcranial direct current stimulation in healthy participants: a pilot study.

BACKGROUND: Transcranial direct current stimulation (tDCS) can potentially enhance brain function and cognition in healthy individuals as well as in patients with cognitive impairment. However, neural correlates of repeated tDCS remain relatively unexplored in a healthy population. PURPOSE: To assess the effects of repeated tDCS on regional cerebral blood flow (rCBF) in healthy volunteers in a pilot investigation. MATERIAL AND METHODS: Five healthy adults received bifrontal tDCS to the dorsolateral prefrontal cortex (F3-F4 montage, 1 mA intensity, 30 minutes/session, five sessions/week) over four weeks. All participants underwent brain single-photon emission computed tomography (SPECT) scans at baseline and one week after the last tDCS session. Changes in rCBF were examined using Statistical Parametric Mapping. RESULTS: Resting rCBF was significantly improved in the right superior frontal gyrus at the follow-up (P < 0.001). Adverse events were not reported and the stimulation was well-tolerated. CONCLUSION: Repeated tDCS may be effective for enhancing brain function in healthy participants. Larger sham-controlled studies should be performed to confirm our preliminary findings.

Krill Oil's Protective Benefits against Ultraviolet B-Induced Skin Photoaging in Hairless Mice and In Vitro Experiments.

Krill oil (KO) shows promise as a natural marine-derived ingredient for improving skin health. This study investigated its antioxidant, anti-inflammatory, anti-wrinkle, and moisturizing effects on skin cells and UVB-induced skin photoaging in hairless mice. In vitro assays on HDF, HaCaT, and B16/F10 cells, as well as in vivo experiments on 60 hairless mice were conducted. A cell viability assay, diphenyl-1-picryhydrazyl (DPPH) radical scavenging activity test, elastase inhibition assay, procollagen content test, MMP-1 inhibition test, and hyaluronan production assay were used to experiment on in vitro cell models. Mice received oral KO administration (100, 200, or 400 mg/kg) once a day for 15 weeks and UVB radiation three times a week. L-Ascorbic acid (L-AA) was orally administered at 100 mg/kg once daily for 15 weeks, starting from the initial ultraviolet B (UVB) exposures. L-AA administration followed each UVB session (0.18 J/cm2) after one hour. In vitro, KO significantly countered UVB-induced oxidative stress, reduced wrinkles, and prevented skin water loss by enhancing collagen and hyaluronic synthesis. In vivo, all KO dosages showed dose-dependent inhibition of oxidative stress-induced inflammatory photoaging-related skin changes. Skin mRNA expressions for hyaluronan synthesis and collagen synthesis genes also increased dose-dependently after KO treatment. Histopathological analysis confirmed that krill oil (KO) ameliorated the damage caused by UVB-irradiated skin tissues. The results imply that KO could potentially act as a positive measure in diminishing UVB-triggered skin photoaging and address various skin issues like wrinkles and moisturization when taken as a dietary supplement.

Epidemiologic and Clinical Features of Campylobacter Enteritis Before and During COVID-19 in Korea.

BACKGROUND: With the increase in meals at home due to coronavirus disease 2019 (COVID-19), the pattern and incidence of enteritis seemed to change. Some types of enteritis, such as Campylobacter enteritis, appear to have increased. Our study aimed to evaluate the change in the trend of enteritis, especially Campylobacter enteritis, before COVID-19 (2016-2019) and at the present time during COVID-19 in South Korea. METHODS: We analyzed data from the Health Insurance Review and Assessment Service. From 2016 to 2020, the International Classification of Diseases codes related to enteritis were examined to distinguish bacterial and viral enteritis and the trends of each were analyzed. The aspects of enteritis, before and after the COVID-19 outbreak, were compared. RESULTS: Both bacterial and viral enteritis declined in all age groups from 2016 to 2020 (P < 0.001). In 2020, the reduction rate of viral enteritis was higher than that of bacterial enteritis. However, unlike other causes of enteritis, even after COVID-19, Campylobacter enteritis increased in all age groups. An increase of Campylobacter enteritis in 2020 was particularly noticeable in children and adolescents. The prevalence of viral and bacterial enteritis was higher in urban areas than in rural areas (P < 0.001). Campylobacter enteritis was more common in the rural areas (P < 0.001). CONCLUSION: Although the prevalence of bacterial and viral enteritis have decreased in COVID-19, Campylobacter enteritis has increased in all age groups and in rural areas compared to urban areas. Recognizing that the trend of Campylobacter enteritis before and during COVID-19 is helpful for future public health measures and interventions.

Sex-Based Outcomes of P2Y12 Inhibitor Monotherapy After Three Months of Dual Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention.

BACKGROUND: In patients undergoing percutaneous coronary intervention (PCI) in the SMART-CHOICE trial, P2Y12 inhibitor monotherapy after three months of dual antiplatelet therapy (DAPT) achieved clinical outcomes comparable to those of 12 months of DAPT. Nonetheless, the effects of sex on these outcomes remain unknown. METHODS: This open-label, non-inferiority, randomized study, conducted in 33 hospitals in South Korea, included 2,993 patients undergoing PCI with drug-eluting stents. Patients were randomly assigned to receive DAPT (aspirin plus a P2Y12 inhibitor) for three months then P2Y12 inhibitor alone for nine months, or DAPT for the entire 12 months. The primary endpoints were major adverse cardiac and cerebrovascular events (a composite of all-cause death, myocardial infarction, or stroke) 12 months after the index procedure. The bleeding endpoints were Bleeding Academic Research Consortium (BARC) bleeding types 2 to 5. RESULTS: Of the patients, 795 (26.6%) were women, who were older and had a higher prevalence of hypertension, diabetes, and dyslipidemia than men. The sexes exhibited comparable primary endpoints (adjusted hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.55-1.55; P = 0.770) and bleeding endpoints (adjusted HR, 1.07; 95% CI, 0.63-1.81; P = 0.811). P2Y12 inhibitor monotherapy vs DAPT was associated with lower risk of BARC type 2 to 5 bleeding in women (adjusted HR, 0.40; 95% CI, 0.16-0.98; P = 0.045) but the difference was not statistically significant when using the Bonferroni correction. The primary endpoints were similar between treatment groups in both sexes. CONCLUSION: In both sexes undergoing PCI, P2Y12 inhibitor monotherapy after three months of DAPT achieved similar risks of the primary endpoints and the bleeding events compared with prolonged DAPT. Therefore, the benefits of early aspirin withdrawal with ongoing P2Y12 inhibitors may be comparable in women and men. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02079194.

Targeting Nociceptive Neurons and Transient Receptor Potential Channels for the Treatment of Migraine.

Migraine is a neurovascular disorder that affects approximately 12% of the global population. While its exact causes are still being studied, researchers believe that nociceptive neurons in the trigeminal ganglia play a key role in the pain signals of migraine. These nociceptive neurons innervate the intracranial meninges and convey pain signals from the meninges to the thalamus. Targeting nociceptive neurons is considered promising due to their accessibility and distinct molecular profile, which includes the expression of several transient receptor potential (TRP) channels. These channels have been linked to various pain conditions, including migraine. This review discusses the role and mechanisms of nociceptive neurons in migraine, the challenges of current anti-migraine drugs, and the evidence for well-studied and emerging TRP channels, particularly TRPC4, as novel targets for migraine prevention and treatment.

Comparative Analysis of Preoperative High Frequency Color Doppler Ultrasound versus MR Lymphangiography versus ICG Lymphography of Lymphatic Vessels in Lymphovenous Anastomosis.

BACKGROUND: Despite the extensive use of various imaging modalities, there is limited literature on comparing the reliability between indocyanine green (ICG) lymphography, MR Lymphangiogram (MRL), and high frequency color Doppler ultrasound (HFCDU) to identify lymphatic vessels. METHOD: In this study of 124 patients, the correlation between preoperative image findings to the actual lymphatic vessel leading to lymphovenous anastomosis (LVA) was evaluated. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and simple detection were calculated. Subgroup analysis was also performed according to the severity of lymphedema. RESULTS: Total of 328 LVAs were performed. The HFCDU overall had significantly higher sensitivity for identifying lymphatic vessels (99%) over MRL (83.5%) and ICG lymphography (82.3%)(p < 0.0001). Both ICG lymphography and HFCDU had 100% specificity and PPV. The NPV was 3.6%, 6.5% and 57.1% respectively for MRL, ICG lymphography, and HFCDU. All modalities showed high sensitivity for early stage 2 lymphedema while HFCDU showed a significantly higher sensitivity for late stage 2 (MRL:79.7%, ICG:83.1%, HFCDU:97%) and stage 3 (MRL:79.7%, ICG:79.7%, HFCDU:100%) over the other two modalities (p < 0.0001). CONCLUSION: This study demonstrated while all three modalities are able to provide good information, the sensitivity may alter as the severity of lymphedema progresses. The HFCDU will provide the best detection for lymphatic vessels throughout all stages of lymphedema. However, as each modality provides different and unique information, combining and evaluating the data according to the stage of lymphedema will be able to maximize the chance for a successful surgical outcome.

Effect of Rowachol on the Gallbladder Dysmotility Disorder Based on Gallbladder Ejection Fraction.

Background and Objectives: Although laparoscopic cholecystectomy is the preferred treatment method in patients who experience typical biliary pain with or without gallstones, medical treatment has not been extensively studied. Rowachol is a potent choleretic agent, comprising six cyclic monoterpenes. This study aimed to investigate the clinical improvement and changes in gallbladder ejection fraction (GBEF) by Rowachol treatment in patients with typical biliary pain. Materials and Methods: We retrospectively reviewed 138 patients with typical biliary pain who underwent cholescintigraphy from July 2016 to April 2022. We included patients who received Rowachol for more than 2 months and underwent follow-up GBEF measurements. Finally, we analyzed pre- and post-treatment symptoms and GBEF. GBEF was calculated using the fatty meal-stimulated cholescintigraphy. Results: This retrospective observational study included 31 patients; their median age was 46.0 (range, 26.0-72.7) years, and 22 (71.0%) were female. Overall, 9 (29.0%) patients had gallbladder stones or sludges (maximum size: 2 mm) on initial transabdominal ultrasonography. During a median follow-up of 23.3 months, the symptoms of 21 (67.7%) patients were resolved after a median Rowachol treatment of 10.0 months. The mean GBEF was significantly improved after Rowachol treatment (initial cholescintigraphy: 42.6% ± 16.2%; follow-up cholescintigraphy: 53.0% ± 18.1%, p = 0.012). In patients with a GBEF ≤35% (n = 9), Rowachol significantly increased the GBEF from 21.3% ± 8.3% to 49.1% ± 20.7% (p = 0.008). Conclusions: Rowachol may have beneficial medical effects that can improve gallbladder dysfunction and treatment response.

The Comparison of Clinical Outcomes in Elderly (≥75 Years) and Non-Elderly (<75 Years) Patients with Acute Cholangitis Due to Choledocholithiasis.

Background and Objectives: Acute cholangitis may be fatal, particularly in elderly patients. According to the Tokyo Guidelines 2018, those aged ≥75 years are classified as moderate (Grade II) severity. However, it has not been established whether age itself is the deciding factor of poor outcomes. We studied the impact of old age (≥75 years) on the mortality and morbidity of acute cholangitis due to choledocholithiasis. Materials and Methods: We retrospectively examined 260 patients with calculous acute cholangitis who had undergone biliary drainage. Patients were divided into two groups: elderly (≥75 years) and non-elderly (<75 years). We aimed to compare organ dysfunction, in-hospital mortality, intensive care unit (ICU) hospitalization, and the severity of acute cholangitis. Results: Of 260 patients, 134 (51.5%) were in the elderly group and 126 (48.5%) were in the non-elderly group. The mean age was 72.3 ± 14.4 years, and 152 (58.5%) were men. The elderly patients showed a higher incidence of shock (12.7% vs. 4.8%, p = 0.029), respiratory dysfunction (7.5% vs. 0%, p = 0.002), and renal dysfunction (8.2% vs. 0.8%, p = 0.006) than the non-elderly patients. The overall in-hospital mortality rate was 2.7%, with no significant differences between the elderly and the non-elderly (4.5% vs. 0.8%, p = 0.121). The incidence of severe acute cholangitis was significantly higher in the elderly group (26.9% vs. 9.5%, p < 0.001). However, there was no significant difference in the rates of ICU hospitalization (9.7% vs. 4%, p = 0.088) and lengths of hospital stay (LOS) (8.3 d vs. 7.1 d, p = 0.086). Conclusions: No difference was observed in the in-hospital mortality, ICU hospitalization, or LOS between the elderly (≥75 years) and the non-elderly (<75 years) with calculous acute cholangitis. However, severe acute cholangitis was significantly more frequent in elderly patients.