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Abstract Neurodegenerative disorders are characterized by the decline of cognitive function and the progressive loss of memory. The dysfunctions of the cognitive and memory system are closely related to the decreases in brain-derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB) signalings. Ribes fasciculatum, a medicinal plant grown in diverse countries, has been reported to pharmacological effects for autoimmune diseases and aging recently. Here we found that afzelin is a major compound in Ribes fasciculatum. To further examine its neuroprotective effect, the afzelin (100 ng/µl, three times a week) was administered into the third ventricle of the hypothalamus of C57BL/6 mice for one month and scopolamine was injected (i.p.) to these mice to impair cognition and memory before each behavior experiment. The electrophysiology to measure long-term potentiation and behavior tests for cognitive and memory functions were performed followed by investigating related molecular signaling pathways. Chronic administration of afzelin into the brain ameliorated synaptic plasticity and cognitive/memory behaviors in mice given scopolamine. Studies of mice’s hippocampi revealed that the response of afzelin was accountable for the restoration of the cholinergic systems and molecular signal transduction via CREB-BDNF pathways. In conclusion, the central administration of afzelin leads to improved neurocognitive and neuroprotective effects on synaptic plasticity and behaviors partly through the increase in CREB-BDNF signaling.

We aimed to compare the associations of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) with coronary artery calcification (CAC). Patients who simultaneously underwent ultrasonography to diagnose hepatic steatosis and cardiac computed tomography to detect CAC were included. The presence and severity of CAC were defined with CAC-score thresholds of > 0 and > 300, respectively, and patients were divided into the following groups: no MASLD or MAFLD (reference), MASLD-only, MAFLD-only, and overlapping groups. Overall, 1,060/2,773 (38.2%) patients had CAC, of which 196 (18.5%) had severe CAC. The MASLD and MAFLD prevalence rates were 32.6% and 45.2%, respectively, with an overlap of 30.7%. In an ASCVD risk score-adjusted model, both MASLD (adjusted odd ratios [aOR], 1.21; 95% confidence interval [CI], 1.02-1.44; p = 0.033) and MAFLD (aOR 1.20; 95% CI 1.01-1.42, p = 0.034) were associated with CAC, whereas only MASLD (aOR 1.38; 95% CI 1.01-1.89, p = 0.041) was associated with severe CAC. Compared to the reference group, the overlapping group showed an association with CAC (aOR 1.22; 95% CI 1.01-1.47; p = 0.038); however, the MASLD and MAFLD subgroups did not differ in their association with CAC. MASLD may predict a higher risk of ASCVD more effectively than MAFLD.

The COVID-19 pandemic has resulted in a massive adaptation in health professions education, with a shift from in-person learning activities to a sudden heavy reliance on internet-mediated education. Some health professions schools will have already had considerable educational technology and cultural infrastructure in place, making such a shift more of a different emphasis in provision. For others, this shift will have been a considerable dislocation for both educators and learners in the provision of education. To aid educators make this shift effectively, this 12 Tips article presents a compendium of key principles and practical recommendations that apply to the modalities that make up online learning. The emphasis is on design features that can be rapidly implemented and optimised for the current pandemic. Where applicable, we have pointed out how these short-term shifts can also be beneficial for the long-term integration of educational technology into the organisations' infrastructure. The need for adaptability on the part of educators and learners is an important over-arching theme. By demonstrating these core values of the health professions school in a time of crisis, the manner in which the shift to online learning is carried out sends its own important message to novice health professionals who are in the process of developing their professional identities as learners and as clinicians.

Modelled water-mass changes in the North Pacific thermocline from CMIP6, both in the subsurface and at the surface, reveal the impact of the competition between anthropogenic aerosols and greenhouse gases (GHGs) over the past 6 decades. The aerosol effect overwhelms the GHG effect during 1950-1985 in driving salinity changes on density surfaces, while after 1985 the GHG effect dominates. These subsurface water-mass changes are traced back to changes at the surface, of which ~70% stems from the migration of density surface outcrops, equatorward due to regional cooling by anthropogenic aerosols and subsequent poleward due to warming by GHGs. Ocean subduction connects these surface outcrop changes to the main thermocline. Both observations and models reveal this transition in climate forcing around 1985 and highlight the important role of anthropogenic aerosol climate forcing on our oceans’ water masses.

Abstract Background Neck pain and primary headache disorders are highly prevalent in populations and clinical cohorts. Medication-overuse headache (MOH) is a treatable secondary headache, mainly developing in migraine sufferers, that accounts for the majority of patients presenting to headache clinics. Nevertheless, the association between neck pain and MOH has not been reported. This study evaluated the prevalence and clinical course of neck pain in patients with MOH before and after MOH treatment. Methods We analyzed 635 MOH patients enrolled in a nationwide, prospective, multicenter MOH registry. Demographics and clinical data were collected at baseline and 3 months to evaluate changes in the status and severity of neck pain and headache. Severity of neck pain was graded into 4 groups, and severe neck pain was defined as grade 3 or 4. Results Among 635 patients with MOH, 366 (57.6%) reported neck pain at baseline. MOH patients with neck pain had an earlier onset of their primary headache disorder (23.4 ± 12.7 vs. 26.2 ± 13.3 years, p = 0.007). Although monthly headache days were comparable between the patients with neck pain and those without neck pain, the neck pain group had higher levels of anxiety (7.4 ± 5.8 vs. 6.4 ± 5.4, p = 0.017), more severe cutaneous allodynia (2.4 ± 3.3 vs. 1.8 ± 3.0, p = 0.038), and poorer quality of life (171.7 ± 70.4 vs. 184.0 ± 68.9, p = 0.029). At 3 months, 456 (71.8%) were followed-up, and 257 (56.4%) were recovered from MOH. Compared to the baseline, the proportion of severe neck pain (40.4% vs. 19.4%, p

Background We explored the utility of a small multi-gene DNA panel for assessing molecular profiles of thyroid nodules and influencing clinical decisions by comparing outcomes between tested and untested nodules. Methods Between April 2022 and May 2023, we prospectively performed fine-needle aspiration (FNA) with gene testing via DNA panel of 11 genes (BRAF, RAS [NRAS, HRAS, KRAS], EZH1, DICER1, EIF1AX, PTEN, TP53, PIK3CA, TERT promoter) in 278 consecutive nodules (panel group). Propensity score-matching (1:1) was performed with 475 nodules that consecutively underwent FNA without gene testing between January 2021 and December 2021 (control group). Results In the panel group, positive call rate for mutations was 41.7% (BRAF 16.2%, RAS 12.6%, others 11.5%, double mutation 1.4%) for all nodules, and 40.0% (BRAF 4.3%, RAS 19.1%, others 15.7%, double mutation 0.9%) for indeterminate nodules. Benign call rate was 69.8% for all nodules, and 75.7% for indeterminate nodules. In four nodules, additional TP53 (in addition to BRAF or EZH1) or PIK3CA (in addition to BRAF or TERT) mutations were co-detected. Sensitivity, specificity, positive predictive value, and negative predictive value were 80.0%, 53.3%, 88.1%, 38.1% for all nodules, and 78.6%, 45.5%, 64.7%, 62.5% for indeterminate nodules, respectively. Panel group exhibited lower surgical resection rates than the control group for all nodules (27.0% vs. 52.5%, P

Abstract Background The efficacy of cell implantation via 3D-spheroids to treat basal tone in fecal incontinence remains unclear. To address this, in this study, we aimed to identify cell differentiation and assess the development of a contractile phenotype corresponding to smooth muscle cells (SMCs) following implantation of 3D-spheroid and 2D-cultured human adipose stem cells (hASCs) in an in vivo internal anal sphincter (IAS)-targeted mouse model. Methods We developed an IAS-targeted in vivo model via rapid freezing (at − 196 °C) of the dorsal layers of the region of interest (ROI) of the IAS ring posterior quarter, between the submucosal and muscular layers, following submucosal dissection (n = 60 rats). After implantation of tetramethylindocarbocyanine perchlorate (Dil)-stained 3D and 2D-cells into randomly allocated cryoinjured rats, the entire sphincter ring or only the cryoinjured ROI was harvested. Expression of SMC markers, RhoA/ROCKII and its downstream molecules, and fibrosis markers was analyzed. Dil, α-smooth muscle actin (α-SMA), and RhoA signals were used for cell tracking. Results In vitro, 3D-spheroids exhibited higher levels of SMC markers and RhoA/ROCKII-downstream molecules than 2D-hASCs. The IAS-targeted cryoinjured model exhibited substantial loss of SMC layers of the squamous epithelium lining of the anal canal, as well as reduced expression of SMC markers and RhoA-related downstream molecules. In vivo, 3D-spheroid implantation induced SMC markers and contractile molecules weakly at 1 week. At 2 weeks, the mRNA expression of aSma, Sm22a, Smoothelin, RhoA, Mypt1, Mlc 20 , Cpi17, and Pp1cd increased, whereas that of fibrosis markers reduced significantly in the 3D-spheroid implanted group compared to those in the sham, non-implanted, and 2D-hASC implanted groups. Protein levels of RhoA, p-MYPT1, and p-MLC20 were higher in the 3D-spheroid-implanted group than in the other groups. At 2 weeks, in the implanted groups, the cryoinjured tissues (which exhibited Dil, α-SMA, and RhoA signals) were restored, while they remained defective in the sham and non-implanted groups. Conclusions These findings demonstrate that, compared to 2D-cultured hASCs, 3D-spheroids more effectively induce a contractile phenotype that is initially weak but subsequently improves, inducing expression of RhoA/ROCKII-downstream molecules and SMC differentiation associated with IAS basal tone.

Abstract We aimed to compare the associations of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated fatty liver disease (MAFLD) with coronary artery calcification (CAC). Patients who simultaneously underwent ultrasonography to diagnose hepatic steatosis and cardiac computed tomography to detect CAC were included. The presence and severity of CAC were defined with CAC-score thresholds of > 0 and > 300, respectively, and patients were divided into the following groups: no MASLD or MAFLD (reference), MASLD-only, MAFLD-only, and overlapping groups. Overall, 1,060/2,773 (38.2%) patients had CAC, of which 196 (18.5%) had severe CAC. The MASLD and MAFLD prevalence rates were 32.6% and 45.2%, respectively, with an overlap of 30.7%. In an ASCVD risk score-adjusted model, both MASLD (adjusted odd ratios [aOR], 1.21; 95% confidence interval [CI], 1.02–1.44; p = 0.033) and MAFLD (aOR 1.20; 95% CI 1.01–1.42, p = 0.034) were associated with CAC, whereas only MASLD (aOR 1.38; 95% CI 1.01–1.89, p = 0.041) was associated with severe CAC. Compared to the reference group, the overlapping group showed an association with CAC (aOR 1.22; 95% CI 1.01–1.47; p = 0.038); however, the MASLD and MAFLD subgroups did not differ in their association with CAC. MASLD may predict a higher risk of ASCVD more effectively than MAFLD.

Background: We present the initial outcomes of transoral robotic parathyroidectomy (TORP) using the transoral vestibular approach in patients with primary hyperparathyroidism (PHPT). Method: A retrospective case series analysis was performed on patients diagnosed with PHPT between October 2016 and July 2019 who underwent transoral robotic surgery for parathyroidectomy. Results: Thirteen patients (five males and eight females) successfully underwent TORP at our institution from October 2016 to July 2019. Eight patients underwent TORP alone, and five underwent TORP combined with transoral robotic thyroidectomy for papillary thyroid carcinoma. No intra- or postoperative complications were observed. Serum levels of parathyroid hormone, total calcium, and ionized calcium decreased to normal postoperatively and continued to decrease during the follow-up period. Conclusion: This study suggests that TORP holds promise for the treatment of patients with PHPT with the advantages of the robotic procedure, including dynamic visualization and meticulous dissection.

Background: /purposeIn cases where oral squamous cell carcinoma (OSCC) invades the jawbone, clinicians frequently observe abnormal attenuation on computed tomography (CT) and pathologic signal intensity (SI) on magnetic resonance (MR) imaging of the affected underlying bone marrow. This study introduced a concept of “underlying bone change” to examine its association with clinicopathological features and prognosis of OSCC, as well as its correlation with medullary invasion. Materials and methods: We enrolled 93 consecutive patients diagnosed with OSCC, who underwent mandibulectomy between 2010 and 2016. CT and MR images, along with electronic medical records, were reviewed to evaluate correlations between underlying bone changes, clinicopathological features, five-year overall survival, and medullary invasion. Results: Of the 93 patients, 69 (74.2%) exhibited underlying bone sclerosis on CT, and 74 (79.6%) displayed pathological SI on MR images. These underlying bone changes correlated with the T stage and recurrence, but not with overall survival.Medullary invasion, observed in 61 (65.6%) patients, was strongly associated with T and TNM stages and was linked to poorer overall survival.The underlying bone changes on CT and MR images were positively associated with medullary invasion; however, no significant differences were found in the occurrence of underlying bone changes between the subtypes based on the extent of medullary invasion. Conclusion: Underlying bone changes on CT and MR images can provide valuable insights into the aggressiveness of bone invasion by OSCC. Accurate interpretation of these imaging findings might be crucial for correctly delineating surgical margins and preventing the overestimation of tumor extent.

This study aims to examine the impact of reduced in-person learning during COVID-19 on students' academic achievement gaps focusing on rural--urban and in-school disparities. To this end, first, we investigated the regional disparity of student performance between Seoul and Gangwon, representative areas of urban and rural regions in South Korea, using t test analysis. Second, we conducted a regression analysis to analyze how the number of in-school days is associated with the student performance gap by controlling the regions. Our findings from the two analyses can be summarized as follows: First, we observed a difference in patterns between the two regions. In Seoul, student performance was polarized at the two ends of the grade spectrum, whereas in Gangwon Province, achievement declined overall between pre- and post-COVID-19. Second, in the case of Seoul, the proportion of mid-range achievement students decreased after COVID-19, whereas in Gangwon Province, COVID-19 did not have a significant effect on students' B, C, and D grades. Third, regardless of region, more in-person learning was associated with a higher portion of mid-range grades. Based on the findings, we suggested several policy implementations to cope with student performance gaps, which can facilitate the governmental response to nationwide crises that may emerge in the future.

Modeled water-mass changes in the North Pacific thermocline, both in the subsurface and at the surface, reveal the impact of the competition between anthropogenic aerosols (AAs) and greenhouse gases (GHGs) over the past 6 decades. The AA effect overwhelms the GHG effect during 1950-1985 in driving salinity changes on density surfaces, while after 1985 the GHG effect dominates. These subsurface water-mass changes are traced back to changes at the surface, of which ~70% stems from the migration of density surface outcrops, equatorward due to regional cooling by AAs and subsequent poleward due to warming by GHGs. Ocean subduction connects these surface outcrop changes to the main thermocline. Both observations and models reveal this transition in climate forcing around 1985 and highlight the important role of AA climate forcing on our oceans' water masses.

Abstract No study has analysed the temporal trends of the long-term results and clinical characteristics of patients with hepatocellular carcinoma (HCC) treated using radiofrequency ablation (RFA). Therefore, we examined temporal trends of characteristics of patients and treatment-naïve HCCs within the Milan criteria treated by RFA over 20 years. We retrospectively analysed 1099 patients with HCC within the Milan criteria treated with percutaneous RFA from January 2000 to December 2019. The overall survival (OS), recurrence-free survival (RFS), and factors affecting survival and local tumor progression were analysed using the Kaplan‒Meier method and Cox proportional hazards model. A trend test was performed to analyse the changing trends in participants and treatment outcomes. The overall and RFS of patients improved during the later period. In addition, viral hepatitis-related HCC incidence decreased, whereas that of alcohol- or non-alcoholic fatty liver disease-related HCC increased from the earlier to the later period (P for trend

Abstract It is still challenging to predict the efficacy of cisplatin-based therapy, particularly in relation to the activation of macroautophagy/autophagy in oral squamous cell carcinoma (OSCC). We studied the effect of selected chromatin remodeling genes on the cisplatin resistance and their interplay with autophagy in 3-dimensional tumor model and xenografts. We analyzed gene expression patterns in the cisplatin-sensitive UMSCC1, and a paired cisplatin-resistant UM-Cis cells. Many histone protein gene clusters involved in nucleosome assembly showed significant difference of expression. Gain- and loss-of-function analyses revealed an inverse correlation between cisplatin resistance and HIST1H3D expression, while a positive correlation was observed with HIST3H2A or HIST3H2B expression. In UM-Cis, HIST3H2A- and HIST3H2B-mediated chromatin remodeling upregulates autophagy status, which results in cisplatin resistance. Additionally, knockdown of HIST3H2A or HIST3H2B downregulated autophagy-activating genes via chromatin compaction of their promoter regions. MiTF, one of the key autophagy regulators upregulated in UM-Cis, negatively regulated transcription of HIST1H3D, suggesting an interplay between chromatin remodeling-dependent cisplatin resistance and autophagy. On comparing the staining intensity between cisplatin-sensitive and –insensitive tissues from OSCC patients, protein expression pattern of the selected histone protein genes were matched with the in vitro data. By examining the relationship between autophagy and chromatin remodeling genes, we identified a set of candidate genes with potential use as markers predicting chemoresistance in OSCC biopsy samples.

Abstract Introduction Electromagnetic navigation bronchoscopy (ENB) and radial probe endobronchial ultrasound (RP‐EBUS) are essential bronchoscopic procedures for diagnosing peripheral lung lesions. Despite their individual advantages, the optimal circumstances for their combination remain uncertain. Methods This single‐center retrospective study enrolled 473 patients with 529 pulmonary nodules who underwent ENB and/or RP‐EBUS biopsies between December 2021 and December 2022. Diagnostic yield was calculated using strict, intermediate, and liberal definitions. In the strict definition, only malignant and specific benign lesions were deemed diagnostic at the time of the index procedure. The intermediate and liberal definitions included additional results from the follow‐up period. Results The diagnostic yield of the strict definition was not statistically different among the three groups (ENB/Combination/RP‐EBUS 63.8%/64.2%/62.6%, p = 0.944). However, the diagnostic yield was superior in the ENB + RP‐EBUS group for nodules with a bronchus type II or III and a solid part

Objective To assess the influence of advanced maternal age on congenital malformations, short- and long-term outcomes in offspring of nulligravida. Methods A retrospective study was conducted using the Korean National Health Insurance Service database spanning from January 2005 to December 2019. All live-born offspring of nulligravida (n=3,685,817) were included. The maternal age was subdivided into the following subgroups: 44 years (n=9,296). Outcomes were assessed based on International Classification of Diseases-10 codes. Adjusted odds ratios (aOR) were calculated with the group of 25-29 years as a reference. Result Most congenital malformations showed an age dependent increase, but cleft lip and abdominal wall defect exhibited a U-shape curve, indicating an increase even in those 44 years old and 1.18 (95% CI, 1.11-1.25) and 1.19 (95% CI, 1.09-1.30) in

Abstract Medication overuse headache (MOH) is a chronic headache disorder that results from excessive use of acutely symptomatic headache medications, leading to more frequent and severe headaches. This study aims to assess the 3-month treatment outcomes in MOH patients, focusing on the types and usage of overused medications, as well as preventive treatments. This prospective cross-sectional study analyzed the treatment outcomes of 309 MOH patients from April 2020 to March 2022. Patients were advised to discontinue overused medications immediately and offered preventive treatments based on clinical judgment. Data on headache characteristics, medication use, and impact on daily life were collected at baseline and 3 months. Results showed overall significant improvements in headache-related variables in patients completing the 3-month treatment follow-up. The median number of headache days per month decreased from 15 days at baseline to 8 days after 3 months (p

Objective Emergency department (ED) triage systems are used to classify the severity and urgency of emergency patients, and Korean medical institutions use the Korean Triage and Acuity Scale (KTAS). During the COVID-19 pandemic, appropriate treatment for emergency patients was delayed due to various circumstances, such as overcrowding of EDs, lack of medical workforce resources, and increased workload on medical staff. The purpose of this study was to evaluate the accuracy of the KTAS in predicting the urgency of emergency patients during the COVID-19 pandemic. Methods This study retrospectively reviewed patients who were treated in the ED during the pandemic period from January 2020 to June 2021. Patients were divided into COVID-19–screening negative (SN) and COVID-19–screening positive (SP) groups. We compared the predictability of the KTAS for urgent patients between the two groups. Results From a total of 107,480 patients, 62,776 patients (58.4%) were included in the SN group and 44,704 (41.6%) were included in the SP group. The odds ratios for severity variables at each KTAS level revealed a more evident discriminatory power of the KTAS for severity variables in the SN group (P

Abstract Background Currently, there is a relative lack of detailed reports regarding clinical presentation and outcome of idiopathic intracranial hypertension in Asians. This study aims to describe the clinical features and treatment outcomes of Korean patients with idiopathic intracranial hypertension. Methods We prospectively recruited patients with idiopathic intracranial hypertension from one hospital and retrospectively analyzed the medical records of 11 hospitals in Korea. We collected data regarding preceding medical conditions or suspected medication exposure, headache phenotypes, other associated symptoms, detailed neuroimaging findings, treatments, and outcomes after 1–2 and 3–6 months of treatment. Results Fifty-nine (83.1% women) patients were included. The mean body mass index was 29.11 (standard deviation, 5.87) kg/m2; only 27 patients (45.8%) had a body mass index of ≥ 30 kg/m2. Fifty-one (86.4%) patients experienced headaches, patterns of which included chronic migraine (15/51 [29.4%]), episodic migraine (8/51 [15.7%]), probable migraine (4/51 [7.8%]), chronic tension-type headache (3/51 [5.9%]), episodic tension-type headache (2/51 [3.9%]), probable tension-type headache (2/51 [3.9%]), and unclassified (17/51 [33.3%]). Medication overuse headache was diagnosed in 4/51 (7.8%) patients. After 3–6 months of treatment, the intracranial pressure normalized in 8/32 (25.0%), improved in 17/32 (53.1%), no changed in 7/32 (21.9%), and worsened in none. Over the same period, headaches remitted or significantly improved by more than 50% in 24/39 patients (61.5%), improved less than 50% in 9/39 (23.1%), and persisted or worsened in 6/39 (15.4%) patients. Conclusion Our findings suggest that the features of Asian patients with idiopathic intracranial hypertension may be atypical (i.e., less likely obese, less female predominance). A wide spectrum of headache phenotypes was observed. Medical treatment resulted in overall favorable short-term outcomes; however, the headaches did not improve in a small proportion of patients.

Abstract Background Many people struggle with the choice in a series of processes, from prostate cancer (PCa) diagnosis to treatment. We investigated the degree of regret after the prostate biopsy (PBx) and relevant factors in patients recommended for biopsy for suspected PCa. Methods From 06/2020 to 05/2022, 198 people who performed PBx at three institutions were enrolled and analyzed through a questionnaire before and after biopsy. Before the biopsy, a questionnaire was conducted to evaluate the sociodemographic information, anxiety scale, and health literacy, and after PBx, another questionnaire was conducted to evaluate the decision regret scale. For patients diagnosed as PCa after biopsy, a questionnaire was conducted when additional tests were performed at PCa staging work-up. Results 190 patients answered the questionnaire before and after PBx. The mean age was 66.2 ± 7.8 years. Overall, 5.5% of men regretted biopsy, but there was no significant difference between groups according to the PCa presence. Multivariate analysis, to identify predictors for regret, revealed that the case when physicians did not properly explain what the prostate-specific antigen (PSA) test was like and what PSA elevation means (OR 20.57, [95% CI 2.45–172.70], p = 0.005), low media literacy (OR 10.01, [95% CI 1.09–92.29], p = 0.042), and when nobody to rely on (OR 8.49, [95% CI 1.66–43.34], p = 0.010) were significantly related. Conclusions Overall regret related to PBx was low. Decision regret was more significantly related to media literacy rather than to educational level. For patients with relatively low media literacy and fewer people to rely on in case of serious diseases, more careful attention and counseling on PBx, including a well-informed explanation on PSA test, is helpful.

Background This study aimed to compare the analgesic effects of programmed intermittent epidural boluses (PIEB) and continuous epidural infusion (CEI) for postoperative analgesia after elective cesarean section (CS). Methods Seventy-four women who underwent elective CS were randomized to receive either PIEB or CEI. The PIEB group received 4 ml-intermittent boluses of 0.11% ropivacaine every hour at a rate of 120 ml/h. The CEI group received a constant rate of 4 ml/h of 0.11% ropivacaine. The primary outcome was the pain score at rest at 36 h after CS. Secondary outcomes included the pain scores during mobilization, time-weighted pain scores, the incidence of motor blockade, and complications-related epidural analgesia during 36 h after CS. Results The pain score at rest at 36 h after CS was significantly lower in the PIEB group compared with that in the CEI group (3.0 vs. 0.0; median difference: 2, 95% CI [1, 2], P < 0.001). The mean time-weighted pain scores at rest and during mobilizations were also significantly lower in the PIEB group than in the CEI group (pain at rest; mean difference [MD]: 37.5, 95% CI [24.6, 50.4], P < 0.001/pain during mobilization; MD: 56.6, 95% CI [39.8, 73.5], P < 0.001). The incidence of motor blockade was significantly reduced in the PIEB group compared with that in the CEI group (P < 0.001). Conclusions PIEB provides superior analgesia with less motor blockade than CEI in postpartum women after CS, without any apparent adverse events.

Abstract Despite clinical data stretching over millennia, the neurobiological basis of the effectiveness of acupuncture in treating diseases of the central nervous system has remained elusive. Here, using an established model of acupuncture treatment in Parkinson's disease (PD) model mice, we show that peripheral acupuncture stimulation activates hypothalamic melanin‐concentrating hormone (MCH) neurons via nerve conduction. We further identify two separate neural pathways originating from anatomically and electrophysiologically distinct MCH neuronal subpopulations, projecting to the substantia nigra and hippocampus, respectively. Through chemogenetic manipulation specifically targeting these MCH projections, their respective roles in mediating the acupuncture‐induced motor recovery and memory improvements following PD onset are demonstrated, as well as the underlying mechanisms mediating recovery from dopaminergic neurodegeneration, reactive gliosis, and impaired hippocampal synaptic plasticity. Collectively, these MCH neurons constitute not only a circuit‐based explanation for the therapeutic effectiveness of traditional acupuncture, but also a potential cellular target for treating both motor and non‐motor PD symptoms.

Abstract Autonomously self‐healing, reversible, and soft adhesive microarchitectures and structured electric elements could be important features in stable and versatile bioelectronic devices adhere to complex surfaces of the human body (rough, dry, wet, and vulnerable). In this study, we propose an autonomous self‐healing multi‐layered adhesive patch inspired by the octopus, which possess self‐healing and robust adhesion properties in dry/underwater conditions. To implement autonomously self‐healing octopus‐inspired architectures, a dynamic polymer reflow model based on structural and material design suggests criteria for three‐dimensional patterning self‐healing elastomers. In addition, self‐healing multi‐layered microstructures with different moduli endows efficient self‐healing ability, human‐friendly reversible bio‐adhesion, and stable mechanical deformability. Through programmed molecular behavior of microlevel hybrid multiscale architectures, the bioinspired adhesive patch exhibited robust adhesion against rough skin surface under both dry and underwater conditions while enabling autonomous adhesion restoring performance after damaged (over 95% healing efficiency under both conditions for 24 h at 30°C). Finally, we developed a self‐healing skin‐mountable adhesive electronics with repeated attachment and minimal skin irritation by laminating thin gold electrodes on octopus‐like structures. Based on the robust adhesion and intimate contact with skin, we successfully obtained reliable measurements during dynamic motion under dry, wet, and damaged conditions.

E-cadherin, a transmembrane protein, is essential for maintaining the integrity and structure of human pluripotent stem cells (hPSCs) by facilitating strong cell–cell adhesion and communication, which is crucial for their colony formation and pluripotency. Here, we used the CRISPR/Cas9 system to introduce the enhanced green fluorescent protein (EGFP)-tagged CDH1 into the AAVS1 locus, a safe harbour site, of human induced pluripotent stem cells (hiPSCs). The engineered cell line, KSCBi002-A-3, expressed functional CDH1-EGFP fusion protein, exhibited normal cell morphology, maintained a normal karyotype, and retained pluripotent state.

Abstract Epithelial‐stromal interplay through chemomechanical cues from cells and matrix propels cancer progression. Elevated tissue stiffness in potentially malignant tissues suggests a link between matrix stiffness and enhanced tumor growth. In this study, employing chronic oral/esophageal injury and cancer models, it is demonstrated that epithelial–stromal interplay through matrix stiffness and Hedgehog (Hh) signaling is key in compounding cancer development. Epithelial cells actively interact with fibroblasts, exchanging mechanoresponsive signals during the precancerous stage. Specifically, epithelial cells release Sonic Hh, activating fibroblasts to produce matrix proteins and remodeling enzymes, resulting in tissue stiffening. Subsequently, basal epithelial cells adjacent to the stiffened tissue become proliferative and undergo epithelial‐to‐mesenchymal transition, acquiring migratory and invasive properties, thereby promoting invasive tumor growth. Notably, transcriptomic programs of oncogenic GLI2, mechano‐activated by actin cytoskeletal tension, govern this process, elucidating the crucial role of non‐canonical GLI2 activation in orchestrating the proliferation and mesenchymal transition of epithelial cells. Furthermore, pharmacological intervention targeting tissue stiffening proves highly effective in slowing cancer progression. These findings underscore the impact of epithelial‐stromal interplay through chemo‐mechanical (Hh‐stiffness) signaling in cancer development, and suggest that targeting tissue stiffness holds promise as a strategy to disrupt chemo‐mechanical feedback, enabling effective cancer treatment.

BackgroundThe association between preterm birth and Mycoplasma species such as Mycoplasma hominis and Ureaplasma urealyticum has been extensively investigated. In a clinical setting, conventional diagnostic methods for them involve culture methods for Mycoplasma spp. and Ureaplasma spp., along with PCR tests. However, the clinical utility of these tests remains controversial, highlighting the necessity for more robust and reliable methods for identifying and understanding Mycoplasma infections.ObjectiveThis study aimed to assess the distribution of microbiota in pregnant women with Mycoplasma hominis and Ureaplasma urealyticum infection by the comparison of conventional diagnostic methods with vaginal microbial community analysis.Study DesignThis prospective case–control study involved 228 Korean pregnant women and utilized vaginal microbial community analysis, Ureaplasma/Mycoplasma culture, and 12-multiplex PCR for sexually transmitted diseases. Cross-correlation analysis in SPSS 27 compared the results of two conventional methods with vaginal microbial community analysis. R software generated box plots depicting the relative abundance of microorganisms. Network analysis was conducted using Cytoscape.ResultsPositive Ureaplasma urealyticum culture findings were observed in 60.2% of patients, with 76.4% positive for Ureaplasma parvum PCR and 13.2% positive for Ureaplasma urealyticum PCR. Mycoplasma hominis culture was positive only in two patients, while Mycoplasma hominis PCR was positive in eight women. Vaginal microbial community analysis identified significant differences in relative abundances of Gardnerella species type I and Fannyhessea vaginae between the Ureaplasma urealyticum PCR positive and negative groups. Mycoplasma hominis PCR positive patients exhibited significant differences in 11 bacterial species, including Gardnerella species I and Fannyhessea vaginae.ConclusionThis study suggests that STD-PCR may be more accurate than Ureaplasma/Mycoplasma culture for the diagnosis of Mycoplasma hominis and Ureaplasma urealyticum infection. Also, the presence of Gardnerella species I and Fannyhessea vaginae implies their potential influences on Ureaplasma urealyticum and Mycoplasma hominis infections based on results of vaginal microbial community analysis. Therefore, vaginal microbial community analysis may give the more information of their pathophysiology.

ObjectivesIn veterinary medicine, attempts to apply artificial intelligence (AI) to ultrasonography have rarely been reported, and few studies have investigated the value of AI in ultrasonographic diagnosis. This study aimed to develop a deep learning-based model for classifying the status of canine chronic kidney disease (CKD) using renal ultrasonographic images and assess its diagnostic performance in comparison with that of veterinary imaging specialists, thereby verifying its clinical utility.Materials and methodsIn this study, 883 ultrasonograms were obtained from 198 dogs, including those diagnosed with CKD according to the International Renal Interest Society (IRIS) guidelines and healthy dogs. After preprocessing and labeling each image with its corresponding IRIS stage, the renal regions were extracted and classified based on the IRIS stage using the convolutional neural network-based object detection algorithm You Only Look Once. The training scenarios consisted of multi-class classification, categorization of images into IRIS stages, and four binary classifications based on specific IRIS stages. To prevent model overfitting, we balanced the dataset, implemented early stopping, used lightweight models, and applied dropout techniques. Model performance was assessed using accuracy, recall, precision, F1 score, and receiver operating characteristic curve and compared with the diagnostic accuracy of four specialists. Inter- and intra-observer variabilities among specialists were also evaluated.ResultsThe developed model exhibited a low accuracy of 0.46 in multi-class classification. However, a significant performance improvement was observed in binary classifications, with the model designed to distinguish stage 3 or higher showing the highest accuracy of 0.85. In this classification, recall, precision, and F1 score values were all 0.85, and the area under the curve was 0.89. Compared with radiologists, whose accuracy ranged from 0.48 to 0.62 in this experimental scenario, the AI model exhibited superiority. Intra-observer reliability among radiologists was substantial, whereas inter-observer variability showed a moderate level of agreement.ConclusionsThis study developed a deep-learning framework capable of reliably classifying CKD IRIS stages 3 and 4 in dogs using ultrasonograms. The developed framework demonstrated higher accuracy than veterinary imaging specialists and provided more objective and consistent interpretations. Therefore, deep-learning-based ultrasound diagnostics are potentially valuable tools for diagnosing CKD in dogs.

Abstract Robotic adrenalectomy (RA) has gained significant popularity in the management of adrenal gland diseases. We report our experience at a single tertiary institution and evaluate the safety and surgical outcomes of RA. The data of 122 consecutive patients who underwent RA from October 2009 to December 2022 at Korea University Anam Hospital (Seoul, Korea) were reviewed. There were no perioperative complications. Clinicopathological features and surgical outcomes were retrospectively analyzed through complete chart reviews. Noteworthy findings include the influence of sex, tumor size, and body mass index on operation time, with the female and small tumor groups exhibiting shorter operation times (P = 0.018 and P = 0.009, respectively). Pheochromocytoma was identified as a significant independent risk factor for a longer operation time in the multivariate analysis [odds ratio (OR), 3.709; 95% confidence interval (CI), 1.127–12.205; P = 0.031]. A temporal analysis revealed a decreasing trend in mean operation times across consecutive groups, reflecting a learning curve associated with RA adoption. RA is a safe and effective operative technique alternative to laparoscopic adrenalectomy that has favorable surgical outcomes and enhances the convenience of the operation.

Objective Adenomyosis impacts pregnancy outcomes, although there is a lack of consensus regarding the actual effects. It is likely, however, that the severity of adenomyosis or ultrasound findings or timing of diagnosis can have different effects on adverse pregnancy outcomes (APOs). Methods In this study, we aimed to investigate the impact of the timing of adenomyosis diagnosis on pregnancy outcomes. Singleton pregnant women who delivered between 2017 and 2022 were analyzed based on the timing of adenomyosis diagnosis, using a national database. The final cohort was classified into three groups: 1) group 1, without adenomyosis; 2) group 2, those diagnosed with adenomyosis before pregnancy; and 3) group 3, those diagnosed with adenomyosis during pregnancy. Results A total of 1,226,475 cases were ultimately included in this study. Women with a diagnosis of adenomyosis had a significantly higher risk of APOs including hypertensive disorder during pregnancy (HDP), gestational diabetes mellitus (GDM), postpartum hemorrhage, placental abruption, preterm birth, and delivery of a small-for-gestational-age infant even after adjusting for covariates. In particular, concerning HDP, the risk was highest in group 3 (group 2: adjusted odds ratio [aOR], 1.15 vs. group 3: aOR, 1.36). However, the highest GDM risk was in group 2 (GDM; group 2: aOR, 1.24 vs. group 3: aOR, 1.04). Conclusion The increased risk of APO differed depending on the timing of adenomyosis diagnosis. Therefore, efforts for more careful monitoring and prevention of APOs may be necessary when such women become pregnant.

Line pattern replication process through nanoimprint lithography (NIL) method has been used in numerous of research fields. NIL technology is not yet utilized for displays industry, and we propose an alignment layer of the sol-gel process using NIL. One-dimensionally nanopatterned by polydimethylsiloxane sheets cause surface changes in hybrid SnGaO thin films mixed in a 3:7 ratio, which aligns the liquid crystals (LCs) uniformly in the line pattern direction. These surface changes are confirmed through atomic force microscopy data analysis, and changes in surface shapes for different the curing temperatures in the furnace are analyzed. X-ray photoelectron spectroscopy shows that the chemical composition of the thin films changes according to curing temperatures, and the intensities of SnO and GaO increase exponentially at 200 °C compared to those at 50 °C. Through this, the van der Waals force increases between surface molecules, in the anisotropic direction to help align the LCs. Furthermore, we performed polarized optical microscopy and pre-tilt angle analysis confirm that the LCs are energized uniformly. Finally, the performance of an actual display device transmittance and electro-optical properties; the transmittance of SnGaO is 4.51p% higher than that of the currently commercialized PI-rubbing, and the voltage-transmittance curve is a perfect graph.

Abstract Skin-like field-effect transistors are key elements of bio-integrated devices for future user-interactive electronic-skin applications. Despite recent rapid developments in skin-like stretchable transistors, imparting self-healing ability while maintaining necessary electrical performance to these transistors remains a challenge. Herein, we describe a stretchable polymer transistor capable of autonomous self-healing. The active material consists of a blend of an electrically insulating supramolecular polymer with either semiconducting polymers or vapor-deposited metal nanoclusters. A key feature is to employ the same supramolecular self-healing polymer matrix for all active layers, i.e., conductor/semiconductor/dielectric layers, in the skin-like transistor. This provides adhesion and intimate contact between layers, which facilitates effective charge injection and transport under strain after self-healing. Finally, we fabricate skin-like self-healing circuits, including NAND and NOR gates and inverters, both of which are critical components of arithmetic logic units. This work greatly advances practical self-healing skin electronics.

Abstract Nanophase mixtures, leveraging the complementary strengths of each component, are vital for composites to overcome limitations posed by single elemental materials. Among these, metal-elastomer nanophases are particularly important, holding various practical applications for stretchable electronics. However, the methodology and understanding of nanophase mixing metals and elastomers are limited due to difficulties in blending caused by thermodynamic incompatibility. Here, we present a controlled method using kinetics to mix metal atoms with elastomeric chains on the nanoscale. We find that the chain migration flux and metal deposition rate are key factors, allowing the formation of reticular nanophases when kinetically in-phase. Moreover, we observe spontaneous structural evolution, resulting in gyrified structures akin to the human brain. The hybridized gyrified reticular nanophases exhibit strain-invariant metallic electrical conductivity up to 156% areal strain, unparalleled durability in organic solvents and aqueous environments with pH 2–13, and high mechanical robustness, a prerequisite for environmentally resilient devices.

Background Few studies have evaluated the use of automated artificial intelligence (AI)-based pain recognition in postoperative settings or the correlation with pain intensity. In this study, various machine learning (ML)-based models using facial expressions, the analgesia nociception index (ANI), and vital signs were developed to predict postoperative pain intensity, and their performances for predicting severe postoperative pain were compared. Methods In total, 155 facial expressions from patients who underwent gastrectomy were recorded postoperatively; one blinded anesthesiologist simultaneously recorded the ANI score, vital signs, and patient self-assessed pain intensity based on the 11-point numerical rating scale (NRS). The ML models’ area under the receiver operating characteristic curves (AUROCs) were calculated and compared using DeLong’s test. Results ML models were constructed using facial expressions, ANI, vital signs, and different combinations of the three datasets. The ML model constructed using facial expressions best predicted an NRS ≥ 7 (AUROC 0.93) followed by the ML model combining facial expressions and vital signs (AUROC 0.84) in the test-set. ML models constructed using combined physiological signals (vital signs, ANI) performed better than models based on individual parameters for predicting NRS ≥ 7, although the AUROCs were inferior to those of the ML model based on facial expressions (all P < 0.05). Among these parameters, absolute and relative ANI had the worst AUROCs (0.69 and 0.68, respectively) for predicting NRS ≥ 7. Conclusions The ML model constructed using facial expressions best predicted severe postoperative pain (NRS ≥ 7) and outperformed models constructed from physiological signals.

Proper placentation during early pregnancy is a key factor for maintaining a healthy pregnancy. Placental insufficiency leads to critical complications such as preeclampsia, fetal growth restriction, and fetal demise. These complications are often associated with pathological findings of restricted remodeling and obstructive lesions of the myometrial spiral arteries, which have high recurrence rates during subsequent pregnancies. Currently, there are no pharmacological interventions other than aspirin for the prevention of preeclampsia. Hydroxychloroquine (HCQ), a well-known antimalarial drug, reduces inflammatory and thrombotic changes in vessels. For decades, the use of HCQ for autoimmune diseases has resulted in the successful prevention of both arterial and venous thrombotic events and has been extended to the treatment of lupus and antiphospholipid antibody syndrome during pregnancy. HCQ reduces the risk of preeclampsia with lupus by up to 90%. Several recent studies have investigated whether HCQ improves pregnancy outcomes in women with a history of poor outcomes. In addition, in vitro and animal studies have demonstrated the beneficial effects of HCQ in improving endothelial dysfunction and alleviating hypertension and proteinuria. Therefore, we hypothesized that HCQ has the potential to attenuate the vascular inflammatory and thrombogenic pathways associated with placental insufficiency and conducted a multicenter clinical trial on the efficacy of combining aspirin with HCQ for pregnancies at high risk for preeclampsia in Korea. This study summarizes the potential effects of HCQ on pregnancies with placental insufficiency and the implications of HCQ treatment in the field of obstetrics.

Abstract Background Neuropsychiatric symptoms and delusions are highly prevalent among people with dementia. However, multiple roots of neurobiological bases and shared neural basis of delusion and cognitive function remain to be characterized. By utilizing a fine-grained multivariable approach, we investigated distinct neuroanatomical correlates of delusion symptoms across a large population of dementing illnesses. Methods In this study, 750 older adults with mild cognitive impairment and Alzheimer’s disease completed brain structural imaging and neuropsychological assessment. We utilized principal component analysis followed by varimax rotation to identify the distinct multivariate correlates of cortical thinning patterns. Five of the cognitive domains were assessed whether the general cognitive abilities mediate the association between cortical thickness and delusion. Results The result showed that distributed thickness patterns of temporal and ventral insular cortex (component 2), inferior and lateral prefrontal cortex (component 1), and somatosensory-visual cortex (component 5) showed negative correlations with delusions. Subsequent mediation analysis showed that component 1 and 2, which comprises inferior frontal, anterior insula, and superior temporal regional thickness accounted for delusion largely through lower cognitive functions. Specifically, executive control function assessed with the Trail Making Test mediated the relationship between two cortical thickness patterns and delusions. Discussion Our findings suggest that multiple distinct subsets of brain regions underlie the delusions among older adults with cognitive impairment. Moreover, a neural loss may affect the occurrence of delusion in dementia largely due to impaired general cognitive abilities.

Abstract Major depressive disorder (MDD) is a common mental illness worldwide and is triggered by an intricate interplay between environmental and genetic factors. Although there are several studies on common variants in MDD, studies on rare variants are relatively limited. In addition, few studies have examined the genetic contributions to neurostructural alterations in MDD using whole-exome sequencing (WES). We performed WES in 367 patients with MDD and 161 healthy controls (HCs) to detect germline and copy number variations in the Korean population. Gene-based rare variants were analyzed to investigate the association between the genes and individuals, followed by neuroimaging-genetic analysis to explore the neural mechanisms underlying the genetic impact in 234 patients with MDD and 135 HCs using diffusion tensor imaging data. We identified 40 MDD-related genes and observed 95 recurrent regions of copy number variations. We also discovered a novel gene, FRMPD3, carrying rare variants that influence MDD. In addition, the single nucleotide polymorphism rs771995197 in the MUC6 gene was significantly associated with the integrity of widespread white matter tracts. Moreover, we identified 918 rare exonic missense variants in genes associated with MDD susceptibility. We postulate that rare variants of FRMPD3 may contribute significantly to MDD, with a mild penetration effect.

Abstract Objectives To assess whether a deep learning-based system (DLS) with black-blood imaging for brain metastasis (BM) improves the diagnostic workflow in a multi-center setting. Materials and methods In this retrospective study, a DLS was developed in 101 patients and validated on 264 consecutive patients (with lung cancer) having newly developed BM from two tertiary university hospitals, which performed black-blood imaging between January 2020 and April 2021. Four neuroradiologists independently evaluated BM either with segmented masks and BM counts provided (with DLS) or not provided (without DLS) on a clinical trial imaging management system (CTIMS). To assess reading reproducibility, BM count agreement between the readers and the reference standard were calculated using limits of agreement (LoA). Readers’ workload was assessed with reading time, which was automatically measured on CTIMS, and were compared between with and without DLS using linear mixed models considering the imaging center. Results In the validation cohort, the detection sensitivity and positive predictive value of the DLS were 90.2% (95% confidence interval [CI]: 88.1–92.2) and 88.2% (95% CI: 85.7–90.4), respectively. The difference between the readers and the reference counts was larger without DLS (LoA: −0.281, 95% CI: −2.888, 2.325) than with DLS (LoA: −0.163, 95% CI: −2.692, 2.367). The reading time was reduced from mean 66.9 s (interquartile range: 43.2–90.6) to 57.3 s (interquartile range: 33.6–81.0) (P

Charcot-Marie-Tooth disease type 1A (CMT1A) is a demyelinating disease caused by PMP22 duplication and an exceedingly rare hereditary peripheral neuropathy, with an incidence of 1 in 2500. Currently, no cure exists for CMT1A; however, various therapeutic approaches are under development. Considering the known therapeutic effects of mesenchymal stem cells (MSCs) and the relation of blood sugar levels with nerve damage in CMT, this study aimed to confirm the therapeutic effects of MSCs and insulin on CMT, using both in-vitro and in-vivo models. CMT1A in-vitro models were exposed to Wharton's jelly-derived MSCs (WJ-MSCs) or insulin, and the resulting proliferation changes were measured. CMT1A mice were treated with WJ-MSCs or insulin, and their phenotypic changes were observed. We observed improvements in myelination of Schwann cells in vitro and motor function in vivo. Insulin also showed therapeutic efficacy by promoting Schwann cell proliferation. Furthermore, combination therapy using insulin and WJ-MSCs was more effective than WJ-MSCs or insulin alone. Insulin promoted the proliferation of Schwann cells and WJ-MSCs through activation of the ATK and PI3K-MAPK signaling pathways. Overall, this study is the first to confirm the therapeutic efficacy of WJ-MSCs and insulin in CMT1A, and their synergistic effect without causing insulin resistance.

Alternative splicing products of AIMP2 and AIMP2-DX2 (DX2) have been reported to be associated with human lung cancer. In fact, DX2 expression is elevated in human lung cancers, and DX2 transgenic mice also develop lung cancer, in particular small cell lung cancer (SCLC). However, the mechanism by which DX2 is induced during cancer progression has not been clearly elucidated. Here, we show that DX2 is induced by nicotine, the main component of smoking-related chemicals, which can stabilize the human epidermal growth factor receptor 2 (HER2) protein and transcriptionally increase sonic hedgehog (Shh). Indeed, nicotine showed tumorigenicity via DX2 by promoting spheroid formation and in vivo lung and kidney cancer progression. Moreover, the elimination of DX2 using small interfering RNA (siRNA) or an optimized inhibitor (SNU-14) blocked the induction of HER2 and Shh and completely suppressed tumor sphere formation in response to nicotine. These results indicate that DX2 is critical for lung cancer progression, and a specific DX2 inhibitor would be useful for the treatment of human cancers, including SCLC and non-SCLC (NSCLC).