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Sei Han Song,1 Seung Ho Choi,2 Hae Ri Park,1 Soo Yeon Jeon,1 Seung Hyun Kim2 1Department of Anesthesiology and Pain Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea; 2Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul, KoreaCorrespondence: Seung Hyun Kim, Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Korea, Tel +82-2-2224-1055, Fax +82-2-2227-7897, Email anesshkim@yuhs.acIntroduction: Anesthesiologists are exposed to the risk of infection from various secretions or droplets from the respiratory tract of patients. We aimed to determine bacterial exposure to anesthesiologists’ faces during endotracheal intubation and extubation.Methods: Six resident anesthesiologists performed 66 intubation and 66 extubation procedures in patients undergoing elective otorhinolaryngology surgeries. Sampling was performed by swabbing the face shields twice in an overlapping slalom pattern, before and after each procedure. Samples for pre-intubation and pre-extubation were collected immediately after wearing the face shield at the time of anesthesia induction and at the end of the surgery, respectively. Post-intubation samples were collected after the injection of anesthetic drugs, positive pressure mask ventilation, endotracheal intubation, and confirmation of intubation success. Post-extubation samples were collected after endotracheal tube suction, oral suction, extubation, and confirmation of spontaneous breathing and stable vital signs. All swabs were cultured for 48 h, and bacterial growth was confirmed by colony forming unit (CFU) count.Results: There was no bacterial growth in either pre- or post-intubation bacterial cultures. In contrast, while there was no bacterial growth in pre-extubation samples, 15.2% of post-extubation samples were CFU+ (0/66 [0%] vs 10/66 [15.2%], p=0.001). All the CFU+ samples belonged to 47 patients with post-extubation coughing, and the CFU count was correlated with the number of coughing episodes during the process of extubation (P < 0.01, correlation coefficient= 0.403).Conclusion: The current study shows the actual chance of bacterial exposure to the anesthesiologist’s face during the patient awakening process after general anesthesia. Given the correlation between the CFU count and the number of coughing episodes, we recommend anesthesiologists to use appropriate facial protection equipment during this procedure.Keywords: bacterial exposure, cough, extubation, face shield, intubation

Rationale: Nasal polyposis implies a refractory clinical course in case of chronic rhinosinusitis (CRS). Although hypoxia is believed to be associated with nasal polyposis, little is known about the mechanism underlying polypogenesis. Objectives: To determine if hypoxia drives nasal polyposis by epithelial-to-mesenchymal transition (EMT). Methods: Immunoblotting, immunofluorescence, flow cytometry, and real-time polymerase chain reaction were performed to evaluate EMT and hypoxic markers in human nasal epithelial cells (hNECs) and in sinonasal tissues from patients with CRS with or without polyps. In addition, the effects of hypoxia-inducible factor (HIF)-1α inhibitors on nasal polypogenesis were investigated in a murine model. Measurements and Main Results: E-cadherin and α-smooth muscle actin (α-SMA) were down-regulated and up-regulated, respectively, in patients with polyps as compared with patients without polyps. Under hypoxia, hNECs transformed to a mesenchymal shape, and demonstrated representative changes in EMT markers; that is, mesenchymal markers (α-SMA, vimentin, and twist) increased but epithelial markers (E-cadherin and β-catenin) decreased. Mechanistically, E-cadherin level was recovered in hypoxia by silencing HIF-1α and decreased in normoxia by expressing HIF-1α. Furthermore, hypoxia was found to down-regulate PP2Ac phosphatase and up-regulate pSmad3, which led to α-SMA induction. In CRS sinonasal specimens, HIF-1α expression was found to correlate with E-cadherin loss and α-SMA expression. Finally, HIF-1α inhibitors suppressed nasal polypogenesis in a murine model. Conclusions: hNECs undergo EMT during hypoxia and this process is critically mediated by HIF-1α and pSmad3. This study shows that hypoxia-induced EMT is likely to contribute to nasal polyposis in CRS, and suggests that HIF-1α be viewed as a therapeutic target for nasal polyposis. [ABSTRACT FROM AUTHOR]

Diffusion-weighted magnetic resonance imaging (DW-MRI) performed before target temperature management, within 6 h of return of spontaneous circulation (ROSC), is defined as ultra-early DW-MRI. In previous studies, high-signal intensity (HSI) on ultra-early DW-MRI can predict poor neurological outcomes (Cerebral Performance Category 3-5 at 6-months post-ROSC). We aimed to assess the optimal-timing for ultra-early DW-MRI to avoid false-negative outcomes post out-of-hospital cardiac arrest, considering cardiopulmonary resuscitation (CPR) factors. The primary outcomes were HSI in the cerebral cortex or deep gray matter on ultra-early DW-MRI. The impact of CPR factors and ROSC to DW-MRI scan-interval on HSI-presence was assessed. Of 206 included patients, 108 exhibited HSI-presence, exclusively associated with poor neurological outcomes. In multivariate regression analysis, ROSC to DW-MRI scan-interval (adjusted odds ratio [aOR], 1.509; 95% confidence interval (CI): 1.113-2.046; P = 0.008), low-flow time (aOR, 1.176; 95%CI: 1.121-1.233; P < 0.001), and non-shockable rhythm (aOR, 9.974; 95%CI: 3.363-29.578; P < 0.001) were independently associated with HSI-presence. ROSC to DW-MRI scan-interval cutoff of ≥ 2.2 h was particularly significant in low-flow time ≤ 21 min or shockable rhythm group. In conclusion, short low-flow time and shockable rhythm require a longer ROSC to DW-MRI scan-interval. Prolonged low-flow time and non-shockable rhythm reduce the need to consider scan-interval., (© 2024. The Author(s).)

We evaluated alterations in cerebrospinal fluid (CSF) flow based on the neurological prognosis of out-of-hospital cardiac arrest (OHCA) patients. This prospective observational study was conducted from May 2023 to June 2024. Stroke distance was measured using magnetic resonance imaging flowmetry immediately and at 72 h after return of spontaneous circulation (ROSC), with negative values indicating caudocranial direction. The caudocranial direction of CSF flow was observed in 17 (56.7%) patients immediately after ROSC, and in 20 (66.7%) patients at 72 h after ROSC. There was no significant difference in the occurrence of caudocranial CSF flow immediately after ROSC between the groups with good and poor neurological prognosis [6 (50.0%) vs. 11 (61.1%); p = 0.55]. However, the occurrence of caudocranial CSF flow at 72 h after ROSC was significantly higher in the group with poor neurological prognosis compared to the group with good neurological prognosis [3 (25.0%) vs. 17 (94.4%); p < 0.001]. This study demonstrated that the occurrence of caudocranial CSF flow at 72 h after ROSC was significantly higher in the group with poor neurological prognosis compared to the group with good neurological prognosis., (© 2024. The Author(s).)

Objective: Height has the strongest correlation with esophageal length among the external anthropometric indices. Based on the association between laryngopharyngeal reflux (LPR) and the upper esophageal sphincter, this study aimed to investigate the relationship between height and LPR., Methods: Retrospective chart analysis of patients who visited an outpatient clinic with symptoms of LPR and underwent a 24-hour hypopharyngeal-esophageal multichannel intraluminal impedance-pH (24-hr HEMII-pH) monitoring. The study analyzed the relationship between height and LPR by (1) in total of 219 patients, (2) in males and females, and (3) in patients under age 60 and over age 60., Results: The relationship between height and LPR was analyzed for a total of 219 patients. There was no statistical significance between the number of pharyngeal reflux episodes and the height of subjects. When same analysis was done according to gender, the number of pharyngeal reflux episodes decreased as height increased in males, which was statistically significant, but not in females. Further analysis was done according to age in male and female, respectively. In male under age 60, there was statistical significance between the number of pharyngeal reflux episodes and the height of subjects, but not in over age 60. Also, in female under age 60 and over age 60, there was no statistical significance between the number of pharyngeal reflux episodes and the height of subjects., Conclusions: This study suggests a correlation between height and pharyngeal reflux events in males and individuals under 60 years old tested with the 24-hr HEMII-pH monitoring., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Younggyu Eun reports financial support was provided by National Research Foundation of Korea. Younggyu Eun reports financial support was provided by Korea Health Technology R&D Project through the Korea Health Industry. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with radiographic axial spondyloarthritis (r-axSpA) are at increased risk of incident cardiovascular events. Tumor necrosis factor inhibitors (TNFi) have shown a protective effect against incident cardiovacular events. However, the incidence of recurrent cardiovascular events in patients with r-axSpA with a history of cardiovascular events, and the effect of TNFi on recurrent cardiovascular events remain unclear. We aimed to assess the incidence rate of recurrent cardiovascular events in patients with r-axSpA with a history of cardiovascular events and evaluate the effect of TNFi on the risk of recurrent cardiovascular events., Methods: This nationwide cohort study used data from the Korean National Claims Database. Data of patients with r-axSpA who had a history of cardiovascular events after being diagnosed with r-axSpA were extracted from the database. The outcome of interest was the recurrence of cardiovascular events (myocardial infarction or stroke). Patients were followed from the index date (date of the first cardiovascular event) to the date of cardiovascular event recurrence, the last date with claims data, or December 31, 2021, whichever occured first. The incidence rate of recurrent cardiovascular events was calculated. An inverse probability weighted Cox model was used to assess the effect of TNFi exposure on the risk of recurrent cardiovascular events., Results: This study included 413 patients (TNFi non-exposure, n = 338; TNFi exposure, n = 75). The incidence rate of recurrent cardiovascular events was 32 (95% confidence interval [CI] 22-42) per 1,000 person-years (TNFi non-exposure, 36 [95% CI 24-48] per 1,000 person-years; TNFi exposure, 19 [95% CI 2-35] per 1,000 person-years). In the inverse probability weighted Cox model, TNFi exposure was significantly associated with a lower risk of recurrent cardiovascular events (hazard ratio 0.33, 95% CI 0.12-0.94)., Conclusions: The incidence rate of recurrent cardiovascular events in patients with r-axSpA is substantial. TNFi exposure was associated with a lower risk of recurrent cardiovascular events., (© 2024. The Author(s).)

Objective: Korea's transition into a super-aged society brings to the forefront the escalating dementia prevalence and the consequent rise in mortality, highlighting the need for effective end-of-life (EOL) care strategies. Despite legislative advancements, gaps remain in addressing the medical and ethical challenges of EOL care for patients with advanced dementia, particularly in evaluating treatment options like nasogastric tube (NGT) use and mechanical ventilation (MV). This study investigates the attitudes of the general population (GP) and clinicians in Korea towards EOL treatment decisions., Methods: A cross-sectional, web-based survey was conducted among 500 members of the GP and 200 clinicians from a university hospital. Case vignettes were used to assess attitudes towards EOL treatment decisions, specifically focusing on NGT and MV use, and to explore the influencing factors., Results: There was a notable difference in favorable attitudes toward NGT withdrawal between the GP (62.2%) and clinicians (39.0%). Otherwise, both groups showed higher acceptance of MV withholding (82.2% [GPs] and 82.5% [clinicians]) when informed of the patient's verbal intention regarding life-sustaining treatment (LST), and attitudes were more positive with written advance directives. Also, it was decreased when patient intentions were unclear., Conclusion: The results suggested the need to consider NGT as a medical intervention requiring a risk-benefit analysis. Although LST decision-making in patients with advanced dementia is still limited in Korea, this study showed the shared recognition among the GP and clinicians of the importance of EOL treatment decisions that consider patient wishes and quality of life for patients with advanced dementia.

Background: The heterogeneity of nasal features across different racial and ethnic groups is evident. This large-scale multicenter study was performed to evaluate the dorsal keystone area and its relation to superficial nasal anatomy through computed tomography (CT) scans., Methods: Six populations were included: South Caucasian, Middle Eastern, Black South African, Eastern Asian, Mestizo, and Eastern European. Each center obtained CT scans performed between January of 2020 and December of 2022 from patients presenting a nasal hump and from an age- and sex-matched control group. Osteocartilaginous measurements in relation to ethmoidal point and to rhinion, as well as their relation to superficial nasal anatomy, were collected from nasal CT scans in midsagittal view. These were compared between populations and, in each center, between patient groups (nasal hump versus no nasal hump)., Results: The study population included 600 patients (254 with nasal hump) with a mean age of 33.98 years (range, 18 to 59 years); 55.6% were women. Average distances from the ethmoidal point were 10.1 ± 3.5 mm to the rhinion and 1.68 ± 0.23 mm to the beginning point of the nasal hump. In 96% of cases, the ethmoidal point was cranial or no more than 5 mm caudal to the beginning of the nasal hump. S-shaped nasal bones were associated with nasal hump, but angulation (kyphion angle) did not correlate with nasal hump height., Conclusions: In most patients, the nasal hump has no ethmoid bone underneath it, and the apex is located over the septal cartilage. The ethmoidal point is a reliable landmark and should be considered when evaluating established and new preservation and structural rhinoplasty approaches., (Copyright © 2023 by the American Society of Plastic Surgeons.)

Background: The caregiving burden of the spousal caregivers (SCGs) to individuals with cognitive impairment poses public health challenges with adverse psychosocial and physiological effects. However, few studies have investigated the neurobiological impact of caregiving, particularly through the investigation of neuroinflammation and neurodegeneration., Methods: Using data from a longitudinal cohort at Chungnam National University Hospital, the relationship between caregiving burden, neuroinflammation and neurodegeneration was examined in 38 older adult couples over a 16-month period. Caregiving burden was assessed through a multifaceted approach. For factors related to the care recipient, we assessed cognitive function and neuropsychiatric symptoms. Factors regarding the SCGs included the measurement of perceived depression. Glial fibrillary acidic protein (GFAP) was used as a plasma biomarker for neuroinflammation and neurofilament light chain (NfL) for neurodegeneration. Regression analyses were adjusted for age, sex, apolipoprotein E status, follow-up interval, vascular risk factors, and physical activity., Results: Changes in depression among SCGs were significantly correlated with increased GFAP levels (p = 0.003), indicating that greater depressive symptoms during caregiving are associated with increased neuroinflammation. In contrast, no significant correlations were found between changes in cognitive function or neuropsychiatric symptoms in care recipients and the plasma biomarker levels of SCGs. Additionally, there was no significant association between changes in depression and NfL levels in SCGs., Conclusions: The psychological stress experienced by SCGs while caring for partners with cognitive impairment actively contributes to neuroinflammation, a well-known risk factor for various diseases. This study emphasizes the need to address psychological stress experienced by older adult caregivers., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America.)

This study investigates the fabrication, microstructural characteristics and plasma resistance of Y-Al-Si-O (YAS) glass-ceramics coated on alumina ceramics. YAS frits were initially prepared using a melt-quenching method, then homogenously milled and coated onto alumina ceramics. The melt-coating process was conducted at 1650 °C for 1 h. The composition and microstructure of the glass frits and coatings were thoroughly characterized using X-ray diffraction, scanning electron microscopy, and energy-dispersive X-ray spectroscopy. These analyses revealed a dense microstructure with a polycrystalline structure predominantly composed of Y 3 Al 5 O 12 (YAG) phase and a minor phase of Y 2 Si 2 O 7 . The YAS coatings on alumina revealed a dense layer with strong adhesion to the substrate. Subsequently, the coatings underwent C 4 F 6 /Ar/O 2 plasma treatment for 1 h. Plasma exposure tests demonstrated that the YAS-coated alumina exhibited significantly better etching resistance compared to uncoated alumina, with minimal surface damage observed on the YAS coating, confirming its protective properties against plasma. The superior plasma resistance of YAS coatings is attributed to the predominance of its YAG phase. This research offers a more stable and cost-efficient solution for protecting ceramics in demanding plasma environments.

Replicative senescence of mesenchymal stem cells (MSCs) caused by repeated cell culture undermines their potential as a cell therapy because of the reduction in their proliferation and therapeutic potential. Glutaminase-1 (GLS1) is reported to be involved in the survival of senescent cells, and inhibition of GLS1 alleviates age-related dysfunction via senescent cell removal. In the present study, we attempted to elucidate the association between MSC senescence and GLS1. We conducted in vitro and in vivo experiments to analyze the effect of GLS1 inhibition on senolysis and the therapeutic effects of MSCs. Inhibition of GLS1 in Wharton's jelly-derived MSCs (WJ-MSCs) reduced the expression of aging-related markers, such as p16, p21, and senescence-associated secretory phenotype genes, by senolysis. Replicative senescence-alleviated WJ-MSCs, which recovered after short-term treatment with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES), showed increased proliferation and therapeutic effects compared to those observed with senescent WJ-MSCs. Moreover, compared to senescent WJ-MSCs, replicative senescence-alleviated WJ-MSCs inhibited apoptosis in serum-starved C2C12 cells, enhanced muscle formation, and hindered apoptosis and fibrosis in mdx mice. These results imply that GLS1 inhibition can ameliorate the therapeutic effects of senescent WJ-MSCs in patients with muscle diseases such as Duchenne muscular dystrophy. In conclusion, GLS1 is a key factor in modulating the senescence mechanism of MSCs, and regulation of GLS1 may enhance the therapeutic effects of senescent MSCs, thereby increasing the success rate of clinical trials involving MSCs., (© The Author(s) 2024. Published by Oxford University Press.)

Background: The vegetative state (VS) after severe acute brain injury (SABI) is associated with significant prognostic uncertainty and poor long-term functional outcomes. However, it is generally distinguished from imminent death and is exempt from the Life-Sustaining Treatment (LST) Decisions Act in Korea. Here, we aimed to examine the perspectives of the general population (GP) and clinicians regarding decisions on mechanical ventilator withdrawal in patients in a VS after SABI., Methods: A cross-sectional survey was undertaken, utilizing a self-reported online questionnaire based on a case vignette. Nationally selected by quota sampling, the GP comprised 500 individuals aged 20 to 69 years. There were 200 doctors from a tertiary university hospital in the clinician sample. Participants were asked what they thought about mechanical ventilator withdrawal in patients in VS 2 months and 3 years after SABI., Results: Two months after SABI in the case, 79% of the GP and 83.5% of clinicians had positive attitudes toward mechanical ventilator withdrawal. In the GP, attitudes were associated with spirituality, household income, religion, the number of household members. On the other hand, clinicians' attitudes were related to their experience of completing advance directives (AD) and making decisions about LST. In this case, 3 years after SABI, 92% of the GP and 94% of clinicians were more accepting of ventilator withdrawal compared to previous responses, based on the assumption that the patient had written AD. However, it appeared that the proportion of positive responses to ventilator withdrawal decreased when the patients had only verbal expressions (82% of the GP; 75.5% of clinicians) or had not previously expressed an opinion regarding LST (58% of the GP; 39.5% of clinicians)., Conclusion: More than three quarters of both the GP and clinicians had positive opinions regarding ventilator withdrawal in patients in a VS after SABI, which was reinforced with time and the presence of AD. Legislative adjustments are needed to ensure that previous wishes for those patients are more respected and reflected in treatment decisions., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Objective: Effective triage of febrile patients in the emergency department is crucial during times of overcrowding to prioritize care and allocate resources, especially during pandemics. However, available triage tools often require laboratory data and lack accuracy. We aimed to develop a simple and accurate triage tool for febrile patients by modifying the quick Sequential Organ Failure Assessment (qSOFA) score., Methods: We retrospectively analyzed data from 7,303 febrile patients and created modified versions of qSOFA using factors identified through multivariable analysis. The performance of these modified qSOFAs in predicting in-hospital mortality and intensive care unit (ICU) admission was compared using the area under the receiver operating characteristic curve (AUROC)., Results: Through multivariable analysis, the identified factors were age ("A" factor), male sex ("M" factor), oxygen saturation measured by pulse oximetry (SpO2; "S" factor), and lactate level ("L" factor). The AUROCs of ASqSOFA (in-hospital mortality: 0.812 [95% confidence interval, 0.789-0.835]; ICU admission: 0.794 [95% confidence interval, 0.771-0.817]) were simple and not inferior to those of other more complex models (e.g., ASMqSOFA, ASLqSOFA, and ASMLqSOFA). ASqSOFA also displayed significantly higher AUROC than other triage scales, such as the Modified Early Warning Score and Korean Triage and Acuity Scale. The optimal cutoff score of ASqSOFA for the outcome was 2, and the score for redistribution to a lower level emergency department was 0., Conclusion: We demonstrated that ASqSOFA can be employed as a simple and efficient triage tool for emergency febrile patients to aid in resource distribution during overcrowding. It also may be applicable in prehospital settings for febrile patient triage.

Adipose tissue engraftment has become a promising strategy in the field of regenerative surgery; however, there are notable challenges associated with it, such as resorption of 50‑90% of the transplanted fat or cyst formation due to fat necrosis after fat transplantation. Therefore, identifying novel materials or methods to improve the engraftment efficiency is crucial. The present study investigated the effects of nervonic acid (NA), a monounsaturated very long‑chain fatty acid, on adipogenesis and fat transplantation, as well as its underlying mechanisms. To assess this, NA was used to treat cells during adipogenesis in vitro , and the expression levels of markers, including PPARγ and CEBPα, and signaling molecules were detected through reverse transcription‑quantitative PCR and western blotting. In addition, NA was mixed with fat grafts in in vivo fat transplantation, followed by analysis through Oil Red O staining, hematoxylin & eosin staining and immunohistochemistry. It was demonstrated that NA treatment accelerated adipogenesis through activation of the Akt/mTOR pathway and inhibition of Wnt signaling. NA treatment enriched the expression of Akt/mTOR signaling‑related genes, and increased the expression of genes involved in angiogenesis and fat differentiation in human mesenchymal stem cells (MSCs). Additionally, NA effectively improved the outcome of adipose tissue engraftment in mice. Treatment of grafts with NA at transplantation reduced the resorption of transplanted fat and increased the proportion of perilipin‑1 + adipocytes with a lower portion of vacuoles in mice. Moreover, the NA‑treated group exhibited a reduced pro‑inflammatory response and had more CD31 + vessel structures, which were relatively evenly distributed among viable adipocytes, facilitating successful engraftment. In conclusion, the present study demonstrated that NA may not only stimulate adipogenesis by regulating signaling pathways in human MSCs, but could improve the outcome of fat transplantation by reducing inflammation and stimulating angiogenesis. It was thus hypothesized that NA could serve as an adjuvant strategy to enhance fat engraftment in regenerative surgery.

Low-dose computed tomography (LDCT) scans are essential in reducing radiation exposure but often suffer from significant image noise that can impair diagnostic accuracy. While deep learning approaches have enhanced LDCT denoising capabilities, the predominant reliance on objective metrics like PSNR and SSIM has resulted in over-smoothed images that lack critical detail. This paper explores advanced deep learning methods tailored specifically to improve perceptual quality in LDCT images, focusing on generating diagnostic-quality images preferred in clinical practice. We review and compare current methodologies, including perceptual loss functions and generative adversarial networks, addressing the significant limitations of current benchmarks and the subjective nature of perceptual quality evaluation. Through a systematic analysis, this study underscores the urgent need for developing methods that balance both perceptual and diagnostic quality, proposing new directions for future research in the field., Competing Interests: Conflict of interestThe authors have no relevant financial or non-financial interests to disclose., (© Korean Society of Medical and Biological Engineering 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disorder caused by abnormal histiocytes and T cell activation. In adults, it is predominantly associated with infections, cancers, and autoimmune diseases. Relapsing polychondritis (RP), another rare disease, is diagnosed based on symptoms without specific tests, featuring cartilage inflammation characterized by swelling, redness, and pain, rarely inducing HLH., Case Summary: A 74-year-old woman visited the emergency room with a fever of 38.6 °C. Blood tests, cultures, and imaging were performed to evaluate fever. Results showed increased fluorescent antinuclear antibody levels and mild cytopenia, with no other specific findings. Imaging revealed lymph node enlargement was observed; however, biopsy results were inconclusive. Upon re-evaluation of the physical exam, inflammatory signs suggestive of RP were observed in the ears and nose, prompting a tissue biopsy for confirmation. Simultaneously, persistent fever accompanied by cytopenia prompted a bone marrow examination, revealing hemophagocytic cells. After finding no significant results in blood culture, viral markers, and tissue examination of enlarged lymph nodes, HLH was diagnosed by RP. Treatment involved methylprednisolone followed by azathioprine. After two months, bone marrow examination confirmed resolution of hemophagocytosis, with normalization of hyperferritinemia and pancytopenia., Conclusion: Thorough physical examination enabled diagnosis and treatment of HLH triggered by RP in patients presenting with fever of unknown origin., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

This study reports intrinsic multimodal memristivity of a nonconjugated radical polymer with ambient stability. Organic memristive devices represent powerful candidates for biorealistic data storage and processing. However, there exists a substantial knowledge gap in realizing the synthetic biorealistic systems capable of effectively emulating the cooperative and multimodal activation processes in biological systems. In addition, conventional organic memristive materials are centered on conjugated small and macromolecules, making them synthetically challenging or difficult to process. In this work, we first describe the intrinsic resistive switching of the radical polymer that resulted in an exceptional state retention of >10 5 s and on/off ratio of >10 6 . Next, we demonstrate its bimodal cooperative switching, in response to the proton accumulation as a biological input. Last, we expand our system toward an advanced in-sensor computing system. Our research demonstrates a nonconjugated radical polymer with intrinsic memristivity, which is directly applicable to future electronics including data storage, neuromorphics, and in-sensor computing.

Interleukin-6 (IL-6) was suggested as a potential target for intervention to mitigate brain injury. However, its neuro-protective effect in post-resuscitation care has not been proven. We investigated the time-course of changes in IL-6 and its association with other markers (systemic inflammation and myocardial and neuronal injury), according to the injury severity of the cardiac arrest. This retrospective study analyzed IL-6 and other markers at baseline and 24, 48, and 72 h after the return of spontaneous circulation. The primary outcome was the association of IL-6 with injury severity as assessed using the revised Post-Cardiac Arrest Syndrome for Therapeutic Hypothermia scoring system (low, moderate, and high severity). Of 111 patients, 22 (19.8%), 61 (55.0%), and 28 (25.2%) had low-, moderate-, and high-severity scores, respectively. IL-6 levels were significantly lower in the low-severity group than in the moderate- and high-severity groups at baseline and at 24 h and 72 h ( p < 0.005). While IL-6 was not independently associated with neuronal injury markers in the low-severity group, it was demonstrated to be associated with it in the moderate-severity (β [95% CI] = 4.3 [0.1-8.6], R 2 = 0.11) and high-severity (β [95% CI] = 7.9 [3.4-12.5], R 2 = 0.14) groups. IL-6 exhibits distinct patterns across severity and shows differential associations with systemic inflammation or neuronal injury.

Rationale: Cholangiocarcinoma (CCA) frequently invades nearby lymph nodes, the liver, and lungs. The liver and lungs are also common anatomic sites for the first recurrence of CCA. However, metastasis to the brain is exceptionally rare., Patient Concerns: A 79-year-old male patient who was diagnosed with distal CCA and underwent pylorus-preserving pancreaticoduodenectomy along with adjuvant chemotherapy 13-years ago visited the neurosurgery outpatient department. He complained of dysarthria and right leg weakness that had started 7 days previously., Diagnoses: Brain computed tomography (CT) showed a 32 mm × 28 mm mass in the left frontal lobe with peripheral ring enhancement and vasogenic edema. A tumor mass removal operation was performed, and pathological examination revealed metastatic adenocarcinoma. Immunohistochemistry analysis revealed negativity for thyroid transcription factor-1 and napsin A, and positivity for cytokeratin (CK)7, CK20, and CK19. Simultaneously, Chest CT, abdomen-pelvis CT and 18-Fluoro-deoxyglucose positron emission tomography showed only two small nodules in the left upper lung, with no evidence of locoregional recurrence in the abdominal cavity. Considering these CT, positron emission tomography-CT, and pathologic findings, very late recurrence of biliary tract cancer with brain and lung metastases was suggested., Interventions and Outcomes: A therapeutic plan involving systemic chemotherapy with gemcitabine and cisplatin was proposed, but the patient refused further chemotherapy., Lessons: This case highlights the unpredictable nature of metastatic patterns in CCA, where brain metastasis occurs very late, preceding locoregional recurrence in the liver. This challenges conventional expectations and underscores the need for vigilant surveillance and consideration of atypical metastatic sites in long-term survivors of CCA., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

The quinoline alkaloid 2-(quinoline-8-carboxamido)benzoic acid (2-QBA), which is isolated from Aspergillus sp. SCSIO06786, a deep sea-derived fungus, has been suggested as a therapeutic candidate for the treatment of Parkinson's disease. We developed an analytical method for 2-QBA using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) in mouse plasma, in which a protein precipitation method for the sample preparation of 2-QBA in mouse plasma was used due to its simplicity and good extraction recovery rates (80.49-97.56%). The linearity of the calibration standard sample, inter- and intraday precision and accuracy, and stability of three quality control samples were suitable based on the assessment criteria and the lower limit of quantification (LLOQ) of the 2-QBA was 1 ng/mL. A pharmacokinetic study of 2-QBA was performed in mice divided into oral (2.0, 5.0, and 15 mg/kg) and intravenous (0.5 and 1.0 mg/kg) administration groups. The absolute oral bioavailability (BA) range of 2-QBA was calculated as 68.3-83.7%. Secondary peaks were observed at approximately 4-8 h after the oral administration of 2-QBA at all doses. The elimination half-life of the orally administered 2-QBA was significantly longer than that of the intravenous 2-QBA. In addition, glucuronide metabolites of 2-QBA were identified. They were transformed into 2-QBA using the β-glucuronidase treatment. Furthermore, the 2-QBA was readily absorbed from the jejunum to lower ileum. Taken together, the secondary peaks could be explained by the enterohepatic circulation of 2-QBA. In conclusion, the reabsorption of orally administered 2-QBA could contribute to the high oral BA of 2-QBA and could be beneficial for the efficacy of 2-QBA. Moreover, the simple and validated analytical method for 2-QBA using LC-MS/MS was applied to the pharmacokinetic study and BA assessments of 2-QBA in mice and would be helpful for subsequent pharmacokinetic studies, as well as for evaluations of the toxicokinetics and pharmacokinetic-pharmacodynamic correlation of 2-QBA to assess its potential as a drug.

Background: Despite medical advancements in neonatal survival rates, many children have poor neurological outcomes. Because the law in Korea restricts the withdrawal of life-sustaining treatment to only cases of imminent death, treatment discontinuation may not be an option, even in patients with poor neurological prognosis. This study investigated the opinions of the general population and clinicians regarding life-sustaining treatment withdrawal in such cases using hypothetical scenarios., Methods: We conducted a cross-sectional study on the general population and clinicians using a web-based questionnaire. The sample of the general population from an online panel comprised 500 individuals aged 20-69 years selected by quota sampling. The clinician sample comprised 200 clinicians from a tertiary university hospital. We created hypothetical vignettes and questionnaire items to assess attitudes regarding mechanical ventilation withdrawal for an infant at risk of poor neurological prognosis due to birth asphyxia at 2 months and 3 years after the incidence., Results: Overall, 73% of the general population and 74% of clinicians had positive attitudes toward mechanical ventilator withdrawal at 2 months after birth asphyxia. The proportion of positive attitudes toward mechanical ventilator withdrawal was increased in the general population (84%, P < 0.001) and clinicians (80.5%, P = 0.02) at 3 years after birth asphyxia. Religion, spirituality, the presence of a person with a disability in the household, and household income were associated with the attitudes of the general population. In the multivariable logistic regression analysis of the general population, respondents living with a person with a disability or having a disability were more likely to find the withdrawal of the ventilator at 2 months and 3 years after birth asphyxia not permissible. Regarding religion, respondents who identified as Christians were more likely to find the ventilator withdrawal at 2 months after birth asphyxia unacceptable., Conclusion: The general population and clinicians shared the perspective that the decision to withdraw life-sustaining treatment in infants with a poor neurological prognosis should be considered before the end of life. A societal discussion about making decisions centered around the best interest of pediatric patients is warranted., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Thymocyte selection-associated high-mobility group box (TOX) is a transcription factor that is crucial for T cell exhaustion during chronic antigenic stimulation, but its role in inflammation is poorly understood. Here, we report that TOX extracellularly mediates drastic inflammation upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by binding to the cell surface receptor for advanced glycation end-products (RAGE). In various diseases, including COVID-19, TOX release was highly detectable in association with disease severity, contributing to lung fibroproliferative acute respiratory distress syndrome (ARDS). Recombinant TOX-induced blood vessel rupture, similar to a clinical signature in patients experiencing a cytokine storm, further exacerbating respiratory function impairment. In contrast, disruption of TOX function by a neutralizing antibody and genetic removal of RAGE diminished TOX-mediated deleterious effects. Altogether, our results suggest an insight into TOX function as an inflammatory mediator and propose the TOX-RAGE axis as a potential target for treating severe patients with pulmonary infection and mitigating lung fibroproliferative ARDS., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Older adults surviving critical illness often experience new or worsening functional impairments. Modifiable positive psychological constructs such as resilience may mitigate post-intensive care morbidity., Research Question: Is pre-ICU resilience associated with: (1) post-ICU survival; (2) the drop in functional independence during the ICU stay; or (3) the trend in predicted independence before vs after the ICU stay?, Study Design and Methods: This retrospective cohort study was performed by using Medicare-linked Health and Retirement Study surveys from 2006 to 2018. Older adults aged ≥ 65 years admitted to an ICU were included. Resilience was calculated prior to ICU admission. The resilience measure was defined from the Simplified Resilience Score, which was previously adapted and validated for the Health and Retirement Study. Resilience was scored by using the Leave-Behind survey normalized to a scale from 0 (lowest resilience) to 12 (highest resilience). Outcomes were survival and probability of functional independence. Survival was modeled by using Gompertz models and independence using joint survival models adjusting for sociodemographic and clinical variables. Average marginal effects were estimated to determine independence probabilities., Results: Across 3,409 patients aged ≥ 65 years old admitted to ICUs, preexisting frailty (30.5%) and cognitive impairment (24.3%) were common. Most patients were previously independent (82.7%). Mechanical ventilation occurred in 14.8% and sepsis in 43.2%. Those in the highest resilience group (vs lowest resilience) had a lower risk of post-ICU mortality (adjusted hazard ratio, 0.81; 95% CI, 0.70-0.94). Higher resilience was associated with greater likelihood of post-ICU functional independence (estimated probability of functional independence 5 years after ICU discharge in highest-to-lowest resilience groups (adjusted hazard ratio [95% CI]): 0.53 (0.33-0.74), 0.47 (0.26-0.68), 0.49 (0.28-0.70), and 0.36 (0.17-0.55); P < .01. Resilience was not associated with a difference in the drop in independence during the ICU stay or a difference in the pre-ICU vs post-ICU trend in predicted independence ., Interpretation: ICU survivors with higher resilience had increased rates of survival and functional independence, although the slope of functional decline before vs after the ICU stay did not differ according to resilience group., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Published by Elsevier Inc.)

Background: Language in nonmedical data sets is known to transmit human-like biases when used in natural language processing (NLP) algorithms that can reinforce disparities. It is unclear if NLP algorithms of medical notes could lead to similar transmissions of biases., Research Question: Can we identify implicit bias in clinical notes, and are biases stable across time and geography?, Study Design and Methods: To determine whether different racial and ethnic descriptors are similar contextually to stigmatizing language in ICU notes and whether these relationships are stable across time and geography, we identified notes on critically ill adults admitted to the University of California, San Francisco (UCSF), from 2012 through 2022 and to Beth Israel Deaconess Hospital (BIDMC) from 2001 through 2012. Because word meaning is derived largely from context, we trained unsupervised word-embedding algorithms to measure the similarity (cosine similarity) quantitatively of the context between a racial or ethnic descriptor (eg, African-American) and a stigmatizing target word (eg, nonco-operative) or group of words (violence, passivity, noncompliance, nonadherence)., Results: In UCSF notes, Black descriptors were less likely to be similar contextually to violent words compared with White descriptors. Contrastingly, in BIDMC notes, Black descriptors were more likely to be similar contextually to violent words compared with White descriptors. The UCSF data set also showed that Black descriptors were more similar contextually to passivity and noncompliance words compared with Latinx descriptors., Interpretation: Implicit bias is identifiable in ICU notes. Racial and ethnic group descriptors carry different contextual relationships to stigmatizing words, depending on when and where notes were written. Because NLP models seem able to transmit implicit bias from training data, use of NLP algorithms in clinical prediction could reinforce disparities. Active debiasing strategies may be necessary to achieve algorithmic fairness when using language models in clinical research., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Published by Elsevier Inc.)

Alzheimer's disease (AD) accounts for 60-70% of the population with dementia. Mild cognitive impairment (MCI) is a diagnostic entity defined as an intermediate stage between subjective cognitive decline and dementia, and about 10-15% of people annually convert to AD. We aimed to investigate the most robust model and modality combination by combining multi-modality image features based on demographic characteristics in six machine learning models. A total of 196 subjects were enrolled from four hospitals and the Alzheimer's Disease Neuroimaging Initiative dataset. During the four-year follow-up period, 47 (24%) patients progressed from MCI to AD. Volumes of the regions of interest, white matter hyperintensity, and regional Standardized Uptake Value Ratio (SUVR) were analyzed using T1, T2-weighted-Fluid-Attenuated Inversion Recovery (T2-FLAIR) MRIs, and amyloid PET (αPET), along with automatically provided hippocampal occupancy scores (HOC) and Fazekas scales. As a result of testing the robustness of the model, the GBM model was the most stable, and in modality combination, model performance was further improved in the absence of T2-FLAIR image features. Our study predicts the probability of AD conversion in MCI patients, which is expected to be useful information for clinician's early diagnosis and treatment plan design., (© 2024. The Author(s).)

Patient-derived organoids (PDOs) are valuable in predicting response to cancer therapy. PDOs are ideal models for precision oncologists. However, their practical application in guiding timely clinical decisions remains challenging. This study focused on patients with advanced EGFR-mutated non-small cell lung cancer and employed a cancer organoid-based diagnosis reactivity prediction (CODRP)-based precision oncology platform to assess the efficacy of EGFR inhibitor treatments. CODRP was employed to evaluate EGFR-tyrosine kinase inhibitors (TKI) drug sensitivity. The results were compared to those obtained using area under the curve index. This study validated this index by testing lung cancer-derived organoids in 14 patients with lung cancer. The CODRP index-based drug sensitivity test reliably classified patient responses to EGFR-TKI treatment within a clinically suitable 10-day timeline, which aligned with clinical drug treatment responses. This approach is promising for predicting and analyzing the efficacy of anticancer, ultimately contributing to the development of a precision medicine platform., (© 2024. The Author(s).)

Background: This study aimed to explore the changes in blood-brain barrier (BBB) permeability and intracranial pressure (ICP) for the first 24 h after the return of spontaneous circulation (ROSC) and their association with injury severity of cardiac arrest., Methods: This prospective study analysed the BBB permeability assessed using the albumin quotient (Qa) and ICP every 2 h for the first 24 h after ROSC. The injury severity of cardiac arrest was assessed using Pittsburgh Cardiac Arrest Category (PCAC) scores. The primary outcome was the time course of changes in the BBB permeability and ICP for the first 24 h after ROSC and their association with injury severity (PCAC scores of 1-4)., Results: Qa and ICP were measured 274 and 197 times, respectively, in 32 enrolled patients. Overall, the BBB permeability increased progressively over time after ROSC, and then it increased significantly at 18 h after ROSC compared with the baseline. In contrast, the ICP revealed non-significant changes for the first 24 h after ROSC. The Qa in the PCAC 2 group was < 0.01, indicating normal or mild BBB disruption at all time points, whereas the PCAC 3 and 4 groups showed a significant increase in BBB permeability at 14 and 22 h, and 12 and 14 h after ROSC, respectively., Conclusion: BBB permeability increased progressively over time for the first 24 h after ROSC despite post-resuscitation care, whereas ICP did not change over time. BBB permeability has an individual pattern when stratified by injury severity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We investigated the agreement between the jugular bulb (JB) and cerebrospinal fluid (CSF) lactate levels. The study was conducted from July 2021 to June 2023 as a prospective observational cohort study at a single center. The right jugular vein was accessed, and the placement of JB catheter tip was confirmed using lateral cervical spine X-ray. A lumbar catheter was inserted between the 3rd and 4th lumbar spine of the patient. Lactate levels were measured immediately, 24 h, 48 h, and 72 h after ROSC. In patients with a good neurological prognosis, kappa between JB and CSF lactate levels measured immediately, at 24 h, 48 h, and 72 h after ROSC were 0.08, 0.36, 0.14, - 0.05 (p = 0.65, 0.06, 0.48, and 0.75, respectively). However, in patients with a poor neurological prognosis, kappa between JB and CSF lactate levels measured immediately, at 24 h, 48 h, and 72 h after ROSC were 0.38, 0.21, 0.22, 0.12 (p = 0.001, 0.04, 0.04, and 0.27, respectively). This study demonstrated that JB lactate levels exhibited significant agreement with arterial lactate levels, compared to CSF lactate levels. Therefore, this should be considered when using JB lactate to monitor cerebral metabolism., (© 2024. The Author(s).)

Competing Interests: The authors have no potential conflicts of interest to disclose.

Background: Patients with atrial fibrillation have a high mortality rate that is only partially attributable to vascular outcomes. The competing risk of death may affect the expected anticoagulant benefit. We determined if competing risks materially affect the guideline-endorsed estimate of anticoagulant benefit., Methods: We conducted a secondary analysis of 12 randomized controlled trials that randomized patients with atrial fibrillation to vitamin K antagonists (VKAs) or either placebo or antiplatelets. For each participant, we estimated the absolute risk reduction (ARR) of VKAs to prevent stroke or systemic embolism using 2 methods-first using a guideline-endorsed model (CHA 2 DS 2 -VASc) and then again using a competing risk model that uses the same inputs as CHA 2 DS 2 -VASc but accounts for the competing risk of death and allows for nonlinear growth in benefit. We compared the absolute and relative differences in estimated benefit and whether the differences varied by life expectancy., Results: A total of 7933 participants (median age, 73 years, 36% women) had a median life expectancy of 8 years (interquartile range, 6-12), determined by comorbidity-adjusted life tables and 43% were randomized to VKAs. The CHA 2 DS 2 -VASc model estimated a larger ARR than the competing risk model (median ARR at 3 years, 6.9% [interquartile range, 4.7%-10.0%] versus 5.2% [interquartile range, 3.5%-7.4%]; P <0.001). ARR differences varied by life expectancies: for those with life expectancies in the highest decile, 3-year ARR difference (CHA 2 DS 2 -VASc model - competing risk model 3-year risk) was -1.3% (95% CI, -1.3% to -1.2%); for those with life expectancies in the lowest decile, 3-year ARR difference was 4.7% (95% CI, 4.5%-5.0%)., Conclusions: VKA anticoagulants were exceptionally effective at reducing stroke risk. However, VKA benefits were misestimated with CHA 2 DS 2 -VASc, which does not account for the competing risk of death nor decelerating treatment benefit over time. Overestimation was most pronounced when life expectancy was low and when the benefit was estimated over a multiyear horizon., Competing Interests: Disclosures M. Ezekowitz is supported by the Sharpe Strumia Foundation based at Bryn Mawr Hospital. Drs Shah, Jeon, Boscardin, and Covinsky reported funding from the National Institute on Aging/National Institutes of Health (NIH) related to the conduct of this study (noted below). Dr Fang reported grants from the National Heart, Lung, and Blood Institute/NIH during the conduct of the study (K24HL141354) and grants from Patient-Centered Outcomes Research Institute outside the submitted work. Dr Singer was supported, in part, by the Eliot B. and Edith C. Shoolman Fund of Massachusetts General Hospital. He has received research support from Bristol Myers Squibb and consultancy fees from Bristol-Myers Squibb, Fitbit, Medtronic, and Pfizer. Professor Hobbs is, in part, supported by the National Institute for Health and Care Research (Oxford and Thames Valley Applied Research Collaboration and Medtech and In vitro diagnostics Co-operatives) and has received occasional consultancy fees from Bayer, BMS Pfizer, Novartis, and AZ unconnected to this study. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the article; and decision to submit the article for publication.

Changes in cerebrospinal fluid (CSF) dynamics can have adverse effects on neuronal function. We hypothesized that patients with hypoxic-ischemic brain injury (HIBI) showing poor neurological outcomes after cardiac arrest (CA) would exhibit changes in CSF dynamics, leading to abnormalities in gas diffusion within the CSF. Therefore, we investigated the prognostic value of the CSF partial pressure of carbon dioxide (PcsfCO 2 ) in CA survivors who underwent targeted temperature management (TTM). We retrospectively analyzed the 6-month neurological outcomes, CSF, and arterial blood gas parameters of 67 CA survivors. Patients were divided into good and poor neurological outcome groups, and the predictive value of PcsfCO 2 for poor neurological outcomes was assessed using receiver operating characteristic curve analysis. Among all patients, 39 (58.2%) had poor neurological outcomes. Significant differences in PcsfCO 2 levels between the groups were observed, with lower PcsfCO 2 levels on Day 1 showing the highest predictive value at a cutoff of 30 mmHg (area under the curve, sensitivity, and specificity were 0.823, 77.8%, and 79.0%, respectively). These results suggest that PcsfCO 2 might serve not only as a unique marker for the severity of hypoxic-ischemic brain injury (HIBI), independent of extracorporeal CO 2 levels, but also as an objective indicator of changes in CSF dynamics. This study highlights the potential prognostic and diagnostic utility of PcsfCO 2 during TTM in CA survivors, emphasizing its importance in evaluating CSF dynamics and neurological recovery post CA. However, larger multicenter studies are warranted to address potential limitations associated with sample size and outcome assessment methods.

Objectives: To assess the validity and reliability of the Korean version of the reflux symptom score (K-RSS)., Materials and Methods: The English version of the RSS was translated into Korean and completed by 77 people (44 and 33 people in the patient group and control group, respectively). They completed the K-RSS (K-RSS-1) and reflux symptom index (RSI) questionnaires and answered questions about age, sex, underlying disease, smoking history, and alcohol and coffee consumption. They completed the K-RSS once more (K-RSS-2) after 1 - 2 weeks. Internal consistency was evaluated using Cronbach's α and test-retest reliability using the intraclass correlation coefficient (ICC). External validity was evaluated using the Spearman rank test between the RSI and K-RSS. The Mann-Whitney U test was used to assess internal validity by comparing the K-RSS-1 scores between the patient and control groups., Results: The most common symptoms were globus sensation, throat clearing, and throat pain. The K-RSS reported high internal consistency (α = 0.894). The ICC for the total score was 0.883, indicating excellent test-retest reliability. According to the Spearman analysis, there was a significant correlation between the total score of the K-RSS and that of the RSI (rs = 0.902; P < 0.001), demonstrating strong external validity. Furthermore, the patient group showed significantly higher values than the control group in all K-RSS scores, suggesting high internal validity., Conclusion: The K-RSS is a patient-reported outcome questionnaire with excellent criterion-referenced validity and ideal reliability., (Copyright © 2021 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

New supplements with preventive effects against skin photodamage are receiving increasing attention. This study evaluated the anti-photoaging effects of salmon nasal cartilage proteoglycan (SPG), acting as a functional material for skin health. We administered SPG to in vitro and in vivo models exposed to ultraviolet B (UVB) radiation and assessed its moisturizing and anti-wrinkle effects on dorsal mouse skin and keratinocytes and dermal fibroblasts cell lines. These results showed that SPG restored the levels of filaggrin, involucrin, and AQP3 in the epidermis of UVB-irradiated dorsal skin and keratinocytes, thereby enhancing the keratinization process and water flow. Additionally, SPG treatment increased the levels of hyaluronan and skin ceramide, the major components of intercellular lipids in the epidermis. Furthermore, SPG treatment significantly increased the levels of collagen and procollagen type 1 by down-regulating matrix metalloproteinase 1, which play a crucial role in skin fibroblasts, in both in vitro and in vivo models. In addition, SPG strongly inhibited mitogen-activated protein kinase (MAPKs) signaling, the including extracellular signal-regulated kinase, c-Jun N-terminal kinase (JNK), and p38. These findings suggest that dietary SPG may be an attractive functional food for preventing UVB-induced photoaging. And this SPG product may provide its best benefit when treating several signs of skin photoaging.

Administration of sedatives for post-resuscitation care can complicate the determination of the optimal timing to avoid inappropriate, pessimistic prognostications. This prospective study aimed to investigate the distribution and elimination kinetics of midazolam (MDZ) and its metabolites, and their association with awakening time. The concentrations of MDZ and its seven metabolites were measured immediately and at 4, 8, 12, and 24 h after the discontinuation of MDZ infusion, using liquid chromatography-tandem mass spectrometry. The area under the time-plasma concentration curve from 0 to 24 h after MDZ discontinuation (AUC last ) was calculated based on the trapezoidal rule. Of the 15 enrolled patients, seven awakened after the discontinuation of MDZ infusion. MDZ and three of its metabolites were major compounds and their elimination kinetics followed a first-order elimination profile. In the multivariable analysis, only MDZ was associated with awakening time (AUC last : R 2  = 0.59, p = 0.03; AUC inf : R 2  = 0.96, p < 0.001). Specifically, a 0.001% increase in MDZ AUC was associated with a 1% increase in awakening time. In the individual regression analysis between MDZ concentration and awakening time, the mean MDZ concentration at awakening time was 16.8 ng/mL. The AUC of MDZ is the only significant factor associated with the awakening time., (© 2024. The Author(s).)

Nonconjugated organic radicals with an open-shell radical active group exhibit unique functionality due to their radical pendant site. Compared with the previously studied doped conjugated polymers, radical polymers reveal superior processability, stability, and optical properties. Despite the success of organic radical polymer conductors based on the TEMPO radicals, it still requires potential design substitutions to meet the fundamental limits of charge transport in the radical polymer. To do so, we demonstrate that the amorphous, nonconjugated radical polymer with backbone-pendant group interaction and low glass transition temperature enables the macromolecules to have rapid charge transport in the solid state, resulting in conductivity higher than 32 S m -1 . This charge transport is due to the formation of the local ordered regime with an energetically favored orientation caused by the strong coupling between the backbone and pendant group, which can significantly modulate the polymer packing with active electronic communications. The nonconjugate nature of the radical polymer maintains an optical transparency up to 98% at a 1.5 μm thick film. Thus, this effort will be a dramatically advanced model in the organic radical community for the creation of next-generation polymer conductors., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: Selection of a suitable training modality according to the status of upper limb function can maximize the effects of robotic rehabilitation; therefore, it is necessary to identify the optimal training modality., Objectives: This study aimed to compare robotic rehabilitation approaches incorporating either resistance training (RET) or active-assisted training (AAT) using the same rehabilitation robot in people with stroke and moderate impairment., Methods: In this randomized controlled trial, we randomly allocated 34 people with stroke who had moderate impairment to either the experimental group (RET, n = 18) or the control group (AAT, n = 16). Both groups performed robot-assisted therapy for 30 min, 5 days per week, for 4 weeks. The same rehabilitation robot provided resistance to the RET group and assistance to the AAT group. Body function and structure, activity, and participation outcomes were evaluated before, during, and after the intervention., Results: RET led to greater improvements than AAT in terms of smoothness (p = 0.006). The Fugl-Meyer Assessment (FMA)-upper extremity (p < 0.001), FMA-proximal (p < 0.001), Action Research Arm Test-gross movement (p = 0.011), and kinematic variables of joint independence (p = 0.017) and displacement (p = 0.011) also improved at the end of intervention more in the RET group., Conclusions: Robotic RET was more effective than AAT in improving upper limb function, structure, and activity among participants with stroke who had moderate impairment., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: Despite the current effective treatments for acute promyelocytic leukemia (APL), early mortality (EM), defined as death within 30 days of presentation, is a major hurdle to long-term survival., Methods: We performed a multicenter retrospective study to evaluate the incidence and clinical characteristics of EM in patients with newly diagnosed APL and to develop a risk stratification model to predict EM., Results: We identified 313 eligible patients diagnosed between 2000 and 2021 from five academic hospitals. The median age was 50 years (range 19-94), and 250 (79.9%) patients were <65 years. Most patients (n=274, 87.5%) received their first dose of all-trans retinoic acid (ATRA) within 24 hours of presentation. EM occurred in 41 patients, with a cumulative incidence of 13.1%. The most common cause of EM was intracranial hemorrhage (n=22, 53.6%), and most EMs (31/41, 75.6%) occurred within the first seven days of APL presentation. In a multivariable analysis, we identified three independent factors predicting EM: age ≥65 years (HR, 2.56), white blood cell count ≥8.0 x 10 9 /L (HR, 3.30), and ATRA administration >24 hours of presentation (HR, 2.95). Based on these factors, patients were stratified into three categories with a significantly increasing risk of EM: 4.1% for low risk (54.3%; no risk factors; HR 1), 18.5% for intermediate risk (34.5%; 1 factor; HR 4.81), and 40.5% for high risk (11.2%; 2-3 factors; HR 13.16)., Discussion: The risk of EM is still not negligible in this era of ATRA-based therapies. Our risk model serves as a clinically useful tool to identify high-risk patients for EM who may be candidates for novel treatments and aggressive supportive strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kim, Jung, Ahn, Kim, Jeon, Lee, Kim, Lee, Sung, Choi, Kim, Kim, Kwak, Park, Ahn and Yhim.)

Background/aim: This study investigated the treatment patterns and prognosis of patients with metastatic or unresectable colorectal cancer (mCRC) treated with chemotherapy with targeting agents., Patients and Methods: This longitudinal multicenter study included 963 patients with mCRC who were treated in Korea between 2016 and 2020. Treatment patterns and efficacy were compared according to the mutation status and clinical factors., Results: As first-line therapy, most of the patients (83.5%) received FOLFOX plus bevacizumab (35.4%), followed by FOLFIRI plus bevacizumab (18.8%), FOLFIRI plus cetuximab (17.0%), and FOLFOX plus cetuximab (12.3%). Bevacizumab was the most frequent agent (78.8%) combined with chemotherapy in RAS-mutated CRC, while cetuximab (57.2%) in RAS wild-type CRC. Cetuximab was frequently combined with a doublet regimen in patients with left-sided CRC than in those with right-sided CRC (34.4% vs. 16%). As second-line therapy, most patients (63.4%) also received doublet regimens with bevacizumab, and FOLFIRI plus aflibercept was administered in 15.1%. The objective response rate with FOLFIRI plus cetuximab was significantly higher in patients with left-sided CRC than in those with right-sided CRC (59.2% vs. 30.8%, p=0.008) and marginally higher in patients with RAS wild-type CRC than in those with RAS-mutated CRC (55.6% vs. 0.0%, p=0.092). Progression-free survival (PFS) with FOLFOX plus bevacizumab was significantly shorter than that with FOLFIRI plus bevacizumab (p=0.030) in RAS-mutated CRC, whereas there were no significant differences between regimens in RAS wild-type CRC., Conclusion: In patients with unresectable metastatic colorectal cancer, doublet chemotherapy with targeting agents is the most common therapy and efficacy depends on the mutation status as well as clinical factors., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Importance: Most older adults living with dementia ultimately need nursing home level of care (NHLOC)., Objective: To develop models to predict need for NHLOC among older adults with probable dementia using self-report and proxy reports to aid patients and family with planning and care management., Design, Setting, and Participants: This prognostic study included data from 1998 to 2016 from the Health and Retirement Study (development cohort) and from 2011 to 2019 from the National Health and Aging Trends Study (validation cohort). Participants were community-dwelling adults 65 years and older with probable dementia. Data analysis was conducted between January 2022 and October 2023., Exposures: Candidate predictors included demographics, behavioral/health factors, functional measures, and chronic conditions., Main Outcomes and Measures: The primary outcome was need for NHLOC defined as (1) 3 or more activities of daily living (ADL) dependencies, (2) 2 or more ADL dependencies and presence of wandering/need for supervision, or (3) needing help with eating. A Weibull survival model incorporating interval censoring and competing risk of death was used. Imputation-stable variable selection was used to develop 2 models: one using proxy responses and another using self-responses. Model performance was assessed by discrimination (integrated area under the receiver operating characteristic curve [iAUC]) and calibration (calibration plots)., Results: Of 3327 participants with probable dementia in the Health and Retirement Study, the mean (SD) age was 82.4 (7.4) years and 2301 (survey-weighted 70%) were female. At the end of follow-up, 2107 participants (63.3%) were classified as needing NHLOC. Predictors for both final models included age, baseline ADL and instrumental ADL dependencies, and driving status. The proxy model added body mass index and falls history. The self-respondent model added female sex, incontinence, and date recall. Optimism-corrected iAUC after bootstrap internal validation was 0.72 (95% CI, 0.70-0.75) in the proxy model and 0.64 (95% CI, 0.62-0.66) in the self-respondent model. On external validation in the National Health and Aging Trends Study (n = 1712), iAUC in the proxy and self-respondent models was 0.66 (95% CI, 0.61-0.70) and 0.64 (95% CI, 0.62-0.67), respectively. There was excellent calibration across the range of predicted risk., Conclusions and Relevance: This prognostic study showed that relatively simple models using self-report or proxy responses can predict need for NHLOC in community-dwelling older adults with probable dementia with moderate discrimination and excellent calibration. These estimates may help guide discussions with patients and families in future care planning.

Background: Recent research underscores the clinical relevance of muscle conditions such as sarcopenia and their links to bone mineral density (BMD), yet notable gaps persist in the understanding of their interconnections. Our study addresses this by introducing a novel approach to decipher the correlation between BMD and the texture of the multifidus muscle, utilizing spinal computed tomography (CT) and dual-energy X-ray absorptiometry (DXA) to evaluate muscle texture, BMD, and bone mineral content (BMC) at the total lumbar vertebra and total hip., Methods: Our single-institution study examined 395 cases collected from 6 May 2012 to 30 November 2021. Each patient underwent a spinal CT scan and a DXA scan within a one-month interval. BMD and BMC at the total lumbar vertebra and total hip were measured. The texture features of the multifidus muscle from the axial cuts of T12 to S1 vertebrae were assessed via gray-level co-occurrence matrices. CT texture analysis values at angles of 45 + 45 and 90 degrees were calculated and correlated with BMD and BMC. A regression model was then constructed to predict BMD values, and the precision of these correlations was evaluated using mean square error (MSE) analysis., Results: Total lumbar BMC showed a correlation of 0.583-0.721 (MSE 1.568-1.842) and lumbar BMD of 0.632-0.756 (MSE 0.068-0.097). Total hip BMC had a correlation of 0.556-0.690 (MSE 0.448-0.495), while hip BMD ranged from 0.585 to 0.746 (MSE 0.072-0.092)., Conclusions: The analysis of spinal CT texture alongside BMD and BMC measures provides a new approach to understanding the relationship between bone and muscle health. The strong correlations expected from our research affirm the importance of integrating bone and muscle measures in the prevention, diagnosis, and management of conditions such as sarcopenia and osteoporosis.

This study evaluated the efficacy of personalized neuromodulation, where treatment modalities are chosen based on the patient's responses in a pilot trial. A total of 71 patients with tinnitus were divided into two groups: a personalized group and a randomized neuromodulation group. In the personalized group ( n = 35), repetitive transcranial magnetic stimulation (rTMS) and transcranial direct-current stimulation (tDCS) were assessed in a pilot trial, and responsive modalities were administered to 16 patients, while the non-responders ( n = 19) were randomly assigned to rTMS, tDCS, or combined modalities. Patients in the randomized group ( n = 36) were randomly allocated to rTMS, tDCS, or combined modalities. The Tinnitus Handicap Inventory (THI) score improvement after 10 sessions of each neuromodulation was significantly greater in the personalized group than in the randomized group ( p = 0.043), with no significant differences in tinnitus loudness, distress, or awareness. The treatment success rate was highest in the personalized responder subgroup (92.3%), and significantly greater than that in the non-responder subgroup (53.0%; p = 0.042) and the randomized group (56.7%; p = 0.033). Personalized neuromodulation, where the treatment modality is chosen based on the patient's responses in a pilot trial, is an advantageous strategy for treating tinnitus.

Nonalcoholic steatohepatitis (NASH) is a severe liver metabolic disorder, however, there are still no effective and safe drugs for its treatment. Previous clinical trials used various therapeutic approaches to target individual pathologic mechanisms, but these approaches were unsuccessful because of the complex pathologic causes of NASH. Combinatory therapy in which two or more drugs are administered simultaneously to patients with NASH, however, carries the risk of side effects associated with each individual drug. To solve this problem, we identified gossypetin as an effective dual-targeting agent that activates AMP-activated protein kinase (AMPK) and decreases oxidative stress. Administration of gossypetin decreased hepatic steatosis, lobular inflammation and liver fibrosis in the liver tissue of mice with choline-deficient high-fat diet and methionine-choline deficient diet (MCD) diet-induced NASH. Gossypetin functioned directly as an antioxidant agent, decreasing hydrogen peroxide and palmitate-induced oxidative stress in the AML12 cells and liver tissue of MCD diet-fed mice without regulating the antioxidant response factors. In addition, gossypetin acted as a novel AMPK activator by binding to the allosteric drug and metabolite site, which stabilizes the activated structure of AMPK. Our findings demonstrate that gossypetin has the potential to serve as a novel therapeutic agent for nonalcoholic fatty liver disease /NASH. SIGNIFICANCE STATEMENT: This study demonstrates that gossypetin has preventive effect to progression of nonalcoholic steatohepatitis (NASH) as a novel AMP-activated protein kinase (AMPK) activator and antioxidants. Our findings indicate that simultaneous activation of AMPK and oxidative stress using gossypetin has the potential to serve as a novel therapeutic approach for nonalcoholic fatty liver disease /NASH patients., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)

Fluorescent dyes have garnered significant attention as theranostic platforms owing to their inherent characteristics. In this study, we present the discovery of Medical Fluorophore 33 ( MF33 ), a novel and potent theranostic agent with a phenaleno-isoquinolinium salt structure that can serve as a cancer therapeutic strategy. The synthesis of MF33 is readily achievable through a simple Rh(III)-catalyzed reaction. Moreover, MF33 displayed strong fluorescence signals, excellent microsomal stability, and high biocompatibility in vivo. It induces significant apoptosis in cancer cells via the p53/p21/caspase-3 signaling pathway, leading to selective cytotoxicity in various cancer cells. In vivo fluorescence imaging with MF33 enabled the visualization of sentinel lymph nodes in living mice. Notably, repeated intraperitoneal administration of MF33 resulted in antitumor activity in mice with colorectal cancer. Collectively, our findings suggest that phenaleno-isoquinolinium salt-based MF33 is a viable theranostic agent for biomedical imaging and cancer treatment.

The aim of this study was to investigate the differences in cerebral metabolism and the prognostic value of cerebrospinal fluid (CSF) lactate 24 h after the return of spontaneous circulation (ROSC) in patients with out-of-hospital cardiac arrest (OHCA). CSF lactate and pyruvate levels were measured immediately and every 2 h for 24 h after the ROSC. The distribution of cerebral mitochondrial dysfunction (MD) and cerebral ischemia was also evaluated. In the moderate-severity group, the absence of cerebral MD or ischemia was observed in six patients (40.0%) immediately after ROSC and in nine patients (60.0%) 24 h after the ROSC. In the high-severity group, the absence of cerebral MD or ischemia was observed in four patients (30.8%) immediately after ROSC and in three patients (23.1%) 24 h after the ROSC. The distribution of cerebral metabolism over time varied depending on the severity of the OHCA. The predictive value of CSF lactate levels for a poor neurological prognosis was better for patients in the moderate-severity group than for the overall patient cohort. Therefore, the severity in the patients with OHCA should be considered when studying cerebral metabolism or using CSF lactate as a prognostic tool.