Search

Drug conjugation with enzymes is one of the innovative antibacterial nanocarriers used as a delivery system for cancer therapy. Zeolitic imidazolate framework-8 (ZIF-8) was synthesized, dual encapsulated with cellulase (CL) enzyme, and resveratrol (Resv) drug formed ZIF-8@CL&Resv. Cellulase and resveratrol hydrophobic nature have bound them together and imparted a negative charge on the ZIF-8, resulting in the decrease of zeta potential from 22.7 mV (ZIF-8) to 3.82 mV (ZIF-8@CL&Resv). The cellulase like a scaffold regulated the pH-responsive release of resveratrol enhancing its bioavailability. Molecular docking studies provided evidence of the major interaction between the biofilm-related proteins with cellulase and resveratrol. The encapsulated cellulase showed high enzymatic activity and possibly exhibited antibacterial effects by dissolving the biofilm and exposing bacteria to resveratrol action. Resveratrol released sustainably exhibited significant antioxidant and antibacterial activity against selected bacterial species. ZIF-8@CL&Resv exhibited high biocompatibility and had a potent cytotoxic effect against triple-negative breast cancer cells MDA MB 231 with an IC 50 -value of 17.18 μg/mL compared to ZIF-8 control with 90.47 μg/mL. ZIF-8@CL&Resv treatment led to 61.81 % cell death, apoptosis induction, increased ROS generation, and decreased mitochondrial membrane potential. Overall, data demonstrated that ZIF-8@CL&Resv is a novel drug release system and a potential catalytic nanoparticle for antimicrobial and anticancer applications., 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. Published by Elsevier B.V.)

Background: This study aims to investigate the association between serum calcium levels and acute coronary syndrome (ACS) risk, examining whether this relationship differs by sex, given the known differences in calcium metabolism and hormonal influences between males and females. Methods: Utilizing the Korean Genome Epidemiology Study (KoGES) prospective cohort data, our primary exposure variables were serum calcium level and sex. The incidence of ACS served as the main outcome of interest. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression analysis. An interaction analysis was conducted to assess the interaction effect of calcium level and sex on ACS incidence. Results: After adjusting for confounding variables, high calcium intake did not significantly increase ACS incidence, with a hazard ratio (HR) of 1.07 (95% CI: 0.90-1.26). There was also no significant difference in ACS risk between females and males (HR: 0.81, 95% CI: 0.61-1.04). However, interaction effect analysis revealed that higher calcium levels were associated with an increased risk of ACS only in females (HR: 1.24, 95% CI: 1.07-1.58), whereas the association in males was not statistically significant (HR: 0.90, 95% CI: 0.71-1.15). Conclusion: Our study results indicate that elevated serum calcium levels alone did not independently increase the risk of ACS; however, high serum calcium levels were associated with an increased risk of ACS in females but not in males, underscoring the importance of sex-specific factors in assessing and managing ACS risk and highlighting the necessity for personalized medical approaches to improve cardiovascular health outcomes for women., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Feature attribution methods can visually highlight specific input regions containing influential aspects affecting a deep learning model's prediction. Recently, the use of feature attribution methods in electrocardiogram (ECG) classification has been sharply increasing, as they assist clinicians in understanding the model's decision-making process and assessing the model's reliability. However, a careful study to identify suitable methods for ECG datasets has been lacking, leading researchers to select methods without a thorough understanding of their appropriateness. In this work, we conduct a large-scale assessment by considering eleven popular feature attribution methods across five large ECG datasets using a model based on the ResNet-18 architecture. Our experiments include both automatic evaluations and human evaluations. Annotated datasets were utilized for automatic evaluations and three cardiac experts were involved for human evaluations. We found that Guided Grad-CAM, particularly when its absolute values are utilized, achieves the best performance. When Guided Grad-CAM was utilized as the feature attribution method, cardiac experts confirmed that it can identify diagnostically relevant electrophysiological characteristics, although its effectiveness varied across the 17 different diagnoses that we have investigated., 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 Ltd. All rights reserved.)

Background: Heparin-induced thrombocytopenia (HIT) is an uncommon complication of heparin therapy with significant risk for severe morbidity and mortality. We investigated the role and outcome of direct oral anticoagulants (DOACs) for the management of HIT., Methods: After institutional review board (IRB) approval, a retrospective review was performed identifying all patients with positive HIT serotonin-release assays between 2020 and 2022 at two hospitals. The demographic and clinical variables were collected as follows: initial anticoagulant, dosing and indication, interval before onset of HIT, thrombotic complications, platelet nadir and recovery, direct thrombin inhibitor (DTI) and DOAC usage, and clinical outcomes., Results: 15 patients were included in the study. 8 underwent a vascular procedure, 3 had cardiac surgery, 1 patient had both and was included in both groups, and 5 patients had either noncardiac, nonvascular surgery, or no surgery. 14 patients received unfractionated heparin (93% with therapeutic dosing), and 1 received prophylactic enoxaparin prior to diagnosis of HIT. The average time to diagnosis of HIT was 10.77 days after initial anticoagulation. In-hospital mortality was 27%, related to Covid-19 infection (3/4) and intracranial hemorrhage (1/4). 40% developed thrombosis (67% venous, 33% arterial) after the diagnosis of HIT. 8/11 survivors were discharged on a DOAC. With DOAC therapy, platelet counts rebounded to an average of 265K ( ± 104.6 K) within an average of 2.3 days and 364K ( ± 273.9 K) within 30 days after initiation of a DOAC. No recurrent thrombosis occurred after DOAC administration and only one patient had persistent thrombocytopenia within 30 days., Conclusions: Mortality and thrombosis (arterial and venous) are common complications in patients diagnosed with HIT. In patients who survive to discharge, DOACs are the most common discharge antithrombotic agent, with low rates of recurrent thrombosis and thrombocytopenia., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Metabolic dysregulation of neurons is associated with diverse human brain disorders. Metabolic reprogramming occurs during neuronal differentiation, but it is not fully understood which molecules regulate metabolic changes at the early stages of neurogenesis. In this study, we report that miR-124 is a driver of metabolic change at the initiating stage of human neurogenesis. Proteome analysis has shown the oxidative phosphorylation pathway to be the most significantly altered among the differentially expressed proteins (DEPs) in the immature neurons after the knockdown of miR-124. In agreement with these proteomics results, miR-124-depleted neurons display mitochondrial dysfunctions, such as decreased mitochondrial membrane potential and cellular respiration. Moreover, morphological analyses of mitochondria in early differentiated neurons after miR-124 knockdown result in smaller and less mature shapes. Lastly, we show the potential of identified DEPs as novel metabolic regulators in early neuronal development by validating the effects of GSTK1 on cellular respiration. GSTK1, which is upregulated most significantly in miR-124 knockdown neurons, reduces the oxygen consumption rate of neural cells. Collectively, our data highlight the roles of miR-124 in coordinating metabolic maturation at the early stages of neurogenesis and provide insights into potential metabolic regulators associated with human brain disorders characterized by metabolic dysfunctions., (© 2024. The Author(s).)

Background: Peyronie's disease (PD) is a fibroproliferative disorder that causes an abnormal curve of the penis resulting in pain, discomfort, and erectile dysfunction with management options including correctional surgery, penile external/internal devices, shock wave therapy (SWT), intralesional Verapamil (IV), and collagenase Clostridium histolyticum injections., Aim: To investigate the insurance coverage of these treatment options., Methods: The authors performed a cross-sectional analysis of the top US insurance policies for coverage of PD. Companies were chosen based on their market share and enrollment. Their policies were identified through a Web-based search and telephone interviews, and the companies' medical necessity criteria were defined. The online policies were then re-examined for interval change 3 years later., Outcomes: There are significant discrepancies for in coverage for the different modalities of Peyronie's treatment., Results: Of the 100 companies examined, only 54% of companies had a policy that directly addressed the treatment coverage for PD. The most covered treatment was CCH injections with 37 companies providing unanimous coverage ( n  = 37, 100%). Within this category, all companies required a palpable plaque as a requirement. Additionally, external/internal devices were unanimous covered by 18 companies ( n  = 18, 100%). Surgical treatment was covered by eight companies with six companies denying coverage ( n  = 8 vs. n  = 6, 57.1% vs. 42.9%). IV was covered by two companies. The least covered treatment option was SWT which was universally denied by 19 companies ( n  = 19, 100%)., Clinical Implications: Insurance coverage of PD should be aligned with current medical literature to better increase access to care., Strengths & Limitations: This study is limited by the updated policies of insurance companies and future applicability. Additionally, this study assumes that a written policy will provide coverage and may overestimate the actual extent of coverage. Finally, this study only addressed some of the common treatment options of PD and did not expand on all possible treatment options., Conclusion: Differing rates for modalities of treatment may present a barrier for patients to receive individualized and adequate treatment for PD., Competing Interests: The authors have no conflict of interests to disclose., (Published by Oxford University Press on behalf of The International Society for Sexual Medicine 2024.)

Extracellular vesicles (EVs) have emerged as valuable biological materials for treating intractable diseases. Extensive studies are conducted on EVs derived from various cellular sources. In this study, EVs derived from Lactobacillus reuteri (L. reuteri), a probiotic, exhibit remarkable cancer therapeutic efficacy when administered orally is reported. These L. reuteri-derived EVs (REVs) demonstrate stability in the gastrointestinal tract and exert significant anti-tumor effects. Using A549 cells and murine models, we confirmed that REVs mediate their therapeutic effects by modulating apoptotic signaling pathways. Furthermore, the combination of REV with drugs enhances tumor ablation and induces immunogenic cell death. In a mouse model, oral administration of REVs encapsulating indocyanine green followed by photothermal therapy led to complete tumor elimination within 32 days. REVs represent a promising biological therapeutic platform for cancer treatment, either independently or in combination with other therapies, depending on the treatment objectives., (© 2024 The Author(s). Small published by Wiley‐VCH GmbH.)

Purpose: Extracranial malignant rhabdoid tumors (eMRT) are a challenging entity. Despite the use of multimodal treatment approaches, therapy failure occurs in 55% to 67% of these. Molecular markers for identification of patients at increased risk for relapse or refractory (R/R) disease are not available. Clinical characteristics may only insufficiently predict the individual course of disease., Experimental Design: Using the EU-RHAB database, we analyzed a cohort of 121 patients with eMRT clinically. For 81 patients, molecular and clinical data were available, which were further complemented with publicly available DNA molecular data from 92 eMRTs. We aimed to delineate molecular risk factors by dissecting the DNA methylome of these tumors. Moreover, we establish clinical characteristics and treatment details of R/R disease in a subcohort of 80 patients., Results: Using consensus hierarchical clustering, we identified three distinct subgroups, one of which (eMRT standard risk) was associated with significantly improved survival, irrespective of germline status and/or localization. At the transcriptome level, this subgroup was characterized by an overexpression of genes involved in muscle development. A relevant proportion of patients developed distant relapses or progressions; the median time to the event was 4 months, underlining the need for early identification and risk stratification of R/R disease. The overall survival was significantly decreased in patients with progressive disease when compared with relapse cases, and reaching complete remission during salvage therapy provided a survival benefit., Conclusions: Our analysis of eMRT in this comprehensive cohort provides novel insights into the patterns of relapse and integrates molecular and clinical risk factors to guide clinical decision-making., (©2024 American Association for Cancer Research.)

Small molecules that exhibit broad-spectrum enteroviral inhibitory activity by targeting viral replication proteins are highly desired in antiviral drug discovery studies. To discover new human rhinovirus (hRV) inhibitors, we performed a high-throughput screening of 100,000 compounds from the Korea Chemical Bank library. This search led to identification of two phosphatidylinositol-4-kinase IIIβ (PI4KIIIβ) inhibitors having the pyrazolo-pyrimidine core structure, which display moderate anti-rhinoviral activity along with mild cytotoxicity. The results of a study aimed at optimizing the activity of the hit compounds showed that the pyrazolo-pyrimidine derivative 6f exhibits the highest activity (EC 50  = 0.044, 0.066, and 0.083 μM for hRV-B14, hRV-A16, and hRV-A21, respectively) and moderate toxicity (CC 50  = 31.38 μM). Furthermore, 6f has broad-spectrum activities against various hRVs, coxsackieviruses and other enteroviruses, such as EV-A71, EV-D68. An assessment of kinase inhibition potencies demonstrated that 6f possesses a high and selective kinase inhibition activity against PI4KIIIβ (IC 50 value of 0.057 μM) and not against PI4KIIIα (>10 μM). Moreover, 6f exhibits modest hepatic stability (46.9 and 55.3 % remaining after 30 min in mouse and human liver microsomes, respectively). Finally, an in vivo study demonstrated that 6f possesses a desirable pharmacokinetic profile reflected in low systemic clearance (0.48 L∙h -1  kg -1 ) and modest oral bioavailability (52.4 %). Hence, 6f (KR-26549) appears to be an ideal lead for the development of new antiviral drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Study Objectives: Considering the increased prevalence and more severe manifestations of insomnia among females along with established sex differences in ischemic stroke (IS) occurrence, this research aimed to examine the potential effects of the interaction between insomnia and sex on the incidence and outcome of IS., Methods: We used data from the Korean Genome and Epidemiology Study. The main exposure variables were insomnia history and sex. The main outcome was the occurrence of IS observed in biennial follow-up surveys. Cox proportional regression analysis was performed to estimate the effects of insomnia and sex on IS incidence. We also conducted interaction analysis to investigate the interaction effects between insomnia and sex on IS incidence., Results: During 19 years of follow-up involving 8,933 individuals, we documented 370 cases of new-onset stroke (2.88 cases per 1,000 person-years). Cox proportional regression analysis showed that insomnia and female sex did not increase the risk of IS (hazard ratio: 1.13 [95% confidence interval: 0.86-1.51] and hazard ratio: 0.86 [95% confidence interval: 0.63-1.17], respectively). Interaction analysis demonstrated that stroke risk was increased only among females with insomnia (hazard ratio: 1.34 [95% confidence interval: 1.05-1.80]) compared with those without insomnia., Conclusions: Our study highlights the significance of considering sex-specific factors when evaluating the relationship between insomnia and IS risk, particularly emphasizing the unique role of insomnia in IS risk among females., Citation: Jung E, Kim DK, Lee SY, Ryu HH. Sex disparity in stroke risk among patients with insomnia: a 19-year prospective cohort study. J Clin Sleep Med. 2024;20(10):1669-1674., (© 2024 American Academy of Sleep Medicine.)

Background: Previous studies reported that vitamin B-12 deficiency is associated with an increased risk of stroke. However, studies examining the association between excessive vitamin B-12 and stroke risk are limited. Our study aimed to investigate the relationship between excessive vitamin B-12 concentrations and risk of stroke and explore whether this association varies according to sex., Methods: Utilizing the Korean Genome Epidemiology Study (KoGES) prospective cohort data, our primary exposure variables were vitamin B-12 plasma concentration and sex. The occurrence of stroke served as the main outcome of interest. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression analysis. An interaction analysis was conducted to assess the interaction effect of vitamin B-12 and sex on stroke incidence., Results: Cox proportional logistic regression analysis, adjusting for confounders, showed that excessive vitamin B-12 did not significantly alter stroke risk (HR: 1.22, 95% CI: 0.82, 1.71) and revealed no significant sex-based differences in stroke risk (HR: 0.90, 95% CI: 0.75, 1.04). However, interaction analysis indicated that excessive vitamin B-12 was linked to a significant increase in stroke risk in males (HR: 1.81, 95% CI: 1.10, 2.99) but not in females (HR: 1.04, 95% CI: 0.66, 1.60), with statistically significant interaction effect (P < 0.01)., Conclusions: Our study demonstrated that although excessive vitamin B-12 alone does not significantly increase stroke risk, it increases risk in males when considering the interaction with sex., (Copyright © 2024 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.)

Ovarian cancer is a leading cause of death for women worldwide in part due to ineffective screening methods. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model with the combined features, we detected ovarian cancer with specificity >99% and sensitivity of 72%, 69%, 87%, and 100% for stages I-IV, respectively. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100% of ovarian cancers for stages I-IV. Our approach differentiated benign masses from ovarian cancers with high accuracy (AUC=0.88, 95% CI=0.83-0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.

Key Message: This study highlights the agronomic potential of rare introgressions, as demonstrated by a major QTL for powdery mildew resistance on chromosome 7D. It further shows evidence for inter-homoeologue recombination in wheat. Agriculturally important genes are often introgressed into crops from closely related donor species or landraces. The gene pool of hexaploid bread wheat (Triticum aestivum) is known to contain numerous such "alien" introgressions. Recently established high-quality reference genome sequences allow prediction of the size, frequency and identity of introgressed chromosome regions. Here, we characterise chromosomal introgressions in bread wheat using exome capture data from the WHEALBI collection. We identified 24,981 putative introgression segments of at least 2 Mb across 434 wheat accessions. Detailed study of the most frequent introgressions identified T. timopheevii or its close relatives as a frequent donor species. Importantly, 118 introgressions of at least 10 Mb were exclusive to single wheat accessions, revealing that large populations need to be studied to assess the total diversity of the wheat pangenome. In one case, a 14 Mb introgression in chromosome 7D, exclusive to cultivar Pamukale, was shown by QTL mapping to harbour a recessive powdery mildew resistance gene. We identified multiple events where distal chromosomal segments of one subgenome were duplicated in the genome and replaced the homoeologous segment in another subgenome. We propose that these examples are the results of inter-homoeologue recombination. Our study produced an extensive catalogue of the wheat introgression landscape, providing a resource for wheat breeding. Of note, the finding that the wheat gene pool contains numerous rare, but potentially important introgressions and chromosomal rearrangements has implications for future breeding., (© 2024. The Author(s).)

High-Grade Serous Ovarian Cancer (HGSOC) originates from fallopian tube (FT) precursors. However, the molecular changes that occur as precancerous lesions progress to HGSOC are not well understood. To address this, we integrated high-plex imaging and spatial transcriptomics to analyze human tissue samples at different stages of HGSOC development, including p53 signatures, serous tubal intraepithelial carcinomas (STIC), and invasive HGSOC. Our findings reveal immune modulating mechanisms within precursor epithelium, characterized by chromosomal instability, persistent interferon (IFN) signaling, and dysregulated innate and adaptive immunity. FT precursors display elevated expression of MHC-class I, including HLA-E, and IFN-stimulated genes, typically linked to later-stage tumorigenesis. These molecular alterations coincide with progressive shifts in the tumor microenvironment, transitioning from immune surveillance in early STICs to immune suppression in advanced STICs and cancer. These insights identify potential biomarkers and therapeutic targets for HGSOC interception and clarify the molecular transitions from precancer to cancer., Competing Interests: DECLARATION OF INTERESTS PKS is a co-founder and member of the BOD of Glencoe Software and member of the SAB for RareCyte, NanoString, and Montai Health; he holds equity in Glencoe and RareCyte. PKS is a consultant for Merck. RD is a member of the SAB for Repare Therapeutics and is a consultant for Light Horse Therapeutics and Abbvie. The other authors declare no outside interests.

Blue light, a high-energy radiation in the visible light spectrum, was recently reported to induce skin pigmentation. In this study, we investigated the involvement of TRPV1-mediated signaling along with OPN3 in blue light-induced melanogenesis as well as its signaling pathway. Operating downstream target of OPN3 in blue light-induced melanogenesis, blue light activated TRPV1 and upregulated its expression, resulting in calcium influx. Calcium ion induced the activation of calcium/calmodulin-dependent protein kinase II and MAPK. It also downregulated clusterin expression, leading to the nuclear translocation of PAX3, ultimately affecting melanin synthesis. In addition, blue light interfered with autophagy-mediated regulation of melanosomes by decreasing not only the interaction between clusterin and LC3B but the expression of activating transcription factor family. These findings demonstrate that the pigmenting effects of blue light are mediated by calcium/calmodulin-dependent protein kinase II- and MAPK-mediated signaling as well as clusterin-dependent inhibition of autophagy through OPN3-TRPV1-calcium influx, suggesting, to our knowledge, a previously unreported signaling pathway through which blue light regulates melanocyte biology. Furthermore, these results suggest that TRPV1 and clusterin could be potential therapeutic targets for blue light-induced pigmentation due to prolonged exposure to blue light., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Our study aimed to investigate both the independent and combined effects of second-hand smoking (SHS) and alcohol intake on the occurrence of stroke., Methods: Utilizing the Korean Genome Epidemiology Study (KoGES) prospective cohort data, our primary exposure variables were SHS exposure and alcohol intake. The occurrence of stroke served as the main outcome of interest. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression analysis. To assess the synergistic influence of SHS and alcohol intake on stroke incidence, a joint test was conducted., Results: SHS exposure correlated with an HR of 1.53 (95% CI, 1.19-1.98) for stroke risk. The combined exposure to SHS and alcohol yielded an elevated stroke risk with an HR of 1.75 (95% CI, 1.20-2.55)., Conclusions: Our research highlights the combined influence of SHS exposure and alcohol intake on stroke susceptibility., Competing Interests: Conflict of interest for all authors: None declared, (Copyright © 2024 American College of Occupational and Environmental Medicine.)

Objectives: Our study aimed to investigate the association between shift work and stroke and determine whether this association varies depending on the presence of insomnia., Methods: Utilizing the KoGES prospective cohort data, our primary exposure variables were shift work and insomnia. The occurrence of stroke was the main outcome of interest. Hazards ratios and 95% confidence intervals were estimated using Cox regression analysis. An interaction analysis was conducted to assess the interaction of shift work and insomnia on stroke incidence., Results: In the interaction analysis, shift work was significantly associated with stroke incidence only in groups with insomnia and a hazards ratio of 2.49 (95% confidence interval, 1.02-6.11)., Conclusions: Our study demonstrated that shift work was associated with a higher risk of stroke among the population with insomnia., Competing Interests: Ju, Jung, Kook, and Ryu have no relationships/conditions/circumstances that present potential conflict of interest., (Copyright © 2024 American College of Occupational and Environmental Medicine.)

Cross-sectional research suggests an association between loneliness and psychotic symptoms, but the causal direction of this association is still unclear. Even though loneliness has been proposed as a potential treatment target to improve psychotherapy for psychosis, not much is known about its role in the treatment process. In this study, we re-analyzed data from a therapy process study to investigate the temporal dynamics between loneliness and psychotic symptoms throughout therapy and to explore whether state-of-the-art CBT for psychosis (CBTp) decreases loneliness. Over the course of up to 45 weekly sessions of CBTp, 57 patients reported their feelings of loneliness and current positive, negative and depressive symptom levels at each session. Multilevel regression revealed a reduction in all symptoms over time, but no reduction in loneliness. Time-lagged multilevel regression showed that loneliness predicted subsequent negative and depressive symptoms, whereas positive symptom levels predicted subsequent loneliness. Thus, changes in loneliness seem to be both cause and consequence of psychotic symptom changes. These findings highlight the importance of loneliness as a treatment target, particularly in patients with negative symptoms and depression. Future research should address loneliness-specific interventions as an augmentation of state-of-the-art CBTp., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: T.M. Lincoln has published German language manuals on CBT for psychosis., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Pulmonary fibrosis is a progressive lung condition characterized by the excessive activation of myofibroblasts. Transforming growth factor beta 1 (TGFβ1) plays a crucial role in the differentiation of fibroblasts into myofibroblasts. In addition, toll-like receptor 2 (TLR2), known for its role in immune responses, contributes to pulmonary fibrosis by promoting myofibroblast differentiation. However, the interplay between TGFβ1 and TLR2 signaling pathways in myofibroblast differentiation has remained elusive. In the present study, we investigated the involvement of TLR2 in TGFβ1-induced fibroblast differentiation into myofibroblasts using IMR-90 human pulmonary fibroblasts as a model cell line. We found that TLR2 activation induced myofibroblast differentiation by enhancing the expression of early growth response 1 (EGR1) via the mitogen-activated protein kinase (MAPK) signaling pathway. Elevated EGR1 levels were detected in the lung tissues of a bleomycin (BLM)-induced mouse model of pulmonary fibrosis. Moreover, the administration of tomaralimab, an antagonistic anti-TLR2 antibody, reduced the EGR1 expression and collagen deposition. Altogether, targeting the TLR2-EGR1 pathway could be a promising therapeutic approach for pulmonary fibrosis by blocking TGFβ1-induced myofibroblast differentiation., 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 Inc. All rights reserved.)

Objective: Preeclampsia, one of the most serious obstetric complications, is a heterogenous disorder resulting from different pathologic processes. However, placental oxidative stress and an anti-angiogenic state play a crucial role. Mitochondria are a major source of cellular reactive oxygen species. Abnormalities in mitochondrial structures, proteins, and functions have been observed in the placentae of patients with preeclampsia, thus mitochondrial dysfunction has been implicated in the mechanism of the disease. Mitochondrial nuclear retrograde regulator 1 (MNRR1) is a newly characterized bi-organellar protein with pleiotropic functions. In the mitochondria, this protein regulates cytochrome c oxidase activity and reactive oxygen species production, whereas in the nucleus, it regulates the transcription of a number of genes including response to tissue hypoxia and inflammatory signals. Since MNRR1 expression changes in response to hypoxia and to an inflammatory signal, MNRR1 could be a part of mitochondrial dysfunction and involved in the pathologic process of preeclampsia. This study aimed to determine whether the plasma MNRR1 concentration of women with preeclampsia differed from that of normal pregnant women., Methods: This retrospective case-control study included 97 women with preeclampsia, stratified by gestational age at delivery into early (<34 weeks, n  = 40) and late (≥34 weeks, n  = 57) preeclampsia and by the presence or absence of placental lesions consistent with maternal vascular malperfusion (MVM), the histologic counterpart of an anti-angiogenic state. Women with an uncomplicated pregnancy at various gestational ages who delivered at term served as controls ( n  = 80) and were further stratified into early ( n  = 25) and late ( n  = 55) controls according to gestational age at venipuncture. Maternal plasma MNRR1 concentrations were determined by an enzyme-linked immunosorbent assay., Results: 1) Women with preeclampsia at the time of diagnosis (either early or late disease) had a significantly higher median (interquartile range, IQR) plasma MNRR1 concentration than the controls [early preeclampsia: 1632 (924-2926) pg/mL vs. 630 (448-4002) pg/mL, p  = .026, and late preeclampsia: 1833 (1441-5534) pg/mL vs. 910 (526-6178) pg/mL, p  = .021]. Among women with early preeclampsia, those with MVM lesions in the placenta had the highest median (IQR) plasma MNRR1 concentration among the three groups [with MVM: 2066 (1070-3188) pg/mL vs. without MVM: 888 (812-1781) pg/mL, p  = .03; and with MVM vs. control: 630 (448-4002) pg/mL, p  = .04]. There was no significant difference in the median plasma MNRR1 concentration between women with early preeclampsia without MVM lesions and those with an uncomplicated pregnancy ( p  = .3). By contrast, women with late preeclampsia, regardless of MVM lesions, had a significantly higher median (IQR) plasma MNRR1 concentration than women in the control group [with MVM: 1609 (1392-3135) pg/mL vs. control: 910 (526-6178), p  = .045; and without MVM: 2023 (1578-8936) pg/mL vs. control, p  = .01]., Conclusions: MNRR1, a mitochondrial regulator protein, is elevated in the maternal plasma of women with preeclampsia (both early and late) at the time of diagnosis. These findings may reflect some degree of mitochondrial dysfunction, intravascular inflammation, or other unknown pathologic processes that characterize this obstetrical syndrome.

Background: The impact of snoring and diabetes on stroke risk is unclear. This study examined the association between snoring and stroke risk and how it varies with diabetes mellitus (DM) status., Methods: This research was conducted as a prospective cohort study. A total of 4,352 subjects were included in the analysis, with a mean follow-up time of 13.7 years. The study used snoring history obtained through interviews as the primary exposure variable and DM as the secondary exposure variable. The main outcome measured was the occurrence of stroke. Cox regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Additionally, a joint test was conducted to evaluate the combined effect of snoring and diabetes on the occurrence of stroke., Results: In our study of 4,352 subjects, 1,135 (26.1%) had a history of snoring, 233 (5.4%) had diabetes mellitus, and over the 18-year observation period, there were 168 cases of new-onset stroke. Snoring was not associated with an increased risk of stroke (HR: 0.95, 95% CI [0.68-1.33]), but DM significantly elevated the risk of stroke (3.02 [1.96-4.65]). In the interaction analysis of snoring and DM status on stroke risk, snoring was a significant risk factor for stroke only in the population with DM (2.89 [1.07-7.60]). Compared to non-snoring and non-DM, the multivariate HRs for stroke were 1.09 (0.76-1.57) for snoring and non-DM, 1.64 (0.83-2.82) for non-snoring and DM, and 2.95 (1.42-5.45) for snoring and DM., Conclusion: Diabetes mellitus was associated with an increased risk of stroke, while a history of snoring was not. In a sub analysis, snoring appeared to be associated with an increased risk of stroke among subjects with diabetes mellitus., Competing Interests: Declarations Ethics approval and consent to participate The study protocol was reviewed and approved by the Institutional Review Board of Chonnam National University Hospital (CNUH-2018–297). The requirement for informed consent from patients was waived because the study was a retrospective analysis of existing data. Competing interests The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: The purpose of this study was to conduct a general educational needs assessment to identify deficiencies in current Army pharmacy education while projecting future educational requirements based on changes in pharmacy practice and evolving demands of military medicine., Materials and Methods: Twelve pharmacists participated in a facilitated discussion using the nominal group technique. Data were analyzed using quantitative and qualitative methods to establish consensus. Member checking was used to verify and validate the findings., Results: Participants generated 190 knowledge, skill, and ability (KSA) statements over 3 sessions. Twenty-one statements achieved consensus. Four consensus statements were skills, 7 were knowledge, and 10 were abilities. KSAs were categorized into pharmaceutical care, military, logistics, or legal domain based on a thematic analysis., Conclusions: With modernized, relevant KSAs, the Army can measure and train a ready pharmacy force. Individual Critical Tasks augmented with KSAs are one potential approach we recommend as a strategy to improve Army pharmacist health profession education., (© The Association of Military Surgeons of the United States 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Filaggrin (FLG) is an essential structural protein expressed in differentiated keratinocytes. Insufficient FLG expression contributes to the pathogenesis of chronic inflammatory skin diseases. Saikosaponin A (SSA), a bioactive oleanane-type triterpenoid, exerts anti-inflammatory activity. However, the effects of topically applied SSA on FLG expression in inflamed skin remain unclear. This study aimed to evaluate the biological activity of SSA in restoring reduced FLG expression. The effect of SSA on FLG expression in HaCaT cells was assessed through various biological methods, including reverse transcription PCR, quantitative real-time PCR, immunoblotting, and immunofluorescence staining. TNFα and IFNγ decreased FLG mRNA, cytoplasmic FLG protein levels, and FLG gene promoter-reporter activity compared to the control groups. However, the presence of SSA restored these effects. A series of FLG promoter-reporter constructs were generated to investigate the underlying mechanism of the effect of SSA on FLG expression. Mutation of the AP1-binding site (mtAP1) in the -343/+25 FLG promoter-reporter abrogated the decrease in reporter activities caused by TNFα + IFNγ, suggesting the importance of the AP1-binding site in reducing FLG expression. The SSA treatment restored FLG expression by inhibiting the expression and nuclear localization of FRA1 and c-Jun, components of AP1, triggered by TNFα + IFNγ stimulation. The ERK1/2 mitogen-activated protein kinase signaling pathway upregulates FRA1 and c-Jun expression, thereby reducing FLG levels. The SSA treatment inhibited ERK1/2 activation caused by TNFα + IFNγ stimulation and reduced the levels of FRA1 and c-Jun proteins in the nucleus, leading to a decrease in the binding of FRA1, c-Jun, p-STAT1, and HDAC1 to the AP1-binding site in the FLG promoter. The effect of SSA was evaluated in an animal study using a BALB/c mouse model, which induces human atopic-dermatitis-like skin lesions via the topical application of dinitrochlorobenzene. Topically applied SSA significantly reduced skin thickening, immune cell infiltration, and the expression of FRA1, c-Jun, and p-ERK1/2 compared to the vehicle-treated group. These results suggest that SSA can effectively recover impaired FLG levels in inflamed skin by preventing the formation of the repressor complex consisting of FRA1, c-Jun, HDAC1, and STAT1.

Pulmonary fibrosis is a severe and progressive lung disease characterized by lung tissue scarring. Transforming growth factor beta 1 (TGFβ1) is crucial in causing pulmonary fibrosis by promoting the activation of fibroblasts and their differentiation into myofibroblasts, which are responsible for excessive extracellular matrix deposition. This study aimed to identify genes activated by TGFβ1 that promote fibrosis and to understand the regulatory pathway controlling myofibroblast. Endothelin-1 (ET-1) was identified as the top-ranking gene in the fibrosis-related gene set using quantitative PCR array analysis. TGFβ1 upregulated EGR1 expression through the ERK1/2 and JNK1/2 MAPK pathways. EGR1 and p-SMAD2 proteins interacted with the ET-1 gene promoter region to regulate TGFβ1-induced ET-1 expression in IMR-90 pulmonary fibroblasts. Mice lacking the Egr1 gene showed reduced ET-1 levels in a model of pulmonary fibrosis induced by intratracheal administration of bleomycin. These findings suggest that targeting EGR1 is a promising approach for treating pulmonary fibrosis, especially idiopathic pulmonary fibrosis, by affecting ET-1 expression and profibrotic reactions., 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 Inc. All rights reserved.)

Case management is a widely utilized service in both youth and adult outpatient community mental health settings. Despite its widespread use, previous findings suggest that youth case management often lacks empirically tested models or frameworks. This article presents the results of a pilot study that involved adapting the Strengths Model, an adult case management model, for the child and adolescent outpatient community mental health population. The newly adapted model, known as the Strengths Model for Youth (SM-Y), was implemented in an urban community mental health center across five different youth case management teams. To assess changes over time in youth receiving SM-Y case management, marginal maximum likelihood multilevel modeling with adaptive Gaussian quadrature methods was applied. The study focused on three domains: socialization, education, and hospitalization. Utilizing the logit link function and Bernoulli conditional distribution due to the binary nature of the outcome data, three individual trajectories were drawn for socialization, education, and hospitalization. Positive findings indicated increases in socialization and educational performance among children and adolescents., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Study Objectives: Connecting resident physician work hours and sleep deprivation to adverse outcomes has been difficult. Our study explores clinical reasoning rather than outcomes. Diagnostic errors are a leading cause of medical error and may result from deficits in clinical reasoning. We used simulated cases to explore relationships between sleep duration and diagnostic reasoning., Methods: Residents were recruited for a 2-month study (inpatient/outpatient). Each participant's sleep was tracked (sleep diary/actigraphy). At the end of each month, residents watched 2 brief simulated clinical encounters and performed "think alouds" of their clinical reasoning. In each session, 1 video was straightforward and the other video contained distracting contextual factors. Sessions were recorded, transcribed, and interpreted. We conducted a thematic analysis using a constant comparative approach. Themes were compared based on sleep duration and contextual factors., Results: Residents (n = 17) slept more during outpatient compared with inpatient months (450.5 ± 7.13 vs 425.6 ± 10.78 hours, P = .02). We found the following diagnostic reasoning themes: uncertainty, disorganized knowledge, error, semantic incompetence, emotional content, and organized knowledge. Themes reflecting suboptimal clinical reasoning (disorganized knowledge, error, semantic incompetence, uncertainty) were observed more in cases with contextual factors (distractors). "Think alouds" from cases with contextual factors following sleep restriction had a greater number of themes concerning for problematic diagnostic reasoning., Conclusions: Residents obtained significantly more sleep during outpatient compared with inpatient months. Several negative clinical reasoning themes emerged with less sleep combined with cases containing contextual distractors. Our findings reinforce the importance of adequate sleep and supervision in house officers, particularly in cases with distracting elements., Citation: Collen J, Durning S, Berk J, Mang J, Alcover K, Jung E. Exploring sleep duration and clinical reasoning process in resident physicians: a thematic analysis. J Clin Sleep Med . 2024;20(8):1279-1289., (© 2024 American Academy of Sleep Medicine.)

Background Context: Cross-modality image generation from magnetic resonance (MR) to positron emission tomography (PET) using the generative model can be expected to have complementary effects by addressing the limitations and maximizing the advantages inherent in each modality., Purpose: This study aims to generate synthetic PET/MR fusion images from MR images using a combination of generative adversarial networks (GANs) and conditional denoising diffusion probabilistic models (cDDPMs) based on simultaneous 18 F-fluorodeoxyglucose (18F-FDG) PET/MR image data., Study Design: Retrospective study with prospectively collected clinical and radiological data., Patient Sample: This study included 94 patients (60 men and 34 women) with thoraco-lumbar pyogenic spondylodiscitis (PSD) from February 2017 to January 2020 in a single tertiary institution., Outcome Measures: Quantitative and qualitative image similarity were analyzed between the real and synthetic PET/ T2-weighted fat saturation MR (T2FS) fusion images on the test data set., Methods: We used paired spinal sagittal T2FS and PET/T2FS fusion images of simultaneous 18F-FDG PET/MR imaging examination in patients with PSD, which were employed to generate synthetic PET/T2FS fusion images from T2FS images using a combination of Pix2Pix (U-Net generator + Least Squares GANs discriminator) and cDDPMs algorithms. In the analyses of image similarity between the real and synthetic PET/T2FS fusion images, we adopted the values of mean peak signal to noise ratio (PSNR), mean structural similarity measurement (SSIM), mean absolute error (MAE), and mean squared error (MSE) for quantitative analysis, while the discrimination accuracy by three spine surgeons was applied for qualitative analysis., Results: Total of 2,082 pairs of T2FS and PET/T2FS fusion images were obtained from 172 examinations on 94 patients, which were randomly assigned to training, validation, and test data sets in 8:1:1 ratio (1664, 209, and 209 pairs). The quantitative analysis revealed PSNR of 30.634 ± 3.437, SSIM of 0.910 ± 0.067, MAE of 0.017 ± 0.008, and MSE of 0.001 ± 0.001, respectively. The values of PSNR, MAE, and MSE significantly decreased as FDG uptake increased in real PET/T2FS fusion image, with no significant correlation on SSIM. In the qualitative analysis, the overall discrimination accuracy between real and synthetic PET/T2FS fusion images was 47.4%., Conclusions: The combination of Pix2Pix and cDDPMs demonstrated the potential for cross-modal image generation from MR to PET images, with reliable quantitative and qualitative image similarities., Competing Interests: Declaration of competing interest All authors have no conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The potential effect of hydrological conditions on distribution and loadings of Hg species was investigated in the microtidal Hyeongsan River Estuary (HRE). Dissolved Hg (DHg) and dissolved methylmercury (DMeHg) from the creek receiving industrial wastes were effectively settled to sediment during the post-typhoon period, while persistent input from the Hg-contaminated creek without settling was observed during the dry periods. The event-based mean approach was applied to explore the hydrological effects on the annual flux of Hg. The largest inputs of DHg and particulate Hg (PHg) were found in the Hg-contaminated creek, and DHg input was higher in the dry than wet periods whereas PHg input was higher in the wet than dry periods. In sediment, Hg and MeHg concentrations decreased after the typhoon, attributed to erosion of surface sediments. Overall, the HRE serves as an effective sink of Hg that reduces the degree of Hg contamination in coastal water., 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 Ltd. All rights reserved.)

The Zika virus (ZIKV), a significant public health threat, is transmitted by Aedes aegypti mosquitoes and is associated with severe neurological disorders, particularly in newborns. Currently, there are no approved vaccines or specific therapeutics for ZIKV. Our study focuses on the identification and optimization of isoxazole-based small molecules, specifically through the structural modification of KR-26827 , to combat ZIKV infections. Among the synthesized derivatives, 7l emerged as the most promising candidate, showing potent antiviral activity against ZIKV strains and an improved safety profile in vitro . This research underlines the potential of 7l for further development as a ZIKV therapeutic agent., Competing Interests: The authors declare no conflicts of interest., (This journal is © The Royal Society of Chemistry.)

Importance: Kidney disease is prevalent among veterinary species, including zoo animals; however, investigations into this condition in striped skunks ( Mephitis mephitis ) are scarce. Diagnostic tools for kidney diseases in this species also remain limited., Objective: This study aimed to assess the utility of symmetric dimethylarginine as a biomarker for kidney disease in captive striped skunks in Korea., Methods: This retrospective study analysed 11 striped skunks housed at the Everland Zoo between 2017 and 2021. Blood samples were collected during health checks. Kidney function was assessed through blood analysis and diagnostic ultrasound, with necropsies conducted on deceased animals. Symmetric dimethylarginine levels were measured in 27 plasma samples collected from 11 skunks., Results: Over the study period, seven skunks were diagnosed with kidney disease. Analysis of 27 blood samples revealed a concurrent increase in SDMA levels with concentrations of blood urea nitrogen and blood creatinine. In 3 of the 7 skunks with kidney disease, symmetric dimethylarginine exceeded 14 µg/dL prior to the elevation of blood urea nitrogen and blood creatinine above the upper reference limit., Conclusions and Relevance: To our knowledge, this is the first study investigating symmetric dimethylarginine in captive striped skunks in Korea. Our findings suggest that symmetric dimethylarginine may serve as an early and consistent biomarker for renal dysfunction in striped skunks. Further studies with larger clinical sample size from striped skunks are needed to validate the clinical utility of blood symmetric dimethylarginine concentration., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Korean Society of Veterinary Science.)

The aberrant assembly of amyloid-β (Aβ) is implicated in Alzheimer's disease (AD). Recent clinical outcomes of Aβ-targeted immunotherapy reinforce the notion that clearing Aβ burden is a potential therapeutic approach for AD. Herein, to develop drug candidates for chemically driven clearance of Aβ aggregates, we synthesized 51 novel polyfunctionalized furo[2,3- b :4,5- b ']dipyridine-chalcone hybrid compounds. After conducting two types of cell-free anti-Aβ functional assays, Aβ aggregation prevention and Aβ aggregate clearance, we selected YIAD-0336, ( E )-8-((1 H -pyrrol-2-yl)methylene)-10-(4-chlorophenyl)-2,4-dimethyl-7,8-dihydropyrido[3',2':4,5]furo[3,2- b ]quinolin-9(6 H )-one, for further in vivo investigations. As YIAD-0336 exhibited a low blood-brain barrier penetration profile, it was injected along with aggregated Aβ directly into the intracerebroventricular region of ICR mice and ameliorated spatial memory in Y-maze tests. Next, YIAD-0336 was orally administered to 5XFAD transgenic mice with intravenous injections of mannitol, and YIAD-0336 significantly removed Aβ plaques from the brains of 5XFAD mice. Collectively, YIAD-0336 dissociated toxic aggregates in the mouse brain and hence alleviated cognitive deterioration. Our findings indicate that chemically driven clearance of Aβ aggregates is a promising therapeutic approach for AD.

Functional movement disorder (FMD) is a type of functional neurological disorder that is common but often difficult to diagnose or manage. FMD can present as various phenotypes, including tremor, dystonia, myoclonus, gait disorders, and parkinsonism. Conducting a clinical examination appropriate for assessing a patient with suspected FMD is important, and various diagnostic testing maneuvers may also be helpful. Treatment involving a multidisciplinary team, either outpatient or inpatient, has been found to be most effective. Examples of such treatment protocols are also discussed in this review. While recognition and understanding of the disorder has improved over the past few decades, as well as the development of treatments, it is not uncommon for patients and physicians to continue to experience various difficulties when dealing with this disorder. In this review, I provide a practical overview of FMD and discuss how the clinical encounter itself can play a role in patients' acceptance of the diagnosis. Recent neuroimaging studies that aid in understanding the pathophysiology are also discussed.

The understanding of the essential environmental factors affecting the spatiotemporal variation in methylmercury (MeHg) in river water is limited to date, despite its importance for predicting the effect of ongoing climate change on MeHg accumulation in freshwater ecosystems. This study aimed to explore the variation in MeHg concentration and related environmental factors in the downstream zone of the Yeongsan River under highly dynamic hydrologic conditions by using water quality and hydrologic data collected from 1997 to 2022, and Hg and MeHg data collected from 2017 to 2022. The mean concentration of unfiltered MeHg was 35.7 ± 13.7 pg L -1 (n = 24) in summer and 26.7 ± 7.43 pg L -1 (n = 24) in fall. Dissolved oxygen (DO), conductivity, nitrate, and dissolved organic carbon (DOC) were determined to be the most influential variables in terms of MeHg variation based on the partial least squares regression model, and their effects on the MeHg concentration were negative, except for DOC. Heatmaps representing the similarity distances between temporal trends of hydrologic and water quality variables were constructed to determine fundamental factors related to the time-based variations in DO, conductivity, nitrate, and DOC using a dynamic time warping algorithm. The heatmap cluster analysis showed that the temporal trends of these variables were closely related to rainfall variation rather than irradiance or water temperature. Overall, biogeochemical factors directly related to in situ methylation rate of Hg(II)-rather than transport of Hg(II) and MeHg from external sources-mainly control the spatiotemporal variation of MeHg in the downstream zone of the Yeongsan River., 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.)

Purpose: As people living with cancer increase in the aging society, cancer-related emergency department (ED) visits are also increasing. This study aimed to investigate the epidemiologic characteristics of non-emergent cancer-related ED visits using a nationwide ED database., Materials and Methods: A cross-sectional study was conducted using the National Emergency Department Information System (NEDIS) database. All cancer-related ED visits between 2016 and 2020 were included. The study outcome was non-emergent ED visits, defined as patients triaged into non-emergent condition at both the time of arrival at ED and discharge from ED and were discharged without hospitalization., Results: Among 1185871 cancer-related ED visits over 5 years, 19.0% (n=225491) were classified as non-emergent visits. While abdominal pain and fever are the top chief complaints in both emergent and non-emergent visits, non-emergent visits had high proportions of abdomen distension (4.8%), ascite (2.4%), and pain in lower limb (2.0%) compared with emergent visits. The cancer types with a high proportion of non-emergent visits were thyroid (32.4%) and prostate cancer (30.4%). Adults compared with children or older adults, female, medical aid insurance, urban/rural ED, direct-in compared with transfer-in, and weekend visit were associated with high odds for non-emergent visits., Conclusion: Approximately 20% of cancer-related ED visits may be potentially non-emergent. A significant number of non-emergent patients visited the ED due to cancer-related symptoms. To improve the quality of care for people living with cancer, the expansion of supportive care resources besides of ED, including active symptom control, is necessary., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2024.)

Osteolytic bone lesion is a major cause of lower quality of life and poor prognosis in patients with multiple myeloma (MM), but molecular pathogenesis of the osteolytic process in MM remains elusive. Fms-like tyrosine kinase 3 ligand (FLT3L) was reported to be elevated in bone marrow (BM) and blood of patients with advanced MM who often show osteolysis. Here, we investigated a functional link of FLT3L to osteolytic process in MM. We recruited 86, 306, and 52 patients with MM, acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL), respectively. FLT3L levels of patients with hematologic malignancies were measured in BM-derived plasma and found to be significantly higher in MM than in AML or ALL, which rarely show osteolysis. FLT3L levels were further elevated in MM patients with bone lesion compared with patients without bone lesion. In vitro cell-based assays showed that the administration of FLT3L to HEK293T, HeLa, and U2OS cells led to an increase in the DKK1 transcript level through STAT3 phosphorylation at tyrosine 705. WNT reporter assay showed that FLT3L treatment reduced WNT signaling and nuclear translocation of β-catenin. These results collectively show that the FLT3L-STAT3-DKK1 pathway inhibits WNT signaling-mediated bone formation in MM, which can cause osteolytic bone lesion. Finally, transcriptomic profiles revealed that FLT3L and DKK1 were predominantly elevated in the hyperdiploidy subtype of MM. Taken together, FLT3L can serve as a promising biomarker for predicting osteolytic bone lesion and also a potential therapeutic target to prohibit the progression of the osteolytic process in MM with hyperdiploidy.

Atopic dermatitis is a chronic inflammatory skin disease characterized by intense itching and frequent skin barrier dysfunctions. EGR-1 is a transcription factor that aggravates the pathogenesis of atopic dermatitis by promoting the production of various inflammatory cytokines. Three 2-(2-oxoindolin-3-ylidene)hydrazinecarbothioamides (IT21, IT23, and IT25) were identified as novel inhibitors of EGR-1 DNA-binding activity. In silico docking experiments were performed to elucidate the binding conditions of the EGR-1 zinc-finger (ZnF) DNA-binding domain. Electrophoretic mobility shift assays confirmed the targeted binding effect on the EGR-1 ZnF DNA-binding domain, leading to dose-dependent dissociation of the EGR-1-DNA complex. At the functional cellular level, IT21, IT23, and IT25 effectively reduced mRNA expression of TNFα-induced EGR-1-regulated inflammatory genes, particularly in HaCaT keratinocytes inflamed by TNFα. In the in vivo efficacy study, IT21, IT23, and IT25 demonstrated the potential to alleviate atopic dermatitis-like skin lesions in the ear skin of BALB/c mice. These findings suggest that targeting the EGR-1 ZnF DNA-binding domain with 2-(2-oxoindolin-3-ylidene)hydrazinecarbothioamide derivatives (IT21, IT23, and IT25) could serve as lead compounds for the development of potential therapeutic agents against inflammatory skin disorders, including atopic dermatitis., 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 Inc. All rights reserved.)

Background: Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Most cases of preterm birth occur spontaneously and result from preterm labor with intact (spontaneous preterm labor [sPTL]) or ruptured (preterm prelabor rupture of membranes [PPROM]) membranes. The prediction of spontaneous preterm birth (sPTB) remains underpowered due to its syndromic nature and the dearth of independent analyses of the vaginal host immune response. Thus, we conducted the largest longitudinal investigation targeting vaginal immune mediators, referred to herein as the immunoproteome, in a population at high risk for sPTB., Methods: Vaginal swabs were collected across gestation from pregnant women who ultimately underwent term birth, sPTL, or PPROM. Cytokines, chemokines, growth factors, and antimicrobial peptides in the samples were quantified via specific and sensitive immunoassays. Predictive models were constructed from immune mediator concentrations., Results: Throughout uncomplicated gestation, the vaginal immunoproteome harbors a cytokine network with a homeostatic profile. Yet, the vaginal immunoproteome is skewed toward a pro-inflammatory state in pregnant women who ultimately experience sPTL and PPROM. Such an inflammatory profile includes increased monocyte chemoattractants, cytokines indicative of macrophage and T-cell activation, and reduced antimicrobial proteins/peptides. The vaginal immunoproteome has improved predictive value over maternal characteristics alone for identifying women at risk for early (<34 weeks) sPTB., Conclusions: The vaginal immunoproteome undergoes homeostatic changes throughout gestation and deviations from this shift are associated with sPTB. Furthermore, the vaginal immunoproteome can be leveraged as a potential biomarker for early sPTB, a subset of sPTB associated with extremely adverse neonatal outcomes., Funding: This research was conducted by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS) under contract HHSN275201300006C. ALT, KRT, and NGL were supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health., Competing Interests: ZS, RR, AT, JG, MA, DG, TC, EJ, MS, KT, NG No competing interests declared

Ebolavirus disease (EVD) outbreaks have intermittently occurred since the first documented case in the 1970s. Due to its transmission characteristics, large outbreaks have not been observed outside Africa. However, within the continent, significant outbreaks have been attributed to factors such as endemic diseases with similar symptoms and inadequate medical infrastructure, which complicate timely diagnosis. In this study, we employed a stochastic modeling approach to analyze the spread of EVD during the early stages of an outbreak, with an emphasis on inherent risks. We developed a model that considers healthcare workers and unreported cases, and assessed the effect of non-pharmaceutical interventions (NPIs) using actual data. Our results indicate that the implementation of NPIs led to a decrease in the transmission rate and infectious period by 30% and 40% respectively, following the declaration of the outbreak. We also investigated the risks associated with delayed outbreak recognition. Our simulations suggest that, when accounting for NPIs and recognition delays, prompt detection could have resulted in a similar outbreak scale, with approximately 50% of the baseline NPIs effect. Finally, we discussed the potential effects of a vaccination strategy as a follow-up measure after the outbreak declaration. Our findings suggest that a vaccination strategy can reduce both the burden of NPIs and the scale of the outbreak., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ko et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Bronchopulmonary dysplasia (BPD) is a serious chronic lung disease affecting extremely preterm infants. While mitochondrial dysfunction has been investigated in various medical conditions, limited research has explored mitochondrial DNA (mtDNA) gene mutations, specifically in BPD. This study aimed to evaluate mitochondrial mtDNA gene mutations in extremely preterm infants with BPD. In this prospective observational study, we enrolled a cohort of extremely preterm infants diagnosed with BPD. Clinical data were collected to provide comprehensive patient profiles. Peripheral blood mononuclear cells were isolated from whole-blood samples obtained within a defined timeframe. Subsequently, mtDNA extraction and sequencing using next-generation sequencing technology were performed to identify mtDNA gene mutations. Among the cohort of ten extremely preterm infants with BPD, mtDNA sequencing revealed the presence of mutations in seven patients, resulting in a total of twenty-one point mutations. Notably, many of these mutations were identified in loci associated with critical components of the respiratory chain complexes, vital for proper mitochondrial function and cellular energy production. This pilot study provides evidence of mtDNA point mutations in a subset of extremely preterm infants with BPD. These findings suggest a potential association between mitochondrial dysfunction and the pathogenesis of BPD. Further extensive investigations are warranted to unravel the mechanisms underlying mtDNA mutations in BPD., 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.)

Background: Right-sided congenital diaphragmatic hernia (RCDH) is a rare and often fatal congenital anomaly, primarily attributed to lung hypoplasia, which is associated with small branch pulmonary artery (PA). This study investigated whether postnatal PA measurements obtained through echocardiography are associated with mortality or the extracorporeal membrane oxygenation (ECMO) requirement in neonates with RCDH., Methods: A retrospective study was conducted on neonates with RCDH born between 2008 and 2022. Echocardiography was performed on the day of birth. The diameter of the main PA (MPA) was measured at the maximal dimension, and the diameters of the left PA (LPA) and right PA (RPA) were measured at the bifurcation. The primary outcome was mortality or ECMO requirement. Parameters, including the LPA:MPA ratio, RPA:MPA ratio, Nakata index, McGoon ratio, and ejection fraction (EF), were analyzed and compared with the observed-to-expected lung-to-head ratio (o/e LHR), initial blood gas, and defect size as predictive values., Results: Among 39 neonates with RCDH, 25 (64.1 %) survived without ECMO. The non-survivor or ECMO group exhibited lower o/e LHR, reduced EF, smaller LPA and RPA diameters, and larger MPA diameter than survivors. Lower LPA:MPA ratio, Nakata index, McGoon ratio, and higher initial PaCO 2 were associated with adverse outcomes. Notably, the LPA:MPA ratio showed the highest predictive capability (area under the curve, 0.983; p < 0.001)., Conclusion: The LPA:MPA ratio is a promising postnatal predictor of mortality or ECMO requirement in neonates with RCDH. Additionally, Nakata index, McGoon ratio, and initial PaCO 2 are significantly correlated with outcomes., Level of Evidence: This is a level III., Type of Study: Prognostic study., Competing Interests: Conflicts of interest The authors have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Clinical reasoning has been characterized as being an essential aspect of being a physician. Despite this, clinical reasoning has a variety of definitions and medical error, which is often attributed to clinical reasoning, has been reported to be a leading cause of death in the United States and abroad. Further, instructors struggle with teaching this essential ability which often does not play a significant role in the curriculum. In this article, we begin with defining clinical reasoning and then discuss four principles from the literature as well as a variety of techniques for teaching these principles to help ground an instructors' understanding in clinical reasoning. We also tackle contemporary challenges in teaching clinical reasoning such as the integration of artificial intelligence and strategies to help with transitions in instruction (e.g., from the classroom to the clinic or from medical school to residency/registrar training) and suggest next steps for research and innovation in clinical reasoning.

We develop a method to use the mixed third and second harmonic electron cyclotron emission (ECE) signal in the DIII-D tokamak to reconstruct the electron temperature profile of a rotating magnetic island. The third harmonic ECE is removed by extracting the rotating-island-associated fluctuations in the mixed signal, and the extracted fluctuation is combined with the equilibrium temperature obtained from other diagnostics after correcting for the third harmonic reabsorption. The accuracy of the reconstruction is studied by considering a DIII-D shot where an unmixed signal from an island is available on the low field side of the plasma and a mixed signal from the same island is available from the high field side. It is found that the reconstruction method successfully reproduces the island shape and temperature perturbation magnitude without the distortion caused by third harmonic ECE mixing. However, the radial location of the reconstructed island is somewhat displaced relative to the location of the q = 2 surface in the axisymmetric equilibrium reconstruction, resulting in a corresponding inaccuracy in the absolute temperature of the island. It is conjectured that this may arise from an inaccuracy of the reconstructed axisymmetric equilibrium in this region., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

The controlled delivery of the desired bioactive molecules is required to achieve the maximum therapeutic effects with minimum side effects. Biopolymer-based hydrogels are ideal platforms for delivering the desired molecules owing to their superior biocompatibility, biodegradability, and low-immune response. However, the prolonged delivery of the drugs through biopolymer-based hydrogels is restricted due to their weak mechanical stability. We developed mechanically tough and biocompatible hydrogels to address these limitations using carboxymethyl chitosan, sodium alginate, and nanocellulose for sustained drug delivery. The hydrogels were cross-linked through calcium ions to enhance their mechanical strength. Nanocellulose-added hydrogels exhibited improved mechanical strength (Young's modulus; 23.36 → 30.7 kPa, Toughness; 1.39 → 5.65 MJm -3 ) than pure hydrogels. The composite hydrogels demonstrated increased recovery potential (66.9 → 84.5 %) due to the rapid reformation of damaged polymeric networks. The hydrogels were stable in an aqueous medium and demonstrated reduced swelling potential. The hydrogels have no adverse effects on embryonic murine fibroblast (3 T3), showing their biocompatibility. No bacterial growth was observed in hydrogels-treated groups, indicating their antibacterial characteristics. The sustained drug released was observed from nanocellulose-assisted hydrogel scaffolds compared to the pure polymer hydrogel scaffold. Thus, hydrogels have potential and could be used as a sustained drug carrier., 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.)