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Deleted in liver cancer 1 (DLC1) is a RhoGTPase activation protein-containing tumor suppressor that associates with various types of cancer. Although DLC2 shares a similar domain structure with that of DLC1, the function of DLC2 is not well characterized. Here, we describe the expression and ablation of DLC2 in mice using a reporter-knockout approach. DLC2 is expressed in several tissues and in endothelial cells (ECs) of blood vessels. Although ECs and blood vessels show no histological abnormalities and mice appear overall healthy, DLC2-mutant mice display enhanced angiogenic responses induced by matrigel and by tumor cells. Silencing of DLC2 in human ECs has reduced cell attachment, increased migration, and tube formation. These changes are rescued by silencing of RhoA, suggesting that the process is RhoA pathway dependent. These results indicate that DLC2 is not required for mouse development and normal vessel formation, but may protect mouse from unwanted angiogenesis induced by, for example, tumor cells.

Shih-Hsiang Lo,1,2 Kai-Chung Cheng,3 Ying-Xiao Li,3,4 Chin-Hong Chang,4,5 Juei-Tang Cheng,4,6 Kung-Shing Lee7,8 1Division of Cardiology, Department of Internal Medicine, Zhongxing Branch of Taipei City Hospital, 2Department of History and Geography, University of Taipei, Taipei, Taiwan; 3Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan; 4Department of Medical Research, 5Department of Neurosurgery, Chi-Mei Medical Center, Yong Kang, 6Institute of Medical Science, College of Health Science, Chang Jung Christian University, Tainan, 7Department of Surgery, Pingtung Hospital, 8Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Chung-Ho Memorial Hospital, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Background: G-protein-coupled bile acid receptor 1, also known as TGR5 is known to be involved in glucose homeostasis. In animal models, treatment with a TGR5 agonist induces incretin secretion to reduce hyperglycemia. Betulinic acid, a triterpenoid present in the leaves of white birch, has been introduced as a selective TGR5 agonist. However, direct activation of TGR5 by betulinic acid has not yet been reported. Methods: Transfection of TGR5 into cultured Chinese hamster ovary (CHO-K1) cells was performed to establish the presence of TGR5. Additionally, TGR5-specific small interfering RNA was employed to silence TGR5 in cells (NCI-H716 cells) that secreted incretins. Uptake of glucose by CHO-K1 cells was evaluated using a fluorescent indicator. Amounts of cyclic adenosine monophosphate and glucagon-like peptide were quantified using enzyme-linked immunosorbent assay kits. Results: Betulinic acid dose-dependently increases glucose uptake by CHO-K1 cells transfected with TGR5 only, which can be considered an alternative method instead of radioligand binding assay. Additionally, signals coupled to TGR5 activation are also increased by betulinic acid in cells transfected with TGR5. In NCI-H716 cells, which endogenously express TGR5, betulinic acid induces glucagon-like peptide secretion via increasing calcium levels. However, the actions of betulinic acid were markedly reduced in NCI-H716 cells that received TGR5-silencing treatment. Therefore, the present study demonstrates the activation of TGR5 by betulinic acid for the first time. Conclusion: Similar to the positive control lithocholic acid, which is the established agonist of TGR5, betulinic acid has been characterized as a useful agonist of TGR5 and can be used to activate TGR5 in the future. Keywords: CHO-K1 cell, lithocholic acid, NCI-H716 cell, transfection, siRNA

Background: Pain after vaginal delivery may result from episiotomy, perineal laceration, or uterine involution. Many women have indwelling epidural catheters in place at delivery. We hypothesized that a small dose of epidural morphine would be an effective strategy for postpartum analgesia.Methods: Eighty-one healthy parturients receiving epidural analgesia for labor were enrolled. Patients were randomized in double-blind fashion to 1 of 3 groups: all groups received a 4-mL volume of epidural solution consisting of saline (group 1, control), 1 mg (group 2), or 2 mg morphine (group 3) after vaginal delivery. During the first 24 hours postpartum, patients were evaluated for the amount of oral pain medication requested; visual analog scale scores for pain at rest and with movement; satisfaction with postpartum pain treatment; and opioid side effects including nausea, pruritus, urinary retention, and respiratory depression.Results: Patients who received 2 mg of epidural morphine used an average of 0.7 (0-1, interquartile range) opioid-containing pain pills (acetaminophen with codeine or oxycodone) compared with 1.2 (0-2) in the 1-mg group and 1.9 (0-3) in the control group ( P = .07). There was a statistically significant difference in oral drug usage between those who received epidural morphine and those who did not ( P < .03). There were no differences in side effects except that at 12 hours postpartum there was an increase in Foley catheterization in the 1-mg morphine group ( P = .007).Conclusions: These results suggest that epidural morphine decreases the need for oral pain medication in the first 24 hours postpartum. No significant dose-dependent side effects were found. [ABSTRACT FROM AUTHOR]

Whether reexposure of varicella-immune persons to varicella-zoster virus would protect against or predispose to development of zoster was analyzed. The rate of zoster in 511 leukemic recipients of varicella vaccine who had 1 or > 1 dose of varicella vaccine and in those who did or did not have a household exposure to varicella was determined. A Kaplan-Meier life-table analysis revealed that the incidence of zoster was lower in those given > 1 dose of vaccine (P < .05). A Cox proportional hazards analysis showed that both household exposure to varicella and receipt of > 1 dose of vaccine were highly protective (P < .01) against zoster. Thus, the risk of zoster is decreased by reexposure to varicella-zoster virus, either by vaccination or by close exposure to varicella. [ABSTRACT FROM AUTHOR]

The mechanisms of ductus arteriosus (DA) closure involve vasoconstriction and vascular remodeling. Previous findings indicate that the glucagon-like peptide-1 receptor agonist (GLP-1RA) exhibits antihypertensive and anti-remodeling effects in the pulmonary circulation. However, its role in the DA remains unknown. This study aimed to investigate whether exendin-4 (Ex-4), a GLP-1RA, can regulate DA patency and elucidate its mechanisms. After confirming the presence of GLP-1R in neonatal rat DA tissue in vivo, the effects of Ex-4 on DA patency in neonatal rats were sequentially examined. Two hours after birth, we observed spontaneous closure of the DA in control rats. In contrast, Ex-4 prevented the closure of DA, accompanied by reduced intimal thickening. Ex-4 attenuated oxygen-induced vasoconstriction in isolated DA rings ex vivo. This effect was diminished in the presence of H89, a PKA inhibitor. In vitro, Ex-4 inhibited platelet-derived growth factor (PDGF)-BB-induced proliferation and migration of DA smooth muscle cells. Additionally, Ex-4 inhibited PDGF-BB-induced reactive oxygen species (ROS) production, calcium mobilization, and signal transduction of MAPK and Akt pathways. Furthermore, Ex-4 preserved the nuclear expression of Nrf2 attenuated by PDGF-BB. Similarly, all these in vitro effects of Ex-4 were blunted by H89. In conclusion, Ex-4 maintains postnatal DA patency through vasodilatation and anti-remodeling via the PKA pathway. The GLP-1R/PKA pathway emerges as a promising target of DA patency in clinical management., Competing Interests: Declaration of competing interest The authors have declared that no competing interest exists., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Nephroureterectomy with bladder cuff excision is the standard treatment for high-risk upper urinary tract urothelial carcinoma (UTUC). The role of minimally invasive surgery in treating locally advanced UTUC remains controversial. This study aimed to compare the outcomes of open, laparoscopic, and robotic surgeries for managing locally advanced UTUC., Methods: We retrospectively reviewed 705 patients with locally advanced UTUC from multiple institutions throughout Taiwan. Perioperative outcomes and oncological outcomes, such as cancer-specific survival, overall survival, disease-free survival and bladder-free survival, were compared between the open, laparoscopic and robotic groups., Results: The minimally invasive group had better overall and cancer-specific survival (CSS) rates. The 2-year CSS rates of the open, laparoscopic and robotic groups were 71%, 83%, and 77% respectively (p < 0.001). The robotic group had similar outcomes to the laparoscopic group. (p = 0.061, 0.825, 0.341 for OS, CSS, DFS respectively.) More lymph node dissections were performed and more lymph nodes were harvested in the robotic group (p = 0.009)., Conclusions: Our results demonstrated that minimally invasive surgery, including laparoscopic and robotic surgery, for locally advanced UTUC resulted in oncological outcomes that are non-inferior to those of open surgery., (© 2024. The Author(s).)

In the era of rapid internet expansion and technological progress, discerning real from fake news poses a growing challenge, exposing users to potential misinformation. The existing literature primarily focuses on analyzing individual features in fake news, overlooking multimodal feature fusion recognition. Compared to single-modal approaches, multimodal fusion allows for a more comprehensive and enriched capture of information from different data modalities (such as text and images), thereby improving the performance and effectiveness of the model. This study proposes a model using multimodal fusion to identify fake news, aiming to curb misinformation. The framework integrates textual and visual information, using early fusion, joint fusion and late fusion strategies to combine them. The proposed framework processes textual and visual information through data cleaning and feature extraction before classification. Fake news classification is accomplished through a model, achieving accuracy of 85% and 90% in the Gossipcop and Fakeddit datasets, with F1-scores of 90% and 88%, showcasing its performance. The study presents outcomes across different training periods, demonstrating the effectiveness of multimodal fusion in combining text and image recognition for combating fake news. This research contributes significantly to addressing the critical issue of misinformation, emphasizing a comprehensive approach for detection accuracy enhancement., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this paper.

Patients with end stage renal disease (ESRD) are at high risk of developing upper tract urothelial carcinoma (UTUC). Due to high recurrence rate of UTUC in contralateral kidney and ureter, and high risk of complications related to surgery and anesthesia, whether it's necessary to remove both kineys and ureters at one time remains in debate. We utilized Taiwanese UTUC Registry Database to valuate the difference of oncological outcomes and perioperative complications between patients with ESRD with unilateral and bilateral UTUC receiving surgical resection. Patients with ESRD and UTUC were divided into three groups, unilateral UTUC, previous history of unilateral UTUC with metachronous contralateral UTUC, and concurrent bilatetral UTUC. Oncological outcomes, perioperative complications, and length of hospital stays were investiaged. We found that there is no diffence of oncological outcomes including overall survival, cancer specific survival, disease free survival and bladder recurrence free survival between these three groups. Complication rate and length of hospital stay are similar. Adverse oncological features such as advanced tumor stage, lymph node involvement, lymphovascular invasion, and positive surgical margin would negatively affect oncological outcomes., (© 2024. The Author(s).)

The cytoskeleton of the cell is constantly exposed to physical forces that regulate cellular functions. Selected members of the LIM (Lin-11, Isl-1, and Mec-3) domain-containing protein family accumulate along force-bearing actin fibers, with evidence supporting that the LIM domain is solely responsible for this force-induced interaction. However, LIM domain's force-induced interactions are not limited to actin. LIMK1 and LMO1, both containing only two tandem LIM domains, are recruited to force-bearing keratin fibers in epithelial cells. This unique recruitment is mediated by their LIM domains and regulated by the sequences outside the LIM domains. Based on in vitro reconstitution of this interaction, LIMK1 and LMO1 directly interact with stretched keratin 8/18 fibers. These results show that LIM domain's mechano-sensing abilities extend to the keratin cytoskeleton, highlighting the diverse role of LIM proteins in force-regulated signaling., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: We tried to identify the risk factor associate with early chronic kidney disease (CKD) in recently diagnosed type 2 diabetes mellitus patients by utilizing real-world data from Taiwan Diabetes Registry., Materials and Methods: Patients with type 2 diabetes mellitus recently diagnosed within 1 year. We divided the study participants into control group and early CKD group. Early CKD was defined as either CKD stage G1 with albuminuria, CKD stage G2 with albuminuria, or CKD stage G3a regardless of albuminuria (Urine-albumin to creatinine ratio (UACR) ≥ 3 mg/mmol). Control group was defined as CKD G1 or CKD G2 without albuminuria. Logistic regression analyses were used to compare differences in clinical characteristics between the subgroups. Linear regression models were employed to examine the factors predicting estimated glomerular filtration rate (eGFR) and UACR., Results: Total 2217 patients with recently diagnosed type 2 diabetes mellitus were included. 1545 patients were assigned to control group and 618 patients were assigned to the early CKD group. Age (odds ratio (OR) 1.215, 95% confidence interval [CI] 1.122-1.316), systolic blood pressure (OR 1.203, 95% CI 1.117-1.296), glycated hemoglobin (OR 1.074, 95% CI 1.023-1.129) and triglyceride (OR 2.18, 95% CI 1.485-3.199) were found to be significant risk factors. Further, presence of bidirectional association between UACR and eGFR was found., Conclusions: We reported factors associated with early CKD in recently diagnosed type 2 diabetes mellitus patients. Variables that associated with eGFR and UACR were identified respectively, included a mutual influence between UACR and eGFR., (© 2024. The Author(s).)

Background: Late cART initiation (CD4 count ≤200 cells/μL or AIDS-defining opportunistic illnesses [AOIs] at cART initiation) impedes CD4 count recovery and virologic suppression after cART initiation. However, studies to evaluate trends of and modifiable factors for optimal immunological response (IR) and virological response (VR) in people living with HIV (PLWH) with late cART initiation with the current HIV treatment strategies are limited., Methods: We retrospectively identified 475 PLWH with late cART initiation in 2009-2020. Patients were grouped based on the presence of IR (CD4 count ≥200 cells/μL) or VR (plasma viral load [PVL] ≤ 50 copies/mL) within 18 months after cART initiation (403 [84.8%] IR(+) and 72 [15.2%] IR(-); 422 [88.8%] VR(+) and 53 [11.2%] VR(-)). We used Joinpoint regression to identify IR (+) and VR(+) proportion changes., Results: From 2009 to 2020, the proportion of IR(+) patients remained unchanged (75% to 90%, P = 0.102), whereas that of VR(+) patients increased significantly (75% to 95%, P = 0.007). No join point was identified for either IR(+) or VR(+), and the annual percentage change was 0.56% (nonsignificant) and 1.35% (significant) for IR(+) and VR(+), respectively. Compared to IR(-) patients, IR(+) patients were more likely to have a higher pre-cART PVL, to start with a first-line INSTI-based regimen, or to start cART within 14 days of HIV diagnosis but were less likely to have chronic kidney disease, composite AOIs, or a lower pre-cART CD4 count. Compared to VR(-) patients, VR(+) patients were more likely to start a single-tablet regimen but were less likely to have a higher pre-cART PVL., Conclusions: Our study identified several modifiable factors for optimal IR (rapid cART initiation and INSTI-based regimen initiation) and for optimal VR (STR initiation) among late initiators, which may guide early treatment modifications to reduce their AIDS-defining event incidence and mortality., 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 © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development 1,2 , and increased stiffness is known to promote HCC progression in cirrhotic conditions 3,4 . Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic β-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-β1-tensin-1-YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: To evaluate predictive factors of increasing intravesical recurrence (IVR) rate in patients with upper tract urothelial carcinoma (UTUC) after receiving radical nephroureterectomy (RNUx) with bladder cuff excision (BCE)., Materials and Methods: A total of 2114 patients were included from the updated data of the Taiwan UTUC Collaboration Group. It was divided into two groups: IVR-free and IVR after RNUx, with 1527 and 587 patients, respectively. To determine the factors affecting IVR, TNM stage, the usage of pre-operative ureteroscopy, and pathological outcomes were evaluated. The Kaplan-Meier estimator was used to estimate the rates of prognostic outcomes in overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and bladder recurrence-free survival (BRFS), and the survival curves were compared using the stratified log-rank test., Results: Based on our research, ureter tumor, female, smoking history, age (< 70 years old), multifocal tumor, history of bladder cancer were determined to increase the risk of IVR after univariate analysis. The multivariable analysis revealed that female (BRFS for male: HR 0.566, 95% CI 0.469-0.681, p < 0.001), ureter tumor (BRFS: HR 1.359, 95% CI 1.133-1.631, p = 0.001), multifocal (BRFS: HR 1.200, 95% CI 1.001-1.439, p = 0.049), history of bladder cancer (BRFS: HR 1.480, 95% CI 1.118-1.959, p = 0.006) were the prognostic factors for IVR. Patients who ever received ureterorenoscopy (URS) did not increase the risk of IVR., Conclusion: Patients with ureter tumor and previous bladder UC history are important factors to increase the risk of IVR after RNUx. Pre-operative URS manipulation is not associated with higher risk of IVR and diagnostic URS is feasible especially for insufficient information of image study. More frequent surveillance regimen may be needed for these patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a human virus that burst at Wuhan in China and spread quickly over the world, leading to millions of deaths globally. The journey of this deadly virus to different mutant strains is still ongoing. The plethora of drugs and vaccines have been tested to cope up this pandemic. The herbal plants and different spices have received great attention during pandemic, because of their anti-inflammatory, and immunomodulatory properties in treating viruses and their symptoms. Also, it has been shown that nano-formulation of phytochemicals has potential therapeutic effect against COVID-19. Furthermore, the plant derived compound nano-formulation specifically increases its antiviral property by enhancing its bioavailability, solubility, and target-specific delivery system. This review highlights the potentiality of herbal plants and their phytochemical against SARS-CoV-2 utilizing different mechanisms such as blocking the ACE-2 receptors, inhibiting the main proteases, binding spike proteins and reducing the cytokine storms., Competing Interests: Conflict of interestAll authors declare no competing interests with the work presented in the manuscript., (© Association of Microbiologists of India 2023. 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.)

Purpose: The purpose of this study is to evaluate the rates of pathological complete response (ypT0N0/X) and pathological response (ypT1N0/X or less) in patients with upper tract urothelial cancer who were treated with neo-adjuvant chemotherapy and to examine their impact on oncological outcomes., Methods: This study is a multi-institutional retrospective analysis of patients with high-risk upper tract urothelial cancer who underwent neoadjuvant chemotherapy and radical nephroureterectomy between 2002 and 2021. Logistic regression analyses were used to investigate all clinical parameters for response after neoadjuvant chemotherapy. Cox proportional hazard models were performed to assess the effect of the response on the oncological outcomes., Results: A total of 84 patients with UTUC who received neo-adjuvant chemotherapy were identified. Among them, 44 (52.4%) patients received cisplatin-based chemotherapy, and 22 (26.2%) patients had a carboplatin-based regimen. The pathological complete response rate was 11.6% (n = 10), and the pathological response rate was 42.9% (n = 36). Multifocal tumors or tumors larger than 3 cm significantly reduced the odds of pathological response. In the multivariable Cox proportional hazard model, pathological response was independently associated with better overall survival (HR 0.38, p = 0.024), cancer-specific survival (HR 0.24, p = 0.033), and recurrence-free survival (HR 0.17, p = 0.001), but it was not associated with bladder recurrence-free survival (HR 0.84, p = 0.69)., Conclusion: Pathological response after neo-adjuvant chemotherapy and radical nephroureterectomy is strongly associated with patient survival and recurrence, and it might be a good surrogate for evaluating the efficacy of neo-adjuvant chemotherapy in the future., Competing Interests: Conflicts of interest The authors have no conflicts of interest relevant to this article., (Copyright © 2023 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: Abusive head trauma (AHT) is the leading cause of death in infants with traumatic brain injury (TBI). Early recognition of AHT is important for improving outcomes, but it can be challenging due to its similar presentations with non-abusive head trauma (nAHT). This study aims to compare clinical presentations and outcomes between infants with AHT and nAHT, and to identify the risk factors for poor outcomes of AHT., Methods: We retrospectively analyzed infants of TBI in our pediatric intensive care unit from January 2014 to December 2020. Clinical manifestations and outcomes were compared between patients with AHT and nAHT. Risk factors for poor outcomes in AHT patients were also analyzed., Results: 60 patients were enrolled for this analysis, including 18 of AHT (30%) and 42 of nAHT (70%). Compared with those with nAHT, patients with AHT were more likely to have conscious change, seizures, limb weakness, and respiratory failure, but with a fewer incidence of skull fractures. Additionally, clinical outcomes of AHT patients were worse, with more cases undergoing neurosurgery, higher Pediatric Overall Performance Category score at discharge, and more anti-epileptic drug (AED) use after discharge. For AHT patients, conscious change is an independent risk factor for a composite poor outcome of mortality, ventilator dependence, or AED use (OR = 21.9, P = 0.04) CONCLUSION: AHT has a worse outcome than nAHT. Conscious change, seizures and limb weaknesses but not skull fractures are more common in AHT. Conscious change is both an early reminder of AHT and a risk factor for its poor outcomes., Competing Interests: Declaration of competing interest 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 © 2023. Published by Elsevier B.V.)

Background: People living with HIV (PLWH) are susceptible to non-AIDS-related events, particularly those with immunological nonresponses (INRs) to highly active antiretroviral therapy (HAART). This study assessed the association of INRs with incident non-AIDS-related events among PLWH., Methods: This multicenter retrospective cohort study enrolled PLWH who had newly diagnosed stage 3 HIV and received HAART between January 1, 2008, and December 31, 2019. The patients were divided into two groups according to their immunological responses on the 360th day after HAART initiation: INR and non-INR groups. Cox regression and sensitivity analyses were conducted to estimate the effects of INRs on overall and individual categories of non-AIDS-related events (malignancies, vascular diseases, metabolic disorders, renal diseases, and psychiatric disorders). Patient observation started on the 360th day after HAART initiation and continued until February 28, 2022, death, or an outcome of interest, whichever occurred first., Results: Among the 289 included patients, 44 had INRs. Most of the included patients were aged 26-45 years (69.55%) and were men who have sex with men (89.97%). Many patients received HIV diagnoses between 2009 and 2012 (38.54%). INRs (vs. non-INRs) were associated with composite non-AIDS-related events (adjusted hazard ratio [aHR] = 1.80; 95% confidence interval [CI]: 1.19-2.73) and metabolic disorders (aHR = 1.75; 95% CI: 1.14-2.68). Sensitivity analyses revealed consistent results for each Cox regression model for both composite non-AIDS-related events and metabolic diseases., Conclusion: Clinicians should be vigilant and implement early intervention and rigorous monitoring for non-AIDS-related events in PLWH with INRs to HAART., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest to this study., (Copyright © 2023. Published by Elsevier B.V.)

Magnusiomyces capitatus is a dimorphic yeast commonly isolated from the environment and was uncommonly reported as a disease in Asia. It may cause invasive infection in patients with hematological malignancies, especially those with neutropenia, and resulting in high mortality. Herein, we reported a man with nasopharyngeal carcinoma and hepatocellular carcinoma suffered from intermittent fever after pulmonary nodules resection. The histopathology showed yeast-like fungal elements. For further identification, we extracted the tissue DNA from formalin-fixed paraffin-embedded tissue and M. capitatus was confirmed using polymerase chain reaction amplification and sequencing of the ITS region of ribosomal DNA. After a 4-week amphotericin B and flucytosine treatment, his condition recovered well and then was followed by a 3-month oral fluconazole treatment. There was no evidence of recurrence within one year. Our case highlights that nucleic acids obtained from formalin-fixed tissue could be a feasible identification method, especially in those whose culture results are unavailable., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Tensins are focal adhesion proteins that regulate various biological processes, such as mechanical sensing, cell adhesion, migration, invasion, and proliferation, through their multiple binding activities that transduce critical signals across the plasma membrane. When these molecular interactions and/or mediated signaling are disrupted, cellular activities and tissue functions are compromised, leading to disease development. Here, we focus on the significance of the tensin family in renal function and diseases. The expression pattern of each tensin in the kidney, their roles in chronic kidney diseases, renal cell carcinoma, and their potentials as prognostic markers and/or therapeutic targets are discussed in this review.

Hypertension and type 2 diabetes mellitus (T2DM) are important, intertwined public health issues. People with both conditions face significantly elevated risks of cardiovascular (CV) and renal complications. To optimize patient care, a multidisciplinary expert panel met to review recent evidence on optimal blood pressure (BP) targets, implications of albuminuria, and treatment regimens for hypertensive patients with T2DM, with the aim of providing recommendations for physicians in Hong Kong. The panel reviewed the relevant literature, obtained by searching PubMed for the publication period from January 2015 to June 2021, to address five discussion areas: (i) BP targets based on CV/renal benefits; (ii) management of isolated systolic or diastolic hypertension; (iii) roles of angiotensin II receptor blockers; (iv) implications of albuminuria for CV/renal events and treatment choices; and (v) roles and tools of screening for microalbuminuria. The panel held three virtual meetings using a modified Delphi method to address the discussion areas. After each meeting, consensus statements were derived and anonymously voted on by every panelist. A total of 17 consensus statements were formulated based on recent evidence and expert insights regarding cardioprotection and renoprotection for hypertensive patients with T2DM.

Background: Tuberous sclerosis complex (TSC) is a rare genetic condition commonly accompanied by neurological and neuropsychological disorders, resulting in a high burden of illness for individuals and a substantial impact on their caregivers. Due to the diversity and complexity of clinical manifestations, patients with TSC need aligned multidisciplinary healthcare services starting in childhood through to adulthood. However, patients and caregivers are sometimes dissatisfied with the care provided, for which one of the most common reasons is a lack of involvement in clinical decision-making. Shared decision-making, whereby clinicians make clinical management decisions together with patients and their caregivers, is advocated for in the management of epilepsy, but evidence of its benefit in managing TSC is currently lacking. In this cross-sectional, UK-based analysis we used an online survey to capture the experiences of primary caregivers for individuals with TSC, including the impact on work productivity, clinical shared decision-making, satisfaction with care, and the impact of the coronavirus disease 2019 (COVID-19) pandemic., Results: In total, 73 eligible caregivers provided consent (analysis set), with 14 completing the survey partially and 59 completing the full survey. Many caregivers (72%) reported receiving recommendations about new treatments from their doctor and discussing the treatment together, with a high proportion (89%) preferring that treatment was initiated at a low dose. Most caregivers (69%) were satisfied or extremely satisfied with pediatric TSC healthcare services, but only 25% were satisfied or extremely satisfied with the transition to adult TSC healthcare services. Several (n = 30) caregivers specified the impact of caring on their work productivity and career in optional open-ended survey responses. Finally, 80% of caregivers indicated that the COVID-19 pandemic had a "large" or "very large" impact on their caring activities, negatively affecting the emotional wellbeing and behavior of individuals with TSC, and caregivers' ability to work and arrange medical appointments., Conclusions: Caregivers largely feel involved in treatment decisions, and the majority were satisfied with healthcare services for children with TSC. However, many highlighted the need for an improved transition from pediatric to adult healthcare services. The survey also showed that COVID-19 has considerably affected caregivers and individuals with TSC., (© 2023. The Author(s).)

Biomolecular condensates are nonmembranous structures that are mainly formed through liquid-liquid phase separation. Tensins are focal adhesion (FA) proteins linking the actin cytoskeleton to integrin receptors. Here, we report that GFP-tagged tensin-1 (TNS1) proteins phase-separate to form biomolecular condensates in cells. Live-cell imaging showed that new TNS1 condensates are budding from the disassembling ends of FAs, and the presence of these condensates is cell cycle dependent. TNS1 condensates dissolve immediately prior to mitosis and rapidly reappear while postmitotic daughter cells establish new FAs. TNS1 condensates contain selected FA proteins and signaling molecules such as pT308Akt but not pS473Akt, suggesting previously unknown roles of TNS1 condensates in disassembling FAs, as the storage of core FA components and the signaling intermediates.

Several recent studies indicate that atypical changes in driving behaviors appear to be early signs of mild cognitive impairment (MCI) and dementia. These studies, however, are limited by small sample sizes and short follow-up duration. This study aims to develop an interaction-based classification method building on a statistic named Influence Score (i.e., I-score) for prediction of MCI and dementia using naturalistic driving data collected from the Longitudinal Research on Aging Drivers (LongROAD) project. Naturalistic driving trajectories were collected through in-vehicle recording devices for up to 44 months from 2977 participants who were cognitively intact at the time of enrollment. These data were further processed and aggregated to generate 31 time-series driving variables. Because of high dimensional time-series features for driving variables, we used I-score for variable selection. I-score is a measure to evaluate variables' ability to predict and is proven to be effective in differentiating between noisy and predictive variables in big data. It is introduced here to select influential variable modules or groups that account for compound interactions among explanatory variables. It is explainable regarding to what extent variables and their interactions contribute to the predictiveness of a classifier. In addition, I-score boosts the performance of classifiers over imbalanced datasets due to its association with the F1 score. Using predictive variables selected by I-score, interaction-based residual blocks are constructed over top I-score modules to generate predictors and ensemble learning aggregates these predictors to boost the prediction of the overall classifier. Experiments using naturalistic driving data show that our proposed classification method achieves the best accuracy (96%) for predicting MCI and dementia, followed by random forest (93%) and logistic regression (88%). In terms of F1 score and AUC, our proposed classifier achieves 98% and 87%, respectively, followed by random forest (with an F1 score of 96% and an AUC of 79%) and logistic regression (with an F1 score of 92% and an AUC of 77%). The results indicate that incorporating I-score into machine learning algorithms could considerably improve the model performance for predicting MCI and dementia in older drivers. We also performed the feature importance analysis and found that the right to left turn ratio and the number of hard braking events are the most important driving variables to predict MCI and dementia., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: Unhealthy lifestyle has been associated with obesity and type 2 diabetes. Whereas its association with vascular complications in patients with long-duration of type 2 diabetes is still uncertain., Methods: A total of 1188 patients with long-duration of type 2 diabetes from the Taiwan Diabetes Registry (TDR) data were analyzed. We stratified the severity of unhealthy lifestyle via scoring three factors (sleep duration <7 or >9 h, sit duration ≥ 8h, and meal numbers ≥ with night snack) and analyzed their associations with the development of vascular complications using logistic regression analysis. Besides, we also included 3285 patients with newly diagnosed type 2 diabetes as the comparison., Results: Increased numbers of factors that stand for unhealthy lifestyle were significantly associated with the development of cardiovascular disease, peripheral arterial occlusion disease (PAOD) and nephropathy in patients with long-duration of type 2 diabetes. After adjusting multiple covariables, having ≥ 2 factors of unhealthy lifestyle remained significant associations with cardiovascular disease and PAOD, with an odds ratio (OR) of 2.09 (95% confidence interval [CI] 1.18-3.69) and 2.68 (95% CI 1.21-5.90), respectively. Among individual factor for unhealthy lifestyle behaviors, we revealed that eating ≥ 4 meals per day with night snack increased the risk of cardiovascular disease and nephropathy after multivariable adjustment (OR of 2.60, 95% CI 1.28-5.30; OR of 2.54, 95% CI 1.52-4.26, respectively). Whereas sit duration for ≥ 8 h per day increased the risk of PAOD (OR of 4.32, 95% CI 2.38-7.84)., Conclusion: Unhealthy lifestyle is associated with increased prevalence of macro- and micro-vascular comorbidities in Taiwanese patients with long-duration type 2 diabetes., (© 2023. The Author(s).)

Introduction: Tuberous sclerosis complex (TSC) is a rare multisystem genetic condition characterised by benign tumours; prevalent manifestations include epilepsy and neuropsychiatric disorders. This study examined the burden of TSC for primary caregivers and families, exploring the impact of characteristics such as seizures., Methods: Primary caregivers of individuals with TSC in the United Kingdom participated in an online survey, comprising the Pediatric Quality of Life Inventory™ Family Impact Module, Hospital Anxiety and Depression Scale (HADS), and TSC-specific items. Responses were analysed using descriptive and regression analysis statistics (closed-ended) or qualitative content analysis (open-ended)., Results: Seventy-three participants partially completed and 59 fully completed the survey; 95% were female, and 90% were parents of an individual with TSC. A median (range) of 2 (1-11) household members were carers. Primary caregivers spent a mean (standard deviation [SD]) of 104.3 (51.7) hours caring in the previous week, reporting high mean (SD) HADS scores of 11.2 (4.8) (anxiety) and 7.9 (4.4) (depression) and considerable family burden. Increased seizure frequency increased hours spent caring by primary caregivers (p = 0.01) and was associated with a decreased mean (SD) family functioning score of 46.2 (23.0) and parent health-related quality of life (HRQL) score of 45.4 (20.3) (both p = 0.03). Multivariable models predicted intellectual disability increased hours spent caring by primary caregivers (p = 0.01-0.04), and neuropsychiatric comorbidities decreased family functioning (p = 0.02) and caregiver HRQL (p < 0.01)., Conclusion: These findings highlight the role of epileptic seizures and neuropsychiatric disorders in the considerable burden of TSC on primary caregivers and families., (© 2023. The Author(s).)

Background: Hereditary transthyretin amyloidosis (ATTRv) is an ultra-rare, life-shortening disease with a high unmet need. This study examined ATTRv caregiver health-related quality of life (HRQoL) and productivity., Methods: A cross-sectional online survey, including EQ-5D-3L, Hospital anxiety and depression scale (HADS), and caregiver and patient characteristics questions, was developed to assess ATTRv caregiver burden. A companion general population survey collected EQ-5D-3L, HADS and chronic health conditions data. Caregiver-control group differences in HRQoL were assessed using t-tests and chi-square tests. Ordinary Least Squares regression was used to estimate the disutility of being a caregiver compared to controls stratified by patient ambulatory status., Results: Thirty-six caregivers and matched controls completed the survey (n = 72). The disease severity of patients they cared for was varied: 33% required no assistance walking, 58% required assistance with walking and 9% required a wheelchair/were bedridden. On average, caregivers spent 6 h daily on practical care and 4 h daily on emotional support. Fifty-six percent indicated that they had changed their employment due to providing ATTRv care. Caregivers reported lower HRQoL, as indicated by lower EQ-5D 3L utility scores (M = 0.772, SD = 0.178 vs. M = 0.849, SD = 0.218) and higher HADS anxiety (9.3 vs. 6.1, p < 0.01) and depression (7.6 vs. 4.4, p < 0.01) scores, compared with matched controls. Caregivers were also more likely to report sleep problems (33% vs. 8%, p < 0.01) and stress (42% vs. 0%, p < 0.001) as chronic conditions than controls., Conclusions: The study results indicate that caring for a person with ATTRv can have a considerable negative impact on caregivers' HRQoL and productivity. The study findings provide important information for economic evaluations of ATTRv treatments., (© 2023. The Author(s).)

Since January 2020, the SARS-CoV-2 pandemic has severely affected hospital systems worldwide. In Europe, the first 3 epidemic waves (periods) have been the most severe in terms of number of infected and hospitalized patients. There are several descriptions of the demographic and clinical profiles of patients with COVID-19, but few studies of their hospital pathways. We used transition matrices, constructed from Markov chains, to illustrate the transition probabilities between different hospital wards for 90,834 patients between March 2020 and July 2021 managed in Paris area. We identified 3 epidemic periods (waves) during which the number of hospitalized patients was significantly high. Between the 3 periods, the main differences observed were: direct admission to ICU, from 14 to 18%, mortality from ICU, from 28 to 24%, length of stay (alive patients), from 9 to 7 days from CH and from 18 to 10 days from ICU. The proportion of patients transferred from CH to ICU remained stable. Understanding hospital pathways of patients is crucial to better monitor and anticipate the impact of SARS-CoV-2 pandemic on health system., (© 2022. The Author(s).)

The differentiation of oligodendroglia from oligodendrocyte precursor cells (OPCs) to complex and extensive myelinating oligodendrocytes (OLs) is a multistep process that involves large-scale morphological changes with significant strain on the cytoskeleton. While key chromatin and transcriptional regulators of differentiation have been identified, their target genes responsible for the morphological changes occurring during OL myelination are still largely unknown. Here, we show that the regulator of focal adhesion, Tensin3 (Tns3), is a direct target gene of Olig2, Chd7, and Chd8, transcriptional regulators of OL differentiation. Tns3 is transiently upregulated and localized to cell processes of immature OLs, together with integrin-β1, a key mediator of survival at this transient stage. Constitutive &lt;i&gt;Tns3&lt;/i&gt; loss of function leads to reduced viability in mouse and humans, with surviving knockout mice still expressing Tns3 in oligodendroglia. Acute deletion of &lt;i&gt;Tns3&lt;/i&gt; in vivo, either in postnatal neural stem cells (NSCs) or in OPCs, leads to a twofold reduction in OL numbers. We find that the transient upregulation of Tns3 is required to protect differentiating OPCs and immature OLs from cell death by preventing the upregulation of p53, a key regulator of apoptosis. Altogether, our findings reveal a specific time window during which transcriptional upregulation of Tns3 in immature OLs is required for OL differentiation likely by mediating integrin-β1 survival signaling to the actin cytoskeleton as OL undergo the large morphological changes required for their terminal differentiation., Competing Interests: EM, HH, CM, PH, HL, AP, JH, AC, YS, SG, SD, PR, SH, SL, BH, CP No competing interests declared, (© 2022, Merour, Hmidan et al.)

Objective: The objective of this study was to explore patient preference for attributes of calcitonin gene-related peptide (CGRP) inhibitors for the preventive treatment of migraine and to describe differences in treatment preferences between patients., Background: CGRP inhibitors are a novel class of migraine drugs specifically developed for the preventive treatment of migraine. Clinicians should understand patient preferences for CGRP inhibitors to inform and support prescribing choices., Methods: Patients with migraine in the US and Germany were recruited to participate in an online discrete choice experiment (DCE) survey, which presented hypothetical treatment choices using five attributes: mode of administration, side effects, migraine frequency, migraine severity, and consistency of treatment effectiveness. Attribute selection was informed by a literature review and semi-structured patient interviews (n = 35), and evaluated using patient cognitive debriefing interviews (n = 5)., Results: Of 680 who consented to participate, 506 participants completed the survey and were included in the study (US = 257; Germany = 249). Overall, participants placed highest importance (preference weight, beta = 1.65, p < 0.001) on the treatment's ability to reduce the severity of migraine (mild vs. unchanged severity), followed by consistent treatment effectiveness (beta = 1.13, p < 0.001), and higher chance of reduced migraine frequency (beta = 1.00, p < 0.001). Participants preferred an oral tablet every other day (beta = 1.00, p < 0.001) over quarterly infusion, quarterly injections (p = 0.019), or monthly injection (p < 0.001). Preference for all treatment attributes were heterogeneous, and the subgroup analyses found that participants naïve to CGRP monoclonal antibody treatments had a stronger preference for oral therapy compared to those with such experience (p = 0.006)., Conclusion: In this DCE assessing CGRP inhibitors attributes, the main driver of patient choice was treatment effectiveness, specifically reduced migraine severity, and consistent treatment effectiveness. Further, patients exhibited an overall preference for an oral tablet every other day over injectables. Patients' experience with previous treatments informs the value they place on treatment characteristics., (© 2022 Biohaven Pharmaceuticals Inc. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Objective: The objective of this study was to select an effective in vitro digestion-fermentation model to estimate the effect of decreasing dietary crude protein (CP) on odor emission during pig production and to suggest potential prediction markers through in vitro and in vivo experiments., Methods: In the in vitro experiment, three diet formulations with different CP contents (170 g/kg, 150 g/kg, and 130 g/kg) but containing the same standardized ileal digestible essential amino acids (SID-EAA) were assessed. Each diet was evaluated by two different in vitro gastric-intestinal phase digestion methods (flask and dialysis), combined with fresh pig feces-ferment inoculation. Eighteen growing barrows (31.9±1.6 kg) were divided into three groups: control diet (180 g CP/kg, without SID-EAA adjustment), 170 g CP/kg diet, and 150 g CP/kg diet for 4 weeks., Results: The in vitro digestion results indicated that in vitro digestibility was affected by the gastric-intestinal phase digestion method and dietary CP level. According to the gas kinetic and digestibility results, the dialysis method showed greater distinguishability for dietary CP level adjustment. Nitrogen-related odor compounds (NH3-N, indole, p-cresol, and skatole) were highly correlated with urease and protease activity. The feeding study indicated that both EAA-adjusted diets resulted in a lower odor emission especially in p-cresol and skatole. Both protease and urease activity in feces were also closely related to odor emissions from nitrogen metabolism compounds., Conclusion: Dialysis digestion in the gastric-intestinal phase followed by fresh fecal inoculation fermentation is suitable for in vitro diet evaluation. The enzyme activity in the fermentation and the fecal samples might provide a simple and effective estimation tool for nitrogen-related odor emission prediction in both in vitro and in vivo experiments.