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Abstract To investigate whether the increased risk of fetal abdominal obesity (FAO) is present in the older (≥ 35 years) and/or obese (≥ body mass index 25 kg/m2) women with normal glucose tolerance, we reviewed medical record of 6721 singleton pregnancy. At 24–28 gestational weeks (GW), fetal abdominal overgrowth was assessed by the fetal abdominal overgrowth ratios (FAORs) of the ultrasonographically estimated gestational age (GA) of abdominal circumference per actual GA by the last menstruation period, estimated GA of biparietal diameter or femur length, respectively. FAO was defined as FAOR ≥ 90th percentile. Compared to young and non-obese women, older women showed significantly higher FAORs irrespective of obesity and the prevalence of FAO in older and non-obese women was significantly higher (11.8% vs. 8.6%, p

Gaskets and seals are essential components in the operation of proton exchange membrane (PEM) fuel cells and are required for keeping hydrogen and air/oxygen within their individual compartments. The durability of these gaskets and seals is necessary, as it influences not only the lifespan but also the electrochemical efficiency of the PEM fuel cell. In this study, the cause of silicon leaching from silicone gaskets under simulated fuel cell conditions was investigated. Additionally, to reduce silicon leaching, the silica surface was treated with methyltrimethoxysilane, vinyltriethoxysilane, and (3,3,3-trifluoropropyl)trimethoxysilane. Changes in the silica surface chemistry were investigated by scanning electron microscopy, energy dispersive X-ray spectroscopy, thermogravimetric analysis, elemental analysis, X-ray photoelectron spectroscopy, and Fourier transform infrared spectroscopy. Inductively coupled plasma-optical emission spectroscopy analysis revealed that surface-treated silica was highly effective in reducing silicon leaching.

Abstract Fetal abdominal obesity (FAO) was detected at the time of gestational diabetes mellitus (GDM) diagnosis at 24–28 gestational weeks (GW) in older (≥ 35 years) and/or obese (≥ body mass index 25 kg/m2) women and persisted until delivery. We investigated whether FAO is already present at 20–24 GW. Medical records of 7820 singleton pregnancy including 384 GDM were reviewed. Fetal abdominal overgrowth was assessed by the fetal abdominal overgrowth ratios (FAORs) of the ultrasonographically estimated gestational age (GA) of abdominal circumference per actual GA by the last menstruation period, biparietal diameter or femur length, respectively. FAO was defined as FAOR ≥ 90th percentile. FAORs measured at 20–24 GW in older and/or obese but not in young and non-obese GDM subjects were significantly higher than those in NGT subjects. Relative to NGT subjects without FAO at 20–24 GW, odds ratios for exhibiting FAO at GDM diagnosis and large for gestational age in GDM with FAO at 20–24 GW were 10.15 and 5.57, and their primary cesarean delivery rate was significantly higher than those in GDM without FAO (44% vs. 29%). Earlier diagnosis and active interventions of GDM well before 20–24 GW might be necessary to prevent FAO in the older and/or obese women.

Background Fetal abdominal obesity (FAO) has been reported to be affected at gestational diabetes mellitus (GDM) diagnosis at 24 to 28 weeks of gestation in older and/or obese women. This study investigated whether the management of GDM improves FAO in GDM subjects near term. Methods Medical records of 7,099 singleton pregnant women delivering at CHA Gangnam Medical Center were reviewed retrospectively. GDM was diagnosed by 100-g oral glucose tolerance test after 50-g glucose challenge test based on Carpenter–Coustan criteria. GDM subjects were divided into four study groups according to maternal age and obesity. FAO was defined as ≥90th percentile of fetal abdominal overgrowth ratios (FAORs) of the ultrasonographically estimated gestational age (GA) of abdominal circumference per actual GA by the last menstruation period, biparietal diameter, or femur length, respectively. Results As compared with normal glucose tolerance (NGT) subjects near term, FAORs and odds ratio for FAO were significantly higher in old and/or obese women with GDM but not in young and nonobese women with GDM. For fetuses of GDM subjects with FAO at the time of GDM diagnosis, the odds ratio for exhibiting FAO near term and being large for GA at birth were 7.87 (95% confidence interval [CI], 4.38 to 14.15) and 10.96 (95% CI, 5.58 to 20.53) compared with fetuses of NGT subjects without FAO at GDM diagnosis. Conclusion Despite treatment, FAO detected at the time of GDM diagnosis persisted until delivery. Early diagnosis and treatment might be necessary to prevent near term FAO in high-risk older and/or obese women.

Irreversible peripheral neurodegenerative diseases such as diabetic peripheral neuropathy are becoming increasingly common due to rising rates of diabetes mellitus; however, no effective therapeutic treatments have been developed. One of main causes of irreversible peripheral neurodegenerative diseases is dysfunction in Schwann cells, which are neuroglia unique to the peripheral nervous system (PNS). Because homeostasis of calcium (Ca2+) and magnesium (Mg2+) is essential for Schwann cell dynamics, the regulation of these cations is important for controlling peripheral nerve degeneration and regeneration. Transient receptor potential melastatin 7 (TRPM7) is a non-selective ion (Ca2+ and Mg2+) channel that is expressed in Schwann cells. In the present study, we demonstrated in an ex vivo culture system that inhibition of TRPM7 during peripheral nerve degeneration (Wallerian degeneration) suppressed dedifferentiable or degenerative features (trans-dedifferentiation and proliferation) and conserved a differentiable feature of Schwann cells. Our results indicate that TRPM7 could be very useful as a molecular target for irreversible peripheral neurodegenerative diseases, facilitating discovery of new therapeutic methods for improving human health.

Peripheral nerve degeneration (PND) is a preparative process for peripheral nerve regeneration and is regulated by Schwann cells, a unique glial cell in the peripheral nervous system. Dysregulated PND induces irreversible peripheral neurodegenerative diseases (e.g., diabetic peripheral neuropathy). To develop novel synthetic drugs for these diseases, we synthesized a set of new cinnamaldehyde (CAH) derivatives and evaluated their activities in vitro, ex vivo, and in vivo. The 12 CAH derivatives had phenyl or naphthyl groups with different substitution patterns on either side of the α,β-unsaturated ketone. Among them, 3f, which had a naphthaldehyde group, was the most potent at inhibiting PND in vitro, ex vivo, and in vivo. To assess their interactions with transient receptor potential cation channel subfamily A member 1 (TRPA1) as a target of CAH, molecular docking studies were performed. Hydrophobic interactions had the highest binding affinity. To evaluate the underlying pharmacological mechanism, we performed bioinformatics analysis of the effect of 3f on PND based on coding genes and miRNAs regulated by CAH, suggesting that 3f affects oxidative stress in Schwann cells. The results show 3f to be a potential lead compound for the development of novel synthetic drugs for the treatment of peripheral neurodegenerative diseases.

N-ethylmaleimide (NEM) inhibits peripheral nerve degeneration (PND) by targeting Schwann cells in a hydrogen sulfide (H2S)-pathway-dependent manner, but the underlying molecular and pharmacological mechanisms are unclear. We investigated the effect of NEM, an α,β-unsaturated carboxyl compound, on H2S signaling in in vitro- and ex vivo-dedifferentiated Schwann cells using global proteomics (LC-MS) and transcriptomics (whole-genome and small RNA-sequencing (RNA-seq)) methods. The multi-omics analyses identified several genes and proteins related to oxidative stress, such as Sod1, Gnao1, Stx4, Hmox2, Srxn1, and Edn1. The responses to oxidative stress were transcriptionally regulated by several transcription factors, such as Atf3, Fos, Rela, and Smad2. In a functional enrichment analysis, cell cycle, oxidative stress, and lipid/cholesterol metabolism were enriched, implicating H2S signaling in Schwann cell dedifferentiation, proliferation, and myelination. NEM-induced changes in the H2S signaling pathway affect oxidative stress, lipid metabolism, and the cell cycle in Schwann cells. Therefore, regulation of the H2S signaling pathway by NEM during PND could prevent Schwann cell demyelination, dedifferentiation, and proliferation.

Although obesity is commonly associated with numerous cardiometabolic pathologies, some people with obesity are resistant to detrimental effects of excess body fat, which constitutes a condition called “metabolically healthy obesity” (MHO). Metabolic features of MHO that distinguish it from metabolically unhealthy obesity (MUO) include differences in the fat distribution, adipokine types, and levels of chronic inflammation. Murine models are available that mimic the phenotype of human MHO, with increased adiposity but preserved insulin sensitivity. Clinically, there is no established definition of MHO yet. Despite the lack of a uniform definition, most studies describe MHO as a particular case of obesity with no or only one metabolic syndrome components and lower levels of insulin resistance or inflammatory markers. Another clinical viewpoint is the dynamic and changing nature of MHO, which substantially impacts the clinical outcome. In this review, we explore the pathophysiology and some murine models of MHO. The definition, variability, and clinical implications of the MHO phenotype are also discussed. Understanding the characteristics that differentiate people with MHO from those with MUO can lead to new insights into the mechanisms behind obesity-related metabolic derangements and diseases.

Silver (Ag) introduced colloidal Sn-doped In2O3 (ITO) ink for transparent conductive electrodes (TCEs) was prepared to overcome the limitation of colloidally prepared thin film; low density thin film, high resistance. ITO@Ag colloid ink was made by controlling the weight ratio of ITO and Ag nanoparticles through ball-milling and fabricated using spin coating. These films were dried at 220 °C and heat-treated at 450–750 °C in an air atmosphere to pyrolyze the organic ligand attached to the nanoparticles. All thin films showed high crystallinity. As the thermal treatment temperature increased, films showed a cracked surface, but as the weight percentage of silver increased, a flattened and smooth surface appeared, caused by the metallic silver filling the gap between the nano-particles. This worked as a bridge to allow electrical conduction, which decreases the resistivity over an order of magnitude, from 309 to 0.396, and 0.107 Ω·cm for the ITO-220 °C, ITO-750 °C, and ITO@Ag (7.5 wt.%)-750 °C, respectively. These films also exhibited >90% optical transparency. Lowered resistivity is caused due to the inclusion of silver, providing a sufficient number of charge carriers. Furthermore, the work function difference between ITO and silver builds an ohmic junction, allowing fluent electrical flow without any barrier.

Background/AimsAcute hepatic dysfunction combined with alcoholic hepatitis (AH) in alcoholic cirrhosis is related to hepatic hypo-perfusion secondary to intrahepatic necroinflammation, neoangiogenesis, and shunt. The hepatic vein arrival time (HVAT) assessed by microbubble contrast-enhanced ultrasonography (CEUS) is closely correlated with the severity of intrahepatic changes. We investigated the usefulness of HVAT to predict short-term mortality of AH in cirrhosis.Methods : Thirty-nine patients with alcoholic cirrhosis (27 males) and AH were prospectively enrolled. HVAT study was performed within 3 days after admission using ultrasonic contrast (SonoVue®). The primary outcome was 12-week mortality.Results : Twelve-week mortality developed in nine patients. HVAT was significantly different between the mortality and survival groups (9.3±2.0 seconds vs 12.6±3.5 seconds, p=0.002). The odds ratio of a shortened HVAT for 12-week mortality was 1.481 (95% confidence interval, 1.050–2.090; p=0.025). The area under the receiver operating characteristic curve of HVAT for 12-week mortality was 0.787 (p=0.010). The combination of MDF and HVAT ≥11.0 seconds resulted in an 87.5% survival rate even if the MDF score ≥32; however, HVAT

Epithelial lining fluid (ELF) is often considered to be the site of extracellular pulmonary infections. During the past 25 years, a limited number of studies have evaluated the intrapulmonary penetration of antifungal, antitubercular, antiparasitic and antiviral agents. For antifungal agents, differences in drug concentrations in ELF or bronchoalveolar lavage (BAL) fluid were observed among various formulations or routes of administration, and between agents within the same class. Aerosolized doses of deoxycholate amphotericin B, liposomal amphotericin B and amphotericin B lipid complex resulted in higher concentrations in ELF or BAL fluid than after intravenous administration. The mean concentrations in ELF following intravenous administration of both anidulafungin and micafungin ranged between 0.04 and 1.38 μg/mL, and the ELF to plasma concentration ratios (based on the area under the concentration-time curve for total drug concentrations) were between 0.18 and 0.22 during the first 3 days of therapy. Among the azole agents, intravenous administration of voriconazole resulted in the highest mean ELF concentrations (range 10.1-48.3 μg/mL) and ratio of penetration (7.1). The range of mean ELF concentrations of itraconazole and posaconazole following oral administration was 0.2-1.9 μg/mL, and the ELF to plasma concentration ratios were <1. A series of studies have evaluated the intrapulmonary penetration of first- and second-line oral antitubercular agents in healthy adult subjects and patients with AIDS. The ELF to plasma concentration ratio was >1 for isoniazid, ethambutol, pyrazinamide and ethionamide. For rifampicin (rifampin) and rifapentine, the ELF to plasma concentration ratio ranged between 0.2 and 0.32, but in alveolar macrophages the concentration of rifampicin was much higher (145-738 μg/mL compared with 3.3-7.5 μg/mL in ELF). No intrapulmonary studies have been conducted for rifabutin. Sex, AIDS status or smoking history had no significant effects on the magnitude of ELF concentrations of antitubercular agents. Subjects who were slow acetylators had higher plasma and ELF concentrations of isoniazid than those who were fast acetylators. Penetration of dapsone into ELF was very good, with the range of mean ELF to plasma concentration ratios being 0.65-2.91 at individual sampling times over 48 hours. Once-daily dosing of aerosolized pentamidine resulted in higher concentrations in BAL fluid than after intravenous administration. The mean BAL concentrations at 15-32 days after once- or twice-monthly administration of aerosolized pentamidine 300 and 600 mg ranged from 6.5 to 28.4 ng/mL. No differences in pentamidine BAL concentrations were observed in symptomatic patients who developed Pneumocystis jirovecii pneumonia compared with patients who did not. Zanamivir concentrations in ELF were similar in magnitude (range 141-326 ng/mL) following administration by continuous intravenous infusion (3 mg/hour), oral inhalation (10 mg every 12 hours) and intravenous bolus (200 mg every 12 hours). Data from case reports have suggested that concentrations of nelfinavir and saquinavir in ELF are undetectable, whereas tipranavir and lopinavir had measureable ELF concentrations (2.20 μmol/L and 14.4 μg/mL, respectively) when these protease inhibitors were co-administrated with ritonavir. While the clinical significance of ELF or BAL concentrations remains unknown for this group of anti-infective agents, the knowledge of drug penetration into the extracellular space of the lung should assist in re-evaluating and designing specific dosing regimens for use against potential pathogens. [ABSTRACT FROM AUTHOR]

Pregabalin is prescribed for neuropathic pain. We report the first case of pregabalin toxicity in a hemodialysis patient and her successful treatment with hemodialysis. The patient was a 30-year-old woman on long-term hemodialysis therapy who experienced significant myoclonus of the arms and legs when her dose of pregabalin was mistakenly increased. The drug has 3 properties that contribute to making it amenable to removal by hemodialysis: relatively low molecular weight (159.23 Da), relatively low volume of distribution (0.5 L/kg), and not bound to plasma proteins. We achieved hemodialysis clearance of 88.8 mL/min, which was associated with resolution of symptoms immediately after hemodialysis. [ABSTRACT FROM AUTHOR]

Background/AimsNon-selective beta blockers (NSBBs) are currently the only accepted regimen for preventing portal hypertension (PHT)-related complications. However, the effect of NSBBs is insufficient in many cases. Bacterial translocation (BT) is one of the aggravating factors of PHT in cirrhosis; therefore, selective intestinal decontamination by rifaximin is a possible therapeutic option for improving PHT. We investigated whether the addition of rifaximin to propranolol therapy can improve hepatic venous pressure gradient (HVPG) response.Methods : Sixty-four cirrhosis patients were randomly assigned to propranolol monotherapy (n=48) versus rifaximin and propranolol combination therapy (n=16). Baseline and post-treatment HVPG values, BT-related markers (lipopolysaccharide [LPS], LPS-binding protein [LBP], interleukin-6 [IL-6], and tumor necrosis factor α [TNF-α]), serological data, and adverse event data were collected. HVPG response rate was the primary endpoint.Results : Combination therapy was associated with better HVPG response rates than monotherapy (56.2% vs 87.5%, p=0.034). In combination therapy, posttreatment BT-related markers were significantly decreased (LPS, p=0.005; LBP, p=0.005; IL-6, p=0.005; TNF-α, p=0.047).Conclusion : sRifaximin combination therapy showed an additive effect in improving PHT compared to propranolol monotherapy. These pilot data suggest that the addition of rifaximin to NSBBs could be a good therapeutic option for overcoming the limited effectiveness of NSBBs.

AIM/BACKGROUND:The prevalence of elderly pregnancy and maternal obesity is increasing worldwide. In old and obese women, metabolic derangement affecting fetal growth might be present earlier than the diagnosis of gestational diabetes mellitus (GDM) or even before pregnancy. We thus investigated whether GDM diagnosed at 24-28 weeks of gestation had already affected fetal abdominal growth and, if so, whether elderly pregnancy and/or maternal obesity aggravate fetal abdominal obesity. METHODS:We retrospectively reviewed the medical records of 7820 singleton pregnant women who had been universally screened using a 50-g glucose challenge test (GCT) at 24-28 weeks of gestation, and underwent a 3-h 100-g oral glucose tolerance test (OGTT) if GCT were ≥140mg/dl. GDM and normal glucose tolerance (NGT) were diagnosed using the Carpenter-Coustan criteria. Fetal abdominal obesity was investigated by assessing the fetal abdominal overgrowth ratios (FAORs) of the ultrasonographically estimated gestational age (GA) of abdominal circumference per actual GA by the last menstruation period, biparietal diameter or femur length, respectively. Fetal abdominal overgrowth was defined as FAOR ≥ 90th percentile. The subjects were divided into four study groups: group 1 (age < 35 years and pre-pregnancy body mass index [BMI] < 25 kg/m2), group 2 (age < 35 years and ≥ 25), group 3 (age ≥ 35 years and BMI < 25), and group 4 (age ≥ 35 years and ≥ 25). RESULTS:The overall prevalence of GDM was 5.1%, with old and obese group 4 exhibiting the highest prevalence (22.4%). FAORs were significantly higher in the fetus of those with GDM than in the NGT subjects. But, in the subgroup analysis, only old and nonobese group 3 and old and obese group 4 with GDM exhibited significantly higher FAORs than the NGT subjects. Also, risk of fetal abdominal overgrowth was increased in group 3 and 4 subjects with GDM but not in young and nonobese group 1 GDM. The risk of fetal abdominal overgrowth significantly increased with maternal age >35 years, pre-pregnancy BMI >20kg/m2, and HbA1c >37.7 mmol/mol (5.6%). In multivariate analyses, maternal age and HbA1c were significantly associated with FAORs. CONCLUSION:GDM diagnosed at 24-28 weeks of gestation already affected fetal abdominal obesity in older and/or obese women, but not in younger and nonobese women. Our data suggest that selective screening and appropriate intervention of GDM earlier than 24-28 weeks of gestation might be necessary for high-risk old and/or obese women.

CRISPR-based homing gene drives have sparked both enthusiasm and deep concerns due to their potential for genetically altering entire species. This raises the question about our ability to prevent the unintended spread of such drives from the laboratory into a natural population. Here, we experimentally demonstrate the suitability of synthetic target site drives as well as split drives as flexible safeguarding strategies for gene drive experiments by showing that their performance closely resembles that of standard homing drives in Drosophila melanogaster. Using our split drive system, we further find that maternal deposition of both Cas9 and gRNA is required to form resistance alleles in the early embryo and that maternally-deposited Cas9 alone can power germline drive conversion in individuals that lack a genomic source of Cas9.

Post-transcriptional gene regulation is an important step in the regulation of eukaryotic gene expression. Subcellular compartmentalization of RNA species plays a crucial role in the control of mRNA turnover, spatial restriction of protein synthesis, and the formation of macromolecular complexes. Although long noncoding RNAs (lncRNAs) are one of the key regulators of post-transcriptional gene expression, it is not heavily studied whether localization of lncRNAs in subcellular organelles has functional consequences. Here, we report on mitochondrial lncRNAs whose expression fluctuates in the process of cellular senescence. One of the mitochondrial lncRNAs, RPPH1 RNA, is overexpressed and accumulates in mitochondria of senescent fibroblasts, possibly modulated by the RNA-binding protein AUF1. In addition, RPPH1 RNA overexpression promotes spontaneous replicative cellular senescence in proliferating fibroblasts. Using MS2 aptamer-based RNA affinity purification strategy, we identified putative target mRNAs of RPPH1 RNA and revealed that partial complementarity of RPPH1 RNA to its target mRNAs prevents those mRNAs decay in proliferating fibroblasts. Altogether, our results demonstrate the role of mitochondrial noncoding RNA in the regulation of mRNA stability and cellular senescence.

Bone marrow‐derived mesenchymal stem cells (BM‐MSCs) are known to have an antifibrotic effect and could be used as vehicles for targeted gene delivery. Decorin plays a protective role against fibrogenesis by modulating the degradation of the extracellular matrix. The aim of this study was to determine whether the antifibrotic effect of a combination treatment consisting of BM‐MSCs and decorin on hepatic fibrosis is superior to BM‐MSCs alone. The effects of BM‐MSCs infected with decorin‐expressing adenovirus (DCN‐MSCs) on hepatic fibrosis were examined in a rat model of thioacetamide (TAA)‐induced cirrhosis. The effects of infection with decorin‐expressing adenovirus and of incubation with the conditioned medium of DCN‐MSCs on transforming growth factor‐β (TGF‐β) signaling were analyzed in immortalized human hepatic stellate cells (HSCs). According to the Laennec fibrosis scoring system, cirrhotic livers from rats treated with DCN‐MSCs exhibited histological improvement compared with cirrhotic livers from rats treated with control adenovirus‐infected MSCs (CA‐MSCs). DCN‐MSC treatment reduced hepatic collagen distribution, lowered the hydroxyproline content, and rescued liver function impairment in rats with TAA‐induced cirrhosis. These protective effects were more potent with DCN‐MSCs than with CA‐MSCs. The upregulation of collagen‐1, α‐smooth muscle actin (α‐SMA), TGF‐β1, and Smad3 phosphorylation in cirrhotic livers was prevented by DCN‐MSC administration. Intriguingly, medium from cultured DCN‐MSCs blocked both Smad3 phosphorylation and exogenous TGF‐β1 stimulated α‐SMA synthesis in HSCs. DCN‐MSCs exert strong protective effects against hepatic fibrosis by suppressing TGF‐β/Smad signaling. Thus, treatment with DCN‐MSCs is a potentially novel and efficient therapeutic approach for patients with intractable cirrhosis. Significance A combination treatment consisting of bone marrow‐derived mesenchymal stem cells (BM‐MSCs) and decorin strongly inhibited the progression of thioacetamide‐induced hepatic fibrosis in rats, compared with BM‐MSCs alone. Furthermore, the significant inhibitory effect of BM‐MSCs infected with decorin‐expressing adenovirus was attributed to suppressing transforming growth factor‐β (TGF‐β)/Smad signaling pathway, supported by attenuation of TGF‐β1 expression and inhibition of Smad3 phosphorylation. Therefore, treatment with BM‐MSCs infected with decorin‐expressing adenovirus could constitute a novel and efficient therapeutic approach for patients with intractable cirrhosis.

Type I interferon (IFN-I, including IFN-α and IFN-β) response has been implicated in eosinophilic inflammation, in addition to antiviral function. This study aimed to investigate the role of IFN-I in the pathogenesis of eosinophilic chronic rhinosinusitis (ECRS). IFN-α, IFN-β, cytokine expression, and IFN-β cellular localization in the sinonasal tissue from control subjects and ECRS patients with nasal polyps (NP) were determined using real time-PCR, ELISA, and immunohistochemistry. ECRS was induced in wild-type (WT) and IFNAR1 knockout (Ifnar1−/−) mice by intranasal challenge with Aspergillus protease and ovalbumin. Stromal cells cultured from NP tissue were stimulated by exogenous IFN-β, and their CCL11 production and IRF3, IRF7, STAT1, STAT2, and IRF9 gene and/or protein expression were measured. IFN-β, IL-5, IL-13, and CCL11 expression was higher in the NP tissue from ECRS patients, compared to the control group. IFN-β was highly colocalized with the CD11c+ cells in NP. IFN-β levels positively correlated with IL-5, IL-13, and CCL11 levels as well as the number of eosinophils in the NP tissue and CT score. The histological severity of ECRS, levels of IL-4, IL-5, IL-13, and CCL11 in the nasal lavage fluid, and total serum IgE levels were less in Ifnar1−/− mice than in WT mice. CCL11 production, and STAT1 and STAT2 mRNA and STAT1, phospho-STAT1, and phospho-STAT2 protein expression were significantly increased by exogenous IFN-β in NP stromal cells. Our data suggest that IFN-β response was upregulated in ECRS and may play role in ECRS development. IFN-β may contribute to ECRS by enhancing CCL11 production. Thus, increased IFN-β response in the sinonasal mucosa may underlie ECRS pathogenesis.

Background/AimsLiver stiffness measurement (LSM) has been proposed as a non-invasive method for estimating the severity of fibrosis and the complications of cirrhosis. Measurement of the hepatic venous pressure gradient (HVPG) is the gold standard for assessing the presence of portal hypertension, but its invasiveness limits its clinical application. In this study we evaluated the relationship between LSM and HVPG, and the predictive value of LSM for clinically significant portal hypertension (CSPH) and severe portal hypertension in cirrhosis.MethodsLSM was performed with transient elastography in 59 consecutive cirrhotic patients who underwent hemodynamic HVPG investigations. CSPH and severe portal hypertension were defined as HVPG ≥10 and ≥12 mmHg, respectively. Linear regression analysis was performed to evaluate the relationship between LSM and HVPG. Diagnostic values were analyzed based on receiver operating characteristic (ROC) curves.ResultsA strong positive correlation between LSM and HVPG was observed in the overall population (r2=0.496, P

Portal hypertension is a direct consequence of hepatic fibrosis, and several hepatic fibrosis markers have been evaluated as a noninvasive alternative to the detection of portal hypertension and esophageal varices. In the present study, we compared the diagnostic and prognostic values of the noninvasive fibrosis markers in patients with alcoholic cirrhosis. A total of 219 consecutive alcoholic cirrhosis patients were included. Biochemical scores and liver stiffness (LS) were compared with hepatic venous pressure gradient (HVPG). For the detection of clinically significant portal hypertension (CSPH; HVPG≥10 mmHg) in compensated patients, LS and LS-spleen diameter to platelet ratio score (LSPS) showed significantly better performance with area under the curves (AUCs) of 0.85 and 0.82, respectively, than aspartate aminotransferase-to-platelet ratio index, FIB-4, Forns' index, Lok index, (platelet count)2/[monocyte fraction (%) × segmented neutrophil fraction (%)], and platelet count-to-spleen diameter ratio (all P

Vaspin is an adipocytokine recently identified in the visceral adipose tissue of diabetic rats and having anti-diabetic effects. We have recently shown that vaspin has anti-atherogenic effect through Akt-mediated inhibition of endothelial cell apoptosis. Decreased activity of endothelial nitric oxide synthase (eNOS) plays an important role in the pathogenesis of atherosclerosis. Asymmetric dimethylarginine (ADMA) is a well-known endogenous competitive inhibitor of eNOS and risk factor of cardiovascular diseases. The aim of this study was to examine whether vaspin might protect against atherosclerosis through its beneficial effects on the ADMA-eNOS system. Treatment of vaspin significantly increased NO secretion from endothelial cells and isolated aorta from Sprague-Dawley (SD) rats. Furthermore, treatment of vaspin prevented fatty acid-induced decrease in endothelium-dependent vasorelaxation in isolated aorta of SD rat. For the mechanism of vaspin-induced NO biosynthesis, vaspin activated the STAT3 signaling pathway and stimulated eNOS phosphorylation (Ser 1177), a marker of eNOS activation, through STAT3-dependent mechanism. Furthermore, vaspin treatment increased the expression of dimethylarginine dimethylaminohydrolase (DDAH) II, the responsible enzyme for the degradation of ADMA, leading to a reduction in ADMA levels. Vaspin-induced increase in DDAH II gene expression was through STAT3-mediated stimulation of DDAH II promoter activity. These results suggest that vaspin increases eNOS activity by reducing ADMA level through STAT3-mediated regulation of DDAH II expression. Our findings provide a novel molecular mechanism of antiatherogenic actions of vaspin.

Abstract Background The PTEN/Phosphatidylinositol 3'-kinase (PI3-kinase) growth factor signaling pathway plays a critical role in epithelial tumor development in a multitude of tissue types. Deletion of the Pten tumor suppressor gene in murine urothelial cells in vivo results in upregulation of cyclin-dependent kinase inhibitor p21. We have previously shown in mice that p21 expression blocks an increase in urothelial cell proliferation due to Pten deletion. In this study, we utilized human urothelial carcinoma cells UMUC-3 and UMUC-14 to identify the signaling pathways downstream of PI3-kinase that regulate p21. Methods Cells were treated with a combination of PI3-kinase stimulating growth factors and kinase inhibitors, or transfected with exogenous genes in order to identify the signaling events that are necessary for p21 induction. Mice with conditional deletion of Pten in bladder urothelium were also examined for evidence of PI3-kinase pathway signaling events that affect p21 expression. Results When cells were treated with PI3-kinase activating growth factors EGF or PDGF, we found that p21 levels increased, in a manner similar to that observed in mice. We used the inhibitors LY294002, Akti-1/2, and rapamycin, to show that p21 induction is dependent upon PI3-kinase and AKT activity, and partially dependent on mTOR. We treated the cells with proteasome inhibitor MG-132 and found that p21 may be degraded in the proteasome to regulate protein levels. Importantly, our findings show that GSK-3β plays a role in diminishing p21 levels in cells. Treatment of cells with the GSK-3β inhibitor SB-216763 increased p21 levels, while exogenous expression of GSK-3β caused a decrease in p21, indicating that GSK-3β actively reduces p21 levels. We found that a combined treatment of LY294002 and SB-216763 improved the cytotoxic effect against UMUC-3 and UMUC-14 carcinoma cells over LY294002 alone, suggesting potential therapeutic uses for GSK-3β inhibitors. Immunohistochemical staining in bladders from wild-type and Pten-deleted mice indicated that GSK-3β inhibitory phosphorylation increases when Pten is deleted. Conclusion PI3-kinase and AKT cause an upregulation of p21 by suppressing GSK-3β activity and activating mTOR in both cultured human urothelial carcinoma cells and mouse urothelial cells in vivo.

Abstract Background Quantum dots (QDs) are crystalline nanoparticles that are compatible with biological systems to provide a chemically and photochemically stable fluorescent label. New ligand probes with fluorescent reporter groups are needed for detection and characterization of G protein-coupled receptors (GPCRs). Results Synthetic strategies for coupling the A2A adenosine receptor (AR) agonist CGS21680 (2-[4-(2-carboxyethyl)phenylethylamino]-5'-N-ethylcarboxamidoadenosine) to functionalized QDs were explored. Conjugates tethered through amide-linked chains and poly(ethyleneglycol) (PEG) displayed low solubility and lacked receptor affinity. The anchor to the dendron was either through two thiol groups of (R)-thioctic acid or through amide formation to a commercial carboxy-derivatized QD. The most effective approach was to use polyamidoamine (PAMAM) D5 dendrons as multivalent spacer groups, grafted on the QD surface through a thioctic acid moiety. In radioligand binding assays, dendron nucleoside conjugate 11 displayed a moderate affinity at the human A2AAR (Kiapp 1.02 ± 0.15 μM). The QD conjugate of increased water solubility 13, resulting from the anchoring of this dendron derivative, interacted with the receptor with Kiapp of 118 ± 54 nM. The fluorescence emission of 13 occurred at 565 nm, and the presence of the pendant nucleoside did not appreciably quench the fluorescence. Conclusions This is a feasibility study to demonstrate a means of conjugating to a QD a small molecular pharmacophore of a GPCR that is relatively hydrophobic. Further enhancement of affinity by altering the pharmacophore or the linking structures will be needed to make useful affinity probes.

Background: Older adults with dementia in long-term care facilities often encounter challenges in self-feeding owing to cognitive and physical impairments. Although direct care workers play a crucial role in facilitating mealtime activities, they lack adequate and specific training. To develop an effective educational training program for this purpose, it is essential to understand the educational needs of direct care workers providing meal assistance. Therefore, this study aimed to identify the educational needs prioritized by direct care workers in long-term care facilities, regarding providing eating assistance to older adults with dementia., Methods: Adopting a mixed-methods approach, this study combined quantitative analysis using Borich's needs assessment and locus for focus models with qualitative insights from focus group interviews. Participants comprised 174 direct care workers and five nursing managers from various long-term care facilities in South Korea., Results: This study identified four main educational priorities: enhancing knowledge regarding swallowing function, understanding institutional support mechanisms, applying multisensory stimulation techniques, and addressing food forgetfulness in older adults with dementia. These findings were aligned with the qualitative data that emphasized the necessity of training in these specific areas to improve the quality of meal assistance provided to this vulnerable population., Conclusion: The findings underscore the critical need for focused educational programs that equip direct care workers with the skills and knowledge necessary to effectively assist older adults with dementia during mealtime. This study advocates the implementation of continuous education and training initiatives led by nursing management to improve the meal assistance environment for older adults with dementia, thereby enhancing their overall care and quality of life., (© 2024. The Author(s).)

Lysine acetyltransferase 8, also known as KAT8, is an enzyme involved in epigenetic regulation, primarily recognized for its ability to modulate histone acetylation. This review presents an overview of KAT8, emphasizing its biological functions, which impact many cellular processes and range from chromatin remodeling to genetic and epigenetic regulation. In many model systems, KAT8's acetylation of histone H4 lysine 16 (H4K16) is critical for chromatin structure modification, which influences gene expression, cell proliferation, differentiation, and apoptosis. Furthermore, this review summarizes the observed genetic variability within the KAT8 gene, underscoring the implications of various single nucleotide polymorphisms (SNPs) that affect its functional efficacy and are linked to diverse phenotypic outcomes, ranging from metabolic traits to neurological disorders. Advanced insights into the structural biology of KAT8 reveal its interaction with multiprotein assemblies, such as the male-specific lethal (MSL) and non-specific lethal (NSL) complexes, which regulate a wide range of transcriptional activities and developmental functions. Additionally, this review focuses on KAT8's roles in cellular homeostasis, stem cell identity, DNA damage repair, and immune response, highlighting its potential as a therapeutic target. The implications of KAT8 in health and disease, as evidenced by recent studies, affirm its importance in cellular physiology and human pathology.

Objectives: To evaluate whether a focused, expert medication management intervention is feasible and potentially effective in preventing anticoagulation-related adverse events for patients transitioning from hospital to home., Design: Randomised, parallel design., Setting: Medical wards at six hospital sites in southern Ontario, Canada., Participants: Adults 18 years of age or older being discharged to home on an oral anticoagulant (OAC) to be taken for at least 4 weeks., Interventions: Clinical pharmacologist-led intervention, including a detailed discharge medication management plan, a circle of care handover and early postdischarge virtual check-up visits to 1 month with 3-month follow-up. The control group received the usual care., Outcomes Measures: Primary outcomes were study feasibility outcomes (recruitment, retention and cost per patient). Secondary outcomes included adverse anticoagulant safety events composite, quality of transitional care, quality of life, anticoagulant knowledge, satisfaction with care, problems with medications and health resource utilisation., Results: Extensive periods of restriction of recruitment plus difficulties accessing patients at the time of discharge negatively impacted feasibility, especially cost per patient recruited. Of 845 patients screened, 167 were eligible and 56 were randomised. The mean age (±SD) was 71.2±12.5 years, 42.9% females, with two lost to follow-up. Intervention patients were more likely to rate their ability to manage their OAC as improved (17/27 (63.0%) vs 7/22 (31.8%), OR 3.6 (95% CI 1.1 to 12.0)) and their continuity of care as improved (21/27 (77.8%) vs 2/22 (9.1%), OR 35.0 (95% CI 6.3 to 194.2)). Fewer intervention patients were taking one or more inappropriate medications (7 (22.5%) vs 15 (60%), OR 0.19 (95% CI 0.06 to 0.62))., Conclusion: This pilot randomised controlled trial suggests that a transitional care intervention at hospital discharge for older adults taking OACs was well received and potentially effective for some surrogate outcomes, but overly costly to proceed to a definitive large trial., Trial Registration Number: NCT02777047., Competing Interests: Competing interests: DMS has received honoraria paid indirectly to her research institute from AstraZeneca, BMS-Pfizer, Roche and Servier. DMS is supported by a Tier 2 Canada Research Chair in Anticoagulant Management of Cardiovascular Disease. The other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cultivating a positive research culture is considered the key to facilitating the utilization of research findings. In the realm of clinical nursing research, nurses conducting research may find the utilization of findings challenging due to the lack of a positive research culture., Objective: This study aims to identify and describe the sociocultural context of nursing research in a clinical setting at a Korean tertiary hospital., Methods: We included participant observation and ethnographic interviews with 6 registered nurses working in a medical-surgical unit in a Korean tertiary hospital who had experience conducting nursing research in clinical settings in this qualitative ethnographic study. The study was conducted from April 2022 to May 2022. Data analysis was conducted using Spradley's ethnographic approach, which includes domain analysis, taxonomic analysis, componential analysis, and theme analysis, and occurred concurrently with data collection., Results: The overarching theme identified for nursing research culture in clinical practice was the development of a driving force for growth within the clinical environment. This theme encompasses (1) balancing positive and negative influences in the research process, (2) fostering transformational change for both nurses and patients, and (3) promoting complementary communication among nurses., Conclusions: Clinical research plays a vital role in nursing practice that requires a balance of supportive elements, such as patient-driven research questions and hospital research support, with practical challenges such as shift work and high work intensity. This study found that a positive clinical nursing research culture can serve as a unifying bridge, connecting researchers, patients, who serve as both the origin and ultimate beneficiaries of research, and hospitals that facilitate research endeavors. Future research should explore whether the themes derived from this study fully reflect a clinical nursing research culture comprising patients, nurses, and the hospital environment and determine what requirements are needed to establish such a nursing research culture., (©Hyeyoung Hwang, Jennie C De Gagne, Leeho Yoo, Miji Lee, Hye Kyung Jo, Ju-eun Kim. Originally published in the Asian/Pacific Island Nursing Journal (https://apinj.jmir.org), 09.01.2024.)

This study analyzed the mealtime structure of older adults with dementia in long-term care facilities. The study conducted video observations at 2 long-term care facilities with 10 residents and 24 staff members, resulting in 41 dyads. The average mealtime duration was 12.21 ± 5.16 minutes; the average time of a single intake was 0.21 ± 0.21 minutes; and the median of the eating interval was 0.17 minutes. The average verbal assistance time was 1.41 ± 1.31 minutes; the average verbal assistance frequency was short (23.92 ± 15.50 times). During mealtime, residents had an average of 5.00 ± 4.07 instances of failing to eat properly. The video analysis emphasized the necessity of implementing a mealtime assistance program that incorporates patient-centered education for the staff and ensures sufficient staffing to provide high-quality meals for residents in long-term care facilities., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To analyze corneal biomechanics, specular microscopy, and optical coherence tomography-angiography findings in children with glaucoma., Methods: Pediatric patients (<18 years of age) with glaucoma (n = 38), increased cup:disk ratio and normal intraocular pressure (IOP) glaucoma suspects (n = 36), and controls (n = 67) were prospectively enrolled. Patients underwent testing with Ocular Response Analyzer, CellChek Specular Microscope, and Heidelberg OCT-A., Results: Average age of participants was 12.4 ± 3.5 years, with no difference between groups (P = 0.71). Glaucoma patients had undergone more intraocular surgeries (P < 0.0001) and showed worse logMAR visual acuity (P < 0.0001) than suspects or controls. Central corneal thickness (CCT) was greater in glaucoma patients (642.8 ± 85.9 μm [P < 0.0001]) and suspects (588 ± 43.7 μm [P = 0.003]) compared with controls (561 ± 39.9 μm). Corneal hysteresis (CH) was decreased in eyes with glaucoma (10.4 ± 3.0) compared with controls (11.7 ± 1.5 [P = 0.006]), but not suspects (11.3 ± 2.0 [P = 0.1]). Glaucoma patients had lower endothelial cell density (2028.4 ± 862.7 [P < 0.0001]) and greater average cell area (547.2 ± 332.4 [P < 0.0005]) compared with suspects (2919.3 ± 319.1, 347.5 ± 46.2) and controls (2913.7 ± 399.2, 350.8 ± 57.7), but there was no difference in polymegathism (P = 0.12) or pleomorphism (P = 0.85). No differences in vessel density or vessel skeletal density in the retinal vascular complex (P = 0.3077, P = 0.6471) or choroidal vascular complex (P = 0.3816, P = 0.7306) were detected., Conclusions: Children with glaucoma showed thicker corneas with lower endothelial cell density and greater cell area, but no difference in retinal/choroidal vascular densities compared with suspects and controls., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

As digital technologies rapidly integrate into Health Professions Education (HPE), understanding cyberethics is increasingly crucial. This scoping review explores the pedagogy of cyberethics in HPE, highlighting a significant gap in explicit definitions and conceptualizations. Additionally, the absence of specific theoretical frameworks in most documents raises concerns about research progression. Only four articles introduce educational interventions in cyberethics, indicating a promising avenue for future research. While comprehensive search methods are employed, limitations, including language biases, exist. Future investigations should broaden the discourse to encompass ethical implications of emerging technologies within HPE. Cultivating comprehensive, culturally sensitive, and inclusive guidelines is vital for ethical digital practices in the health care community.

Among adults with inflammatory bowel disease (IBD), self-reported sleep disturbances are associated with active symptoms, but the association between sleep measures and endoscopic disease activity is unknown. This study aimed to (1) compare sleep-wake behaviors among IBD patients based on endoscopic and clinical disease activity and (2) describe associations between actigraphy, self-reported sleep measures, and symptoms of fatigue, anxiety, and depression. Participants wore a wrist actigraph for 10 consecutive days and completed self-reported sleep questionnaires (Pittsburgh Sleep Quality Index [PSQI] and Patient-Reported Outcome Measures System [PROMIS] Sleep Disturbance and Sleep Interference questionnaires). Clinical and endoscopic disease activity were assessed. Based on actigraphic recordings ( n = 26), average total nighttime sleep was 437 minutes and sleep efficiency was 84%. Objective sleep measures did not differ based on endoscopic or clinical disease activity. Individuals with active clinical disease had higher PROMIS Sleep Disturbance (57.3 vs. 49.7, d = 1.28) and PROMIS Sleep-Related Impairment (58.1 vs. 52.8, d = 0.51) compared with those with inactive clinical disease. Self-reported sleep was significantly associated with anxiety, depression, and fatigue. Further research is needed to better characterize the relationship between sleep and endoscopic disease activity, and determine underlying mechanisms related to poor sleep in the IBD population., Competing Interests: Kindra Clark-Snustad serves on advisory boards for Takeda, BMS, Pfizer, and AbbVie. Scott Lee has received research support from AbbVie, Janssen, Takeda, Celgene, and Pfizer and serves on advisory boards for Cornerstones Health, Janssen, Eli Lilly, Bristol-Myers Squibb, and Pfizer. The remaining authors have no conflicts of interest to declare., (Copyright © 2023 Society of Gastroenterology Nurses and Associates.)

Background: Despite pharmacological treatment, individuals with inflammatory bowel disease (IBD) experience a variety of symptoms, including abdominal pain, fatigue, anxiety, and depression. Few nonmedical self-management interventions are available for people with IBD. A validated comprehensive self-management (CSM) intervention is effective for patients with irritable bowel syndrome who can have symptoms similar to those of individuals with IBD. We created a modified CSM intervention tailored to individuals with IBD (CSM-IBD). The CSM-IBD is an 8-session program delivered over 8-12 weeks with check-ins with a registered nurse., Objective: The primary objective of this pilot study is to determine the feasibility and acceptability of study procedures and the CSM-IBD intervention and to evaluate preliminary efficacy on quality of life and daily symptoms for a future randomized controlled trial. Additionally, we will examine the association of socioecological, clinical, and biological factors with symptoms at baseline and response to intervention., Methods: We are conducting a pilot randomized controlled trial of the CSM-IBD intervention. Participants aged 18-75 years who are experiencing at least 2 symptoms are eligible for inclusion. We plan to enroll 54 participants who will be randomized (2:1) into the CSM-IBD program or usual care. Patients in the CSM-IBD program will have 8 intervention sessions. Primary study outcomes include the feasibility of recruitment, randomization, and data or sample collection, as well as the acceptability of study procedures and interventions. Preliminary efficacy outcome variables include quality of life and symptoms. Outcomes data will be assessed at baseline, immediately post intervention, and 3 months post intervention. Participants in the usual care group will have access to the intervention after study participation., Results: This project is funded by the National Institutes of Nursing Research and reviewed by the University of Washington's institutional review board. Recruitment began in February 2023. As of April 2023, we have enrolled 4 participants. We expect the study to be completed by March 2025., Conclusions: This pilot study will evaluate the feasibility and efficacy of a self-management intervention (a web-based program with weekly check-ins with a registered nurse) that aims to improve symptom management in individuals with IBD. In the long term, we aim to validate a self-management intervention to improve patient quality of life, reduce direct and indirect costs related to IBD, and be culturally appropriate and accessible, particularly in rural and underserved communities., Trial Registration: ClinicalTrials.gov NCT05651542; https://clinicaltrials.gov/ct2/show/NCT05651542., International Registered Report Identifier (irrid): PRR1-10.2196/46307., (©Kendra Kamp, Kindra Clark-Snustad, Linda Yoo, Samantha Winders, Kevin Cain, Rona L Levy, Neelendu Dey, Scott Lee, Laurie Keefer, Margaret Heitkemper. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 07.06.2023.)

Aim: To examine the individual-level factors and social determinants of health (SDOH) linked to sleep health among individuals with inflammatory bowel disease (IBD)., Design: Systematic review without meta-analysis., Data Sources: Four databases (PubMed, Web of Science, CINAHL and PsycINFO) were searched in February 2022., Review Methods: Databases were searched with keywords related to IBD and sleep. The review was conducted per the PRISMA protocol. The checklist for analytical cross-sectional studies published by the Joanna Briggs Institute was used for quality appraisal. Factors were organized by individual, social and societal levels according to the social-ecological model of sleep health., Results: In the review, 45 studies were identified and synthesized. All studies examined individual-level factors with sleep, with age being the most common factor studied. Only nine studies considered a social determinant of health which included marital status, number of children, education level, annual income, employment status, work tenure, type of employment, area of residence, minority status/ethnicity and COVID-19. However, the source of information for the social determinant of health was not clearly defined for more than half of these studies., Conclusion: Although IBD sleep research has explored individual-level factors (i.e. age) that impact sleep health, there is a lack of information on the SDOH that can contribute to sleep health., Impact: This review provides insight into the different factors that have been examined in IBD sleep research. By determining the SDOH that impact sleep, nursing research can inform sustainable and tailored interventions that focus on changing behaviour and improving sleep of individuals of varying backgrounds and life experiences. There is a continued need for nurses in practice and research to explore the SDOH that influence health outcomes and the daily lives of those with IBD., (© 2023 John Wiley & Sons Ltd.)

Background: Imbalance of the tryptophan (TRP) pathway may influence symptoms among patients with irritable bowel syndrome (IBS). This study explored relationships among different components that contribute to TRP metabolism (dietary intake, stool metabolite levels, predicted microbiome metabolic capability) in females with IBS and healthy controls (HCs). Within the IBS group, we also investigated relationships between TRP metabolic determinants, Bifidobacterium abundance, and symptoms of IBS., Methods: Participants with IBS (Rome III) and HCs completed a 28-day diary of gastrointestinal symptoms and a 3-day food record for TRP intake. They provided a stool sample for shotgun metagenomics, 16 S rRNA analyses, and quantitative measurement of TRP by mass spectrometry., Results: Our cohort included 115 females, 69 with IBS and 46 HCs, with a mean age of 28.5 years (SD 7.4). TRP intake (p = 0.71) and stool TRP level (p = 0.27) did not differ between IBS and HC. Bifidobacterium abundance was lower in the IBS group than in HCs (p = 0.004). Predicted TRP metabolism gene content was higher in IBS than HCs (FDR-corrected q = 0.006), whereas predicted biosynthesis gene content was lower (q = 0.045). Within the IBS group, there was no association between symptom severity and TRP intake or stool TRP, but there was a significant interaction between Bifidobacterium abundance and TRP intake (q = 0.029) in predicting stool character., Conclusions: Dietary TRP intake, microbiome composition, and differences in TRP metabolism constitute a complex interplay of factors that could modulate IBS symptom severity., (© 2023 John Wiley & Sons Ltd.)

How macroautophagy/autophagy influences neurofilament (NF) proteins in neurons, a frequent target in neurodegenerative diseases and injury, is not known. NFs in axons have exceptionally long half-lives in vivo enabling formation of large stable supporting networks, but they can be rapidly degraded during Wallerian degeneration initiated by a limited calpain cleavage. Here, we identify autophagy as a previously unrecognized pathway for NF subunit protein degradation that modulates constitutive and inducible NF turnover in vivo . Levels of NEFL/NF-L, NEFM/NF-M, and NEFH/NF-H subunits rise substantially in neuroblastoma (N2a) cells after blocking autophagy either with the phosphatidylinositol 3-kinase (PtdIns3K) inhibitor 3-methyladenine (3-MA), by depleting ATG5 expression with shRNA , or by using both treatments. In contrast, activating autophagy with rapamycin significantly lowers NF levels in N2a cells. In the mouse brain, NF subunit levels increase in vivo after intracerebroventricular infusion of 3-MA. Furthermore, using tomographic confocal microscopy, immunoelectron microscopy, and biochemical fractionation, we demonstrate the presence of NF proteins intra-lumenally within autophagosomes (APs), autolysosomes (ALs), and lysosomes (LYs). Our findings establish a prominent role for autophagy in NF proteolysis. Autophagy may regulate axon cytoskeleton size and responses of the NF cytoskeleton to injury and disease.

Aims: To understand the experiences and needs of symptom management among individuals with irritable bowel syndrome and concurrent symptoms of anxiety and/or depression., Design: This study used a qualitative descriptive research design., Methods: Individuals with a diagnosis of irritable bowel syndrome and concurrent symptoms of anxiety and/or depression participated were recruited through an online ResearchMatch and a listserv. Semi-structured interviews focused on symptoms and experiences with symptom management interventions conducted from June to August 2020. Interviews were transcribed and data were analysed based on thematic analysis., Results: Twelve individuals participated in this study; all reported current irritable bowel syndrome and anxiety/depression symptoms. The data analysis cumulated with three themes related to symptom management: (a) irritable bowel syndrome negatively impacts physical and mental well-being; (b) a trial and error approach to symptom management; and (c) challenges with healthcare professionals supporting symptom management including negative interactions with healthcare professionals and lack of nutritional expertize and support., Conclusion: There is a need for individualized approaches which consider patients' current symptoms of anxiety and depression, previous experiences with the trial-and-error process and consideration for intervention delivery methods., Impact: There is a limited qualitative research focusing on the experiences of individuals with irritable bowel syndrome and concurrent symptoms of anxiety and/or depression. This research highlights the need for individualized approaches to enhance symptom management that acknowledges patients' psychological state and past negative experiences with providers and prior dietary regimens., (© 2022 John Wiley & Sons Ltd.)

Background: Oral anticoagulants (OACs) are commonly prescribed, have well-documented benefits for important clinical outcomes but have serious harms as well. Rates of OAC-related adverse events including thromboembolic and hemorrhagic events are especially high shortly after hospital discharge. Expert OAC management involving virtual care is a research priority given its potential to reach remote communities in a more feasible, timely, and less costly way than in-person care. Our objective is to test whether a focused, expert medication management intervention using a mix of in-person consultation and virtual care follow-up, is feasible and effective in preventing anticoagulation-related adverse events, for patients transitioning from hospital to home., Methods and Analysis: A randomized, parallel, multicenter design enrolling consenting adult patients or the caregivers of cognitively impaired patients about to be discharged from medical wards with a discharge prescription for an OAC. The interdisciplinary multimodal intervention is led by a clinical pharmacologist and includes a detailed discharge medication reconciliation and management plan focused on oral anticoagulants at hospital discharge; a circle of care handover and coordination with patient, hospital team and community providers; and early post-discharge follow-up virtual medication check-up visits at 24 h, 1 week, and 1 month. The control group will receive usual care plus encouragement to use the Thrombosis Canada website. The primary feasibility outcomes include recruitment rate, participant retention rates, trial resources management, and the secondary clinical outcomes include adverse anticoagulant safety events composite (AASE), coordination and continuity of care, medication-related problems, quality of life, and healthcare resource utilization. Follow-up is 3 months., Discussion: This pilot RCT tests whether there is sufficient feasibility and merit in coordinating oral anticoagulant care early post-hospital discharge to warrant a full sized RCT., Trial Registration: NCT02777047., (© 2022. The Author(s).)

Background: In older patients with dementia, functional dependence on individuals affects their eating behavior, leading to difficulties with meals. In addition to individual factors, several social, cultural, and environmental factors influence mealtime difficulties in older individuals with dementia. Therefore, a measure is required to evaluate the difficulty of eating, considering the different interacting phenomena., Methods: Mealtime Difficulties Scale for older adults with Dementia (MDSD) was developed through a literature review. A pilot test was undertaken to confirm the meaning of the items and the relevance of mealtime difficulties for older patients with dementia. A panel of six experts examined the content validity of the MDSD. Convenience sampling was used to recruit direct care workers from long-term care facilities, of which 150 were recruited for exploratory factor analysis (EFA) and 208 for confirmatory factor analysis (CFA)., Results: The final version of the MDSD included 19 items, with a Cronbach's α of 0.91. The EFA identified three factors ("functional," "caregiving," and "behavioral") that account for 54.6% of the total variance. The CFA confirmed the validity of the instrument., Conclusions: Evidence to substantiate the validity and reliability of MDSD was found. While this tool has limitations in that it does not ensure convergent validity, it can be considered significant as it can assess the mealtime difficulty among older patients with dementia from different perspectives., (© 2022. The Author(s).)

Dysfunction and mistrafficking of organelles in autophagy- and endosomal-lysosomal pathways are implicated in neurodegenerative diseases. Here, we reveal selective vulnerability of maturing degradative organelles (late endosomes/amphisomes) to disease-relevant local calcium dysregulation. These organelles undergo exclusive retrograde transport in axons, with occasional pauses triggered by regulated calcium efflux from agonist-evoked transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1) channels-an effect greatly exaggerated by exogenous agonist mucolipin synthetic agonist 1 (ML-SA1). Deacidification of degradative organelles, as seen after Presenilin 1 (PSEN1) loss of function, induced pathological constitutive "inside-out" TRPML1 hyperactivation, slowing their transport comparably to ML-SA1 and causing accumulation in dystrophic axons. The mechanism involved calcium-mediated c-Jun N-terminal kinase (JNK) activation, which hyperphosphorylated dynein intermediate chain (DIC), reducing dynein activity. Blocking TRPML1 activation, JNK activity, or DIC1B serine-80 phosphorylation reversed transport deficits in PSEN1 knockout neurons. Our results, including features demonstrated in Alzheimer-mutant PSEN1 knockin mice, define a mechanism linking dysfunction and mistrafficking in lysosomal pathways to neuritic dystrophy under neurodegenerative conditions.