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OBJECTIVES: This study aimed to investigate the impact of hepatic steatosis on cardiometabolic outcomes in young adults with prediabetes. METHODS: A nationwide cohort study was conducted with 896,585 young adults under 40 years old without diabetes or previous history of cardiovascular disease. Hepatic steatosis was identified using a fatty liver index of ≥ 60. The outcomes of this study were incident diabetes (DM) and composite major adverse cardiovascular events (MACE), including myocardial infarction, stroke, or cardiovascular death. RESULTS: During a median follow-up of 11.8 years, 27,437 (3.1%) incident DM cases and 6,584 (0.7%) MACE cases were recorded. Young adults with prediabetes had a significantly higher risk of incident DM (hazard ratio [HR]: 2.81; 95% confidence interval [CI]: 2.74-2.88; P-value:

Abstract Background 18F-Florbetaben amyloid positron emission tomography (PET) scan is crucial for diagnosing Alzheimer’s disease, typically involving a 20 min acquisition. However, maintaining such prolonged scans can be challenging in some cases. This study explores the diagnostic impact and feasibility of reducing scan durations by comparing quantitative measures between shortened and standard scans. Additionally, we identified the optimal Centiloid threshold to distinguish between positive and negative amyloid results. Results We analyzed 307 PET scans from our memory clinic, each followed up for a minimum of two years. The scans, conducted 90 to 110 min after approximately 300 MBq of 18F-Florbetaben injection, were categorized into four sets of 5 min durations: 5, 10, 15, and 20 min. Nuclear medicine physicians validated and rated each scan as either amyloid-positive or negative. For quantitative assessments, we employed the standardized uptake value ratio (SUVR) and Centiloid scales, comparing total SUVR and Centiloid values across five subregions (global, frontal, posterior cingulate-precuneus, lateral temporal, and parietal) using Bland–Altman analysis. Receiver operator characteristic (ROC) curves were utilized to develop optimal Centiloid thresholds. Comparing the images at 5, 10, 15, and 20 min images, SUVR and Centiloid values gradually increased with prolonged scan times. The mean SUVR difference between 5 and 20 min was 0.03 for the amyloid-positive and 0.01 for the amyloid-negative groups; Centiloid differences were 4.60 and 2.38, respectively. Additionally, no significant variation was observed in total SUVR and Centiloid values among the durations across all subregions in positive and negative groups (all p > 0.1). ROC analysis indicated that a Centiloid threshold of 21.86 at 5 min provided optimal agreement with visual assessments (AUC = 0.985, sensitivity = 0.950, specificity = 0.972), especially using the global area. Conclusions This study demonstrated that 5 min image scans with an optimal threshold of CL = 21.86 exhibited minimal bias in SUVR and Centiloid values compared to longer scans (10, 15, and 20 min). Our findings suggest that shorter scan times are a viable and effective option for brain amyloid PET imaging in clinical settings.

Abstract Background Endovascular therapy (EVT) is the treatment of choice for acute ischemic stroke (AIS) with large vessel occlusion. However, in many patients, successful EVT recanalization does not correspond to a clinical improvement, called futile recanalization (FR). We aimed to identify stroke risk factors and patient characteristics associated with FR in AIS with large core infarct (LCI). Methods A total of 137 patients with AIS with LCI treated by EVT at a single stroke center were retrospectively included from January 2016 to June 2023. LCI was defined by Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomography Score (DWI-ASPECT)

Abstract It is uncertain whether the prognostic power of white matter hyperintensity (WMH) on post-stroke outcomes is modulated as a function of initial neurological severity, a critical determinant of outcome after stroke. This multi-center MRI study tested if higher WMH quintiles were associated with 3-month poor functional outcome (modified Rankin Scale ≥ 3) for mild versus moderate-to-severe ischemic stroke. Mild and moderate-to-severe stroke were defined as admission National Institute of Health Stroke Scale scores of 1–4 and ≥ 5, respectively. Mean age of the enrolled patients (n = 8918) was 67.2 ± 12.6 years and 60.1% male. The association between WMH quintiles and poor functional outcome was modified by stroke severity (p-for-interaction = 0.008). In mild stroke (n = 4994), WMH quintiles associated with the 3-month outcome in a dose-dependent manner for the 2nd to 5th quintile versus the 1st quintile, with adjusted-odds-ratios (aOR [95% confidence interval]) being 1.29 [0.96–1.73], 1.37 [1.02–1.82], 1.60 [1.19–2.13], and 1.89 [1.41–2.53], respectively. In moderate-to-severe stroke (n = 3924), however, there seemed to be a threshold effect: only the highest versus the lowest WMH quintile was significantly associated with poor functional outcome (aOR 1.69 [1.29–2.21]). WMH burden aggravates 3-month functional outcome after mild stroke, but has a lesser modulatory effect for moderate-to-severe stroke, likely due to saturation effects.

Background and objectives: The effects of noninvasive focused magnetothermal brain stimulation using magnetic nanoparticles (MNPs) on post-stroke motor deficits and metabolic dormancy in subacute ischemic injury are not well-established. This study examined if magnetothermal brain stimulation using magnetic nanoparticles (Nano-MS) enhances motor recovery after stroke. Methods: We randomly distributed rats into Sham, Control, MNP injection only, and Nano-MS groups. We administered focused magnetic stimulation for 30 min daily following an MNP injection (15 mg/mL) into the targeted motor cortex via the carotid artery three weeks after the transient (90 min) middle cerebral artery occlusion. We assessed motor functionality via behavioral tests and conducted positron emission tomography (PET) imaging to verify cerebral metabolic activity. We assessed neuronal excitability, neuroinflammation, blood-brain barrier (BBB) integrity, and neurogenesis four weeks post-stroke. Results: The Nano-MS group exhibited significantly improved motor deficits and cerebral metabolic activity compared to the Control and MNP groups (p

Flavin adenine dinucleotide (FAD) interacts with flavoproteins to mediate oxidation-reduction reactions required for cellular energy demands. Not surprisingly, mutations that alter FAD binding to flavoproteins cause rare inborn errors of metabolism (IEMs) that disrupt liver function and render fasting intolerance, hepatic steatosis, and lipodystrophy. In our study, depleting FAD pools in mice with a vitamin B2-deficient diet (B2D) caused phenotypes associated with organic acidemias and other IEMs, including reduced body weight, hypoglycemia, and fatty liver disease. Integrated discovery approaches revealed B2D tempered fasting activation of target genes for the nuclear receptor PPARα, including those required for gluconeogenesis. We also found PPARα knockdown in the liver recapitulated B2D effects on glucose excursion and fatty liver disease in mice. Finally, treatment with the PPARα agonist fenofibrate activated the integrated stress response and refilled amino acid substrates to rescue fasting glucose availability and overcome B2D phenotypes. These findings identify metabolic responses to FAD availability and nominate strategies for the management of organic acidemias and other rare IEMs.

ObjectiveMitophagy removes damaged mitochondria to maintain cellular homeostasis. Aryl hydrocarbon receptor (AhR) expression in the liver plays a crucial role in supporting normal liver functions, but its impact on mitochondrial function is unclear. Here, we identified a new role of AhR in the regulation of mitophagy to control hepatic energy homeostasis.MethodsIn this study, we utilized primary hepatocytes from AhR knockout (KO) mice and AhR knockdown AML12 hepatocytes. An endogenous AhR ligand, kynurenine (Kyn), was used to activate AhR in AML12 hepatocytes. Mitochondrial function and mitophagy process were comprehensively assessed by MitoSOX and mt-Keima fluorescence imaging, Seahorse XF-based oxygen consumption rate measurement, and Mitoplate S-1 mitochondrial substrate utilization analysis.ResultsTranscriptomic analysis indicated that mitochondria-related gene sets were dysregulated in AhR KO liver. In both primary mouse hepatocytes and AML12 hepatocyte cell lines, AhR inhibition strongly suppressed mitochondrial respiration rate and substrate utilization. AhR inhibition also blunted the fasting response of several essential autophagy genes and the mitophagy process. We further identified BCL2 interacting protein 3 (BNIP3), a mitophagy receptor that senses nutrient stress, as an AhR target gene. AhR is directly recruited to the Bnip3 genomic locus, and Bnip3 transcription was enhanced by AhR endogenous ligand treatment in wild-type liver and abolished entirely in AhR KO liver. Mechanistically, overexpression of Bnip3 in AhR knockdown cells mitigated the production of mitochondrial reactive oxygen species (ROS) and restored functional mitophagy.ConclusionsAhR regulation of the mitophagy receptor BNIP3 coordinates hepatic mitochondrial function. Loss of AhR induces mitochondrial ROS production and impairs mitochondrial respiration. These findings provide new insight into how endogenous AhR governs hepatic mitochondrial homeostasis.

The widespread dissemination of the COVID-19 pandemic precipitated a transition from traditional, in-person pedagogy to online methods within higher vocational education. The inherent limitations of online learning have become progressively conspicuous. Given its pivotal role amidst the pandemic, numerous institutions have endeavored to integrate technology with traditional classroom pedagogies. Consequently, blended learning has emerged as a focal point within vocational education, garnering notable attention and interest. The question arises: which learning method proves most effective for vocational skills development? This study endeavored to ascertain the comparative effectiveness of various learning methods for vocational skills training. Specifically, employing a quantitative approach, the study conducted a comprehensive questionnaire survey of graduates of higher vocational institutions in China. Participants have undergone training via exclusively physical, thoroughly online, and blended learning formats, respectively. The objective was to evaluate the efficacy of these three methods as perceived by higher vocational graduates. In addition, the study aimed to analyze the personal and pedagogical factors that influence the effectiveness of these learning methods. The collected data underwent analysis utilizing SPSS software. One-way analysis of variance (ANOVA) tests, correlation analyses, and subsequent least significant difference (LSD) post-hoc analyses were employed to investigate the correlations between demographic variables and factors related to teachers and educational resources across the three learning methods. These findings indicate that blended learning is the most efficient approach, with a notable preference among vocational graduates. Physical learning demonstrated superior effectiveness, particularly in functional skills training. In divergence, online learning ranked the lowest among graduates' preference, efficiency, and efficacy in functional skills training. Among the demographic factors examined, gender and duration of graduation exhibited notable variances across the effectiveness of different learning methods. However, there are no significant differences in the area of origin, economic region, type of higher vocational institution, and majors. These insights provide valuable guidance for higher vocational institutions in selecting the most suitable learning methods for enhancing functional skills training.

Abstract Microbubbles (MBs) combined with focused ultrasound (FUS) has emerged as a promising noninvasive technique to permeabilize the blood–brain barrier (BBB) for drug delivery into the brain. However, the safety and biological consequences of BBB opening (BBBO) remain incompletely understood. This study aims to investigate the effects of two parameters mediating BBBO: microbubble volume dose (MVD) and mechanical index (MI). High-resolution MRI-guided FUS was employed in mouse brains to assess BBBO by manipulating these two parameters. Afterward, the sterile inflammatory response (SIR) was studied 6 h post-FUS treatment. Results demonstrated that both MVD and MI significantly influenced the extent of BBBO, with higher MVD and MI leading to increased permeability. Moreover, RNA sequencing revealed upregulation of major inflammatory pathways and immune cell infiltration after BBBO, indicating the presence and extent of SIR. Gene set enrichment analysis identified 12 gene sets associated with inflammatory responses that were significantly upregulated at higher MVD or MI. A therapeutic window was established between therapeutically relevant BBBO and the onset of SIR, providing operating regimes to avoid damage from stimulation of the NFκB pathway via TNFɑ signaling to apoptosis. These results contribute to the optimization and standardization of BBB opening parameters for safe and effective drug delivery to the brain and further elucidate the underlying molecular mechanisms driving sterile inflammation.

Abstract The polymeric gel electrolytes are attractive owing to their higher ionic conductivities than those of dry polymer electrolytes and lowered water activity for enlarged potential window. However, the ionic conductivity and mechanical strength of the Na‐ion conducting polymeric gel electrolytes are limited by below 20 mS cm−1 and 2.2 MPa. Herein, we demonstrate Na‐ion conducting and flexible polymeric hydrogel electrolytes of the chemically coupled poly(diallyldimethylammonium chloride)‐dextrin‐N,N′‐methylene‐bis‐acrylamide film immersed in NaClO4 solution (ex‐DDA‐Dex + NaClO4) for flexible sodium‐ion hybrid capacitors (f‐NIHC). In particular, the anion exchange reaction and synergistic interaction of ex‐DDA‐Dex with the optimum ClO4− enable to greatly improve the ionic conductivity up to 27.63 mS cm−1 at 25°C and electrochemical stability window up to 2.6 V, whereas the double networking structure leads to achieve both the mechanical strength (7.48 MPa) and softness of hydrogel electrolytes. Therefore, the f‐NIHCs with the ex‐DDA‐Dex + NaClO4 achieved high specific and high‐rate capacities of 192.04 F g−1 at 500 mA g−1 and 116.06 F g−1 at 10 000 mA g−1, respectively, delivering a large energy density of 120.03 W h kg−1 at 906 W kg−1 and long cyclability of 70% over 500 cycles as well as demonstrating functional operation under mechanical stresses.

Research shows teacher influence in school decision-making is related to improving individual job satisfaction and professional commitment. However, few empirical studies investigate how different domains of school decision-making may have a distinct relationship with both individual teacher job satisfaction and professional commitment. Using the Schools and Staffing Survey 2011-2012 and the National Teacher and Principal Survey 2015-2016 which are national samples of U.S. primary and secondary schools, this study examines teacher influence in managerial and instruction domains of school decision-making and whether both are associated with job satisfaction and professional commitment. Results showed that teacher influence in the instruction domain has a statistically stronger relationship with teacher professional commitment than job satisfaction. In contrast, teacher influence in the managerial domain of school decision-making has a statistically stronger relationship with teacher job satisfaction than professional commitment. The results have policy implications for involving teachers in school decision-making and improving their overall job satisfaction.

BackgroundPreclinical data suggest circadian variation in ischemic stroke progression, with more active cell death and infarct growth in rodent models with inactive phase (daytime) than active phase (nighttime) stroke onset. We aimed to examine the association of stroke onset time with presenting severity, early neurological deterioration (END), and long-term functional outcome in human ischemic stroke.Methods and findingsIn a Korean nationwide multicenter observational cohort study from May 2011 to July 2020, we assessed circadian effects on initial stroke severity (National Institutes of Health Stroke Scale [NIHSS] score at admission), END, and favorable functional outcome (3-month modified Rankin Scale [mRS] score 0 to 2 versus 3 to 6). We included 17,461 consecutive patients with witnessed ischemic stroke within 6 hours of onset. Stroke onset time was divided into 2 groups (day-onset [06:00 to 18:00] versus night-onset [18:00 to 06:00]) and into 6 groups by 4-hour intervals. We used mixed-effects ordered or logistic regression models while accounting for clustering by hospitals. Mean age was 66.9 (SD 13.4) years, and 6,900 (39.5%) were women. END occurred in 2,219 (12.7%) patients. After adjusting for covariates including age, sex, previous stroke, prestroke mRS score, admission NIHSS score, hypertension, diabetes, hyperlipidemia, smoking, atrial fibrillation, prestroke antiplatelet use, prestroke statin use, revascularization, season of stroke onset, and time from onset to hospital arrival, night-onset stroke was more prone to END (adjusted incidence 14.4% versus 12.8%, p = 0.006) and had a lower likelihood of favorable outcome (adjusted odds ratio, 0.88 [95% CI, 0.79 to 0.98]; p = 0.03) compared with day-onset stroke. When stroke onset times were grouped by 4-hour intervals, a monotonic gradient in presenting NIHSS score was noted, rising from a nadir in 06:00 to 10:00 to a peak in 02:00 to 06:00. The 18:00 to 22:00 and 22:00 to 02:00 onset stroke patients were more likely to experience END than the 06:00 to 10:00 onset stroke patients. At 3 months, there was a monotonic gradient in the rate of favorable functional outcome, falling from a peak at 06:00 to 10:00 to a nadir at 22:00 to 02:00. Study limitations include the lack of information on sleep disorders and patient work/activity schedules.ConclusionsNight-onset strokes, compared with day-onset strokes, are associated with higher presenting neurologic severity, more frequent END, and worse 3-month functional outcome. These findings suggest that circadian time of onset is an important additional variable for inclusion in epidemiologic natural history studies and in treatment trials of neuroprotective and reperfusion agents for acute ischemic stroke.

The nutrient sensing nuclear receptor peroxisome proliferator-activated receptor-α (PPARα) regulates the host response to short-term fasting by inducing hepatic transcriptional programming of ketogenesis, fatty acid oxidation and transport, and autophagy. This adaptation is ineffective in chronically undernourished individuals, among whom dyslipidemia and hepatic steatosis are common. We recently reported that hepatic PPARα protein is profoundly depleted in male mice undernourished by a low-protein, low-fat diet. Here, we identify PPARα as a deacetylation target of the NAD-dependent deacetylase sirtuin-1 (SIRT1) and link this to the decrease in PPARα protein levels in undernourished liver. Livers from undernourished male mice expressed high levels of SIRT1, with decreased PPARα acetylation and strongly decreased hepatic PPARα protein. In cultured hepatocytes, PPARα protein levels were decreased by transiently transfecting constitutively active SIRT1 or by treating cells with the potent SIRT1 activator resveratrol, while silencing SIRT1 increased PPARα protein levels. SIRT1 expression is correlated with increased PPARα ubiquitination, suggesting that protein loss is due to proteasomal degradation. In accord with these findings, the dramatic loss of hepatic PPARα in undernourished male mice was completely restored by treating mice with the proteasome inhibitor bortezomib. Similarly, treating undernourished mice with the SIRT1 inhibitor selisistat/EX-527 completely restored hepatic PPARα protein. These data suggest that induction of SIRT1 in undernutrition results in hepatic PPARα deacetylation, ubiquitination, and degradation, highlighting a new mechanism that mediates the liver's failed adaptive metabolic responses in chronic undernutrition.