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• GO nanosheets can function as an "ion transport highway" to improve the ion conductivity of PGA hydrogel electrolytes. • The PGA hydrogel electrolyte with 3D cross-linking network structure exhibited much enhanced mechanical strength. • The PGA hydrogel electrolyte can induce the preferential orientation on the (002) crystal plane of Zn surface, effectively suppressing the Zn dendrite growth. • The Zn//PGA//Zn cell achieved superior long-term cyclability for Zn anode at a high Zn utilization rate. • The PGA hydrogel with a favorable mechanical property ensured the safe use of flexible cells under harsh conditions. The progress of zinc (Zn) metal batteries (ZMBs) is greatly limited by poor cycling stability because of the mutual restrictions of dendrite growth, corrosion reactions, and passivation. In this work, an ultra-long lifespan (∼7800 h), dendrite-free Zn metal anode is enabled via fabricating a functional hydrogel electrolyte out of polyacrylamide/graphene oxide (GO)/agarose (PGA) with a multifully cross-linked network. The synergetic integration of GO nanosheets and double-network structure endows the PGA hydrogel electrolyte with high ionic conductivity and excellent mechanical performance. More importantly, the abundant hydrophilic groups and stable three-dimensional cross-linked network of PGA electrolyte effectively constrain Zn2+ diffusion laterally along the Zn surface, which simultaneously prohibits water-induced corrosion and thus significantly enhances Zn anode reversibility. Both theoretical simulations and experiments reveal that the PGA electrolyte is capable of optimizing de-solvation kinetics and harmonizing Zn2+ flux at the electrolyte–electrode interface, ensuring uniform Zn2+ deposition. Consequently, an ultra-long lifespan of 7800 h is achieved in the symmetric cell with the PGA electrolyte. Even at a high Zn utilization of 42.7 %, it still delivers stable cycling over 1100 h. This work provides a practical and beneficial approach to dramatically extending the lifespan of the Zn anode and thus achieving high-performance ZMBs. [Display omitted] [ABSTRACT FROM AUTHOR]

IMPORTANCE: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant tumor, and durable disease control is rare with the current standard of care, even for patients who undergo surgical resection. OBJECTIVE: To assess whether neoadjuvant modified 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFIRINOX) leads to early control of micrometastasis and improves survival. DESIGN, SETTING, AND PARTICIPANTS: This open-label, single-arm, phase 2 nonrandomized clinical trial for resectable PDAC was conducted at the Yale Smilow Cancer Hospital from April 3, 2014, to August 16, 2021. Pancreatic protocol computed tomography was performed at diagnosis to assess surgical candidacy. Data were analyzed from January to July 2023. INTERVENTIONS: Patients received 6 cycles of neoadjuvant mFOLFIRINOX before surgery and 6 cycles of adjuvant mFOLFIRINOX. Whole blood was collected and processed to stored plasma for analysis of circulating tumor DNA (ctDNA) levels. Tumors were evaluated for treatment response and keratin 17 (K17) expression. MAIN OUTCOMES AND MEASURES: The primary end point was 12-month progression-free survival (PFS) rate. Additional end points included overall survival (OS), ctDNA level, tumor molecular features, and K17 tumor levels. Survival curves were summarized using Kaplan-Meier estimator. RESULTS: Of 46 patients who received mFOLFIRINOX, 31 (67%) were male, and the median (range) age was 65 (46-80) years. A total of 37 (80%) completed 6 preoperative cycles and 33 (72%) underwent surgery. A total of 27 patients (59%) underwent resection per protocol (25 with R0 disease and 2 with R1 disease); metastatic or unresectable disease was identified in 6 patients during exploration. Ten patients underwent surgery off protocol. The 12-month PFS was 67% (90% CI, 56.9-100); the median PFS and OS were 16.6 months (95% CI, 13.3-40.6) and 37.2 months (95% CI, 17.5-not reached), respectively. Baseline ctDNA levels were detected in 16 of 22 patients (73%) and in 3 of 17 (18%) after 6 cycles of mFOLFIRINOX. Those with detectable ctDNA levels 4 weeks postresection had worse PFS (hazard ratio [HR], 34.0; 95% CI, 2.6-4758.6; P = .006) and OS (HR, 11.7; 95% CI, 1.5-129.9; P = .02) compared with those with undetectable levels. Patients with high K17 expression had nonsignificantly worse PFS (HR, 2.7; 95% CI, 0.7-10.9; P = .09) and OS (HR, 3.2; 95% CI, 0.8-13.6; P = .07). CONCLUSIONS AND RELEVANCE: This nonrandomized clinical trial met its primary end point, and perioperative mFOLFIRINOX warrants further evaluation in randomized clinical trials. Postoperative ctDNA positivity was strongly associated with recurrence. K17 and ctDNA are promising biomarkers that require additional validation in future prospective studies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02047474

BackgroundThe early detection of individuals who require palliative care is essential for the timely initiation of palliative care services. This systematic review and meta-analysis aimed to (1) Identify the screening instruments used by health professionals to promote early identification of patients who may benefit from palliative care; and (2) Assess the psychometric properties and clinical performance of the instruments.MethodsA comprehensive literature search was conducted in PubMed, Embase, CINAHL, Scopus, CNKI and Wanfang from inception to May 2023. We used the COnsensus-based Standards for the Selection of Health Measurement INstruments to assess the methodological quality of the development process for the instruments. The clinical performance of the instruments was assessed by narrative summary or meta-analysis. Subgroup analyses were conducted where necessary. The quality of included studies was assessed using the Newcastle-Ottawa Scale and the Cochrane Collaboration’s risk of bias assessment tool.ResultsWe included 31 studies that involved seven instruments. Thirteen studies reported the development and validation process of these instruments and 18 studies related to assessment of clinical performance of these instruments. The content validity of the instruments was doubtful or inadequate because of very low to moderate quality evidence. The pooled sensitivity (Se) ranged from 60.0% to 73.8%, with high heterogeneity (I2 of 88.15% to 99.36%). The pooled specificity (Sp) ranges from 70.4% to 90.2%, with high heterogeneity (I2 of 96.81% to 99.94%). The Supportive and Palliative Care Indicators Tool (SPICT) had better performance in hospitals than in general practice settings (Se=79.8% vs 45.3%, p=0.004; Sp=59.1% vs 97.0%, p=0.000).ConclusionThe clinical performance of existing instruments in identifying patients with palliative care needs early ranged from poor to reasonable. The SPICT is used most commonly, has better clinical performance than other instruments but performs better in hospital settings than in general practice settings.

Objectives(1) To compare palliative care needs of patients admitted primarily with stroke and (2) to determine how the care needs of these patients affect their use of different types of specialist palliative care services.MethodsObservational study based on point-of-care data from the Australian Palliative Care Outcomes Collaboration. Multivariate logistic regression models were used to explore the association between patients’ palliative care needs and use of community versus inpatient specialist palliative care services.ResultsThe majority of patients who had a stroke in this study population had mild or no symptom distress, but experienced a high degree of functional impairment and needed substantial help with basic tasks of daily living. A lower Australia-modified Karnofsky Performance Status score (OR=1.82, 95% CI 1.06 to 3.13) and occurrence of an ‘unstable’ palliative care phase (OR=28.34, 95% CI 9.03 to 88.94) were associated with use of inpatient versus community palliative care, but otherwise, no clear association was observed between the majority of symptoms and use of different care services.ConclusionsMany people with stroke could potentially have been cared for and could have experienced the terminal phases of their condition in a community setting if more community support services were available for their families.

Background: Hepatocellular adenoma (HCA) in the pediatric population is very rare and there are only limited studies, especially with molecular characterization of the tumors. Main HCA subtypes recognized in the current WHO classification include HNF1A-inactivated HCA (H-HCA), inflammatory HCA (IHCA), β-catenin-activated HCA (b-HCA), and β-catenin-activated IHCA (b-IHCA) and sonic hedgehog HCA (shHCA) is reported as an emerging subtype.Methods: Clinical history, pathological information, and molecular studies for a series of 2 cases of pediatric HCA were reviewed.Results: Case 1 was a b-HCA characterized by somatic CTNNB1S45 mutation in a 11-year-old male with Abernethy malformation. Case 2 was a H-HCA characterized by germline HNF1Avariant (c.526+1G>A) in a 15-year-old male associated with maturity-onset diabetes of the young type 3 (MODY3).Conclusion: Our findings highlight the rarity of these 2 cases associated with adenomatosis, and the contribution of molecular/genetic analysis for proper sub-typing, prognosis and family surveillance.

The pathologic characteristics of squamous cell/adenosquamous carcinomas (SC/ASC) have not been well clarified. As a rare subtype of gallbladder cancer (GBC), no biological markers for diagnosis and prognosis are available. This research evaluated the expression of FOXP1 and FOXO3a in 69 SC/ASC, and 146 adenocarcinoma (AC) samples were analyzed via immunohistochemistry. SC/ASCs were associated with higher rates of lymph node metastasis, invasion, and patients older than 45 years comparing to ACs. FOXP1 and FOXO3a positivity rates were significantly lower in SC/ASC and AC samples from patients with large tumor size, a high TNM stage, lymph node metastasis, invasion, and no history of tumor resection (biopsy only). Positive FOXP1 expression levels were significantly decreased in cases of poorly differentiated AC. The univariate Kaplan-Meier analysis revealed that negative FOXP1 and FOXO3a expression, poor differentiation, large tumor size, high TNM stage, lymph node metastasis, invasion, and an inability to undergo curative resection were all closely associated with decreased overall survival in SC/ASC and AC patients. The multivariate cox regression analysis showed that negative FOXP1 and FOXO3a expression levels were independent predictors of poor prognosis in SC/ASC and AC patients. Our results indicate that negative FOXP1 and FOXO3a expression are closely associated with the pathogenesis, clinicopathologic properties, and prognosis of GBC patients. FOXP1 and FOXO3a may thus be biomarkers of GBC carcinogenesis, progression, and prognosis.

Using data from the 2014 China Family Panel Studies, this study investigates whether diversifying agricultural production can enhance dietary diversity, particularly by increasing the consumption of animal-based foods. We introduced refined measures of dietary diversity and categorized them into animal-based household dietary diversity scores (A-HDDS) and plant-based household dietary diversity scores (P-HDDS). Additionally, we categorize production diversity into crop production diversity (CPD), livestock and aquaculture production diversity (LAPD), and mixed production diversity (MPD). Our results show that most households exhibited high dietary diversity, except for low-income and hilly households. Specifically, CPD positively influenced dietary diversity, and all three types of production diversity promoted A-HDDS. Moreover, CPD primarily serves as a substitute for enhancing household self-sufficiency, affecting all three dietary diversity measures, especially among hilly households. Increasing LAPD and MPD can improve A-HDDS through self-sufficiency and agricultural commercialization income pathways, benefiting farmers in hilly and mountainous regions.

Four novel lanthanide(III)-based metal–organic frameworks (MOFs), formulated as [Ln3(HDDB)(DDB)(H2O)6]·NMP·3H2O (Ln = Eu (1), Tb (2), Dy (3), Gd (4)), were successfully constructed with a rigid pentacarboxylate ligand 3,5-di(2′,4′-dicarboxylphenyl) benzoic acid (H5DDB). Complexes 1–4are isostructural and exhibit a new 3,4,4,6-connected network. 1–2exhibit excellent fluorescence properties and good water stability. The emissions of the doped bimetallic EuxTb1–x-MOFs can be adjusted by varying the Eu(III)/Tb(III) ratios used in the reaction. Furthermore, 2presents excellent sensitivity and selectivity to sense vitamin B6(VB6) and the pesticide 2,6-dichloro-4-nitroaniline (DCN) as a multiresponsive luminescent sensor. Compound 2is the first MOF-based luminescent sensor for detecting VB6with a low detection limit (LOD) of 9.5 × 10–8M (∼58.4 ppb) in phosphate buffer solution (pH = 6.86), which also displays a high-sensitivity sensing activity for VB6in human serum. Moreover, 2exhibits high-sensitivity sensing for the pesticide DCN with an LOD value of 1.4 × 10–7M (∼86.1 ppb) in aqueous solution, and it also can be successfully used for detecting DCN in the extracts of carrots, grapes, and nectarines.

Liver transplantation is an effective treatment for end-stage liver disease, acute liver failure, and primary hepatic malignancy. However, the limited availability of donor organs remains a challenge. Severe large-droplet fat (LDF) macrovesicular steatosis, characterized by cytoplasmic replacement with large fat vacuoles, can lead to liver transplant complications. Artificial intelligence models, such as segmentation and detection models, are being developed to detect LDF hepatocytes. The Segment-Anything Model, utilizing the DEtection TRansformer architecture, has the ability to segment objects without prior knowledge of size or shape. We investigated the Segment-Anything Model's potential to detect LDF hepatocytes in liver biopsies. Pathologist-annotated specimens were used to evaluate model performance. The model showed high sensitivity but compromised specificity due to similarities with other structures. Filtering algorithms were developed to improve specificity. Integration of the Segment-Anything Model with rule-based algorithms accurately detected LDF hepatocytes. Improved diagnosis and treatment of liver diseases can be achieved through advancements in artificial intelligence algorithms for liver histology analysis.

The 24-hour rhythm substantially affects the daily life activities of all living organisms on Earth. In this review, we unravel the role of marine n-3 polyunsaturated fatty acids (PUFAs) as circadian rhythm regulators in glycolipid metabolism disorders. As two major types of n-3 PUFAs, docosahexaenoic acid (DHA) improves circadian rhythms by insulin-induced gene 2–sterol-regulatory element–binding protein pathway, while eicosapentaenoic acid (EPA) targets melatonin to regulate circadian rhythms. Given GABAergic neurons in the hypothalamic suprachiasmatic nucleus clock to the hypothalamic–pituitary–adrenal axis, DHA and EPA directly target G protein–coupled receptor 120 (GPR120) on cellular membrane and then manipulate circadian rhythm genes Rev-erband RORαto improve glucose metabolism. Furthermore, n-3 PUFAs directly respond on GPR120 and PPARγ, which in turn affect circadian genes Per, Bmal1, and Rev-erbαand then ameliorate lipid metabolism disorders. The current review broadens the functionality of n-3 PUFAs in the field of circadian rhythm regulation and concludes molecular mechanisms on regulating glycolipid metabolism through adjusting circadian rhythms.

Furan and its derivatives are prevalent contaminants in thermally processed foods, known for their potential health risk. This review explores the formation mechanisms, analytical techniques, occurrence, and toxicological aspects of furan and its major derivatives in thermally processed foods. Furan, furfuryl alcohol, furfural, and 5-hydroxymethylfurfural are implicated in carcinogenicity, genotoxicity, and other adverse health effects. The development of robust chronic toxicity data along with refined dietary exposure assessments of these compounds warrants further investigation. Recent statistical methods, including weighted quantile sum, quantile g-computation, and Bayesian kernel machine regression, provide valuable tools for assessing the combined effects of these contaminants. Understanding the complex interplay of furan derivatives in thermally processed foods is essential for comprehensive risk assessment and future research directions.

Post-infantile giant cell hepatitis (PIGCH) is a rare hepatitis pattern in adults with variable etiologies and clinical outcomes. We conducted a multi-institutional retrospective study to define the clinicopathologic characteristics of patients with PIGCH. A total of 70 PIGCH cases were identified and reviewed for pathological features including fibrosis, cholestasis, inflammation, steatosis, necrosis, and apoptosis, as well as the distribution of giant cells, and the maximum number of giant cells per high power field. Demographic and clinical data including age, gender, laboratory results, etiologies and follow-up results were recorded. Among the 70 cases, 40% (28/70) were associated with autoimmune liver diseases, followed by 9 (13%) with unknown etiology, 8 (11%) with viral infection, 5 (7%) with medications, 5 with combined etiologies, and 4 (6%) with malignancies (mostly chronic lymphocytic leukemia). Notably, another 16% were de novoPIGCH in liver allografts, most of which occurred after a rejection event. During follow-up, 26 (37%) patients died of the disease and 44 (63%) were alive. Deceased patients were characterized by older age (mean age 54.9 vs 45.5 years, p=0.02), higher alkaline phosphatase (ALP) level (mean value 253.3U/L vs 166.3 U/L p=0.03), higher fibrosis stage (stage 3-4: 57.7% vs stage 0-2: 29.6%, p=0.03), more likely to have de novoPIGCH after transplantation (23.1% vs 11.4%, p=0.04), and less likely to have primary autoimmune liver disease etiology (26.9% vs 47.7%, p=0.04). These results indicate PIGCH is a rare pattern of liver injury associated with different etiologies and variable clinical outcomes. Autoimmune liver disease with PIGCH is associated with better survival, whereas de novoPIGCH in allografts is associated with poorer survival. Older age, higher ALP, and advanced fibrosis are adverse prognostic factors.

This review will summarize the most significant work that contributed to the understanding of liver fibrosis progression and resolution, which in turn has yielded new areas of therapeutic targeting.

Environmental and dietary exposures to acrylamide (AA) have been linked with various metabolic-related outcomes, but the results are mixed. However, the association between long-term exposure to AA and the prevalence of metabolic syndrome (MetS) remains unknown. In this study, we aimed to assess the relationship between hemoglobin adducts of AA, biomarkers of internal exposure to AA, and MetS prevalence among a U.S. nationwide population. MetS patients were defined by meeting three or more of the following five characteristics: elevated blood pressure, high fasting glucose, abdominal obesity, hypertriglyceridemia, and lower high-density lipoprotein cholesterol (HDL-C). Multivariate-adjusted logistic regression models and restricted cubic spline models were used to analyze the associations between AA hemoglobin biomarkers and MetS prevalence. A total of 1552 MetS cases were documented. After adjustment for the potential confounders, the odds ratios (95% confidence intervals) of MetS prevalence in the highest quartile of AA hemoglobin biomarkers were 0.60 (0.40–0.89), 1.26 (0.84–1.89), 0.93 (0.71–1.21), and 1.61 (1.18–2.20) for HbAA, HbGA, the sum of HbAA and HbGA (HbAA + HbGA), and the ratio of HbGA to HbAA (HbGA/HbAA), compared with the lowest quartile, respectively. HbAA was significantly and inversely associated with blood pressure, fasting glucose, abdominal obesity, hypertriglyceridemia, and low HDL-C, while the HbGA/HbAA ratio was also positively associated with abdominal obesity, hypertriglyceridemia, and low HDL-C. The restricted cubic spline models revealed a positive relationship between the HbGA/HbAA ratio and the prevalence of MetS, while the HbAA level was inversely associated with MetS prevalence. Our current findings provided epidemiological evidence that HbAA and the HbGA/HbAA ratio were significantly associated with MetS prevalence among general U.S. adults. Further studies should be conducted to examine the association between internal exposure to AA and MetS prevalence.

AbstractIsotope dilution liquid chromatography coupled with electrospray ionization tandem mass spectrometry (LC-MS/MS) was applied to the quantification of acrylamide in chocolate matrixes (dark chocolate, milk chocolate, chocolate with nuts, chocolate with almonds, and chocolate with wheat best element). The method included defatting with petroleum ether, extracting with aqueous solution of 2 mol l−1sodium chloride and clean-up by solid-phase (SPE) with OASIS HLB 6 cm3cartridges. Acrylamide was detected with an Atlantis dC185 µm 210 × 1.5 mm column using 10% methanol/0.1% formic acid in water as the mobile phase. The analytical method was in-house validated and good results were obtained with respect to repeatability (RSD < 3.5%) and recovery (86–93%), which fulfilled the requirements defined by European Union legislation. The acrylamide levels in chocolate were 23–537 µg kg−1. Therefore, the method was successfully used for the quantitative analysis of acrlyamide in various chocolate products.

Acrylamide has been reported as an important dietary risk factor from carbohydrate-rich processing food. However, systemic biological effects on the serum metabolomics induced by acrylamide have poorly been understood. In the present study, we evaluated the metabolic profiles in a rat serum after exposure to acrylamide using ultrahigh-performance liquid chromatography combined with quadrupole-orbitrap high-resolution mass spectrometry. The serum biochemical parameters of the treated and control groups were also determined using an automatic biochemical analyzer. Compared with the control group, 10 metabolites were significantly upregulated, including citric acid, d-(−)-fructose, gluconic acid, l-ascorbic acid 2-sulfate, 2-hydroxycinnamic acid, valine, l-phenylalanine, prolylleucine, succinic acid, and cholic acid, while 5 metabolites were significantly downregulated, including 3-hydroxybutyric acid, 4-oxoproline, 2,6-xylidine, 4-phenyl-3-buten-2-one, and N-ethyl-N-methylcathinone in the serum of 4-week-old rats exposed to acrylamide in the high-dose group (all P< 0.05). Importantly, acrylamide exposure affected metabolites mainly involved in the citrate cycle, valine, leucine, and isoleucine biosyntheses, phenylalanine, tyrosine and tryptophan biosyntheses, and pyruvate metabolism. These results suggested that exposure to acrylamide in rats exhibited marked systemic metabolic changes and affected the cardiovascular system. This study will provide a theoretical basis for exploring the toxic mechanism and will contribute to the diagnosis and prevention of acrylamide-induced cardiovascular toxicity.

ObjectiveTo assess the association of dietary fatty acids with cardiovascular disease mortality and total mortality among patients with type 2 diabetes.DesignProspective, longitudinal cohort study.SettingHealth professionals in the United States.Participants11 264 participants with type 2 diabetes in the Nurses’ Health Study (1980-2014) and Health Professionals Follow-Up Study (1986-2014).ExposuresDietary fat intake assessed using validated food frequency questionnaires and updated every two to four years.Main outcome measureTotal and cardiovascular disease mortality during follow-up.ResultsDuring follow-up, 2502 deaths including 646 deaths due to cardiovascular disease were documented. After multivariate adjustment, intake of polyunsaturated fatty acids (PUFAs) was associated with a lower cardiovascular disease mortality, compared with total carbohydrates: hazard ratios comparing the highest with the lowest quarter were 0.76 (95% confidence interval 0.58 to 0.99; P for trend=0.03) for total PUFAs, 0.69 (0.52 to 0.90; P=0.007) for marine n-3 PUFAs, 1.13 (0.85 to 1.51) for α-linolenic acid, and 0.75 (0.56 to 1.01) for linoleic acid. Inverse associations with total mortality were also observed for intakes of total PUFAs, n-3 PUFAs, and linoleic acid, whereas monounsaturated fatty acids of animal, but not plant, origin were associated with a higher total mortality. In models that examined the theoretical effects of substituting PUFAs for other fats, isocalorically replacing 2% of energy from saturated fatty acids with total PUFAs or linoleic acid was associated with 13% (hazard ratio 0.87, 0.77 to 0.99) or 15% (0.85, 0.73 to 0.99) lower cardiovascular disease mortality, respectively. A 2% replacement of energy from saturated fatty acids with total PUFAs was associated with 12% (hazard ratio 0.88, 0.83 to 0.94) lower total mortality.ConclusionsIn patients with type 2 diabetes, higher intake of PUFAs, in comparison with carbohydrates or saturated fatty acids, is associated with lower total mortality and cardiovascular disease mortality. These findings highlight the important role of quality of dietary fat in the prevention of cardiovascular disease and total mortality among adults with type 2 diabetes.

There is a pressing need for the development of novel approaches to treat and prevent hepatocellular carcinoma (HCC). The S100 calcium-binding protein S100A4 is associated with poor prognosis and metastasis in several human cancers. In addition, a role for S100A4 in modulating cancer-initiating cells stemness properties was recently proposed in head and neck and gastric cancers. Whether S100A4+stromal cells contribute to tumor onset remains, however, an unanswered question. To address that question, we generated a new mouse model allowing for the depletion of S100A4+cells in a mouse model of HCC with stemness properties, by crossing mice with hepatic deletion of phosphatase and tensin homolog (PTEN) with mice expressing viral thymidine kinase under the control of S100A4 promoter. Depletion of S100A4+cells by ganciclovir injection did not prevent the development of HCC but reduced the stemness phenotype of the tumor as measured by the expression of progenitor cell, biliary cell and hepatocyte markers. The results were further confirmed by histology analysis showing reduction of cholangiolar tumor components and degree of oval cell hyperplasia in the adjacent liver. Depletion of S100A4+cells had also some beneficial effect on the underlying liver disease with a reduction of NAS score, largely due to the reduction of inflammation. In conclusion, this study demonstrated that S100A4+cells do not contribute to HCC onset but maintain the stemness phenotype of the tumor. This study also suggests for the first time a crosstalk between inflammation and stemness.