Radiation-induced chronic pain plagues head and neck cancer survivors: A cross-sectional analysis from the Cohort in Radiotherapy-related Nervous System Complications.

The epidemiology and prognosis of radiation-induced chronic pain, especially chronic neuropathic pain (CNP), are the understudied domain among head and neck cancer (HNC) survivors after radiotherapy (RT). This study aimed to estimate the prevalence of such chronic pain, and explore their correlations with mental health, sleep disorders, cognitive function, and quality of life (QOL) within these patients. This research encompassed HNC survivors post-RT. The determination of radiation-induced chronic pain and CNP adhered to the guidelines outlined by the International Association for the Study of Pain (IASP). Multivariable regression analyses were employed to explore the relationship between pain and anxiety, depression, sleep disturbances, cognitive function, and QOL. A total of 1071 HNC survivors post-RT were included in this study. The prevalence of radiation-induced chronic pain was 67.1%, and the prevalence of RT-associated CNP was 38.3%,. Compared with those reporting no pain, patients with radiation-induced chronic pain had a significantly increased risk of anxiety, depression and sleep disorders (all p < 0.001). And there was a significantly negative association between chronic pain and QOL across physiological (p < 0.001), psychological (p < 0.001), social relationships (p = 0.001) and environmental (p = 0.009) domains. Compared with non-CNP, patients with RT-related CNP had a higher risk of anxiety (p= 0.027) and sleep disorders (p= 0.013). The significantly negative associations were found between CNP and the physiological (p = 0.001), psychological (p = 0.012) and social score (p = 0.035) in WHOQOL-BREF. This study underscores the substantial prevalence of chronic pain, particularly CNP, and their potential impact on the mental health, sleep, and QOL among HNC survivors post-RT. PERSPECTIVE: This study highlights the high prevalence of radiation-induced chronic pain and CNP, and their potential impacts on anxiety, depression, sleep and QOL among the HNC survivors. Clinically, these findings have important implications for improving the care and outcomes of HNC survivors.

Progression rate of radiation-induced carotid stenosis in head and neck cancer survivors after statin treatment: a retrospective cohort study.

BACKGROUND AND AIMS: Whether statin treatment is effective in retarding the progression of radiation-induced carotid stenosis (RICS) in head and neck cancer (HNC) survivors has not been well studied. The purpose of this study was to assess the association of statin treatment with RICS progression rate in HNC survivors after radiotherapy. METHODS: We conducted a retrospective cohort study at Sun Yat-sen Memorial Hospital, Sun Yat-sen University in Guangzhou, China. Between January 2010 and December 2021, we screened HNC survivors whose carotid ultrasound scans had shown stenosis of the common and/or internal carotid arteries. The primary outcome was the RICS progression rate. We compared eligible patients treated with statins with those who did not in multivariable Cox regression models. RESULTS: A total of 200 patients were included in this study, of whom 108 received statin treatment and 92 did not. Over a mean follow-up time of 1.5 years, 56 (28.0%) patients showed RICS progression, 24 (42.9%) and 32 (57.1%) in the statin and control groups, respectively. The statin group showed less RICS progression than the control group (adjusted-HR 0.49, 95% CI 0.30-0.80, P = 0.005). In the subgroup analysis, there was no significant interaction in the effect of statins on lowering RICS progression rate in the subgroups stratified by baseline low-density lipoprotein cholesterol (LDL-C) levels (P for interaction = 0.53) or baseline degrees of stenosis (P for interaction = 0.50). CONCLUSIONS: Statin treatment was associated with a lower risk of RICS progression in patients with HNC after radiotherapy, regardless of baseline LDL-C level and baseline stenosis degrees.

Progression of cognitive dysfunction in NPC survivors with radiation-induced brain necrosis: A prospective cohort.

BACKGROUND AND PURPOSE: The evidence of longitudinal changes in cognition in nasopharyngeal carcinoma (NPC) survivors with radiation-induced brain necrosis (RIBN) after radiotherapy (RT) remained insufficient. We aimed to estimate the clinical progression rate of cognitive decline and identify patients with differential decline rates. MATERIALS AND METHODS: Based on an ongoing prospective cohort study, NPC patients aged ≥18 years old and diagnosed with RIBN were included in this current analysis if they finished the time frame of 3-year follow-up and had at least twice cognition assessments. The Chinese version of the Montreal Cognitive Assessment (MoCA) was used to assess the cognitive state. Linear mixed-effect models were used to analyze the annual progression rates of MoCA total and seven sub-items scores. RESULTS: Among 134 patients in this study, the transition probability from normal to mild/moderate cognitive dysfunction were 14.2 % (19/134) and 1.49 % (2/134) respectively during the median follow-up time of 2.35 years. The total MoCA score declined by -0.569 (SE 0.208) points annually (p = 0.008). Patients with ≤6 years of duration from RT to RIBN have higher annual progression rate of total scores [-0.851 (SE 0.321), p = 0.013; p for interaction = 0.041]. CONCLUSION: Our findings of the annual decline rate of cognition in NPC patients with RIBN from a 3-year longitudinal data, particularly for those who developed RIBN rapidly after RT, have important implications for the upcoming clinical trials designed to prevent or decrease cognitive decline in NPC patients with RIBN, regarding the selection of study patients and the calculation of sample size.

Efficacy of transcutaneous auricular vagus nerve stimulation on radiotherapy-related neuropathic pain in patients with head and neck cancers (RELAX): protocol for a multicentre, randomised, double-blind, sham-controlled trial.

INTRODUCTION: Radiotherapy-related neuropathic pain (RRNP) is one of the most distressing complications after radiotherapy for head and neck cancers. Drug therapy is not sufficiently effective and has limitations in terms of dose titration period and side effects. Transcutaneous auricular vagus nerve stimulation (taVNS), which stimulates the auricular branches of the vagus nerve through electrical impulses, has been proven to have analgesic effects in certain diseases. However, it is unknown whether taVNS can relieve RRNP. METHODS AND ANALYSIS: This is a multicentre, randomised, double-blind, parallel, sham-controlled trial. We will include adult patients newly diagnosed with neuropathic pain after radiotherapy for head and neck cancers. One hundred and sixteen individuals will be recruited and randomly assigned in a 1:1 ratio to receive taVNS or sham stimulation. The interventions will last for 7 days, twice daily for 30 min each. The primary efficacy outcome is pain reduction on day 7. The secondary outcomes are changes in functional interference, psychological distress, fatigue, quality of life and serum inflammatory factors. The study may provide a new early intervention strategy for RRNP among patients with head and neck cancers. ETHICS AND DISSEMINATION: This study has been approved by the Medical Research Ethics Committee of Sun Yat-sen University (SYSKY-2022-109-01) and will be conducted in strict accordance with the Declaration of Helsinki. Ethical approvals will be obtained separately for all centres involved in the study. Study results will be published in peer-reviewed academic journals. The database of the study will be available from the corresponding author on reasonable request. TRIAL REGISTRATION NUMBER: NCT05543239.

Different types of milk consumption and the risk of dementia: Analysis from a large-scale cohort study.

BACKGROUND & AIMS: Previous studies have investigated whether milk consumption has a role in preventing the development of cognitive impairment, but the results were inconsistent. Importantly, most of them have disregarded the role of different types of milk. This study aimed to examine the associations between different types of milk consumption and the risk of dementia. METHODS: In this large-scale cohort study, participants without cognitive impairment at baseline were included from the UK Biobank. The type of milk mainly used was self-reported at baseline, including full-cream milk, skimmed-milk, soy milk, other milk, and no milk. The primary outcome was all-cause dementia. Secondary outcomes included Alzheimer's disease and vascular dementia. RESULTS: Of the 307,271 participants included in the study (mean age 56.3 [SD 8.1] years), 3789 (1.2%) incident all-cause dementia cases were observed over a median follow-up of 12.3 years. After adjustment for potential confounders, only soy milk consumers had a statistically significantly lower risk of all-cause dementia compared with no milk consumers (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.54 to 0.90). When compared with soy milk non-consumers consisting of full-cream milk, skimmed-milk, and other milk consumers, soy milk consumers still showed a lower risk of all-cause dementia (HR, 0.76; 95% CI, 0.63 to 0.92), and there was no significant interaction with genetic risk for dementia (P for interaction = 0.15). Soy milk consumers showed a lower risk of Alzheimer's disease (HR, 0.70; 95% CI, 0.51 to 0.94; P = 0.02), while the association was not significant for vascular dementia (HR, 0.72; 95% CI, 0.47 to 1.12; P = 0.14). CONCLUSIONS: The main consumption of soy milk was associated with a lower risk of dementia, particularly non-vascular dementia. Additional studies are needed to investigate how this association varies with the dose or frequency of the consumption of soy milk and to examine the generalizability of these findings in different populations.

Platelet-activating factor antagonist-based intensive antiplatelet strategy in acute ischemic stroke: A propensity score matched with network pharmacology analysis.

BACKGROUND: Diterpene ginkgolides meglumine injection (DGMI) is a platelet-activating factor receptor (PAFR) antagonist that can be used to treat acute ischemic stroke (AIS). This study evaluated the efficacy and safety of an intensive antiplatelet strategy based on PAFR antagonists and explored the underlying mechanisms of PAFR antagonists in AIS treatment. METHODS: This is a retrospective study applying propensity score methods to match AIS patients treated with DGMI to nontreated patients. The primary outcome was functional independence (modified Rankin Scale [mRS] 0-2) at 90 days. The safety outcome was bleeding risk. We used McNemar test to compare the efficacy outcome. Subsequently, the network pharmacology analysis was performed. RESULTS: 161 AIS patients treated with DGMI in the study were matched with 161 untreated patients. Compared with untreated patients, DGMI-treated patients had a significantly higher rate of mRS ranking 0-2 at 90 days (82.0% vs. 75.8%, p < 0.001), without increased risk of bleeding. The gene enrichment analysis showed that the overlap genes of DGMI targeted and AIS-related enriched in thrombosis and inflammatory-related signaling pathways. CONCLUSIONS: An intensive antiplatelet strategy of DGMI plus traditional antiplatelet agents is effective in treating AIS and may work by mediating post-stroke inflammation and thrombosis.

Prognostic Value of Nutritional Assessments on Overall Survival in Head and Neck Cancer Survivors with Radiation-Induced Brain Necrosis.

Malnutrition is related to worsened prognosis, but the association between nutritional risk status and overall survival in radiation-induced brain necrosis (RN) has never been studied. We included consecutive patients who had received radiotherapy for head and neck cancer (HNC) and subsequently developed RN from 8 January 2005 through to 19 January 2020. The primary outcome was overall survival. We utilized three commonly-used nutritional assessments: the Geriatric Nutritional Risk Index (GNRI), Prognostic Nutritional Index (PNI), and the COntrolling NUTritional Status (CONUT) measure, to quantify the baseline nutritional risk. A total of 398 eligible patients were included. During a median follow-up of 2.3 years, 42 (10.6%) patients died of any cause. Malnutrition at admission was associated with an increased risk of future death, as assessed by the GNRI (per 1-point decreased, HR 1.05, 95%CI 1.02-1.09, p = 0.001), the PNI (per 1-point decreased, HR 1.07, 95%CI 1.03-1.12, p = 0.002), and the CONUT (per 1-point increased, HR 1.22, 95%CI 1.08-1.37, p = 0.001). There were no nonlinear correlations between all three indices and post-RN survival. Among HNC survivors with RN, the assessment of nutritional risk by composite indices upon admission could help identify patients who might be at high risk of future death and deliver better nutritional management.

CB2R activation ameliorates late adolescent chronic alcohol exposure-induced anxiety-like behaviors during withdrawal by preventing morphological changes and suppressing NLRP3 inflammasome activation in prefrontal cortex microglia in mice.

BACKGROUND: Chronic alcohol exposure (CAE) during late adolescence increases the risk of anxiety development. Alcohol-induced prefrontal cortex (PFC) microglial activation, characterized by morphological changes and increased associations with neurons, plays a critical role in the pathogenesis of anxiety. Alcohol exposure increases NLRP3 inflammasome expression, increasing cytokine secretion by activated microglia. Cannabinoid type 2 receptor (CB2R), an essential receptor of the endocannabinoid system, regulates microglial activation and neuroinflammatory reactions. We aimed to investigate the role of CB2R activation in ameliorating late adolescent CAE-induced anxiety-like behaviors and microglial activation in C57BL/6J mice. METHODS: Six-week-old C57BL/6J mice were acclimated for 7 days and then were administered alcohol by gavage (4 g/kg, 25 % w/v) for 28 days. The mice were intraperitoneally injected with the specific CB2R agonist AM1241 1 h before alcohol treatment. Anxiety-like behaviors during withdrawal were assessed by open field test and elevated plus maze test 24 h after the last alcohol administration. Microglial activation, microglia-neuron interactions, and CB2R and NLRP3 inflammasome-related molecule expression in the PFC were measured using immunofluorescence, immunohistochemical, qPCR, and Western blotting assays. Microglial morphology was evaluated by Sholl analysis and the cell body-to-total cell size index. Additionally, N9 microglia were activated by LPS in vitro, and the effects of AM1241 on NLRP3 and N9 microglial activation were investigated. RESULTS: After CAE, mice exhibited severe anxiety-like behaviors during withdrawal. CAE induced obvious microglia-neuron associations, and increased expression of microglial activation markers, CB2R, and NLRP3 inflammasome-related molecules in the PFC. Microglia also showed marked filament retraction and reduction and cell body enlargement after CAE. AM1241 treatment ameliorated anxiety-like behaviors in CAE model mice, and it prevented microglial morphological changes, reduced microglial activation marker expression, and suppressed the microglial NLRP3 inflammasome activation and proinflammatory cytokine secretion induced by CAE. AM1241 suppressed the LPS-induced increase in NLRP3 inflammasome-related molecules, IL-1ß release, and M1 phenotype markers (iNOS and CD86) in N9 cell, which was reversed by CB2R antagonist treatment. CONCLUSIONS: CAE caused anxiety-like behaviors in late adolescent mice at least partly by inducing microglial activation and increasing microglia-neuron associations in the PFC. CB2R activation ameliorated these effects by preventing morphological changes and suppressing NLRP3 inflammasome activation in PFC microglia.

5-Aza-2'-Deoxycytidine Regulates White Adipocyte Browning by Modulating miRNA-133a/Prdm16.

The conversion of white adipocytes into brown adipocytes improves their thermogenesis and promotes energy consumption. Epigenetic modifications affect related genes and interfere with energy metabolism, and these are the basis of new ideas for obesity treatment. Neonatal mice show high levels of DNA hypermethylation in white adipose tissue early in life and low levels in brown adipose tissue. Thus, we considered that the regulation of DNA methylation may play a role in the conversion of white adipose to brown. We observed growth indicators, lipid droplets of adipocytes, brown fat specific protein, and miRNA-133a after treatment with 5-Aza-2'-deoxycytidine. The expression of Prdm16 and Ucp-1 in adipocytes was detected after inhibiting miRNA-133a. The results showed a decrease in total lipid droplet formation and an increased expression of the brown fat specific proteins Prdm16 and Ucp-1. This study indicated that 5-Aza-2'-deoxycytidine promotes white adipocyte browning following DNA demethylation, possibly via the modulation of miR-133a and Prdm16.

Notch Signaling Mediates Radiation-Induced Smooth Muscle Cell Hypermuscularization and Cerebral Vasculopathy.

BACKGROUND: Emerging evidence highlighted vascular injury in aggravating radiation-induced brain injury (RIBI), a common complication of radiotherapy. This study aimed to delineate the pathological feature of cerebral small vessel and investigate the functional roles of Notch signaling in RIBI. METHODS: Brain tissue and functional MRI from RIBI patients were collected and analyzed for radiation-induced vasculopathy. A RIBI mouse model was induced by a single dose of 30-Gy cranial irradiation. Vascular morphology, pulsatility, and reactivity to pharmacological interventions, such as nimodipine and 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid, were monitored by 2-photon imaging in mice at 6 weeks postirradiation. Western blot, real-time quantitative PCR, immunofluorescence staining, and behavioral tests were performed. The effect of N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-s-phenylglycinet-butyl ester, a Notch inhibitor, was used to investigate the vascular pathogenesis of RIBI mouse model. RESULTS: Morphologically, radiation resulted in vascular malformation featured by focal contractile rings together with general stenosis. Functionally, radiation also led to hypoperfusion, attenuated vascular pulsatility, and decreased dilation to nimodipine and 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid. Mechanically, Notch activation and increased expression of α-SMA protein were found in both surgical specimens of RIBI patients and the irradiated mice. Importantly, Notch inhibition by N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-s-phenylglycinet-butyl ester significantly alleviated cerebral hypoperfusion, vasculopathy, and cognitive deficits in the RIBI mouse model. CONCLUSIONS: Radiation-induced cerebral vasculopathy showed bead-like shape and increased contractile state. Inhibition of Notch signaling by N-[N-(3, 5-difluorophenacetyl)-l-alanyl]-s-phenylglycinet-butyl ester effectively attenuated vasculopathy and relieved cognitive impairment, suggesting Notch signaling as a therapeutic target for the treatment of RIBI.

Cdk5 Promotes Mitochondrial Fission via Drp1 Phosphorylation at S616 in Chronic Ethanol Exposure-Induced Cognitive Impairment.

Excessive alcohol consumption can lead to alterations in brain structure and function, even causing irreversible learning and memory disorders. The hippocampus is one of the most sensitive areas to alcohol neurotoxicity in the brain. Accumulating evidence indicates that mitochondrial dysfunction contributes to alcohol neurotoxicity. However, little is known about the underlying molecular mechanisms. In this study, we found that chronic exposure to ethanol caused abnormal mitochondrial fission/fusion and morphology by activating the mitochondrial fission protein dynamin-related protein 1 (Drp1) and upregulating Drp1 receptors, such as fission protein 1 (Fis1), mitochondrial dynamics protein of 49 kDa (Mid49), and mitochondrial fission factor (Mff), combined with decreasing optic atrophy 1 (Opa1) and mitochondrial fusion protein mitofusin 1 (Mfn1) levels. In addition, mitochondrial division inhibitor 1 (mdivi-1) abrogated ethanol-induced mitochondrial dysfunction and improved hippocampal synapses and cognitive function in ethanol-exposed mice. Chronic ethanol exposure also resulted in cyclin-dependent kinase 5 (Cdk5) overactivation, as shown by the increase in the levels of Cdk5 and its activator P25 in the hippocampus. Furthermore, a Cdk5/P25 inhibitor (roscovitine) or Cdk5 knockdown using small interfering RNA (LVi-Cdk5) exerted neuroprotection by inhibiting abnormal mitochondrial fission through Drp1 phosphorylation at Ser616 and mitochondrial translocation after chronic ethanol exposure. Taken together, the present study demonstrated that inhibition of aberrant Cdk5 activation attenuates hippocampal neuron injury and cognitive deficits induced by chronic exposure to ethanol through Drp1-mediated mitochondrial fission and mitochondrial dysfunction. Interfering with this pathway might serve as a potential therapeutic approach to prevent ethanol-induced neurotoxicity in the brain.

Male mice exposed to chronic intermittent ethanol exposure exhibit significant upregulation or downregulation of circular RNAs.

B a ckground: Circular RNAs (circRNAs) have been crucially implicated in various diseases, however, their involvement in chronic intermittent ethanol (CIE) exposure remains unclear.O bjective: The present study was conducted to evaluate the circular RNA expression alteration in brain samples and to identify the molecular mechanisms underlying chronic intermittent ethanol exposure.M ethods: Male C57BL/6J mice (10 for each group) were given 4 weeks of chronic intermittent ethanol exposure. Whole brain samples were collected for high-throughput sequencing and circRNA bioinformatic analysis. Real-time quantitative PCR (RI-qPCR) and agarose electrophoresis were used to validate the differentially expressed circRNAs. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) analysis were performed. A p level < 0.05 was considered statistically significant.R esults: Compared with the control group and baseline values, the CIE group showed a significant increase in ethanol intake. High-throughput sequencing revealed 399 significantly different circRNAs in CIE mice, including 150 up-regulated circRNAs and 249 down-regulated circRNAs. GO analysis showed that the most significantly enriched term for biological process, cellular component, and molecular function were GO:0050885, GO:0016020 and GO:0005515, respectively. The most enriched pathways in KEGG analysis were GABAergic synapse (mmu04727), followed by retrograde endocannabinoid (eCB) signaling (mmu04723) and morphine addiction (mmu05032). Among the circRNAs, RT-qPCR confirmed 14 upregulated and 13 downregulated circRNAs in the brain tissues with 9 upregulated and 10 downregulated circRNAs being observed in blood samples.C onclusions: Our study suggests that chronic ethanol exposure upregulates or downregulates circRNAs in the brain, which, in turn, could alter neurotransmitter release and signal transduction.

Proteome-wide analysis of the hippocampus in adolescent male mice with learning and memory impairment caused by chronic ethanol exposure.

Alcohol consumption may cause various impairments in the brain. The hippocampus is particularly vulnerable to alcohol exposure, which may cause learning and memory deficits. Recently, proteomics analysis has become a popular approach to explore the pathogenesis of various diseases. The present study was conducted to investigate protein expression alteration in the hippocampus and to identify the molecular mechanisms underlying ethanol-induced learning and memory impairments. Mouse models of chronic ethanol intoxication were established by intragastrical administration for 28 consecutive days, and hippocampal neuronal damage was assessed by Nissl staining. Recognition memory was evaluated by Novel object recognition and Morris water maze tests, and hippocampus tissues were collected for label-free quantitative proteomics and analyzed using bioinformatics methods. Our study showed that chronic ethanol exposure prompted marked changes in protein expression in the hippocampus. We identified 32 differentially expressed proteins, of which 21 were upregulated and 11 downregulated. Gene Ontology analysis suggested that the identified differentially proteins were mainly involved in cytoskeleton and signal transduction mechanisms. Further verification using Western blotting and real-time quantitative PCR revealed that the hippocampal CTSL (cathepsin L), and PVALB (Parvalbumin) showed strongest expression changes, the latter being specifically expressed in GABAergic interneurons. These two proteins might serve as candidate protein biomarkers, providing new prospects for the diagnosis and treatment of ethanol-induced learning and memory disorders.

Chronic exposure of alcohol triggers microglia-mediated synaptic elimination inducing cognitive impairment.

BACKGROUND AND AIMS: Long-term alcohol intake leads to cognitive impairment and dementia. The impairment of the cerebral cortex and limbic structures in alcoholics is associated with the loss of synapses instead of neurons. Synapse loss is considered to be an early and key feature of many neurodegenerative diseases, in which microglia-mediated synapse elimination is vital. However, the underlying mechanisms of synapse loss and cognitive impairment caused by long-term alcohol intake are still largely unknown. METHODS: We investigated the relationship of synapse impairment, the microglial innate immune receptor-TREM2, and microglia-mediated synaptic elimination in long-term alcohol exposure. RESULTS: We found that long-term alcohol exposure increased expression of TREM2, decreased expression of synaptic proteins and glutamate receptor subunits, reduced dendrite spine density, and impaired long-term potentiation (LTP) in the hippocampus. Minocycline reduced the amount of the postsynaptic marker PSD95 in microglia, attenuated dendrite spine density loss, and slow down the forgetting process of already-formed memory. Furthermore, we found that TREM2 participated in microglia-mediated synapse elimination in chronic alcohol exposure in vivo. Significantly fewer PSD95 were detectable in microglial phagolysosomes in TREM2 knockdown mice. Besides, TREM2 gene silencing ameliorated synapse loss, LTP impairment, and forgetting of remote memories. CONCLUSIONS: Our data suggests that TREM2 is associated with synaptic plasticity impairment and memory deficits, indicating microglia-mediated synaptic pruning might be the underlying mechanism involved in synapse loss and memory impairment induced by long-term alcohol intake. These findings provide new evidence for the receptor's participation in neurodegeneration diseases.

Baseline Objective Malnutritional Indices as Immune-Nutritional Predictors of Long-Term Recurrence in Patients with Acute Ischemic Stroke.

Background: The controlling nutritional status (CONUT) score and the prognostic nutritional index (PNI) score were designed as indicators of patients' immune-nutritional status. This study aimed to investigate the prognostic impact of the CONUT and PNI scores on long-term recurrent ischemic stroke (RIS) and adverse outcomes for adults with acute ischemic stroke (AIS). Methods: This retrospective study enrolled 991 AIS patients. Multivariable Cox regression models were used to assess the relationships of the malnutritional indices and RIS and major cardiovascular events (MACEs). Results: During a median follow-up at 44 months (IQR 39−49 months), 203 (19.2%) patients had RIS and 261 (26.3%) had MACEs. Compared with normal nutritional status, moderate to severe malnutrition was significantly related to an increased risk of RIS in the CONUT score (adjusted hazard ratio (HR) 3.472, 95% confidence interval (CI) 2.223−5.432, p < 0.001). A higher PNI value tertile (tertile two, adjusted HR 0.295, 95% CI 0.202−0.430; tertile three, adjusted HR 0.445, 95% CI 0.308−0.632, all p < 0.001) was related to a lower risk of RIS. Similar results were found for MACEs. The PNI exhibited nonlinear association with the RIS and both two malnutritional indices improved the model's discrimination when added to the model with other clinical risk factors. Conclusions: This study demonstrated that the CONUT and PNI are promising, straightforward screening indicators to identify AIS patients with impaired immune-nutritional status at higher risk of long-term RIS and MACEs.

Genetic liability for prescription opioid use and risk of cardiovascular diseases: a multivariable Mendelian randomization study.

BACKGROUND AND AIMS: Observational studies have yielded conflicting results on the association of prescription opioid use (POU) with the risk of cardiovascular diseases (CVD). Residual confounding and potential reverse causality are inevitable in such conventional observational studies. This study used Mendelian randomization (MR) design to estimate the causal effect of POU on the risk of CVD, including coronary heart disease (CHD), myocardial infarction (MI) and ischemic stroke (IS), as well as their common risk factors. DESIGN: We estimated the causal effect of genetic liability for POU on CVD in a two-sample MR framework. Complementary sensitivity analyses were conducted to test the robustness of our results. SETTING: Genome-wide association studies (GWAS) that were based on predominantly European ancestry. PARTICIPANTS: The sample sizes of the GWAS used in this study ranged from 69 033 to 757 601 participants. MEASUREMENTS: Genetic variants predictive of the POU and their corresponding summary-level information in the outcomes were retrieved and extracted from the respective GWAS. FINDINGS: Using univariable MR, we found evidence for a causal effect of genetic liability for POU on an increased risk of CHD [odds ratio (OR) = 1.09; 95% confidence interval (CI) = 1.02-1.16; P = 0.008] and MI (OR = 1.13; 95% CI = 1.04-1.22; P = 0.002). In multivariable MR, the association remained after accounting for comorbid pain conditions, but was attenuated with adjustment for potential mediators, including body mass index (BMI), waist circumference (WC) and type 2 diabetes (T2D). CONCLUSION: Mendelian randomization estimates provide robust evidence for the causal effects of genetic liability for prescription opioid use on an increased risk of coronary heart disease and myocardial infarction, which might be mediated by obesity-related traits.

Widely Targeted Metabolomics Analysis Reveals Great Changes in Nonvolatile Metabolites of Oolong Teas during Long-Term Storage.

As a semifermented tea, oolong is exceedingly popular worldwide for its elegant, flowery aroma and mellow, rich taste. However, recent marketing trends for old oolong teas and their chemical quality largely remain unexplored. In this study, we applied widely targeted metabolomics using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) combined with multivariate analysis to investigate the chemical change of oolong teas in the aging process. With the increasing of store time, most nongalloylated catechins; tannins, including TFs and proanthocyanidins; flavonols and glycosylated flavonols; amino acids and their derivatives; nucleotides and their derivatives; and lots of alkaloids and phospholipids declined, while most fatty acids and organic acids increased, and galloylated catechins, GA, and caffeine were almost stable. The result also suggested that approximately seven years (but not an infinite extension) was a special period for oolong tea storage, which brings about excellent taste.

Prdm16-Mediated Browning is Involved in Resistance to Diet-Induced and Monosodium Glutamate-Induced Obesity.

PURPOSE: To investigate resistance to diet-induced obesity (DIO) and monosodium glutamate (MSG)-induced obesity as well as the underlying mechanisms. METHODS: Newborn mice were used to construct DIO and MSG-induced obesity models. Obesity indices, such as body weight, body length, Lee index, body temperature, food intake, fat weight, and leptin level, were examined. Mice that did not exhibit obesity were defined as the obesity-resistant group. The morphological changes of white adipose tissue were observed by hematoxylin and eosin staining, and expression levels of PR domain containing 16 (Prdm16) and uncoupling protein-1 (Ucp-1) in white adipose tissue were measured by Western blot. RESULTS: Obesity-resistant mice fed a high-fat diet showed resistance beginning at week 5 along with lower weights and lengths than those in the obesity group from weeks 5 to 12. MSG-induced obesity-resistant mice showed features consistent with resistance to obesity from week 1 along with higher body lengths relative to the obesity group; however, the weight difference was not significant until week 10, when body weights decreased significantly in obesity-resistant mice. The Lee index was lower in obesity-resistant mice than in the obesity group and the normal group, further suggesting obesity resistance. Additionally, obesity-resistant mice showed higher levels of leptin, whereas obese mice induced by a high-fat diet showed leptin resistance. Furthermore, Prdm16 and Ucp-1 levels were both downregulated in the obesity group and upregulated in obesity-resistant mice, showing that white fat browning was highest in obesity-resistant mice. CONCLUSION: The phenotypes of mice with DIO and MSG-induced obesity differed. Obesity resistance might be related to Prdm16 and Ucp-1-mediated white adipocyte browning.

Plasma Retinol Binding Protein 4 as a Biomarker for Detecting Progressive Stroke and Prediction of Early Prognosis in Patients with Acute Ischemic Stroke.

Aim and Purpose: Progressive Stroke (PS) lacks effective treatment measures and leads to serious disability or death. Retinol binding protein 4 (RBP4) could be closely associated with acute ischemic stroke (AIS). We aimed to explore plasma RBP4 as a biomarker for detecting the progression in patients with AIS. METHODS: Participants of this retrospective study were 234 patients with AIS within the 48 h onset of disease. The primary endpoint was to ascertain if there was PS through the National Institute of Health stroke scale (NIHSS); the early prognosis was confirmed through the modified Rankin scale score (mRS) at discharge or 14 days after the onset of stroke, and the significance of demographic characteristics and clinical data was determined. RESULTS: In this study, 43 of 234 patients demonstrated PS. The level of plasma RBP4 in patients with progressive stroke was significantly lower (29 mg/L, 22.60-40.38 mg/L) than that without progression (38.70 mg/L, 27.28-46.40 mg/L, P = 0.003). In patients with lower plasma RBP4, the proportion of patients with progression (χ2 = 9.63, P = 0.008) and with mRS scores ≥2 (χ2 = 6.73, P = 0.035) was significantly higher. Multivariate logistic regression analysis showed that a lower RBP4 level on admission was an independent risk factor for progressive stroke during hospitalization with an OR value of 2.70 (P = 0.03, 95% CI: 1.12-6.52). CONCLUSION: A low plasma RBP4 level on admission could be an independent risk factor of PS during hospitalization.

Blood-Brain Barrier Repair of Bevacizumab and Corticosteroid as Prediction of Clinical Improvement and Relapse Risk in Radiation-Induced Brain Necrosis: A Retrospective Observational Study.

BACKGROUND: Blood-brain barrier (BBB) disruption after endothelial damage is a crucial part of radiation-induced brain necrosis (RN), but little is known of BBB disruption quantification and its role in the evaluation of therapeutic effect and prognosis for drug treatment. In this retrospective study, BBB repair by bevacizumab and corticosteroid and the correlation between BBB permeability and treatment response and relapse were evaluated by dynamic contrast-enhanced MRI (DCE-MRI). METHODS: Forty-one patients with RN after radiotherapy for nasopharyngeal carcinoma (NPC) (28 treated with bevacizumab and 13 with corticosteroid), 12 patients with no RN after NPC radiotherapy, and 12 patients with no radiotherapy history were included as RN, non-RN, and normal groups, respectively. DCE-MRI assessed BBB permeability in white matter of bilateral temporal lobe. DCE parameters were compared at baseline among the three groups. DCE parameters after treatment were compared and correlated with RN volume decrease, neurological improvement, and relapse. RESULTS: The extent of BBB leakage at baseline increased from the normal group and non-RN group and to RN necrosis lesions, especially K trans (Kruskal-Wallis test, P < 0.001). In the RN group, bevacizumab-induced K trans and v e decrease in radiation necrosis lesions (both P < 0.001), while corticosteroid showed no obvious effect on BBB. The treatment response rate of bevacizumab was significantly higher than that of corticosteroid [30/34 (88.2%) vs. 10/22 (45.4%), P < 0.001]. Spearman analysis showed baseline K trans, K ep, and v p positively correlated with RN volume decrease and improvement of cognition and quality of life in bevacizumab treatment. After a 6-month follow-up for treatment response cases, the relapse rate of bevacizumab and corticosteroid was 10/30 (33.3%) and 2/9 (22.2%), respectively, with no statistical difference. Post-bevacizumab K trans level predicted relapse in 6 months with AUC 0.745 (P < 0.05, 95% CI 0.546-0.943, sensitivity = 0.800, specificity = 0.631). CONCLUSIONS: Bevacizumab improved BBB leakage in RN necrosis. DCE parameters may be useful to predict therapeutic effect and relapse after bevacizumab.