The association between dynamic changes in vitamin D and frailty alterations: A prospective analysis of UK Biobank participants.

BACKGROUND: Frailty is a common geriatric syndrome associated with reduced reserves and increased vulnerability to stressors among older adults. Vitamin D deficiency has been implicated in frailty, as it is essential for maintaining musculoskeletal functions. The relationship between dynamic changes in vitamin D levels and frailty over time has not been extensively studied. METHODS: This study utilized data from the UK Biobank. Baseline and longitudinal changes in vitamin D levels were measured. Frailty status was assessed using both the frailty phenotype and frailty index approaches and classified as robust, pre-frail, or frail. Changes in frailty status were assessed by frailty phenotype at baseline (2006-2010) and the follow-up (2012-2013). Mixed effect model was performed to examine the association between vitamin D levels and frailty status. Using multistate transition models, we assessed the impact of increasing vitamin D levels on the probabilities of transitioning between robust, pre-frail, and frail states. RESULTS: Based on the frailty phenotype, 287 926 individuals (64.8%) were identified as having various degrees of frailty (median age 58.00 [51.00, 64.00] years, 55.9% females). Using the frailty index approach, 250 566 individuals (56%) were found to have different levels of frailty (median age 59.00 [51.00, 64.00] years, 55.3% females). Baseline vitamin D levels were found to be significantly associated with frailty status (frailty phenotype: ORfrail 0.78, 95% CI [0.76, 0.79], P < 0.001; frailty index: ORfrail 0.80, 95% CI [0.78, 0.81], P < 0.001). Dynamic changes in vitamin D levels were also found to be associated with changes in frailty over time. Furthermore, increasing vitamin D levels were associated with a transition from frailty to a healthier status. A higher degree of vitamin D (estimated at 1 nmol/L) was associated with a lower risk of transitioning from robust to prefrail (HR 0.997, 95% CI [0.995, 0.999]) and from prefrail to frail (HR 0.992, 95% CI [0.988, 0.995]). CONCLUSIONS: This study highlights the importance of vitamin D in the context of frailty. Low vitamin D levels are associated with increased frailty risk, while increasing vitamin D levels may contribute to improving frailty status. Recognizing the relationship between vitamin D levels and frailty can inform personalized management and early interventions for frail individuals. Further research is needed to explore the potential effects of vitamin D interventions on frailty and deepen our understanding of the biological connections between vitamin D and frailty.

Ventriculoperitoneal shunting obstruction: a multicentre clinical audit for cerebrospinal fluid parameters and its prediction role.

BACKGROUND: Shunt obstruction is a type of ventriculoperitoneal shunt (VPS) failure. Whether changes in cerebrospinal fluid (CSF) parameters can influence shunt outcomes or not is debatable. METHODS: In this study, we retrospectively included adult hydrocephalus patients who received VPS from 6 general hospitals in different provinces of China from November 2013 to September 2021. The inclusion criteria: Patients with hydrocephalus of all etiologies underwent shunt surgery from 6 general hospitals in different provinces of China were included in the study. The exclusion criteria: 1.Patients under the age of 18; 2.Patients who had previous shunt surgery; 3. Shunt failure from other factors; 4.Patients died from other causes; 5. Patients with incomplete data. The CSF of shunt patients had been analyzed at the time of shunt insertion. The CSF samples were collected and analyzed when the shunt was implanted. The relationship between CSF parameters and the incidence rate of shunt obstruction in one year was analyzed. RESULTS: A total of 717 eligible patients from 6 hospitals were included, of whom 59(8.23%) experienced obstruction. Multivariate logistic regression analysis identified that protein level(odds ratio [OR] 1.161, 95% CI 1.005 ~ 1.341, p = 0.043), decreased glucose level(< 2.5 mmol/L)(odds ratio 3.784, 95% confidence interval 1.872 ~ 7.652, p = 0.001) and protein level increase(> 0.45 g/L) (odds ratio 3.653, 95% confidence interval 1.931 ~ 6.910, p = 0.001)were independent risk factors of shunt obstruction. CONCLUSION: This study suggested that increased protein level (> 0.45 g/L) and decreased glucose level (< 2.5 mmol/L) in CSF indicated an increased risk of shunt obstruction in a patient with hydrocephalus. Thus, shunt surgery should be more carefully considered when the CSF glucose and protein were abnormal.

Dietary Flavonoid Intake and Carotid Calcification in Patients with Ischemic Stroke.

INTRODUCTION: Owing to the antioxidant and anti-inflammatory effects, flavonoids can influence the initiation and development of atherosclerosis, but the underlying mechanisms remain largely undetermined. This study aimed to evaluate the associations between dietary flavonoids and carotid calcification in patients with ischemic stroke. METHODS: This study screened consecutive patients with ischemic stroke via Nanjing Stroke Registry Program from February 2016 to April 2021. A semiquantitative food frequency questionnaire was used to evaluate dietary consumption of flavonoids and other nutritional components. Presence and degree of carotid calcification were determined according to Agatston scores on computer tomography angiography. Logistic regression was performed to evaluate the association between dietary flavonoids (total flavonoids, flavonols, flavones, flavanones, flavan-3-ols, anthocyanins, and isoflavones) and carotid calcification. RESULTS: Of the 601 enrolled patients, 368 (61.2%) were detected with carotid calcification. Patients with high intake of total flavonoids (the fifth quintile) had a 52% lower carotid calcification risk than those with low intake (the first quintile; odds ratio [OR] = 0.48; 95% confidence interval [CI], 0.26-0.90; p = 0.007 for trends) after adjusting for major confounders. Patients with high intake of flavan-3-ols (the fifth quintile) had a 51% lower carotid calcification risk than those with low intake (the first quintile; OR = 0.49; 95% CI, 0.25-0.97; p = 0.016 for trends). CONCLUSION: Dietary flavonoid intake is associated with carotid calcification, and, therefore, may influence the risk of stroke occurrence and recurrence.

Heavy macrophage infiltration identified by optical coherence tomography relates to plaque rupture.

OBJECTIVE: Risk stratification plays a critical role in patients with asymptomatic carotid atherosclerotic stenosis. Heavy macrophage infiltration (HMC) is an important factor of plaque destabilization. However, in vivo imaging technologies and screening criteria for HMC remain limited. We aimed to (i) introduce algorithms for in vivo detection of macrophage infiltrations using optical coherence tomography (OCT) and (ii) to investigate the threshold of HMC and its association with plaque vulnerability. METHODS: Ex vivo OCT images were co-registered with histopathology in 282 cross-sectional pairs from 19 carotid endarterectomy specimens. Of these, 197 randomly selected pairs were employed to define the parameters, and the remaining 85 pairs were used to evaluate the accuracy of the OCT-based algorithm in detecting macrophage infiltrations. Clinical analysis included 93 patients receiving carotid OCT evaluation. The prevalence and burden of macrophage infiltration were analyzed. Multivariable and subgroup analysis were performed to investigate the association between HMC and plaque rupture. RESULTS: The sensitivity and specificity of algorithm for detecting macrophage infiltration were 88.0% and 74.9%, respectively. Of 93 clinical patients, ruptured plaques exhibited higher prevalence of macrophage infiltration than nonruptured plaques (83.7% [36/43] vs 32.0% [16/50], p < 0.001). HMC was identified when the macrophage index was greater than 60.2 (sensitivity = 74.4%, specificity = 84.0%). Multivariable analysis showed that HMC and multiple calcification were independent risk factors for non-lipid-rich plaque rupture. INTERPRETATION: This study provides a novel approach and screening criteria for HMC, which might be valuable for atherosclerotic risk stratification.

Stimulated thyroglobulin and pre-ablation antithyroglobulin antibody products can predict the response to radioiodine therapy of TgAb-positive differentiated thyroid cancer patients: a retrospective study.

Objective: We aimed to explore the predictive value of stimulated thyroglobulin (sTg) and pre-ablation antithyroglobulin (pa-TgAb) products for the effect of radioiodine therapy (RAIT) on TgAb-positive differentiated thyroid cancer (DTC) patients. Methods: In this study, we enrolled 265 patients with TgAb-positive DTC who underwent RAIT after total thyroidectomy (TT). Based on the last follow-up result, the patients were divided into two groups: the excellent response (ER) group and the non-excellent response (NER) group. We analyzed the factors related to the effect of RAIT. Results: The ER group consisted of 197 patients. The NER group consisted of 68 patients. For the univariate analysis, we found that the maximal tumor diameter, whether with extrathyroidal extension (ETE), bilateral or unilateral primary lesion, multifocality, preoperative TgAb (preop-TgAb), pa-TgAb, sTg × pa-TgAb, initial RAIT dose, N stage, and surgical extent (modified radical neck dissection or not), showed significant differences between the ER group and NER group (all p-values <0.05). The receiver operating characteristic (ROC) curves showed that the cutoff value was 724.25 IU/ml, 424.00 IU/ml, and 59.73 for preop-TgAb, pa-TgAb, and sTg × pa-TgAb, respectively. The multivariate logistic regression analysis results indicated that pa-TgAb, sTg × pa-TgAb, initial RAIT dose, and N stage were independent risk factors for NER (all p-values <0.05). For the Kaplan-Meier analysis of disease-free survival (DFS), the median DFS of the patients with sTg × pa-TgAb < 59.73 and initial RAIT dose ≤ 100 mCi was significantly longer than that of the patients with sTg × pa-TgAb ≥ 59.73 (50.27 months vs. 48.59 months, p = 0.041) and initial RAIT dose >100 mCi (50.50 months vs. 38.00 months, p = 0.030). Conclusion: We found the sTg and pa-TgAb conducts is a good predictor of the efficacy of RAIT in TgAb-positive DTC patients. It can play a very positive and important role in optimizing treatment, improving prognosis, and reducing the burden of patients.

Differentiating tumour progression from pseudoprogression in glioblastoma patients: a monoexponential, biexponential, and stretched-exponential model-based DWI study.

BACKGROUND: To investigate the diagnostic performance of parameters derived from monoexponential, biexponential, and stretched-exponential diffusion-weighted imaging models in differentiating tumour progression from pseudoprogression in glioblastoma patients. METHODS: Forty patients with pathologically confirmed glioblastoma exhibiting enhancing lesions after completion of chemoradiation therapy were enrolled in the study, which were then classified as tumour progression and pseudoprogression. All patients underwent conventional and multi-b diffusion-weighted MRI. The apparent diffusion coefficient (ADC) from a monoexponential model, the true diffusion coefficient (D), pseudodiffusion coefficient (D*) and perfusion fraction (f) from a biexponential model, and the distributed diffusion coefficient (DDC) and intravoxel heterogeneity index (α) from a stretched-exponential model were compared between tumour progression and pseudoprogression groups. Receiver operating characteristic curves (ROC) analysis was used to investigate the diagnostic performance of different DWI parameters. Interclass correlation coefficient (ICC) was used to evaluate the consistency of measurements. RESULTS: The values of ADC, D, DDC, and α values were lower in tumour progression patients than that in pseudoprogression patients (p < 0.05). The values of D* and f were higher in tumour progression patients than that in pseudoprogression patients (p < 0.05). Diagnostic accuracy for differentiating tumour progression from pseudoprogression was highest for α(AUC = 0.94) than that for ADC (AUC = 0.91), D (AUC = 0.92), D* (AUC = 0.81), f (AUC = 0.75), and DDC (AUC = 0.88). CONCLUSIONS: Multi-b DWI is a promising method for differentiating tumour progression from pseudoprogression with high diagnostic accuracy. In addition, the α derived from stretched-exponential model is the most promising DWI parameter for the prediction of tumour progression in glioblastoma patients.

Evolutionary origin of genomic structural variations in domestic yaks.

Yak has been subject to natural selection, human domestication and interspecific introgression during its evolution. However, genetic variants favored by each of these processes have not been distinguished previously. We constructed a graph-genome for 47 genomes of 7 cross-fertile bovine species. This allowed detection of 57,432 high-resolution structural variants (SVs) within and across the species, which were genotyped in 386 individuals. We distinguished the evolutionary origins of diverse SVs in domestic yaks by phylogenetic analyses. We further identified 334 genes overlapping with SVs in domestic yaks that bore potential signals of selection from wild yaks, plus an additional 686 genes introgressed from cattle. Nearly 90% of the domestic yaks were introgressed by cattle. Introgression of an SV spanning the KIT gene triggered the breeding of white domestic yaks. We validated a significant association of the selected stratified SVs with gene expression, which contributes to phenotypic variations. Our results highlight that SVs of different origins contribute to the phenotypic diversity of domestic yaks.

Long-term prognostic analysis of children and adolescents with differentiated thyroid carcinoma based on therapeutic response to initial radioiodine therapy.

Background: The clinical features and prognosis of children and adolescents with differentiated thyroid carcinoma (caDTC) are different from that of adults. Postoperative radioiodine therapy (RIT) was recommended for some intermediate and high risk caDTC patients. The objective of this study was to evaluate the long-term prognosis of pediatric caDTC patients with different responses to initial RIT and to explore the related influencing factors. Methods: All subjects were assigned to no clinical evidence of disease (NED) group, biochemical persistent disease (BPD) group, or structural/functional persistent disease (S/FPD) group based on the therapeutic response to initial RIT. Then, disease status was evaluated in all three groups at the last follow-up using ATA guidelines. Meanwhile, disease-free survival (DFS) for NED group and the progression-free survival (PFS) for the BPD and S/FPD groups were also assessed. Results: 117 subjects were divided into NED group (n=29), BPD group (n=48) and S/FPD group (n=34) after initial RIT. At the last follow-up, excellent response (ER), indeterminate response (IDR), biochemically incomplete response (BIR) and structurally incomplete response (SIR) rates were 93.10%, 6.90%, 0% and 0% in NED group; 29.17%, 25.00%, 43.75% and 2.08% in BPD group; and 11.77%, 2.94%, 0%, and 85.29% in S/FPD group. The 5-year DFS rate in NED group was 95.5%. The 5-year PFS rates in BPD and S/FPD groups were 79.2% and 48.6%, respectively. For children with structural or functional lesions, longer PFS were found in male children with 131I-avid lesions, and post-operative stimulated serum thyroglobulin (sti-Tg) < 149.80 ng/ml. Conclusion: The response to initial RIT could be helpful for defining subsequent treatment and follow-up strategies for caDTC patients. Post-operative sti-Tg and 131I-avidity of lesions are correlated with PFS.

Lipocalin-2-mediated astrocyte pyroptosis promotes neuroinflammatory injury via NLRP3 inflammasome activation in cerebral ischemia/reperfusion injury.

BACKGROUND: Neuroinflammation is a vital pathophysiological process during ischemic stroke. Activated astrocytes play a major role in inflammation. Lipocalin-2 (LCN2), secreted by activated astrocytes, promotes neuroinflammation. Pyroptosis is a pro-inflammatory form of programmed cell death that has emerged as a new area of research in stroke. Nevertheless, the potential role of LCN2 in astrocyte pyroptosis remains unclear. METHODS: An ischemic stroke model was established by middle cerebral artery occlusion (MCAO) in vivo. In this study, in vitro, oxygen-glucose deprivation and reoxygenation (O/R) were applied to cultured astrocytes. 24p3R (the LCN2 receptor) was inhibited by astrocyte-specific adeno-associated virus (AAV-GFAP-24p3Ri). MCC950 and Nigericin sodium salt (Nig) were used to inhibit or promote the activation of NLRP3 inflammasome pharmacologically, respectively. Histological and biochemical analyses were performed to assess astrocyte and neuron death. Additionally, the neurological deficits of mice were evaluated. RESULTS: LCN2 expression was significantly induced in astrocytes 24 h after stroke onset in the mouse MCAO model. Lcn2 knockout (Lcn2-/-) mice exhibited reduced infarct volume and improved neurological and cognitive functions after MCAO. LCN2 and its receptor 24p3R were colocalized in astrocytes. Mechanistically, suppression of 24p3R by AAV-GFAP-24p3Ri alleviated pyroptosis-related pore formation and the secretion of pro-inflammatory cytokines via LCN2, which was then reversed by Nig-induced NLRP3 inflammasome activation. Astrocyte pyroptosis was exacerbated in Lcn2-/- mice by intracerebroventricular administration of recombinant LCN2 (rLCN2), while this aggravation was restricted by blocking 24p3R or inhibiting NLRP3 inflammasome activation with MCC950. CONCLUSION: LCN2/24p3R mediates astrocyte pyroptosis via NLRP3 inflammasome activation following cerebral ischemia/reperfusion injury.

Association between dietary antioxidant capacity and atherosclerotic carotid stenosis in patients with ischemic stroke.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate the relationship between dietary total antioxidant capacity (DTAC) and atherosclerotic carotid stenosis in patients with ischemic stroke. METHODS: Patients with acute ischemic stroke were consecutively enrolled. Daily food consumption was estimated by a semi-quantitative food frequency questionnaire (FFQ). DTAC was calculated based on classified food intake. Antioxidant potential value was measured by ferric-reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) methods. Evaluation of carotid artery stenosis was based on computed tomography angiography (CTA). Logistic regression was used to assess the relationship between DTAC and degree of carotid stenosis. RESULTS: Of the 608 enrolled, 232 patients (38.2%) had moderate or severe carotid stenosis. After adjusting for major confounding factors, FRAP (OR =0.640; 95% CI: 0.410-0.998; P =0.049) and ORAC (OR =0.625; 95% CI: 0.400-0.976; P =0.039) were associated with lower degree of carotid artery stenosis (third vs first tertile). Spearman analysis indicated that FRAP (r =-0.121, P =0.003) and ORAC (r =-0.147, P <0.001) were correlated with degree of carotid stenosis. CONCLUSIONS: DTAC may influence the initiation and development of atherosclerosis, and, therefore, the risk of ischemic stroke.

Immediate and long-term changes in the epidemiology, infection spectrum, and clinical characteristics of viral and bacterial respiratory infections in Western China after the COVID-19 outbreak: a modeling study.

BACKGROUND: The impact of COVID-19 on the epidemiology, clinical characteristics, and infection spectrum of viral and bacterial respiratory infections in Western China is unknown. METHODS: We conducted an interrupted time series analysis based on surveillance of acute respiratory infections (ARI) in Western China to supplement the available data. RESULTS: The positive rates of influenza virus, Streptococcus pneumoniae, and viral and bacterial coinfections decreased, but parainfluenza virus, respiratory syncytial virus, human adenovirus, human rhinovirus, human bocavirus, non-typeable Haemophilus influenzae, Mycoplasma pneumoniae, and Chlamydia pneumoniae infections increased after the onset of the COVID-19 epidemic. The positive rate for viral infection in outpatients and children aged <5 years increased, but the positive rates of bacterial infection and viral and bacterial coinfections decreased, and the proportion patients with clinical symptoms of ARI decreased after the onset of the COVID-19 epidemic. Non-pharmacological interventions reduced the positive rates of viral and bacterial infections in the short term but did not have a long-term limiting effect. Moreover, the proportion of ARI patients with severe clinical symptoms (dyspnea and pleural effusion) increased in the short term after COVID-19, but in the long-term, it decreased. CONCLUSIONS: The epidemiology, clinical characteristics, and infection spectrum of viral and bacterial infections in Western China have changed, and children will be a high-risk group for ARI after the COVID-19 epidemic. In addition, the reluctance of ARI patients with mild clinical symptoms to seek medical care after COVID-19 should be considered. In the post-COVID-19 era, we need to strengthen the surveillance of respiratory pathogens.

Efficacy evaluation and influencing factor analysis of postoperative 131I for the treatment of primary hyperthyroidism combined with differentiated thyroid cancer (DTC)-a retrospective cohort study.

Background: 131I treatment is one of the important methods of comprehensive postoperative treatment for patients with hyperthyroidism complicated with differentiated thyroid cancer (DTC). Early identification of patients with poor treatment efficacy of 131I is particularly important. Current studies mainly focus on the relationship between hyperthyroidism and the occurrence and development of DTC, and there are few studies on the factors affecting the curative effect. The purpose of this study was to find the influencing factors of efficacy evaluation and provide evidence for early identification of patients with poor efficacy in DTC combined with primary hyperthyroidism patients. Methods: This was a retrospective analysis of DTC patients with primary hyperthyroidism who received 131I treatment in our department from 2012 to 2021. Follow-up intervals were 3 months within 1 year, 6 months within 1 to 2 years, and annual follow-up thereafter, the median follow-up time was 12.0 (3.0, 24.0) months. Serological examination and imaging examination were used to evaluate the efficacy. Patients were classified into an excellent response (ER) group and a non-ER group based on treatment response more than 6 months after 131I treatment. Univariate analysis and multivariate logistic regression analysis were performed on the basic clinical characteristics, pathological characteristics and curative effect of the patients, in order to find independent risk factors affecting the curative effect. Results: Eighty-nine patients were mostly female (80.9%), the average age was 43.47±11.88 years old, and tumor size was 1.2 (0.75, 1.80) cm, 56 patients (62.9%) in the ER group. psTg [odds ratio (OR): 1.325; 95% confidence interval (CI): 1.135-1.547; P<0.001], maximum tumor diameter (OR: 2.428; 95% CI: 1.392-4.235; P=0.002) and pathology-confirmed combined HT (OR: 8.669; 95% CI: 1.877-40.038; P=0.006) were independent risk factors for predicting ER. Conclusions: Our findings demonstrate that most hyperthyroidism combined with DTC patients could get favorable clinical outcomes from 131I treatment. The tumor diameter, pathology-confirmed diagnosis of combined HT, and psTg level can be used to identify patients who can get ER by the effect of 131I in hyperthyroidism combined with DTC at an early stage.

Genetically Predicted Sleep Traits and Functional Outcome After Ischemic Stroke: A Mendelian Randomization Study.

BACKGROUND AND OBJECTIVES: Sleep traits can have implications for ischemic stroke recovery in observational studies. The purpose of our present study was to explore the relationship between genetically predicted sleep traits and poststroke functional outcomes with Mendelian randomization (MR) method. METHODS: Instrumental variables for insomnia and sleep duration were adopted from genome-wide association studies data of European ancestry individuals. Summary data for functional outcome after ischemic stroke were retrieved from the Genetics of Ischemic Stroke Functional Outcome network. Inverse-variance weighted approach was adopted as the main analyses. Alternative MR approaches were used in sensitivity analyses. I2 and Q value statistics were used to appraise the heterogeneity among genetic variants. RESULTS: In univariable analysis, genetic liability to insomnia was significantly associated with worse functional outcome (modified Rankin Scale ≥3) after ischemic stroke (odds ratio [OR] = 1.30; 95% CI: 1.10-1.54, p = 0.002). Genetic liability to short sleep, long sleep, and continuous sleep duration were not associated with poststroke functional outcome (all p > 0.05). Sensitivity analyses without adjustment for stroke severity also supported that insomnia was causally associated with poor functional outcome (OR = 1.25; 95% CI: 1.08-1.44, p = 0.003). In the multivariable MR analysis adjusting for potentially confounding traits including body mass index, depression, type 2 diabetes, smoking, and alcohol consumption, the overall patterns between genetic liability to insomnia and poststroke outcome remained (all p < 0.05). DISCUSSION: This MR study supports potential adverse effects of liability to insomnia on functional outcome after ischemic stroke. Interventions that address insomnia may offer a therapeutic target to improve recovery after ischemic stroke and warrant exploration in a clinical context.

The influence of stimulated thyroglobulin and lymphocyte subsets before radioiodine therapy on the therapeutic response in patients with intermediate- and high-risk papillary thyroid carcinoma.

The aim of the present study was to investigate the factors influencing the short-term response to the initial radioiodine therapy (RT) course in patients with intermediate- and high-risk papillary thyroid carcinoma (PTC). A total of 182 patients with intermediate- and high-risk PTC who underwent RT in our hospital from March 2018 to October 2020 were retrospectively enrolled. The patients were divided into incomplete response (IR) and nonincomplete response (Non-IR) groups according to the response observed in clinical follow-up within 6-12 months after RT. Univariate and multivariate logistic regression analyses were used to investigate the effects of 15 observed factors on the response to RT. Receiver operating characteristic (ROC) curve analysis was used to determine the value of factors found to be significant in multivariate analyses for predicting an IR. A total of 182 patients with intermediate- and high-risk PTC were analyzed; the percentage of patients with a Non-IR was 61.54% (112/182), and the percentage of patients with an IR was 38.46% (70/182). The CD4+ T-cell percentage (t = 4.757, P = 0.000), CD4/CD8 (z = - 2.632, P = 0.008), stimulated thyroglobulin (sTg) level (z = - 8.273, P = 0.000) and M stage (χ2 = 17.823, P = 0.000) of the two groups were significantly different. Multivariate analysis showed that only the sTg level (OR: 1.116, 95% CI 1.068-1.165, P < 0.001) and CD4+ T-cell percentage (OR: 0.909, 95% CI 0.854-0.968, P = 0.003) were independent factors associated with the therapeutic response to RT. The cutoff sTg level and CD4+ T-cell percentage for predicting an IR were 7.62 µg/L and 40.95%, respectively. The sTg level and CD4+ T-cell percentage were verified to be independent predictive factors of RT response. Higher sTg levels and lower CD4+ T-cell percentages were related to an IR in patients with intermediate- and high-risk PTC.

The ACORNS grading scale: a novel tool for the prediction of malignant brain edema after endovascular thrombectomy.

BACKGROUND: To develop and validate a novel tool for predicting the development of malignant brain edema (MBE) in large vessel occlusion stroke patients after endovascular thrombectomy (EVT). METHODS: We used a prospectively registered population of EVT patients from three comprehensive stroke centers. The population was randomly divided into two subsets (7:3): a training cohort and an internal validation cohort. External validation was performed using the Endovascular Treatment for Acute Anterior Circulation Ischemic Stroke Registry in China (ACTUAL) database. MBE was defined as (1) hypodense parenchyma in at least 50% of the middle cerebral artery and signs of local brain swelling, and (2) a midline shift of ≥5 mm at the septum pellucidum or pineal gland with obliteration of the basal cisterns. The model was constructed using logistic regression analysis. The performance of the model was examined in terms of discrimination and calibration. RESULTS: After adjusting for other confounders, baseline National Institutes of Health Stroke Scale (NIHSS) and Alberta Stroke Program Early CT (ASPECT) scores, a clinical history of hypertension, collateral status, intravenous thrombolysis before thrombectomy, fasting blood glucose, reperfusion status, and occlusion site were found to be independent predictors of MBE. These variables were combined to create the ACORNS grading scale. The areas under the curve in receiver operating curve analysis were 0.850 (95% CI 0.816 to 0.884), 0.874 (95% CI 0.821 to 0.926), and 0.785 (95% CI 0.740 to 0.829) for the training, internal validation, and external validation cohorts, respectively, indicating good discriminative performance in the validation cohorts. CONCLUSIONS: The ACORNS grading scale is an accurate and easily applicable model for the prediction of the development of MBE after EVT.

Endothelial caveolin-1 regulates cerebral thrombo-inflammation in acute ischemia/reperfusion injury.

BACKGROUND: Thrombo-inflammation is an important checkpoint that orchestrates infarct development in ischemic stroke. However, the underlying mechanism remains largely unknown. Here, we explored the role of endothelial Caveolin-1 (Cav-1) in cerebral thrombo-inflammation. METHODS: The correlation between serum Cav-1 level and clinical outcome was analyzed in acute ischemic stroke patients with successful recanalization. Genetic manipulations by endothelial-specific adeno-associated virus (AAV) and siRNA were applied to investigate the effects of Cav-1 in thrombo-inflammation in a transient middle cerebral artery occlusion (tMCAO) model. Thrombo-inflammation was analyzed by microthrombosis formation, myeloid cell infiltration, and endothelial expression of adhesion molecules as well as inflammatory factors. FINDINGS: Reduced circulating Cav-1, with the potential to predict microembolic signals, was more frequently detected in recanalized stroke patients without early neurological improvement. At 24 h after tMCAO, serum Cav-1 was consistently reduced in mice. Endothelial Cav-1 was decreased in the peri-infarct region. Cav-1-/- endothelium, with prominent barrier disruption, displayed extensive microthrombosis, accompanied by increased myeloid cell inflammatory infiltration after tMCAO. Specific enhanced expression of endothelial Cav-1 by AAV-Tie1-Cav-1 remarkably reduced infarct volume, attenuated vascular hyper-permeability and alleviated thrombo-inflammation in both wild-type and Cav-1-/- tMCAO mice. Transcriptome analysis after tMCAO further designated Rxrg as the most significantly changed molecule resulting from the knockdown of Cav-1. Supplementation of RXR-γ siRNA reversed AAV-Tie1-Cav-1-induced amelioration of thrombo-inflammation without affecting endothelial tight junction. INTERPRETATION: Endothelial Cav-1/RXR-γ may regulate infarct volume and neurological impairment, possibly through selectively controlling thrombo-inflammation coupling, in cerebral ischemia/reperfusion. FUNDING: This work was supported by National Natural Science Foundation of China.

Genetically Predicted Smoking and Alcohol Consumption and Functional Outcome After Ischemic Stroke.

OBJECTIVE: Smoking and alcohol consumption have been adversely associated with post-stroke outcome in traditional epidemiological studies. The present study explored the association of genetically predicted smoking and alcohol consumption on post-stroke outcomes using the Mendelian randomization (MR) framework. METHODS: Instrumental variables for smoking initiation and alcohol consumption were selected from a genome-wide association study (GWAS) data of European ancestry individuals. Summary-level data for functional outcome after ischemic stroke was obtained from the Genetics of Ischemic Stroke Functional Outcome network study of European ancestry patients. The univariable and multivariable inverse-variance weighted MR methods were performed to obtain the causal estimates. The weighted median, MR-Robust Adjusted Profile Score and MR-Egger regression approaches were adopted as sensitivity analyses. Q and I 2 statistics were used to evaluate heterogeneity in MR estimates across variants. RESULTS: Genetic predisposition to smoking initiation was associated with worse functional outcome after ischemic stroke in univariable IVW MR analysis (OR = 1.48; 95% CI: 1.08-2.01, P = 0.013). This association remained significant when adjusting for genetically predicted alcohol consumption in multivariable MR analyses (OR = 1.56; 95% CI: 1.05-2.32, P = 0.027). Genetically predicted alcohol consumption was not associated with functional outcome after ischemic stroke (P > 0.05). Sensitivity analyses with other approaches and in analyses restricted to models without adjustment for baseline stroke severity produced similar results, and no evidence of heterogeneity in MR estimates between variants was detected (P > 0.05). CONCLUSION: Our results provide genetic support for a causal association of smoking with worse functional outcome after ischemic stroke, and have important implications for post stroke recovery. Smoking cessation and avoidance should be promoted in ischemic stroke patients.

miR-489 Confines Uncontrolled Estrogen Signaling through a Negative Feedback Mechanism and Regulates Tamoxifen Resistance in Breast Cancer.

Approximately 75% of diagnosed breast cancer tumors are estrogen-receptor-positive tumors and are associated with a better prognosis due to response to hormonal therapies. However, around 40% of patients relapse after hormonal therapies. Genomic analysis of gene expression profiles in primary breast cancers and tamoxifen-resistant cell lines suggested the potential role of miR-489 in the regulation of estrogen signaling and development of tamoxifen resistance. Our in vitro analysis showed that loss of miR-489 expression promoted tamoxifen resistance, while overexpression of miR-489 in tamoxifen-resistant cells restored tamoxifen sensitivity. Mechanistically, we found that miR-489 is an estrogen-regulated miRNA that negatively regulates estrogen receptor signaling by using at least the following two mechanisms: (i) modulation of the ER phosphorylation status by inhibiting MAPK and AKT kinase activities; (ii) regulation of nuclear-to-cytosol translocation of estrogen receptor α (ERα) by decreasing p38 expression and consequently ER phosphorylation. In addition, miR-489 can break the positive feed-forward loop between the estrogen-Erα axis and p38 MAPK in breast cancer cells, which is necessary for its function as a transcription factor. Overall, our study unveiled the underlying molecular mechanism by which miR-489 regulates an estrogen signaling pathway through a negative feedback loop and uncovered its role in both the development of and overcoming of tamoxifen resistance in breast cancers.

Extracellular vesicles carrying proinflammatory factors may spread atherosclerosis to remote locations.

Most cells involved in atherosclerosis release extracellular vesicles (EVs), which can carry bioactive substances to downstream tissues via circulation. We hypothesized that EVs derived from atherosclerotic plaques could promote atherogenesis in remote locations, a mechanism that mimics the blood metastasis of cancer. Ldlr gene knockout (Ldlr KO) rats were fed on a high cholesterol diet and underwent partial carotid ligation to induce local atherosclerosis. EVs were separated from carotid artery tissues and downstream blood of carotid ligation by centrifugation. MiRNA sequencing and qPCR were then performed to detect miRNA differences in EVs from rats with and without induced carotid atherosclerosis. Biochemical analyses demonstrated that EVs derived from atherosclerosis could increase the expression of ICAM-1, VCAM-1, and E-selectin in endothelial cells in vitro. EVs derived from atherosclerosis contained a higher level of miR-23a-3p than those derived from controls. MiR-23a-3p could promote endothelial inflammation by targeting Dusp5 and maintaining ERK1/2 phosphorylation in vitro. Inhibiting EV release could attenuate atherogenesis and reduce macrophage infiltration in vivo. Intravenously administrating atherosclerotic plaque-derived EVs could induce intimal inflammation, arterial wall thickening and lumen narrowing in the carotids of Ldlr KO rats, while simultaneous injection of miR-23a-3p antagomir could reverse this reaction. The results suggested that EVs may transfer atherosclerosis to remote locations by carrying proinflammatory factors, particularly miR-23a-3p.

Evaluation of Biological Effects and Transcriptome Changes Induced by LED-Based Narrow-Band UVB Phototherapy.

Ultraviolet (UV), particularly UVB, is widely used in the treatment of skin diseases including psoriasis, atopic dermatitis, vitiligo, mycosis fungoides and pruritus. Recently, there has been a trend of replacing broad-band UVB (BB-UVB) units with narrow-band UVB (NB-UVB), as studies have demonstrated that NB-UVB is more efficacious in the treatment of psoriasis. The purpose of this study is to evaluate the biological effects and transcriptome changes induced by light-emitting diode-based NB-UVB (NB-UVB LED) phototherapy. Cell viability and the cell migration ability were significantly decreased posttreatment, as well as apoptosis and ROS levels were remarkably increased. NB-UVB-induced S phase arrest was observed 12 h postirradiation. Bioinformatics analysis of transcriptome sequencing data revealed that NB-UVB LED irradiation induced dose-depended changes in multiple key signaling pathways, such as PI3K and cytoskeletal-related pathways. The depolymerization of cytoskeleton induced by NB-UVB was observed 24 h posttreatment. In addition, the expression levels of cytoskeleton-related proteins FN1, ITGB4, ITGA1, RAC2 and DOCK1 decreased significantly 12 h after irradiation. Our results indicated that NB-UVB LED may serve as a novel option for the development of NB-UVB phototherapy devices.