The secreted micropeptide C4orf48 enhances renal fibrosis via an RNA-binding mechanism.

Renal interstitial fibrosis is an important mechanism in the progression of chronic kidney disease (CKD) to end-stage kidney disease. However, we lack specific treatments to slow or halt renal fibrosis. Ribosome profiling identified upregulation of a secreted micropeptide, C4orf48 (Cf48), in mouse diabetic nephropathy. Cf48 RNA and protein levels were upregulated in tubular epithelial cells in human and experimental CKD. Serum Cf48 levels were increased in human CKD and correlated with loss of kidney function, increasing CKD stage, and the degree of active interstitial fibrosis. Cf48 overexpression in mice accelerated renal fibrosis, while Cf48 gene deletion or knockdown by antisense oligonucleotides significantly reduced renal fibrosis in CKD models. In vitro, recombinant Cf48 (rCf48) enhanced TGF-ß1-induced fibrotic responses in renal fibroblasts and epithelial cells independently of Smad3 phosphorylation. Cellular uptake of Cf48 and its profibrotic response in fibroblasts operated via the transferrin receptor. RNA immunoprecipitation-sequencing identified Cf48 binding to mRNA of genes involved in the fibrotic response, including Serpine1, Acta2, Ccn2, and Col4a1. rCf48 binds to the 3'UTR of Serpine1 and increases mRNA half-life. We identify the secreted Cf48 micropeptide as a potential enhancer of renal fibrosis that operates as an RNA-binding peptide to promote the production of extracellular matrix.

Single-cell transcriptome atlas in C57BL/6 mice encodes morphological phenotypes in the aging kidneys.

C57BL/6 mice are frequently utilized as murine models with the desired genetic background for altertion in multiple research contexts. So far, there is still a lack of comprehensive kidney morphology and single-cell transcriptome atlas at all stages of growth of C57BL/6 mice. To provide an interactive set of reference standards for the scientific community, we performed the current study to investigate the kidney's development throughout the capillary-loop stage until senescence. Eight groups, with five to six mice each, represented embryonic stage (embryos 18.5 days), suckling period (1 day after birth), juvenile stage (1 month old), adulthood (containing 3 months old, 6 months old and 10 months old), reproductive senescence stage (20 months old), and post-senescence stage (30 months old), respectively. With age, the thickness of the glomerular basement membrane (GBM) was increased. Notably, GBM knobs appeared at three months and became frequent with age. Using single-cell transcriptome data, we evaluated how various biological process appear in particular cell types and investigated the potential mechanism of formation of GBM konbs. In conclusion, having access to detailed kidney morphology and single-cell transcriptome maps from C57BL/6 mice at various developmental stages of C57BL/6 mice would be a novel and major resource for biological research and testing of prospective therapeutic approaches.

Altered functional connectivity of brainstem nuclei in new daily persistent headache: Evidence from resting-state functional magnetic resonance imaging.

OBJECTIVES: The new daily persistent headache (NDPH) is a rare primary headache disorder. However, the underlying mechanisms of NDPH remain incompletely understood. This study aims to apply seed-based analysis to explore the functional connectivity (FC) of brainstem nuclei in patients with NDPH using resting-state functional magnetic resonance imaging (MRI). METHODS: The FC analysis from the region of interest (ROI) to whole brain voxels was used to investigate 29 patients with NDPH and 37 well-matched healthy controls (HCs) with 3.0 Tesla MRI. The 76 nuclei in the brainstem atlas were defined as ROIs. Furthermore, we explored the correlations between FC and patients' clinical characteristics and neuropsychological evaluations. RESULTS: Patients with NDPH exhibited reduced FC in multiple brainstem nuclei compared to HCs (including right inferior medullary reticular formation, right mesencephalic reticular formation, bilateral locus coeruleus, bilateral laterodorsal tegmental nucleus-central gray of the rhombencephalon, median raphe, left medial parabrachial nucleus, periaqueductal gray, and bilateral ventral tegmental area-parabrachial pigmented nucleus complex) and increased FC in periaqueductal gray. No significant correlations were found between the FC of these brain regions and clinical characteristics or neuropsychological evaluations after Bonferroni correction (p > 0.00016). CONCLUSIONS: Our results demonstrated that patients with NDPH have abnormal FC of brainstem nuclei involved in the perception and regulation of pain and emotions.

Safety, pharmacokinetics, and pharmacodynamics of anti-IL-4Rα antibody SHR-1819 in healthy subjects: A randomized, controlled phase I study.

SHR-1819 is a novel anti-IL-4Rα monoclonal antibody currently under clinical development for use in patients with type 2 inflammatory diseases. In this randomized, double-blind, placebo-controlled, single-dose escalation phase I trial, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of SHR-1819 in healthy subjects. Subjects received a single subcutaneous injection of SHR-1819 or placebo, with dose escalation starting at 60 mg and subsequently increasing to 120, 240, 360, and 720 mg. A total of 42 eligible subjects were randomized, and 33 received SHR-1819 (1 subject in the 60 mg cohort and 8 subjects each in the 120, 240, 360 , and 720 mg cohorts) and 9 received placebo. SHR-1819 was well-tolerated, with the majority of adverse events being mild in severity. The exposure of SHR-1819 increased in a manner greater than proportionally with a dose range of 120 to 720 mg. The median Tmax was within 4-7 days (60-720 mg), and the mean half-life ranged from 2.88 to 5.97 days (120-720 mg). The clearance rate of SHR-1819 exhibited a decrease with increasing dose level. Administration of SHR-1819 resulted in a certain degree of reduction in the percentage change from baseline in concentrations of inflammatory biomarkers TARC/CCL17 and IgE, while the reduction of TARC/CCL17 concentrations showed a dose-dependent trend. More than half of the total subjects treated with SHR-1819 were reported antidrug antibody-negative. The preliminary data from this phase I study support further development of SHR-1819 for the treatment of type 2 inflammatory diseases.

Nogo-B Promotes Endoplasmic Reticulum Stress-Mediated Autophagy in Endothelial Cells of Diabetic Nephropathy.

Aims: Endothelial cells are the critical targets of injury in diabetic nephropathy (DN), and endothelial cell lesions contribute to the disease progression. Neurite outgrowth inhibitor B (Nogo-B), an endoplasmic reticulum (ER)-resident protein, plays a pivotal role in vascular remodeling after injury, and maintains the structure and function of the ER. Yet, the role of Nogo-B in the regulation of ER stress and endothelial cell injury remains largely unknown. Herein, we tested the hypothesis that Nogo-B activates ER stress-mediated autophagy and protects endothelial cells in DN. Results: The level of Nogo-B was decreased in glomerular endothelial cells in biopsy specimens from DN patients. In vivo and in vitro studies have shown that silencing Nogo-B activated ER stress signaling, and affected the expression of autophagy-related marker early growth response 1 and microtubule-associated protein light chain 3 (LC3) in endothelial cells in hyperglycemic condition. Conclusion and Innovation: These results denote that Nogo-B contributes to ER stress-mediated autophagy and protects endothelial cells in DN, providing new evidence for understanding the role of ER stress-mediated autophagy in endothelial cells of DN.

Development of an electrochemical separation-Rhodopseudomonas palustris electrolysis cell-coupled system for resourceful treatment of mature leachate landfill.

Electrochemical technology is a promising technique for separating ammonia from mature landfill leachate. However, the accompanying migration and transformation of coexisting pollutants and strategies for further high-value resourceful utilization of ammonia have rarely received attention. In this study, an electrochemical separation-Rhodopseudomonas palustris electrolysis cell coupled system was initially constructed for efficient separation and conversion of nitrogen in mature landfill leachate to microbial protein with synchronously tracking the transport and conversion of coexisting heavy metals accompanying the process. The results revealed that ammonia concentration in the cathode increased from 40.3 to 49.8% with increasing the current density from 20 to 40 mA/cm2, with less than 3% of ammonia transformation to NO2--N and NO3--N. During ammonia separation, approximately 95% of HM-DOMs (Cr, Cu, Ni, Pb, and Zn) were released into the anolyte due to humus degradation and further diffused to the cathode. A significant correlation was observed between the releases of HM-DOMs. Cu-DOMs accounted for 70.2% of the total Cu content, which was the highest proportion among the heavy metals (HMs). Among the HMs in anolyte, 57.4% of Pb, 52.5% of Ni, and 50.6% of Zn diffused to the cathode, and most of the HMs were removed in the form of hydroxide precipitations due to heavy alkaline catholyte. Compared with the open-circuit condition, the utilization efficiency of NH4+-N in the R. palustris electrolysis cell increased by 445.1% with 47% and 50% increases in final NH4+-N conversion rate and R. palustris biomass, respectively, due to bio-electrochemical enhanced phototrophic metabolism and acid generation for buffering the strong alkalinity of the electrolyte to maintain suitable growth conditions for R. palustris.

Photochemical behaviors of sludge extracellular polymeric substances from bio-treated effluents towards antibiotic degradation: Distinguish the main photosensitive active component and its environmental implication.

Activated sludge extracellular polymeric substances (ASEPSs) comprise most dissolved organic matters (DOMs) in the tail water. However, the understanding of the link between the photolysis of antibiotic and the photo-reactivity/photo-persistence of ASEPS components is limited. This study first investigated the photochemical behaviors of ASEPS's components (humic acids (HA), hydrophobic substances (HOS) and hydrophilic substances (HIS)) separated from municipal sludge's EPS (M-EPS) and nitrification sludge's EPS (N-EPS) in the photolysis of sulfadiazine (SDZ). The results showed that 60% of SDZ was removed by the M-EPS, but the effect in the separated components was weakened, and only 24% - 39% was degraded. However, 58% of SDZ was cleaned by HOS in N-EPS, which was 23% higher than full N-EPS. M-EPS components had lower steady-state concentrations of triplet intermediates (3EPS*), hydroxyl radicals (·OH) and singlet oxygen (1O2) than M-EPS, but N-EPS components had the highest concentrations (5.96 ×10-15, 8.44 ×10-18, 4.56 ×10-13 M, respectively). The changes of CO, C-O and O-CO groups in HA and HOS potentially correspond to reactive specie's generation. These groups change little in HIS, which may make it have radiation resistance. HCO-3 and NO-3 decreased the indirect photolysis of SDZ, and its by-product N-(2-Pyrimidinyl)1,4-benzenediamine presents high environmental risk.

Identifying IDH-mutant and 1p/19q noncodeleted astrocytomas from nonenhancing gliomas: Manual recognition followed by artificial intelligence recognition.

Background: The T2-FLAIR mismatch sign (T2FM) has nearly 100% specificity for predicting IDH-mutant and 1p/19q noncodeleted astrocytomas (astrocytomas). However, only 18.2%-56.0% of astrocytomas demonstrate a positive T2FM. Methods must be considered for distinguishing astrocytomas from negative T2FM gliomas. In this study, positive T2FM gliomas were manually distinguished from nonenhancing gliomas, and then a support vector machine (SVM) classification model was used to distinguish astrocytomas from negative T2FM gliomas. Methods: Nonenhancing gliomas (regardless of pathological type or grade) diagnosed between January 2022 and October 2022 (N = 300) and November 2022 and March 2023 (N = 196) will comprise the training and validation sets, respectively. Our method for distinguishing astrocytomas from nonenhancing gliomas was examined and validated using the training set and validation set. Results: The specificity of T2FM for predicting astrocytomas was 100% in both the training and validation sets, while the sensitivity was 42.75% and 67.22%, respectively. Using a classification model of SVM based on radiomics features, among negative T2FM gliomas, the accuracy was above 85% when the prediction score was greater than 0.70 in identifying astrocytomas and above 95% when the prediction score was less than 0.30 in identifying nonastrocytomas. Conclusions: Manual screening of positive T2FM gliomas, followed by the SVM classification model to differentiate astrocytomas from negative T2FM gliomas, may be a more effective method for identifying astrocytomas in nonenhancing gliomas.

A novel alginate-embedded magnetic biochar-anoxygenic photosynthetic bacteria composite microspheres for multipollutant removal: Mechanisms of photo-bioelectrochemical enhancement and excellent reusability performance.

Existing wastewater treatment technologies face the key challenge of simultaneously removing emerging contaminants and nutrients from wastewater efficiently, with a simplified technological process and minimized operational costs. In this study, a novel alginate-embedded magnetic biochar-anoxygenic photosynthetic bacteria composite microspheres (CA-MBC-PSB microspheres) was prepared for efficient, cost-effective and one-step removal of antibiotics and NH4+-N from wastewater. Our results demonstrated that the CA-MBC-PSB microspheres removed 97.23% of sulfadiazine (SDZ) within 7 h and 91% of NH4+-N within 12 h, which were 21.23% and 38% higher than those achieved by pure calcium alginate-Rhodopseudomonas palustris microspheres (53% and 45.7%), respectively. The enhanced SDZ and NH4+-N removal were attributed to the enhanced photoheterotrophic metabolism and excretion of extracellular photosensitive active substances from R. Palustris through the photo-bioelectrochemical interaction between R. Palustris and magnetic biochar. The long-term pollutants removal performance of the CA-MBC-PSB microspheres was not deteriorated but continuously improved with increasing ruse cycles with a simultaneous removal efficiency of 99% for SDZ and 92% for NH4+-N after three cycles. The excellent stability and reusability were due to the fact that calcium alginate acts as an encapsulating agent preventing the loss and contamination of R. palustris biomass. The CA-MBC-PSB microspheres also exhibited excellent performance for simultaneous removal of SDZ (89% in 7 h) and NH4+-N (90.7% in 12 h) from the secondary effluent of wastewater treatment plant, indicating the stable and efficient performance of CA-MBC-PSB microspheres in practical wastewater treatment.

Selective Access to Functional Fluoroenones via Palladium-Catalyzed Selenofluoroalkylacylation of Terminal Alkynes.

The trifluoromethylacyl group (-COCF3) is an important motif and widely studied in catalysis, medicinal chemistry, and materials science. Herein, a novel palladium-catalyzed selenofluoroalkylacylation of terminal alkynes with commercially available fluoroalkyl anhydride and diorganyl diselenides to afford ß-seleno and aryl/alkyl disubstituted enones under mild conditions is disclosed. In addition, selenodifluoroacetylations and selenoperfluoroacetylations are also suitable for this reaction. Mechanistic studies reveal that this reaction proceeds via an oxidative radical-polar crossover process.

Evaluating Middle Cerebral Artery Plaque Characteristics and Lenticulostriate Artery Morphology Associated With Subcortical Infarctions at 7T MRI.

BACKGROUND: Lenticulostriate artery (LSA) obstruction is a potential cause of subcortical infarcts. However, MRI LSA evaluation at 3T is challenging. PURPOSE: To investigate middle cerebral artery (MCA) plaque characteristics and LSA morphology associated with subcortical infarctions in LSA territories using 7-T vessel wall MRI (VW-MRI) and time-of-flight MR angiography (TOF-MRA). STUDY TYPE: Prospective. POPULATION: Sixty patients with 80 MCA atherosclerotic plaques (37 culprit and 43 non-culprit). FIELD STRENGTH/SEQUENCE: 7-T with 3D TOF-MRA and T1-weighted 3D sampling perfection with application-optimized contrast using different flip angle evolutions (SPACE) sequences. ASSESSMENT: Plaque distribution (superior, inferior, ventral, or dorsal walls), LSA origin involvement, LSA morphology (numbers of stems, branches, and length), and plaque characteristics (normalized wall index, maximal wall thickness, plaque length, remodeling index, intraplaque hemorrhage, and plaque surface morphology (regular or irregular)) were assessed. STATISTICAL TESTS: Least absolute shrinkage and selection operator regression, generalized estimating equations regression, receiver operating characteristic curve, independent t-test, Mann-Whitney U test, Chi-square test, Fisher's exact test, and intra-class coefficient. A P value <0.05 was considered statistically significant. RESULTS: Plaque irregular surface, superior wall plaque, longer plaque length, LSA origin involvement, fewer LSA stems, and shorter total and average lengths of LSAs were significantly associated with culprit plaques. Multivariable logistic analysis confirmed that LSA origin involvement (OR, 28.51; 95% CI, 6.34-181.02) and plaque irregular surface (OR, 8.32; 95% CI, 1.41-64.73) were independent predictors in differentiating culprit from non-culprit plaques. A combination of LSA origin involvement and plaque irregular surface (area under curve = 0.92; [95% CI, 0.86-0.98]) showed good performance in identifying culprit plaques, with sensitivity and specificity of 86.5% and 86.0%, respectively. DATA CONCLUSION: 7-T VW-MRI and TOF-MRA can demonstrate plaque involvement with LSA origins. MCA plaque characteristics derived from 7-T VW-MRI showed good diagnostic accuracy in determining the occurrence of subcortical infarctions. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Glymphatic system impairment in Alzheimer's disease: associations with perivascular space volume and cognitive function.

OBJECTIVES: To investigate glymphatic function in Alzheimer's disease (AD) using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method and to explore the associations between DTI-ALPS index and perivascular space (PVS) volume, as well as between DTI-ALPS index and cognitive function. METHODS: Thirty patients with PET-CT-confirmed AD (15 AD dementia; 15 mild cognitive impairment due to AD) and 26 age- and sex-matched cognitively normal controls (NCs) were included in this study. All participants underwent neurological MRI and cognitive assessments. Bilateral DTI-ALPS indices were calculated. PVS volume fractions were quantitatively measured at three locations: basal ganglia (BG), centrum semiovale, and lateral ventricle body level. DTI-ALPS index and PVS volume fractions were compared among three groups; correlations among the DTI-ALPS index, PVS volume fraction, and cognitive scales were analyzed. RESULTS: Patients with AD dementia showed a significantly lower DTI-ALPS index in the whole brain (p = 0.009) and in the left hemisphere (p = 0.012) compared with NCs. The BG-PVS volume fraction in patients with AD was significantly larger than the fraction in NCs (p = 0.045); it was also negatively correlated with the DTI-ALPS index (r = - 0.433, p = 0.021). Lower DTI-ALPS index was correlated with worse performance in the Boston Naming Test (ß = 0.515, p = 0.008), Trail Making Test A (ß = - 0.391, p = 0.048), and Digit Span Test (ß = 0.408, p = 0.038). CONCLUSIONS: The lower DTI-ALPS index was found in patients with AD dementia, which may suggest impaired glymphatic system function. DTI-ALPS index was correlated with BG-PVS enlargement and worse cognitive performance in certain cognitive domains. CLINICAL RELEVANCE STATEMENT: Diffusion tensor image analysis along the perivascular space index may be applied as a useful indicator to evaluate the glymphatic system function. The impaired glymphatic system in patients with Alzheimer's disease (AD) dementia may provide a new perspective for understanding the pathophysiology of AD. KEY POINTS: • Patients with Alzheimer's disease dementia displayed a lower diffusion tensor image analysis along the perivascular space (DTI-ALPS) index, possibly indicating glymphatic impairment. • A lower DTI-ALPS index was associated with the enlargement of perivascular space and cognitive impairment. • DTI-ALPS index could be a promising biomarker of the glymphatic system in Alzheimer's disease dementia.

Differentiation Between the Low and High Trans-Stenotic Pressure Gradient in Patients With Idiopathic Intracranial Hypertension Using 4D Flow MRI-Derived Hemodynamic Parameters.

BACKGROUND: Trans-stenotic pressure gradient (TPG) measurement is essential for idiopathic intracranial hypertension (IIH) patients with transverse sinus (TS) stenosis. Four-D flow MRI may provide a noninvasive imaging method for differentiation of IIH patients with different TPG. PURPOSE: To investigate the associations between 4D flow parameters and TPG, and to evaluate the diagnostic performance of 4D flow parameters in differentiating patients with high TPG (GroupHP) from low TPG (GroupLP). STUDY TYPE: Prospective. POPULATION: 31 IIH patients with TS stenosis (age, 38 ± 12 years; 23 females) and 5 healthy volunteers (age, 25 ± 1 years; 2 females). FIELD STRENGTH/SEQUENCE: 3T, 3D phase contrast MR venography, and gradient recalled echo 4D flow sequences. ASSESSMENT: Scan-rescan reproducibility of 4D flow parameters were performed. The correlation between TPG and flow parameters was analyzed. The netflow and velocity difference between inflow plane, outflow plane, and the stenosis plane were calculated and compared between GroupHP and GroupLP. STATISTICAL TESTS: Pearson's correlation or Spearman's rank correlation coefficient, Independent samples t-test or Wilcoxon rank-sum test, Intra-class correlation coefficient (ICC), Bland-Altman analyses, Receiver operating characteristic curves. A P value <0.05 was considered significant. RESULTS: Significant correlations were found between TPG and netflow parameters including Favg,out-s, Favg,in-s, Fmax,out-s, and Fmax,in-s (r = 0.525-0.565). Significant differences were found in Favg,out-s, Fmax,out-s, Favg,in-s, and Fmax,in-s between GroupHP and GroupLP. Using the cut-off value of 2.19 mL/sec, the Favg,out-s showed good estimate performance in distinguishing GroupHP from GroupLP (AUC = 0.856). The ICC (ranged 0.905-0.948) and Bland-Altman plots indicated good scan-rescan reproducibility. DATA CONCLUSIONS: 4D flow MRI derived flow parameters showed good correlations with TPG in IIH patients with TS stenosis. Netflow difference between outflow and stenosis location at TS shows the good performance in differentiating GroupHP and GroupLP cases. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Trajectories of depressive symptoms in young and middle-aged men who have sex with men with new HIV-diagnosis: a 1-year prospective cohort study in Beijing, China.

Introduction: Due to the sexual orientation and HIV diagnosis, young and middle-aged men who have sex with men (MSM) with new HIV-diagnosis may experience more depressive syndromes and face greater psychological stress. The study explored trajectories of depressive symptoms of young and middle-aged MSM within 1 year after new HIV-diagnosis and analyze the related factors. Methods: From January 2021 to March 2021, 372 young and middle-aged MSM who were newly diagnosed as HIV-infection were recruited in two hospitals in Beijing. Self-rating Depression Scale was used to measure the participants' depressive symptom in 1st month, 3rd month, 6th month, 9th month and 12th month after HIV diagnosis. The latent class growth model was used to identify trajectories of the participants' depressive symptoms. Multinomial logistic regression was used to analyse factors related with the trajectories. Results: Three hundred and twenty-eight young and middle-aged MSM with new HIV-diagnosis completed the research. Depressive symptom in 328 young and middle-aged MSM was divided into three latent categories: non-depression group (56.4%), chronic-mild depression group (28.1%), and persistent moderate-severe depression group (15.5%). The participants assessed as non-depression (non-depression group) or mild depression (chronic-mild depression group) at the baseline were in a non-depression state or had a downward trend within one-year, and the participants assessed as moderate and severe depression (persistent moderate-severe depression group) at the time of diagnosis were in a depression state continuously within 1-year. Multinomial logistic regression analysis showed that, compared with the non-depression group, monthly income of 5,000 ~ 10,000 RMB (equal to 690 ~ 1,380 USD) was the risk factor for the chronic-mild depression group, and self-rating status being fair/good and self-disclosure of HIV infection were protective factors for the persistent moderate-severe depression group while HIV-related symptoms was the risk factor. Conclusion: Depressive symptoms in young and middle-aged MSM is divided into three latent categories. Extra care must be given to young and middle-aged MSM assessed as moderate or severe depression at the time of HIV-diagnosis, especially to those who had poor self-rating health status, did not tell others about their HIV-infection and experienced HIV-related symptoms.

Increased glymphatic system activity in migraine chronification by diffusion tensor image analysis along the perivascular space.

BACKGROUND: Preliminary evidence suggests that several headache disorders may be associated with glymphatic dysfunction. However, no studies have been conducted to examine the glymphatic activity in migraine chronification. PURPOSES: To investigate the glymphatic activity of migraine chronification in patients with episodic migraine (EM) and chronic migraine (CM) using the diffusion tensor image analysis along the perivascular space (DTI-ALPS) method. METHODS: In this cross-sectional study, patients with EM, CM, and healthy controls (HCs) were included. All participants underwent a standard brain magnetic resonance imaging (MRI) examination. Bilateral DTI-ALPS indexes were calculated for all participants and compared among EM, CM, and HC groups. Correlations between the DTI-ALPS index and clinical characteristics were analyzed. RESULTS: A total of 32 patients with EM, 24 patients with CM, and 41 age- and sex-matched HCs were included in the analysis. Significant differences were found in the right DTI-ALPS index among the three groups (p = 0.011), with CM showing significantly higher values than EM (p = 0.033) and HCs (p = 0.015). The right DTI-ALPS index of CM group was significantly higher than the left DTI-ALPS index (p = 0.005). And the headache intensity was correlated to DTI-ALPS index both in the left hemisphere (r = 0.371, p = 0.011) and in the right hemisphere (r = 0.307, p = 0.038), but there were no correlations after Bonferroni correction. CONCLUSIONS: Glymphatic system activity is shown to be increased instead of impaired during migraine chronification. The mechanism behind this observation suggests that increased glymphatic activity is more likely to be a concomitant phenomenon of altered vascular reactivity associated with migraine pathophysiology rather than a risk factor of migraine chronification.

Hyperperfusion of bilateral amygdala in patients with chronic migraine: an arterial spin-labeled magnetic resonance imaging study.

BACKGROUND: Amygdala, an essential element of the limbic system, has served as an important structure in pain modulation. There is still a lack of clarity about altered cerebral perfusion of amygdala in migraine. This study aimed to investigate the perfusion variances of bilateral amygdala in episodic migraine (EM) and chronic migraine (CM) using multi-delay pseudo-continuous arterial spin-labeled magnetic resonance imaging (pCASL-MRI). METHODS: Twenty-six patients with EM, 55 patients with CM (33 CM with medication overuse headache (MOH)), and 26 age- and sex-matched healthy controls (HCs) were included. All participants underwent 3D multi-delay pCASL MR imaging to obtain cerebral perfusion data, including arrival-time-corrected cerebral blood flow (CBF) and arterial cerebral blood volume (aCBV). The CBF and aCBV values in the bilateral amygdala were compared among the three groups. Correlation analyses between cerebral perfusion parameters and clinical variables were performed. RESULTS: Compared with HC participants, patients with CM were found to have increased CBF and aCBV values in the left amygdala, as well as increased CBF values in the right amygdala (all P < 0.05). There were no significant differences of CBF and aCBV values in the bilateral amygdala between the HC and EM groups, the EM and CM groups, as well as the CM without and with MOH groups (all P > 0.05). In patients with CM, the increased perfusion parameters of bilateral amygdala were positively correlated with MIDAS score after adjustments for age, sex, and body mass index (BMI). CONCLUSION: Hyperperfusion of bilateral amygdala might provide potential hemodynamics evidence in the neurolimbic pain network of CM.

Development of a clinical automatic calculation of hypoglycemia during hemodialysis risk in patients with diabetic nephropathy.

BACKGROUND: Hypoglycemia is one of the most common complications in patients with DN during hemodialysis. The purpose of the study is to construct a clinical automatic calculation to predict risk of hypoglycemia during hemodialysis for patients with diabetic nephropathy. METHODS: In this cross-sectional study, patients provided information for the questionnaire and received blood glucose tests during hemodialysis. The data were analyzed with logistic regression and then an automated calculator for risk prediction was constructed based on the results. From May to November 2022, 207 hemodialysis patients with diabetes nephropathy were recruited. Patients were recruited at blood purifying facilities at two hospitals in Beijing and Inner Mongolia province, China. Hypoglycemia is defined according to the standards of medical care in diabetes issued by ADA (2021). The blood glucose meter was used uniformly for blood glucose tests 15 minutes before the end of hemodialysis or when the patient did not feel well during hemodialysis. RESULTS: The incidence of hypoglycemia during hemodialysis was 50.2% (104/207). The risk prediction model included 6 predictors, and was constructed as follows: Logit (P) = 1.505×hemodialysis duration 8~15 years (OR = 4.506, 3 points) + 1.616×hemodialysis duration 16~21 years (OR = 5.032, 3 points) + 1.504×having hypotension during last hemodialysis (OR = 4.501, 3 points) + 0.788×having hyperglycemia during the latest hemodialysis night (OR = 2.199, 2 points) + 0.91×disturbance of potassium metabolism (OR = 2.484, 2 points) + 2.636×serum albumin<35 g/L (OR = 13.963, 5 points)-4.314. The AUC of the prediction model was 0.866, with Matthews correlation coefficient (MCC) of 0.633, and Hosmer-Lemeshow χ2 of 4.447(P = 0.815). The automatic calculation has a total of 18 points and four risk levels. CONCLUSIONS: The incidence of hypoglycemia during hemodialysis is high in patients with DN. The risk prediction model in this study had a good prediction outcome. The hypoglycemia prediction automatic calculation that was developed using this model can be used to predict the risk of hypoglycemia in DN patients during hemodialysis and also help identify those with a high risk of hypoglycemia during hemodialysis.

Efficacy, safety and dose selection of AZD3759 in patients with untreated EGFR-mutated non-small-cell lung cancer and central nervous system metastases in China (CTONG1702-Arm 8): a multi-center, single-arm, phase 2 trial.

Background: Central nervous system (CNS) metastases is inevitable for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). AZD3759 is a novel EGFR-TKI with impressive CNS penetration. Methods: We initiated a phase 2, multi-center, umbrella trial (CTONG1702, NCT03574402). The eighth arm assessed the efficacy and safety of AZD3759 in untreated EGFR-mutated NSCLC with CNS metastases. The primary objective was the objective response rate (ORR). Simon's minimax two-stage design was used to calculate the sample size. Dose optimal selection was performed using 200- and 300-mg bid cohorts. Findings: Between Oct 18, 2018 and Sep 14, 2020, 30 patients received AZD3759 at 200 mg (n = 15) or 300 mg (n = 15) bid. At data cutoff (Dec 31, 2022), median follow-up was 35.4 months. The primary endpoint was reached, with a confirmed ORR of 70% (21/30) (200 mg, 80%; 300 mg, 60%). The median progression-free survival was 12.9 months (200 mg, 15.8 months; 300 mg, 10.7 months). Grade 3 or 4 treatment-related adverse events occurred in 73% (22/30) of the patients (200 mg: 60%; 300 mg: 87%). 59% (10/17) of the patients developed a T790M mutation at disease progression. The median overall survival was 33.7 months, and 34.1 months and 25.3 months in patient treated with or without osimertinib in a later-line setting, respectively. Interpretation: AZD3759 showed promising efficacy and tolerable safety as a first-line therapy in EGFR-mutated NSCLC with CNS metastases. The 200-mg bid cohort had better clinical outcomes. Sequential use of AZD3759 and third-generation EGFR-TKIs represents a new option. Funding: Chinese Thoracic Oncology Group (CTONG).

Ru(OAc)3-Catalyzed Regioselective Difunctionalization of Alkynes: Access to (E)-2-Bromo-1-alkenyl Sulfonates.

A new approach is proposed for the divergent and regioselective synthesis of (E)-2-bromo-1-phenylvinyl trifluoromethanesulfonates through alkyne difunctionalization by employing a compatible system of abundantly available alkynes, N-bromosuccinimide (NBS), and trimethylsilyl trifluoromethanesulfonate (TMSOTf) catalyzed by ruthenium(III) acetate [Ru(OAc)3]. It is a novel method for the preparation of vinyl triflate and it offers a fundamental basis for the development of advanced functional compounds, including drugs and organic functional materials. Unlike previously reported methods, the proposed protocol can tolerate a broad range of functional groups. Alkynes derived from bioactive molecules, such as l(-)-borneol, demonstrate the potential value of this new reaction in organic synthesis.

Micro-structural white matter abnormalities in new daily persistent headache: a DTI study using TBSS analysis.

BACKGROUND: New daily persistent headache (NDPH) is a rare primary headache disorder characterized by daily and persistent sudden onset headaches. The pathogenesis of NDPH remains unclear, and there are few white matter imaging studies related to NDPH. The purpose of this study was to investigate the micro-structural abnormalities of white matter in NDPH and provided insights into the pathogenesis of this disease based on tract-based spatial statistics (TBSS). METHODS: Twenty-one patients with NDPH and 25 healthy controls (HCs) were included in this study. T1 structural and diffusion magnetic resonance imaging (MRI) were acquired from all participants. Differences in the fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) between patients with NDPH and HCs were investigated using TBSS analysis. RESULTS: Significantly decreased FA, increased MD and RD were found in patients with NDPH compared to HCs. White matter regions overlaid with decreased FA, increased MD and RD were found in 16 white matter tracts from the Johns Hopkins University ICBM-DTI-81 White-Matter Atlas and Johns Hopkins University White-Matter Tractography Atlas. Specifically, these white matter regions included the right anterior thalamic radiation (ATR), body of the corpus callosum (BCC), bilateral cingulum, left hippocampal cingulum (CGH), left corticospinal tract (CST), forceps major, fornix, left inferior fronto-occipital fasciculus (IFOF), bilateral inferior longitudinal fasciculus (ILF), left posterior limb of the internal capsule (PLIC), right retrolenticular part of the internal capsule (RPIC), splenium of the corpus callosum (SCC), right superior longitudinal fasciculus (SLF) and left uncinate fasciculus (UF). After Bonferroni correction, there were no correlations between the FA, MD, AD and RD values and the clinical characteristics of patients with NDPH (p > 0.05/96). CONCLUSION: The results of our research indicated that patients with NDPH might have widespread abnormalities in the white matter of the brain.