Glutathione peroxidase 4-regulated neutrophil ferroptosis induces systemic autoimmunity.

The linkage between neutrophil death and the development of autoimmunity has not been thoroughly explored. Here, we show that neutrophils from either lupus-prone mice or patients with systemic lupus erythematosus (SLE) undergo ferroptosis. Mechanistically, autoantibodies and interferon-α present in the serum induce neutrophil ferroptosis through enhanced binding of the transcriptional repressor CREMα to the glutathione peroxidase 4 (Gpx4, the key ferroptosis regulator) promoter, which leads to suppressed expression of Gpx4 and subsequent elevation of lipid-reactive oxygen species. Moreover, the findings that mice with neutrophil-specific Gpx4 haploinsufficiency recapitulate key clinical features of human SLE, including autoantibodies, neutropenia, skin lesions and proteinuria, and that the treatment with a specific ferroptosis inhibitor significantly ameliorates disease severity in lupus-prone mice reveal the role of neutrophil ferroptosis in lupus pathogenesis. Together, our data demonstrate that neutrophil ferroptosis is an important driver of neutropenia in SLE and heavily contributes to disease manifestations.

Role of protease-activated receptor 4 in mouse models of acute and chronic kidney injury.

Protease-activated receptor 4 (PAR4) is a G protein-coupled receptor activated by thrombin. In the platelet, response to thrombin PAR4 contributes to the predominant procoagulant microparticle formation, increased fibrin deposition, and initiation of platelet-stimulated inflammation. In addition, PAR4 is expressed in other cell types, including endothelial cells. Under inflammatory conditions, PAR4 is overexpressed via epigenetic demethylation of the PAR4 gene, F2RL3. PAR4 knockout (KO) studies have determined a role for PAR4 in ischemia-reperfusion injury in the brain, and PAR4 KO mice display normal cardiac function but present less myocyte death and cardiac dysfunction in response to acute myocardial infarction. Although PAR4 has been reported to be expressed within the kidney, the contribution of PAR4 to acute kidney injury (AKI) and chronic kidney disease (CKD) is not well understood. Here we report that PAR4 KO mice are protected against kidney injury in two mouse models. First, PAR4 KO mice are protected against induction of markers of both fibrosis and inflammation in two different models of kidney injury: 1) 7 days following unilateral ureter obstruction (UUO) and 2) an AKI-CKD model of ischemia-reperfusion followed by 8 days of contralateral nephrectomy. We further show that PAR4 expression in the kidney is low in the control mouse kidney but induced over time following UUO. PAR4 KO mice are protected against blood urea nitrogen (BUN) and glomerular filtration rate (GFR) kidney function pathologies in the AKI-CKD model. Following the AKI-CKD model, PAR4 is expressed in the collecting duct colocalizing with Dolichos biflorus agglutinin (DBA), but not in the proximal tubule with Lotus tetragonolobus lectin (LTL). Collectively, the results reported in this study implicate PAR4 as contributing to the pathology in mouse models of acute and chronic kidney injury.NEW & NOTEWORTHY The contribution of the thrombin receptor protease-activated receptor 4 (PAR4) to acute kidney injury (AKI) and chronic kidney disease (CKD) is not well understood. Here we report that PAR4 expression is upregulated after kidney injury and PAR4 knockout (KO) mice are protected against fibrosis following kidney injury in two mouse models. First, PAR4 KO mice are protected against unilateral ureter obstruction. Second, PAR4 KO mice are protected against an AKI-CKD model of ischemia-reperfusion followed by contralateral nephrectomy.

Efficacy and Safety of Tofacitinib in Patients with Polymyalgia Rheumatica (EAST PMR): An open-label randomized controlled trial.

BACKGROUND: Polymyalgia rheumatica (PMR) is a common inflammatory disease in elderly persons whose mechanism of pathogenesis has not been elucidated. Glucocorticoids are the main first-line treatments but result in numerous side effects. Therefore, there is a need to explore pathogenetic factors and identify possible glucocorticoid-sparing agents. We aimed to study the pathogenetic features of the disease and assess the efficacy and safety of Janus tyrosine kinase (JAK)-inhibitor tofacitinib in patients with PMR. METHODS AND FINDINGS: We recruited treatment-naïve PMR patients from the First Affiliated Hospital, Zhejiang University School of Medicine, between September 2020 and September 2022. In the first cohort, we found that the gene expression patterns of peripheral blood mononuclear cells (PBMCs) in 11 patients (10 female, 1 male, age 68.0 ± 8.3) with newly diagnosed PMR were significantly different from 20 healthy controls (17 female, 3 male, age 63.7 ± 9.8) by RNA sequencing. Inflammatory response and cytokine-cytokine receptor interaction were the most notable pathways affected. We observed marked increases in expression of IL6R, IL1B, IL1R1, JAK2, TLR2, TLR4, TLR8, CCR1, CR1, S100A8, S100A12, and IL17RA, which could trigger JAK signaling. Furthermore, tofacitinib suppressed the IL-6R and JAK2 expression of CD4+T cells from patients with PMR in vitro. In the second cohort, patients with PMR were randomized and treated with tofacitinib or glucocorticoids (1/1) for 24 weeks. All PMR patients underwent clinical and laboratory examinations at 0, 4, 8, 12, 16, 20, and 24 weeks, and PMR activity disease scores (PMR-AS) were calculated. The primary endpoint was the proportion of patients with PMR-AS ≤10 at weeks 12 and 24. Secondary endpoints: PMR-AS score, c-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) at weeks 12 and 24. Thirty-nine patients with newly diagnosed PMR received tofacitinib, and 37 patients received glucocorticoid. Thirty-five patients (29 female, 6 male, age 64.4 ± 8.4) and 32 patients (23 female, 9 male, age 65.3 ± 8.7) patients completed the 24-week intervention, respectively. There were no statistically significant differences in primary or secondary outcomes. At weeks 12 and 24, all patients in both groups had PMR-AS <10. PMR-AS, CRP, and ESR were all significantly decreased in both groups. No severe adverse events were observed in either group. Study limitations included the single-center study design with a short observation period. CONCLUSIONS: We found that JAK signaling was involved in the pathogenesis of PMR. Tofacitinib effectively treated patients with PMR as glucocorticoid does in this randomized, monocenter, open-label, controlled trial (ChiCTR2000038253). TRIAL REGISTRATION: This investigator-initiated clinical trial (IIT) had been registered on the website (http://www.chictr.org.cn/, ChiCTR2000038253).

Ischaemic heart disease in Behçet's syndrome: a systematic review and meta-analysis.

OBJECTIVES: Behçet's syndrome (BS) has been reported with cardiovascular involvement. It's still unclear that BS is associated with the increased risk of ischaemic heart disease (IHD). We aimed to conduct a meta-analysis concerning the incidence of IHD in BS and identify the relationship between IHD and BS. METHODS: We performed a comprehensive literature search based on PubMed and Embase databases up to 7 July, 2021. Incidence of IHD was calculated by metaproportion. Pooled risk ratio and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS: Four studies with 9237 patients with IHD in BS and 40353 controls were identified and included in our meta-analysis. The pooled risk ratio of IHD in patients with BS was 1.30 and achieved statistical significance (95% CI 1.04-1.64). The statistical heterogeneity was low with an I2 of 39% (p=0.18). CONCLUSIONS: In this meta-analysis the presence of BS was associated with an increased risk of IHD. Prospective researches should be done to determine the pathophysiological and prognostic implications of increased IHD in BS.

Impact of Sublingual Nitroglycerin on the Assessment of Computed Tomography-derived Fractional Flow Reserve: An Intraindividual Comparison Study.

OBJECTIVE: The aim of this study was to investigate the impact of nitroglycerin (NTG) on the assessment of computed tomography-derived fractional flow reserve (CT-FFR). MATERIALS AND METHODS: Seventy-seven patients with suspected coronary artery disease were recruited, and they underwent computed tomography angiography (CCTA) before and after NTG administration. The CT-FFRs were compared at 2 CCTAs. The difference was compared using the Wilcoxon signed rank test. Patients were divided into normal and stenosis groups according to CCTA results. Vessels in the stenosis group were further divided into different groups based on coronary artery calcium score (CACS) and stenosis degree. The poststenotic CT-FFR differences before and after NTG (DCT-FFR) were calculated to evaluate the impact of stenosis degree and CACS. Terminal CT-FFRs derived from CCTAs before and after NTG in total and vessel-specific levels were compared in the normal group. RESULTS: Of 47 patients in the stenosis group, poststenotic CT-FFR was significantly increased after NTG at per-vessel level. By taking CT-FFR of 0.75 or lower as the threshold, 5 and 4 patients showed abnormal CT-FFR before and after NTG, respectively. No significant differences were noted among the various stenosis degree and CACS groups regarding DCT-FFR. Of 30 patients in the normal group, terminal CT-FFR was significantly increased after NTG in total level and vessel-specific level of left anterior descending and right coronary artery, but not in the left circumflex. CONCLUSIONS: Both post lesion and distal vessel CT-FFR significantly improved after the administration of GTN with the degree of change not affected by stenosis severity or CACS.

The Combination of N60 with Mismatch Negativity Improves the Prediction of Awakening from Coma.

BACKGROUND: Our objective was to evaluate the use of event-related potentials and the middle-latency somatosensory evoked potential (MLSEP) for the prediction of awakening in coma, determine the evaluation day that evoked potentials (EPs) best predict an awakening outcome, and determine whether the mismatch negativity (MMN) combined with the MLSEP, when recorded at 7 days after coma, improved the prediction of awakening from coma. METHODS: Design prospective blinded cohort study. Setting neurointensive care unit of a university hospital. Patients 113 consecutive patients who were severely comatose, whose etiologies of coma included stroke (65 patients), hypoxic-ischemic encephalopathy (28 patients), intracranial infection (6 patients), and other (14 patients). Interventions none. Measurements we gathered Glasgow Coma Scale scores and recorded EPs for all patients who were comatose at 7, 14, and 30 days after coma onset, unless the patients returned to consciousness. The EPs examined included the MLSEP, the middle-latency auditory evoked potential, the N100, and the MMN. With telephone follow-up after 3 months, the patients were classified as awakening or nonawakening according to Glasgow Outcome Scale. RESULTS: When predicting an awakening outcome, at least the unilateral presence of the N60 had the highest sensitivity (82.7%), whereas the presence of the MMN showed the highest specificity (82.0%). The area under the receiver operating characteristic curve for the EPs were high at 7 days after coma onset. At 7 days after coma onset, the combination of the N60 and MMN offered good predictive performance for awakening (area under the receiver operating characteristic curve = 0.852, 95% confidence interval 0.765-0.940), with increased sensitivity (70.0%) and improved specificity (91.7%). CONCLUSIONS: The N60 and MMN were the strongest prognostic factors for an awakening outcome. Furthermore, at 7 days after coma onset, the combination of the N60 and MMN improved the prediction of an awakening outcome in patients who were comatose.

Clinical manifestations and long-term prognosis of Good syndrome: Results from a single-center cohort study from China.

OBJECTIVE: To describe clinical features and long-term prognosis in patients with Good syndrome (GS). METHODS: We retrospectively reviewed medical records of GS patients at Peking Union Medical College Hospital from January 2001 to May 2019. Data regarding clinical manifestations and treatments were collected. Patients were routinely followed-up via clinical and telephone interviews, and survival analysis was performed with Kaplan-Meier analysis. RESULTS: Twenty-four patients were identified, including eight males and 16 females, with a median age at diagnosis of 58 years (interquartile range [IQR], 52-62 years). Twelve patients (50%) had autoimmune manifestations. Multi-organ involvements included musculoskeletal (37.5%), respiratory (33.3%), gastrointestinal (29.2%), hematologic (29.2%) systems, et.al. Infections were detected in 23 (95.8%) patients, mostly located in lung (69.6%), blood (26.1%), and gastrointestinal tract (21.7%). Thymectomy was performed in 23 patients, with the most common histology of type AB (10, 47.6%). Twenty-one patients were consecutively followed-up with a median follow-up of 84 (IQR, 48-116) months and 11 (52.4%) died, mainly due to infection (8/11, 72.7%). The 5- and 10-year survival rates were 90% (95% confidence interval [CI], 77.8-100%) and 38.5% (95% CI, 19.6-75.5%), respectively. CONCLUSION: GS patients tended to present with various infections and autoimmune manifestations. The 10-year survival rate from the Chinese population was poor, mainly due to infections.

Early Consciousness Disorder in Acute Large Hemispheric Infarction: An Analysis Based on Quantitative EEG and Brain Network Characteristics.

BACKGROUND: Large hemispheric infarction (LHI) is an ischemic stroke affecting at least two-thirds of the middle cerebral artery territory, with or without involvement of the anterior cerebral artery or posterior cerebral artery, and approximately 77% of LHI patients have early consciousness disorder (ECD). We constructed a functional brain network for LHI patients with an acute consciousness disorder to identify new diagnostic markers related to ECDs by analyzing brain network characteristics and mechanisms. METHODS: Between August 1, 2017, and September 30, 2018, patients with acute (< 1 month) LHI were admitted to the neurocritical care unit at Xuanwu Hospital of Capital Medical University. Electroencephalography (EEG) data were recorded, and the MATLAB platform (2017b) was used to calculate spectral power, entropy, coherence and phase synchronization. The quantitative EEG and brain network characteristics of different consciousness states and different frequency bands were analyzed (α = 0.05). EEG data were recorded 38 times in 30 patients, 25 of whom were in the ECD group, while 13 patients were in the conscious group. RESULTS: (1) Spectral power analysis: The conscious group had higher beta relative spectral power across the whole brain, higher alpha spectral power in the frontal-parietal lobe on the infarction contralateral side, and lower theta and delta spectral power in the central-occipital lobe on the infarction contralateral side than the ECD group. (2) Entropy analysis: The conscious group had higher approximate entropy (ApEn) and permutation entropy (PeEn) across the whole brain than the ECD group. (3) Coherence: The conscious group had higher alpha coherence in nearly the whole brain and higher beta coherence in the bilateral frontal-parietal and parietal-occipital lobes than the ECD group. (4) Phase synchronization: The conscious group had higher alpha and beta synchronization in nearly the whole brain, particularly in the frontal-parietal and parietal-occipital lobes, than the ECD group. (5) Graph theory: The conscious group had higher small-worldness in each frequency band than the ECD group. CONCLUSION: In patients with LHI, higher levels of consciousness were associated with more alpha and beta oscillations and fewer delta and theta oscillations. Higher ApEn, PeEn, total brain connectivity, and small-worldness and a wider signal distribution range corresponded to a higher consciousness level.

Why don't phenophase dates in the current year affect the same phenophase dates in the following year?

Examining whether a phenophase occurrence date in the current year affects the same phenophase occurrence date in the following year is crucial for developing cross-year phenological prediction models. Here, we carried out correlation analyses between leaf unfolding start (LUS)/leaf fall end (LFE) dates in the current and following years for four dominant tree species in temperate northern China from 1981 to 2012. Then, we calculated the recurrence intervals of LUS and LFE between two adjacent years for each species. Moreover, we investigated temperature effects on LUS/LFE dates, growing season and non-growing season lengths. Results show that correlation coefficients between LUS/LFE dates in the current and following years are nonsignificant at most stations. The recurrence interval of a phenophase has slight interannual variation and correlates significantly (and negatively) with the phenophase occurrence date of the current year. Further analyses indicate that LUS dates correlate significantly (and negatively) with spring mean temperatures, while LFE dates correlate significantly (and positively) with autumn mean temperatures, but negatively with growing season mean temperatures. In addition, spring mean temperatures can influence growing season length by controlling LUS date but cannot influence the following non-growing season length. Similarly, autumn mean temperatures and growing season mean temperatures can influence the subsequent non-growing season length but cannot influence the growing season length of the following year. Our study highlights that recurrence interval and time restrictions in the effects of seasonal temperatures on phenophase dates are the main environmental causes of nonsignificant correlations between phenophase occurrence dates in the current and following years.

Clinical Characteristics and Prognosis of Severe Anti-N-methyl-D-aspartate Receptor Encephalitis Patients.

BACKGROUND AND PURPOSE: Data concerning the characteristics and duration of the critical manifestations, treatment response, and long-term outcomes of severe anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis patients compared to those of non-severe patients are limited. This observational study was performed to explore the clinical characteristics and long-term outcomes of severe anti-NMDAR encephalitis patients. METHODS: According to their characteristics on admission to the neurology intensive care unit, patients with anti-NMDAR encephalitis were divided into a severe group and a non-severe group. The demographics, clinical manifestations, main accessory examinations, immunotherapy, and outcomes of patients were recorded. Statistical analyses were employed to examine the differences in each observed indicator between the severe and non-severe groups. RESULTS: This study enrolled 111 patients with anti-NMDAR encephalitis, including 59 males and 52 females with a mean age of 27.7 ± 13.7 years; 39 (35.1%) patients were in the severe group, and 72 (64.9%) patients were in the non-severe group. Compared to the non-severe group, the severe group exhibited a higher proportion of epilepsy, involuntary movement, disturbance of consciousness, autonomic dysfunction, and central hypoventilation. The cerebrospinal fluid (CSF) of all patients was positive for the NMDAR antibody, but only 57 patients (51.4%) tested positive for the NMDAR antibody in the blood. The proportion of patients with a strong positive NMDAR antibody titer in the severe group (48.7%) was higher than that in the non-severe group (29.2%). The proportion of patients receiving intravenous gamma immunoglobulin in the severe group was higher than that in the non-severe group (P = 0.003), and only patients in the severe group received plasma exchange, intravenous rituximab, and cyclophosphamide treatment. No significant difference was observed in the prognosis between the severe group and the non-severe group after 6 months and during long-term follow-up. CONCLUSION: Most severe anti-NMDAR encephalitis patients will eventually achieve good long-term prognoses after receiving early, positive and unremitting combined immunotherapy and life support.

An externally validated clinical-laboratory nomogram for myocardial involvement in adult idiopathic-inflammatory-myopathy patients.

OBJECTIVES: This study aimed at identifying clinical and laboratory risk factors for myocardial involvement (MI) in idiopathic inflammatory myopathies (IIMs) patients as well as constructing a risk-predicted nomogram for prediction and early identification of MI. METHODS: An IIMs cohort in southeastern China was constructed, including 504 adult IIMs patients who met the inclusion and exclusion criteria, and were hospitalized at four divisions of the First Affiliated Hospital, Zhejiang University School of Medicine from January 1st 2018 to April 30st 2022. After dividing patients into the training cohort and the validation cohort, risk factors for MI were identified through least absolute shrinkage and selection operator regression and multivariate logistic regression. A risk-predicted nomogram was established and validated internally and externally for discrimination, calibration and practicability. RESULTS: In this cohort, 17.7% of patients developed MI and the survival was significantly inferior to that of IIMs patients without MI (P < 0.001). In the training cohort, age > 55 years old (P < 0.001), disease activity > 10 points (P < 0.001), interleukin-17A (IL-17A) > 7.5 pg/ml (P < 0.001), lactic dehydrogenase (LDH) > 425 U/L (P < 0.001), anti-mitochondrial antibodies (AMAs, P = 0.017), and anti-MDA5 antibody (P = 0.037) were significantly correlated with development of MI. A nomogram was established by including the above values to predict MI and was found efficient in discrimination, calibration, and practicability through internal and external validation. CONCLUSION: This study developed and validated a nomogram model to predict the risk of MI in adult IIMs patients, which can benefit the prediction and early identification of MI as well as timely intervention in these patients.

Quantitative EEG reactivity induced by electrical stimulation predicts good outcome in comatose patients after cardiac arrest.

BACKGROUND: EEG reactivity is a predictor for neurological outcome in comatose patients after cardiac arrest (CA); however, its application is limited by variability in stimulus types and visual assessment. We aimed to evaluate the prognostic value of the quantitative analysis of EEG reactivity induced by standardized electrical stimulation and for early prognostication in this population. METHODS: This prospective observational study recruited post-CA comatose patients in Xuanwu Hospital, Capital Medical University (Beijing, China) between January 2016 and June 2023. EEG reactivity to electrical or traditional pain stimulation was randomly performed via visual and quantitative analysis. Neurological outcome within 6 months was dichotomized as good (Cerebral Performance Categories, CPC 1-2) or poor (CPC 3-5). RESULTS: Fifty-eight post-CA comatose patients were admitted, and 52 patients were included in the final analysis, of which 19 (36.5%) had good outcomes. EEG reactivity induced with the electrical stimulation had superior performance to the traditional pain stimulation for good outcome prediction (quantitative analysis: AUC 0.932 vs. 0.849, p = 0.048). When using the electrical stimulation, the AUC of EEG reactivity to predict good outcome by visual analysis was 0.838, increasing to 0.932 by quantitative analysis (p = 0.039). Comparing to the traditional pain stimulation by visual analysis, the AUC of EEG reactivity for good prognostication by the electrical stimulation with quantitative analysis was significantly improved (0.932 vs. 0.770, p = 0.004). CONCLUSIONS: EEG reactivity induced by the standardized electrical stimulation in combination with quantitative analysis is a promising formula for post-CA comatose patients, with increased predictive accuracy.

Persistently elevated sFlt-1 and recovery of reduced ADAMTS13 activity in malignant hypertension.

BACKGROUND AND OBJECTIVES: Malignant hypertension (MHT) characterized by acute hypertension with retinopathy or multiorgan damage, is a severe form of hypertensive emergency and associated with target organ involvement and poor kidney outcome. However, the underlying mechanisms are unclear. METHODS: Eighty-four patients with acute severe hypertension from the Nephrology Department and Emergency Department in a single center during January 2016 and December 2017 were prospectively enrolled and divided into MHT ( n  = 48) and non-MHT ( n  = 36) subgroups according to target organ evaluation. Forty healthy controls were recruited. Serum soluble Fms-like tyrosine kinase-1 (sFlt-1) levels and plasma ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) activity were examined at baseline and 12-month follow-up. Renal endpoints were defined as a significant decrease in the estimated glomerular filtration rate (eGFR) of more than 40% or the occurrence of end-stage renal disease. RESULTS: Serum sFlt-1 levels were persistently elevated in MHT. Baseline serum sFLT-1 levels were correlated with plasma ADAMTS13 activity and markers of target organ damage. Plasma ADAMTS13 activity was reduced in both MHT and non-MHT patients and recovered to the normal range at 12-month follow-up. During an average follow-up time of 53 ±â€Š13 months, the restoration of reduced ADAMTS13 activity was correlated with the improvement of kidney function and independently reduced the risk of renal endpoints. CONCLUSIONS: Abnormal angiogenesis and endothelial damage are involved in the pathophysiology of hypertensive emergency. Evaluation of ADAMTS13 and sFlt-1 may help in the diagnosis and assessment of MHT. Recovery of ADAMTS13 predicts better renal outcome in patients with hypertensive emergencies.

Clonal hematopoiesis of indeterminate potential contributes to accelerated chronic kidney disease progression.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a common inflammatory condition of aging that causes myriad end-organ damage. We have recently shown associations for CHIP with acute kidney injury and with kidney function decline in the general population, with stronger associations for CHIP driven by mutations in genes other than DNMT3A (non- DNMT3A CHIP). Longitudinal kidney function endpoints in individuals with pre-existing chronic kidney disease (CKD) and CHIP have been examined in two previous studies, which reported conflicting findings and were limited by small sample sizes. Methods: In this study, we examined the prospective associations between CHIP and CKD progression events in four cohorts of CKD patients (total N = 5,772). The primary outcome was a composite of 50% kidney function decline or kidney failure. The slope of eGFR decline was examined as a secondary outcome. Mendelian randomization techniques were then used to investigate potential causal effects of CHIP on eGFR decline. Finally, kidney function was assessed in adenine-fed CKD model mice having received a bone marrow transplant recapitulating Tet2 -CHIP compared to controls transplanted wild-type bone marrow. Results: Across all cohorts, the average age was 66.4 years, the average baseline eGFR was 42.6 ml/min/1.73m 2 , and 24% had CHIP. Upon meta-analysis, non- DNMT3A CHIP was associated with a 59% higher relative risk of incident CKD progression (HR 1.59, 95% CI: 1.02-2.47). This association was more pronounced among individuals with diabetes (HR 1.29, 95% CI: 1.03-1.62) and with baseline eGFR ≥ 30 ml/min/1.73m (HR 1.80, 95% CI: 1.11-2.90). Additionally, the annualized slope of eGFR decline was steeper among non- DNMT3A CHIP carriers, relative to non-carriers (ß -0.61 ± 0.31 ml/min/1.73m 2 , p = 0.04). Mendelian randomization analyses suggested a causal role for CHIP in eGFR decline among individuals with diabetes. In a dietary adenine mouse model of CKD, Tet2 -CHIP was associated with lower GFR as well as greater kidney inflammation, tubular injury, and tubulointerstitial fibrosis. Conclusion: Non- DNMT3A CHIP is a potentially targetable novel risk factor for CKD progression.

Quantitative EEG and brain network analysis: predicting awakening from early coma after cardiopulmonary resuscitation.

OBJECTIVE: For patients in early coma after cardiopulmonary resuscitation (CPR), quantitative electroencephalogram (EEG) and brain network analysis was performed to identify relevant indicators of awakening. METHODS: A prospective cohort study was conducted on comatose patients after CPR in the neuro-critical care unit. The included patients received clinical evaluation. The bedside high-density (64-lead) EEG monitoring was performed for visual grading and calculation of power spectrum and brain network parameters. A 3-month prognostic assessment was performed and the patients were dichotomized into the awakening group and the unawakening group. RESULTS: A total of 25 patients were included. The awakening group had higher GCS score, more slow wave pattern and reactive EEG than the unawakening group (P = 0.003, P < 0.001, P < 0.001, respectively). Compared with the unawakening group, (1) the awakening group had significantly higher absolute and relative θ power and slow/fast band ratio of the whole brain (P < 0.05), (2) the awakening group had stronger connection based on coherence, phase synchronization, phase lag index and cross-correlation (P < 0.05), (3) the awakening group had higher small-worldness, clustering coefficient and average path length based on graph theory (P < 0.05). CONCLUSIONS: The power spectrum and brain network characteristics in patients in early coma after CPR have predictive value for recovery.

Long-term follow-up of phenobarbital versus valproate for generalized convulsive status epilepticus in adults: A randomized clinical trial.

OBJECTIVE: Intravenous phenobarbital is frequently offered to patients with generalized convulsive status epilepticus (GCSE) in China, but its long-term benefits are unclear. We aimed to evaluate the long-term effects of intravenous phenobarbital on adult patients with GCSE. METHODS: This randomized clinical trial with a 12-month follow-up was performed in Xuanwu Hospital, Capital Medical University (Beijing, China) between February 2011 and December 2021. After the failure of intravenous diazepam treatment, adult patients with GCSE were randomized to receive either intravenous phenobarbital or valproate. Neurological outcome within 12-month was dichotomized as good (modified Rankin scale, mRS 0-2) or poor (mRS 3-6). Cognitive function was measured by mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA). Hamilton anxiety scale (HAMA) and Hamilton depression scale (HAMD) were tested for mood disorders. RESULTS: We consecutively recruited 166 patients with GCSE. After excluding individuals with termination after intravenous diazepam (n = 61), and with other exclusion criteria (n = 7), 98 patients were included and 88.0% (66/75) of survivors achieved seizure freedom at 12-month. Forty-five patients (45.92%) had good outcomes at 3-month and 57 patients (58.16%) had good outcomes at 12-month. And 46.67% (35/75) of survivors showed mRS improvement at 12-month (phenobarbital group, n = 17 vs. valproate group, n = 18, P = 0.321). Despite there was no significant difference with respect to good outcomes at 3-month (54.0% vs. 37.5%, P = 0.101), the rate of good outcomes in phenobarbital group was higher than valproate group at 12-month (68.0% vs. 47.92%, P = 0.044). A total of 43 patients successfully participated cognitive and emotional tests. Mild cognitive impairment was found in 7.14% of phenobarbital group and 50.0% in valproate group (P = 0.026). In addition, there were no significant differences with respect to anxiety (36.36% vs. 38.10%) and depression (31.82% vs. 47.62%) between the phenobarbital and valproate groups. CONCLUSIONS: Combined with long term conventional therapy, intravenous phenobarbital group had more good outcomes than intravenous valproate group in Chinese adult patients with GCSE up to 12-month follow-up. This finding may prompt the option of intravenous phenobarbital especially in patients with limited access to new antiseizure drugs.

Primary Sjögren's syndrome with type II respiratory failure caused by myotonic dystrophy type 1: A case report and literature review.

Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by the involvement of exocrine glands with dryness of mouth and eyes as typical clinical manifestations, and may also have extra-glandular organ involvement. Myotonic dystrophy type 1 (DM1) is the most common type of adult-onset muscular dystrophy, which can lead to progressive muscle weakness and myotonia. The coexistence of pSS with DM1 was rarely reported. We here report a Chinese female pSS patient with progressive type II respiratory failure as a major manifestation and finally diagnosed with DM1 by genetic testing.

The predictive value of EEG reactivity by electrical stimulation and quantitative analysis in critically ill patients with large hemispheric infarction.

PURPOSE: The intensive care of critically ill patients with large hemispheric infarction improves the survival rate. However, established prognostic markers for neurological outcome show variable accuracy. We aimed to assess the value of electrical stimulation and quantitative analysis of EEG reactivity for early prognostication in this critically ill population. MATERIALS AND METHODS: We prospectively enrolled consecutive patients between January 2018 and December 2021. EEG reactivity was randomly performed by pain or electrical stimulation via visual and quantitative analysis. Neurological outcome within 6-month was dichotomized as good (modified Rankin Scale, mRS 0-3) or poor (mRS 4-6). RESULTS: Ninety-four patients were admitted, and 56 were included in the final analysis. EEG reactivity using electrical stimulation was superior to pain stimulation for good outcome prediction (visual analysis: AUC 0.825 vs. 0.763, P = 0.143; quantitative analysis: AUC 0.931 vs. 0.844, P = 0.058). The AUC of EEG reactivity by pain stimulation with visual analysis was 0.763, which increased to 0.931 by electrical stimulation with quantitative analysis (P = 0.006). When using quantitative analysis, the AUC of EEG reactivity increased (pain stimulation 0.763 vs. 0.844, P = 0.118; electrical stimulation 0.825 vs. 0.931, P = 0.041). CONCLUSION: EEG reactivity by electrical stimulation and quantitative analysis seems a promising prognostic factor in these critical patients.

Epidermal growth factor receptor activation is essential for kidney fibrosis development.

Fibrosis is the progressive accumulation of excess extracellular matrix and can cause organ failure. Fibrosis can affect nearly every organ including kidney and there is no specific treatment currently. Although Epidermal Growth Factor Receptor (EGFR) signaling pathway has been implicated in development of kidney fibrosis, underlying mechanisms by which EGFR itself mediates kidney fibrosis have not been elucidated. We find that EGFR expression increases in interstitial myofibroblasts in human and mouse fibrotic kidneys. Selective EGFR deletion in the fibroblast/pericyte population inhibits interstitial fibrosis in response to unilateral ureteral obstruction, ischemia or nephrotoxins. In vivo and in vitro studies and single-nucleus RNA sequencing analysis demonstrate that EGFR activation does not induce myofibroblast transformation but is necessary for the initial pericyte/fibroblast migration and proliferation prior to subsequent myofibroblast transformation by TGF-ß or other profibrotic factors. These findings may also provide insight into development of fibrosis in other organs and in other conditions.

Comatose Patients After Cardiopulmonary Resuscitation: An Analysis Based on Quantitative Methods of EEG Reactivity.

Objective: Every year, approximately 50-110/1,00,000 people worldwide suffer from cardiac arrest, followed by hypoxic-ischemic encephalopathy after cardiopulmonary resuscitation (CPR), and approximately 40-66% of patients do not recover. The purpose of this study was to identify the brain network parameters and key brain regions associated with awakening by comparing the reactivity characteristics of the brain networks between the awakening and unawakening groups of CPR patients after coma, thereby providing a basis for further awakening interventions. Method: This study involved a prospective cohort study. Using a 64-electrode electroencephalography (EEG) wireless 64A system, EEG signals were recorded from 16 comatose patients after CPR in the acute phase (<1 month) from 2019 to 2020. MATLAB (2017b) was used to quantitatively analyze the reactivity (power spectrum and entropy) and brain network characteristics (coherence and phase lag index) after pain stimulation. The patients were divided into an awakening group and an unawakening group based on their ability to execute commands or engage in repeated and continuous purposeful behavior after 3 months. The above parameters were compared to determine whether there were differences between the two groups. Results: (1) Power spectrum: the awakening group had higher gamma, beta and alpha spectral power after pain stimulation in the frontal and parietal lobes, and lower delta and theta spectral power in the bilateral temporal and occipital lobes than the unawakening group. (2) Entropy: after pain stimulation, the awakening group had higher entropy in the frontal and parietal lobes and lower entropy in the temporal occipital lobes than the unawakening group. (3) Connectivity: after pain stimulation, the awakening group had stronger gamma and beta connectivity in nearly the whole brain, but weaker theta and delta connectivity in some brain regions (e.g., the frontal-occipital lobe and parietal-occipital lobe) than the unawakening group. Conclusion: After CPR, comatose patients were more likely to awaken if there was a higher stimulation of fast-frequency band spectral power, higher entropy, stronger whole-brain connectivity and better retention of frontal-parietal lobe function after pain stimulation.