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 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.

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.

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.

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.

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.

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.

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).

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.

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.

Association between different infection profiles and one-year outcomes in ANCA-associated vasculitis: a retrospective study with monthly infection screening.

OBJECTIVES: This study aimed to explore clinical features of early infection in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and to identify the association between the infection profile of patients with AAV during the first 3 months and 1-year survival. METHODS: A total of 415 newly diagnosed patients with AAV in the Department of Nephrology at Shanghai Ruijin Hospital from 2000 to 2018 were included. Four Cox regression models were used to analyse the association based on demographics, comorbidities, laboratory baseline index and therapy parameter. Infection screening was carried out monthly during the first 3 months after diagnosis. RESULTS: In all, 377 episodes of infection were identified among 220 patients during the first 3 months. The overall survival after 1 year was 73.0%. Respiratory infection (210 episodes/164 persons) accounted for more than half of infections. Infection was independently associated with 1-year mortality (adjusted HR 2.32, 95% CI 1.27 to 4.23, p=0.006) after adjustment. Respiratory infection (adjusted HR 4.36, 95% CI 2.86 to 8.06, p<0.001), Gram-negative bacterial infection (adjusted HR 1.71, 95% CI 1.01 to 2.91, p=0.047) and fungal infection (adjusted HR 1.77, 95% CI 1.07 to 2.94, p=0.026) was identified as a risk factor for 1-year mortality. Trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis (adjusted HR 0.55, 95% CI 0.31 to 0.97, p=0.040) was protective for 1-year mortality. CONCLUSIONS: Infections, particularly respiratory infections, are a common and important class of complication in patients with AAV and are associated with early mortality. TMP-SMX prophylaxis might be necessary to improve short-term outcome. More consideration of infectious risk and regular infection screening should be given.

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.

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.

ZLN005 protects against ischemia-reperfusion-induced kidney injury by mitigating oxidative stress through the restoration of mitochondrial fatty acid oxidation.

To date, the treatment of acute kidney injury (AKI) remains a difficult problem for clinicians. In the present study, we assessed whether ZLN005, a novel peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) agonist, can protect against ischemic AKI in vivo and in vitro. Notably, ZLN005 treatment significantly alleviated Ischemia-reperfusion (I/R)-induced tubular injury and reversed the decrease in hypoxia-reoxygenation-induced cell viability by restoring PGC-1α expression in a dose-dependent manner. This beneficial effect of ZLN005 was associated with the preservation of mitochondrial fatty acid oxidation (MitoFAO) and the alleviation of oxidative stress. Cotreatment with etomoxir, a specific inhibitor of carnitine palmitoyltransferase-1α (CPT-1α) activity, or CPT-1α siRNA abrogated ZLN005-induced antistress responses by mitigating reactive oxygen species production and decreasing apoptosis under ischemia-hypoxia conditions by suppressing MitoFAO. Further studies revealed that activation of endoplasmic reticulum (ER) stress may be involved in the effect of CPT-1α inhibition observed in vivo and in vitro. Collectively, our results suggest that ZLN005 confers a protective effect on I/R-induced kidney injury by mitigating ER stress through the restoration of MitoFAO by targeting PGC-1α.

Phenobarbital versus valproate for generalized convulsive status epilepticus in adults (2): A multicenter prospective randomized controlled trial in China (China 2-P vs. V).

OBJECTIVE: A multicenter study of phenobarbital versus valproate (i.e., the China 2-P vs. V study) was conducted to compare the efficacy and safety of phenobarbital and valproate for generalized convulsive status epilepticus (SE) in a multicenter trial design. METHODS: Three improvements (uniform intravenous pumping, pump speed adjustment according to adverse events and blood drug level monitoring) over a previous study were made regarding an intravenous regimen of phenobarbital and valproate in a multicenter, prospective, randomized, controlled study. Long-term electroencephalography (EEG) monitoring was performed after initial drug treatment. Termination, relapse, adverse event and poor prognosis rates in patients with generalized convulsive status epilepticus (GCSE) were compared. RESULTS: The rate of GCSE termination within one hour were significantly higher in the phenobarbital group (33 cases) than in the valproate group (36 cases) (84.8 % vs. 63.9 %, P = 0.048), but the rates of nontermination of EEG epileptic discharge within one hour were similar between the two groups (12.1 % vs. 8.3 %, P = 0.702). The relapse and adverse event rates were not significantly different between groups, but 3 hypoventilation events and 1 hypotension event occurred in the phenobarbital group compared to 0 in the valproate group. There were no cases of epileptiform EEG discharge relapse in the phenobarbital group, compared to 1 case in the valproate group. CONCLUSIONS: The phenobarbital regimen evaluated in this study has a higher GCSE termination rate than the valproate regimen, indicating that the former is suitable for countries, regions and individuals with limited access to new antiepileptic drugs or limited economic means.

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.

Risk factors for mortality of diffuse alveolar hemorrhage in systemic lupus erythematosus: a systematic review and meta-analysis.

BACKGROUND: Diffuse alveolar hemorrhage (DAH) is a rare but life-threatening complication of systemic lupus erythematosus (SLE). The current knowledge of the prognostic factors for SLE-associated DAH is controversial. This meta-analysis was undertaken to investigate the relevant risk factors for mortality in SLE-associated DAH. METHODS: Studies were searched from PubMed, EMBASE, and Web of Science databases published up to May 27, 2020, and were selected or removed according to the inclusion and exclusion criteria. Two reviewers extracted data independently from the enrolled studies, and the odds ratios (OR) or the standardized mean difference (SMD) was utilized to identify and describe the prognostic factors for mortality. RESULTS: Eight studies encompassing 251 patients with SLE-associated DAH were included in the meta-analysis. No significant publication bias was shown. Age at the diagnosis of DAH (SMD = 0.35, 95% confidence interval (CI) (0.08, 0.61), P = 0.01, I2 = 0.0%) was found to be an independent risk factor of mortality. Longer lupus disease duration (SMD = 0.28, 95% CI (0.01, 0.55), P = 0.042, I2 = 0.0%), concurrent infection (OR = 2.77, 95% CI (1.55, 4.95), P = 0.001, I2 = 37.5%), plasmapheresis treatment (OR = 1.96, 95% CI (1.04, 3.70), P = 0.038, I2 = 14.6%), and mechanical ventilation (OR = 6.11, 95% CI (3.27, 11.39), P < 0.0001, I2 = 23.3%) were also related to poor survival, whereas no noticeable relationships were revealed between survival and concurrent lupus nephritis (OR = 5.45, 95% CI (0.52, 56.95), P = 0.16, I2 = 58.4%) or treatment of cyclophosphamide (CTX) (OR = 0.74, 95% CI (0.16, 3.41), P = 0.70, I2 = 75.5%). CONCLUSIONS: Older age at the diagnosis of DAH, longer disease duration of SLE, concurrent infection, plasmapheresis treatment, and mechanical ventilation were found related to increased mortality in patients with SLE-associated DAH according to our meta-analysis. However, due to limited studies with heterogeneity, these results should be interpreted cautiously. Notably, severe diseases rendered the requirement of plasmapheresis treatment and mechanical ventilation are themselves associated with poor outcome. Randomized trials of therapeutics are needed to determine the most efficacious strategies for SLE-associated DAH for better management of this life-threatening complication.