SCD1 sustains brown fat sympathetic innervation and thermogenesis during the long-term cold exposure.

Brown fat adipose tissue (BAT) is a therapeutic potential target to improve obesity, diabetes and cold acclimation in mammals. During the long-term cold exposure, the hyperplastic sympathetic network is crucial for BAT the maintain the highly thermogenic status. It has been proved that the sympathetic nervous drives the thermogenic activity of BAT via the release of norepinephrine. However, it is still unclear that how the thermogenic BAT affects the remodeling of the hyperplastic sympathetic network, especially during the long-term cold exposure. Here, we showed that following long-term cold exposure, SCD1-mediated monounsaturated fatty acid biosynthesis pathway was enriched, and the ratios of monounsaturated/saturated fatty acids were significantly up-regulated in BAT. And SCD1-deficiency in BAT decreased the capacity of cold acclimation, and suppressed long-term cold mediated BAT thermogenic activation. Furthermore, by using thermoneutral exposure and sympathetic nerve excision models, we disclosed that SCD1-deficiency in BAT affected the thermogenic activity, depended on sympathetic nerve. In mechanism, SCD1-deficiency resulted in the unbalanced ratio of palmitic acid (PA)/palmitoleic acid (PO), with obviously higher level of PA and lower level of PO. And PO supplement efficiently reversed the inhibitory role of SCD1-deficiency on BAT thermogenesis and the hyperplastic sympathetic network. Thus, our data provided insight into the role of SCD1-mediated monounsaturated fatty acids metabolism to the interaction between thermogenic activity BAT and hyperplastic sympathetic networks, and illustrated the critical role of monounsaturated fatty acids biosynthetic pathway in cold acclimation during the long-term cold exposure.

A comparative study of hypothalamic involvement in patients with myelin oligodendrocyte glycoprotein antibody-associated disease, neuromyelitis optica spectrum disorder, and multiple sclerosis.

BACKGROUND AND PURPOSE: We aimed to characterize hypothalamic involvement in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and compare it with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). METHODS: A retrospective study was performed to identify hypothalamic lesions in patients diagnosed with MOGAD, NMOSD, or MS from January 2013 to May 2020. The demographic, clinical, and radiological features were recorded. Hypothalamic dysfunction and prognosis were assessed through physical examination, biochemical testing, sleep monitoring, and magnetic resonance imaging. RESULTS: Hypothalamic lesions were observed in seven of 96 patients (7.3%) with MOGAD, 34 of 536 (6.3%) with NMOSD, and 16 of 356 (4.5%) with MS (p = 0.407). The time from disease onset to development of hypothalamic lesions was shortest in MOGAD (12 months). The frequency of bilateral hypothalamic lesions was the lowest in MOGAD (p = 0.008). The rate of hypothalamic dysfunction in MOGAD was 28.6%, which was lower than that in NMOSD (70.6%) but greater than that in MS patients (18.8%; p = 0.095 and p = 0.349, respectively). Hypothalamic dysfunction in MOGAD manifests as hypothalamic-pituitary-adrenal axis dysfunction and hypersomnia. The proportion of complete regression of hypothalamic lesions in MOGAD (100%) was much greater than that in NMOSD (41.7%) and MS patients (18.2%; p = 0.007 and p = 0.001, respectively). An improvement in hypothalamic dysfunction was observed in all MOGAD patients after immunotherapy. CONCLUSIONS: MOGAD patients have a relatively high incidence of asymptomatic hypothalamic lesions. The overall prognosis of patients with hypothalamic involvement is good in MOGAD, as the lesions completely resolve, and dysfunction improves after immunotherapy.

[3 + 2] Cycloaddition Reaction of Vinylsulfonium Salts with Hydrazonoyl Halides: Synthesis of Pyrazoles.

An efficient [3 + 2] cycloaddition reaction between in situ generated nitrile imines from hydrazonoyl halides and vinylsulfonium salts is developed. The nitrile imines are demonstrated to be a new class of reaction partner for vinylsulfonium salts to conduct the [3 + 2] cycloaddition reaction. The process provides a concise and efficient method for the construction of pyrazole derivatives under mild reaction conditions with broad substrate scope, good product yields, and high regioselectivity.

Predictors of mortality and poor outcome for patients with severe infectious encephalitis in the intensive care unit: a cross-sectional study.

BACKGROUND: There are few thorough studies assessing predictors of severe encephalitis, despite the poor prognosis and high mortality associated with severe encephalitis. The study aims to evaluate the clinical predictors of mortality and poor outcomes at hospital discharge in patients with severe infectious encephalitis in intensive care units. METHOD: In two Chinese hospitals, a retrospective cohort study comprising 209 patients in intensive care units suffering from severe infectious encephalitis was carried out. Univariate and multivariate logistic regression analyses were used to identify the factors predicting mortality in all patients and poor outcomes in all survivors with severe infectious encephalitis. RESULTS: In our cohort of 209 patients with severe encephalitis, 22 patients died, yielding a mortality rate of 10.5%. Cerebrospinal fluid pressure ≥ 400mmH2O (OR = 7.43), abnormal imaging (OR = 3.51), abnormal electroencephalogram (OR = 7.14), and number of rescues (OR = 1.12) were significantly associated with an increased risk of mortality in severe infectious encephalitis patients. Among the 187 survivors, 122 (65.2%) had favorable outcomes, defined as the modified Rankine Scale (mRS) score (0 ~ 3), and 65(34.8%) had poor outcomes (mRS scores 4 ~ 5). Age (OR = 1.02), number of rescues (OR = 1.43), and tubercular infection (OR = 10.77) were independent factors associated with poor outcomes at discharge in all survivors with severe infectious encephalitis. CONCLUSIONS: Multiple clinical, radiologic, and electrophysiological variables are independent predictive indicators for mortality and poor outcomes in patients with severe encephalitis in intensive care units. Identifying these outcome predictors early in patients with severe encephalitis may enable the implementation of appropriate medical treatment and help reduce mortality rates.

Morphological measurements and classification of the navicular bone: a study based on computed tomography imaging.

OBJECTIVE: The purpose of this study was to present the classification of navicular bones and the anatomical basis for the diagnosis and treatment of navicular fractures of the foot. METHOD: 351 computed tomographic (CT) images of the navicular bone were analyzed and classified. The navicular bone's anatomical morphology was measured by three independent researchers in each type. Analysis and recording of the measurement results followed. RESULT: Navicular bones were assorted into three types: I shape(37.04%), II shape(54.41%), and III shape(8.55%). The left and right sides did not differ in any appreciable ways, except ab, bc, and ∠abc (P < 0.05); And all data were statistically different between men and women except for ∠abc (p > 0.05). CONCLUSION: The classification of the navicular bone in this study may be helpful in making the treatment decision for navicular fracture. LEVEL OF CLINICAL EVIDENCE: 4.

Remyelination in neuromyelitis optica spectrum disorder is promoted by edaravone through mTORC1 signaling activation.

Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory autoimmune disease of the central nervous system that is manifested as secondary myelin loss. Oligodendrocyte progenitor cells (OPCs) are the principal source of myelinating oligodendrocytes (OLs) and are abundant in demyelinated regions of NMOSD patients, thus possibly representing a cellular target for pharmacological intervention. To explore the therapeutic compounds that enhance myelination due to endogenous OPCs, we screened the candidate drugs in mouse neural progenitor cell (NPC)-derived OPCs. We identified drug edaravone, which is approved by the Food and Drug Administration (FDA), as a promoter of OPC differentiation into mature OLs. Edaravone enhanced remyelination in organotypic slice cultures and in mice, even when edaravone was administered following NMO-IgG-induced demyelination, and ameliorated motor impairment in a systemic mouse model of NMOSD. The results of mechanistic studies in NMO-IgG-treated mice and the biopsy samples of the brain tissues of NMOSD patients indicated that the mTORC1 signaling pathway was significantly inhibited, and edaravone promoted OPC maturation and remyelination by activating mTORC1 signaling. Furthermore, pharmacological activation of mTORC1 signaling significantly enhanced myelin regeneration in NMOSD. Thus, edaravone is a potential therapeutic agent that promotes lesion repair in NMOSD patients by enhancing OPC maturation.

Bruton tyrosine kinase inhibitors preserve anti-CD19 chimeric antigen receptor T-cell functionality and reprogram tumor micro-environment in B-cell lymphoma.

BACKGROUND AIMS: Combination therapy is being actively explored to improve the efficacy and safety of anti-CD19 chimeric antigen receptor T-cell (CART19) therapy, among which Bruton tyrosine kinase inhibitors (BTKIs) are highly expected. BTKIs may modulate T-cell function and remodel the tumor micro-environment (TME), but the exact mechanisms involved and the steps required to transform different BTKIs into clinical applications need further investigation. METHODS: We examined the impacts of BTKIs on T-cell and CART19 phenotype and functionality in vitro and further explored the mechanisms. We evaluated the efficacy and safety of CART19 concurrent with BTKIs in vitro and in vivo. Moreover, we investigated the effects of BTKIs on TME in a syngeneic lymphoma model. RESULTS: Here we identified that the three BTKIs, ibrutinib, zanubrutinib and orelabrutinib, attenuated CART19 exhaustion mediated by tonic signaling, T-cell receptor (TCR) activation and antigen stimulation. Mechanistically, BTKIs markedly suppressed CD3-ζ phosphorylation of both chimeric antigen receptor and TCR and downregulated the expression of genes associated with T-cell activation signaling pathways. Moreover, BTKIs decreased interleukin 6 and tumor necrosis factor alpha release in vitro and in vivo. In a syngeneic lymphoma model, BTKIs reprogrammed macrophages to the M1 subtype and polarized T helper (Th) cells toward the Th1 subtype. CONCLUSIONS: Our data revealed that BTKIs preserved T-cell and CART19 functionality under persistent antigen exposure and further demonstrated that BTKI administration was a potential strategy for mitigating cytokine release syndrome after CART19 treatment. Our study lays the experimental foundation for the rational application of BTKIs combined with CART19 in clinical practice.

IL-10 plus the EASIX score predict bleeding events after anti-CD19 CAR T-cell therapy.

Chimeric antigen receptor (CAR) T-cell-associated coagulopathy can cause bleeding events. To explore risk factors for hemorrhage after CAR T-cell therapy, we retrospectively analyzed routine indicators in 56 patients with non-Hodgkin lymphoma and B-cell acute lymphoblastic leukemia who received anti-CD19 CAR T-cell therapy. Disturbance of coagulation occurred mainly within one month post infusion, especially on day 7 and 14. The cumulative incidence of bleeding events within one month was 32.8%, with the median onset of 7 (range, 0-28) days. All bleeding events were grade 1-3. Patients who experienced bleeding events within one month had longer prothrombin time, higher IL-6, higher IL-10, and lower platelets before lymphodepletion. There were also correlations among coagulation-, inflammatory-, and tumor burden-related markers. Multi-variate analysis showed IL-10 (> 7.98 pg/mL; adjusted odds ratio [OR], 13.84; 95% confidence interval [CI], 2.03-94.36; P = 0.007) and the endothelial activation and stress index (EASIX, defined as dehydrogenase [U/L] × creatinine [mg/dL] / platelets [×109 cells/L]; >7.65; adjusted OR, 7.06; 95% CI, 1.03-48.23; P = 0.046) were significant risk factors for bleeding events. IL-10 plus the EASIX defined three risk groups for bleeding events with cumulative incidence of 100% (hazard ratio [HR], 14.47; 95% CI, 2.78-75.29; P < 0.0001), 38.5% (HR, 3.68; 95% CI, 0.82-16.67; P = 0.089), and 11.8% (reference), respectively. Future studies are needed to verify the risk assessment models for bleeding events after CAR T-cell treatment in larger cohorts.

Characteristics and influencing factors of corneal higher-order aberrations in patients with cataract.

PURPOSE: To observe the distribution characteristics of corneal higher-order aberrations (HOAs) in cataract patients, and analyze the relationship of HOAs with patients' age and ocular biometric parameters. METHODS: This retrospective study reviews the patients with cataract in Wuhan Aier Eye Department from January to August 2022. Root mean square (RMS) of the total HOA (tHOA), spherical aberration (SA), coma and trefoil aberration of the anterior cornea at central 4 and 6 mm optic zone were measured by the Wavefront Aberrometer (OPD-Scan III; Nidek Inc, Tokyo, Japan). The biometric parameters including axial length (AL), keratometry (K), central corneal thickness (CCT) and lens thickness (LT) were measured by swept-source coherence laser interferometry (OA-2000; TOMEY Corp, Aichi, Japan). Subgroup analyses and multiple linear regression analyses were used to determine whether HOAs were associated with age and ocular biometric parameters. RESULTS: A total of 976 patients (976 eyes) were included, averagely aged 65 years. At central 4 and 6 mm optic zone, the mean RMS of tHOA were respectively 0.20 and 0.65 µm, the SA were 0.06 and 0.30 µm, the coma aberration were 0.11 and 0.35 µm, and the trefoil aberration were 0.12 and 0.30 µm. The tHOA decreased with age until 60 years and then started to increase afterwards. The tHOA, coma and trefoil aberration increased with corneal astigmatism. The tHOA, SA, and coma aberration differ among different AL groups, and emmetropes had the smallest tHOA, SA, and coma aberration. CONCLUSIONS: With increasing age, the value of tHOA decrease first and started increasing at 60 years. The trends of corneal HOAs are consistent with corneal low-order aberrations. The values of tHOA, SA and coma aberration were the smallest in emmetropic eyes.

A strong culture of clinical research is essential for the training of medical postgraduates in China.

Postgraduate medical students are the mainstay of future medical research, and clinical research is one of the most important components of medical research. In recent years, the Chinese government has increased the number of postgraduate students in China. Therefore, the quality of postgraduate training has received widespread attention. This article discusses the advantages and challenges faced by Chinese graduate students when they conduct their clinical research. To address the current misconception that Chinese graduate students only focus on developing their competence in basic biomedical research, the authors call for increased support for clinical research from the Chinese government as well as from schools and teaching hospitals.

TREM2 expression on the microglia resolved lead exposure-induced neuroinflammation by promoting anti-inflammatory activities.

Neurotoxicity caused by environmental lead (Pb) pollution is a worldwide public health concern, and developing a therapeutic strategy against Pb-induced neurotoxicity is an important area in the current research. Our prior research has demonstrated the significant involvement of microglia-mediated inflammatory responses in the manifestation of Pb-induced neurotoxicity. Additionally, the suppression of proinflammatory mediator activity significantly mitigated the toxic effects associated with Pb exposure. Recent studies have highlighted the critical role of the triggering receptor expressed on myeloid cells 2 (TREM2) in the pathogenesis of neurodegenerative disorders. TREM2 exerted protective effects on inflammation, but whether TREM2 is involved in Pb-induced neuroinflammation is poorly understood. In the present study, cell culture experiments and animal models were designed to investigate the role of TREM2 in Pb's neuroinflammation. We examined the impact of pro- and anti-inflammatory cytokines involved in Pb-induced neuroinflammation. Flow cytometry and microscopy techniques were applied to detect microglia phagocytosis and migration ability. Our results showed that Pb treatment significantly downregulated TREM2 expression and altered the localization of TREM2 expression in microglia. The protein expression of TREM2 was restored, and the inflammatory responses provoked by Pb exposure were ameliorated upon the overexpression of TREM2. Furthermore, the phagocytosis and migratory capabilities of microglia, which were impaired due to Pb exposure, were alleviated by TREM2 overexpression. Our in vitro findings were corroborated in vivo, demonstrating that TREM2 regulates the anti-inflammatory functions of microglia, thereby mitigating Pb-induced neuroinflammation. Our results provide insights into the detailed mechanism by which TREM2 alleviates Pb-induced neuroinflammation and suggest that activating the anti-inflammatory functions of TREM2 may represent a potential therapeutic strategy against environmental Pb-induced neurotoxicity.

Lead exposure disturbs ATP7B-mediated copper export from brain barrier cells by inhibiting XIAP-regulated COMMD1 protein degradation.

The brain barrier is an important structure for metal ion homeostasis. According to studies, lead (Pb) exposure disrupts the transportation of copper (Cu) through the brain barrier, which may cause impairment of the nervous system; however, the specific mechanism is unknown. The previous studies suggested the X-linked inhibitor of apoptosis (XIAP) is a sensor for cellular Cu level which mediate the degradation of the MURR1 domain-containing 1 (COMMD1) protein. XIAP/COMMD1 axis was thought to be an important regulator in Cu metabolism maintenance. In this study, the role of XIAP-regulated COMMD1 protein degradation in Pb-induced Cu disorders in brain barrier cells was investigated. Pb exposure significantly increased Cu levels in both cell types, according to atomic absorption technology testing. Western blotting and reverse transcription PCR (RT-PCR) showed that COMMD1 protein levels were significantly increased, whereas XIAP, ATP7A, and ATP7B protein levels were significantly decreased. However, there were no significant effects at the messenger RNA (mRNA) level (XIAP, ATP7A, and ATP7B). Pb-induced Cu accumulation and ATP7B expression were reduced when COMMD1 was knocked down by transient small interfering RNA (siRNA) transfection. In addition, transient plasmid transfection of XIAP before Pb exposure reduced Pb-induced Cu accumulation, increased COMMD1 protein levels, and decreased ATP7B levels. In conclusion, Pb exposure can reduce XIAP protein expression, increase COMMD1 protein levels, and specifically decrease ATP7B protein levels, resulting in Cu accumulation in brain barrier cells.

Knowledge, attitudes, and practice of Endocrinology healthcare workers regarding screening for pre-ulcerative diabetic foot lesions.

OBJECTIVE: To investigate knowledge, attitude and practice of screening pre-ulcerative lesions among endocrinology healthcare workers. METHODS: A new questionnaire was developed and distributed online and 1004 valid questionnaires were returned. T-test, ANOVA, Pearson correlation analysis, and multiple linear regression were used for statistical analysis. RESULTS: A total of 1100 questionnaires were returned, and 96 were excluded. The scores of endocrinology healthcare workers' knowledge, attitude, and practice for screening for pre-ulcerative lesions were 45.46 ± 16.26, 92.11 ± 10.50, and 72.27 ± 17.63 respectively. 60.2% participants had been trained to screen for pre-ulcerative lesions, but 39.8% had not been trained. 31.8% of healthcare professionals claimed that their hospital did not have a screening project for pre-ulcer diabetic foot lesions. Positive relationships were found between knowledge and practice and between attitude and practice. Multiple linear regression analysis showed that: level II hospital and tertiary hospital were the main factors influencing the knowledge scores; Undergraduate and participating in relevant training were the main factors influencing the attitude scores; participating in relevant training, hospital conducts relevant projects, and patient cooperation, and working hours were the main factors influencing the practice score. CONCLUSIONS: Endocrinology healthcare workers need more knowledge regarding pre-ulcerative lesions, and their screening practices need to be strengthened. Increased education and training for pre-ulcerative lesion screening should be implemented among healthcare workers in endocrinology departments.

The tolerance of refractive errors of extended depth of focus intraocular lens in patients with previous corneal refractive surgery.

PURPOSE: To evaluate the tolerance for refractive errors and visual outcomes of extended depth of focus intraocular lens (EDOF IOLs) in patients with previous corneal refractive surgery for myopia. METHODS: Patients from Aier Eye Hospital of Wuhan University with previous myopia excimer laser correction underwent cataract surgery and implantation of an EDOF IOL. The follow-up period was three months. The uncorrected distance, intermediate, and near visual acuities (UDVA, UIVA, UNVA), corrected distance visual acuity (CDVA), spherical equivalent (SE), defocus curve, optical quality, including modulation transfer functions (MTF) and Strehl ratio (SR), National Eye Institute Visual Functioning Questionnaire-14 for Chinese people (VF-14-CN), spectacle independence, and dysphotopsia were assessed. RESULTS: At the final visit, UDVA, CDVA, UIVA, and UNVA (LogMAR) were 0.06 ± 0.09, 0.01 ± 0.06, 0.11 ± 0.08, 0.20 ± 0.10, respectively. The mean spherical equivalent (SE) was - 0.57 ± 0.58D, sphere and cylinder were - 0.24 ± 0.60D, - 0.70 ± 0.58D respectively. No statistical difference in UDVA between eyes with SE in ± 0.50 D and in ± 1.0 D (p > 0.05). Corneal astigmatism > 1.00D has no significant effect on postoperative visual acuity (p > 0.05). The defocus curve showed that visual acuity could reach 0.2 in the refractive range of + 0.50D ~ - 1.50D. SR and MTF values were all higher than before the surgery. In bilateral implantation patients, the VF-14-CN questionnaire score and visual quality were quite excellent. CONCLUSION: The EDOF IOL have a certain tolerance for refractive errors and corneal astigmatism, and it's recommended for patients with prior myopia excimer laser surgery to achieve satisfactory visual performance.

Inside information: Systematic within-node functional connectivity changes observed across tasks or groups.

Mapping the human connectome and understanding its relationship to brain function holds tremendous clinical potential. The connectome has two fundamental components: the nodes and the sconnections between them. While much attention has been given to deriving atlases and measuring the connections between nodes, there have been no studies examining the networks within nodes. Here we demonstrate that each node contains significant connectivity information, that varies systematically across task-induced states and subjects, such that measures based on these variations can be used to classify tasks and identify subjects. The results are not specific for any particular atlas but hold across different atlas resolutions. To date, studies examining changes in connectivity have focused on edge changes and assumed there is no useful information within nodes. Our findings illustrate that for typical atlases, within-node changes can be significant and may account for a substantial fraction of the variance currently attributed to edge changes .

Serum neurofilament light chain in adult and pediatric patients with myelin oligodendrocyte glycoprotein antibody-associated disease: Correlation with relapses and seizures.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) causes major disability as a consequence of recurrent demyelinating events and neuronal loss. Biomarkers identifying different phenotypes of recurrence or tissue damage might be useful to guide individualized therapy. Herein, we evaluated serum neurofilament light chain (sNfL) as a potential biomarker in both adult and pediatric MOGAD patients. Forty-nine patients with MOGAD (37 adults, 12 children) and 71 healthy controls (HCs) (56 adults, 15 children) were enrolled prospectively from September 2019 to April 2021 at the Third Affiliated Hospital of Sun Yat-sen University and the Children's Hospital, Zhejiang University School of Medicine. sNfL levels were determined using ultrasensitive single-molecule array assay and correlated with clinical parameters. The sNfL levels in MOGAD adults in a relapsed state (median: 31.0 pg/ml) were higher than those in a remission state (8.1 pg/ml, p = 0.001) and in HC adults (10.3 pg/ml, p = 0.004). Similar results were observed in children (relapse: 46.8 pg/ml vs. remission: 13.1 pg/ml, p = 0.001; and vs. HCs: 8.2 pg/ml, p = 0.007) sNfL levels were correlated with recent relapses within 60 days (multivariate: ß = 2.02, p = 0.003), seizures (multivariate: ß = 2.50, p = 0.021) and brain lesions on magnetic resonance imaging (MRI) of a recent relapse (multivariate: ß = 1.72, p = 0.012). Our study showed that sNfL levels are beneficial for identifying recent relapses and seizures and suggest that adult and pediatric MOGAD patients had similar sNfL levels.

Adverse effects in hematologic malignancies treated with chimeric antigen receptor (CAR) T cell therapy: a systematic review and Meta-analysis.

BACKGROUND: Recently, chimeric antigen receptor-modified (CAR) T cell therapy for hematological malignancies has shown clinical efficacy. Hundreds of clinical trials have been registered and lots of studies have shown hematologic toxic effects were very common. The main purpose of this review is to systematically analyze hematologic toxicity in hematologic malignancies treated with CAR-T cell therapy. METHODS: We searched databases including PubMed, Web of Science, Embase and Cochrane up to January 2021. For safety analysis of overall hematologic toxicity, the rate of neutrophil, thrombocytopenia and anemia were calculated. Subgroup analysis was performed for age, pathological type, target antigen, co-stimulatory molecule, history of hematopoietic stem cell transplantation (HSCT) and prior therapy lines. The incidence rate of aspartate transferase (AST) increased, alanine transaminase (ALT) increased, serum creatine increased, APTT prolonged and fibrinogen decreased were also calculated. RESULTS: Overall, 52 studies involving 2004 patients were included in this meta-analysis. The incidence of any grade neutropenia, thrombocytopenia and anemia was 80% (95% CI: 68-89%), 61% (95% CI: 49-73%), and 68% (95%CI: 54-80%) respectively. The incidences of grade ≥ 3 neutropenia, thrombocytopenia and anemia were 60% (95% CI: 49-70%), 33% (95% CI: 27-40%), and 32% (95%CI: 25-40%) respectively. According to subgroup analysis and the corresponding Z test, hematological toxicity was more frequent in younger patients, in patients with ≥4 median lines of prior therapy and in anti-CD19 cases. The subgroup analysis of CD19 CAR-T cell constructs showed that 41BB resulted in less hematological toxicity than CD28. CONCLUSION: CAR-T cell therapy has dramatical efficacy in hematological malignancies, but the relevant adverse effects remain its obstacle. The most common ≥3 grade side effect is hematological toxicity, and some cases die from infections or severe hemorrhage in early period. In long-term follow-up, hematological toxicity is less life-threatening generally and most suffered patients recover to adequate levels after 3 months. To prevent life-threatening infections or bleeding events, clinicians should pay attention to intervention of hematological toxicity in the early process of CAR-T cell therapy.

QKI regulates adipose tissue metabolism by acting as a brake on thermogenesis and promoting obesity.

Adipose tissue controls numerous physiological processes, and its dysfunction has a causative role in the development of systemic metabolic disorders. The role of posttranscriptional regulation in adipose metabolism has yet to be fully understood. Here, we show that the RNA-binding protein quaking (QKI) plays an important role in controlling metabolic homeostasis of the adipose tissue. QKI-deficient mice are resistant to high-fat-diet (HFD)-induced obesity. Additionally, QKI depletion increased brown fat energy dissipation and browning of subcutaneous white fat. Adipose tissue-specific depletion of QKI in mice enhances cold-induced thermogenesis, thereby preventing hypothermia in response to cold stimulus. Further mechanistic analysis reveals that QKI is transcriptionally induced by the cAMP-cAMP response element-binding protein (CREB) axis and restricts adipose tissue energy consumption by decreasing stability, nuclear export, and translation of mRNAs encoding UCP1 and PGC1α. These findings extend our knowledge of the significance of posttranscriptional regulation in adipose metabolic homeostasis and provide a potential therapeutic target to defend against obesity and its related metabolic diseases.

Serum NfL associated with anti-NMDA receptor encephalitis.

INTRODUCTION: Neurofilament light chains (NfL) have been reported as potential markers for neuronal-axonal injury in neuroinflammatory diseases. In the current study, we describe serum NfL levels as a prognostic marker for anti-N-methyl-D-aspartate receptor encephalitis (NMDARE). METHODS: Serum levels of NfL of 64 patients with anti-NMDARE and 84 healthy controls were measured by Simoa. The anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score, Modified Rankin Scale (mRS) scores, and clinical and cerebrospinal fluid parameters were evaluated in patients with anti-NMDARE. Meanwhile, we performed a receiver-operator characteristic analysis to assess the power of the serum NFL in predicting the 1-year functional status. RESULTS: Serum NfL levels were significantly elevated in patients with anti-NMDARE compared to healthy controls (p < 0.001, padjusted < 0.001), especially in patients with severe impairments (mRS > 3 vs ≤ 3, p = 0.035) or with limited response to treatment (vs. favorable outcome, p = 0.011). Serum NFL was positively associated with the initial admission mRS (r = 0.23, p = 0.072) and 1-year mRS (r = 0.29, p = 0.018). The AUC of serum NfL and NEOS score for 1-year poor functional status was 0.697 (95% CI 0.527-0.866, p = 0.011), 0.753 (95% CI 0.616-0.890, p = 0.001), respectively. Furthermore, AUC of the combination of serum NfL and NEOS was 0.815 (95% CI 0.680-0.950, p < 0.001). CONCLUSION: Our findings show that serum NfL levels evaluated in anti-NMDAR encephalitis may be a good predictor of the risk of 1-year poor functional status.

Development of a Prognostic Model for Predicting Multiple Sclerosis After Optic Neuritis: A Secondary Analysis of Data From the Optic Neuritis Treatment Trial.

BACKGROUND: Optic neuritis can be the initial manifestation of multiple sclerosis (MS). The purpose of this study was to develop a prognostic model for predicting the risk of MS development among patients with optic neuritis. METHODS: The data from 388 patients with optic neuritis were retrieved from the Optic Neuritis Treatment Trial (ONTT). Cox proportional hazards regression analysis was used to develop a prognostic model. The performance of the model was assessed by using Harrell's C-index and calibration curves. The rates of MS development were estimated using the Kaplan-Meier method. RESULTS: Among the enrolled subjects, a total of 154 (39.7%) patients developed clinically definite MS during a median follow-up period of 15.8 years (interquartile range, 7.2-16.9 years). The factors associated with the development of MS were the presence of brain lesions as on baseline MRI, previous nonspecific neurologic symptoms, commencing low-dose corticosteroids treatment, ocular pain, and absence of optic disc/peripapillary hemorrhage. After incorporating these 5 factors into the prognostic model, a C-index of 0.72 (95% confidence interval [CI], 0.69-0.76) and good calibration curves were obtained. The C-index of the model was significantly higher than the C-indexes of any single factor (P < 0.001 in all cases). The model was able to stratify the ONTT patient cohort into 3 risk groups with significantly different intergroup rates of developing MS (rates for developing MS within a 15-year period: high-risk group, 75.7% [95% CI, 65.6%-82.9%], intermediate-risk group, 44.7% [95% CI, 31.4%-55.4%]; and low-risk group, 20.8% [95% CI, 14.2%-26.8%]; log-rank P < 0.001). CONCLUSIONS: This prognostic model had a better prediction ability when compared with the standard practice that relies solely on using brain lesions on MRI. It can, therefore, help guide decision-making to initiate earlier disease-modifying therapy for patients with optic neuritis at risk of developing MS.