Empirical dynamic modeling of the association between ambient PM2.5 and under-five mortality across 2851 counties in Mainland China, 1999-2012.

BACKGROUND: Ambient fine particulate matter (PM2.5) pollution has been associated with mortality from various diseases, however, its association with under-five mortality rate (U5MR) has remained largely unknown. METHODS: Based on the U5MR data across 2851 counties in Mainland China from 1999 to 2012, we employed approximate Bayesian latent Gaussian models to assess the association between ambient PM2.5 and U5MR at the county level for the whole nation and sub-regions. GDP growth rate, normalized difference vegetation index (NDVI), temperature, and night-time light were included as covariates using a smoothing function. We further implemented an empirical dynamic model (EDM) to explore the potential causal relationship between PM2.5 and U5MR. RESULTS: We observed a declining trend in U5MR in most counties throughout the study period. Spatial heterogeneity in U5MR was observed. Nationwide analysis suggested that each 10 µg/m3 increase in annual concentration of PM2.5 was associated with an increase of 1.2 (95% CI: 1.0 - 1.3) per 1000 live births in U5MR. Regional analyses showed that the strongest positive association was located in the Northeastern part of China [1.8 (95% CI: 1.4 - 2.1)]. The EDM showed a significant causal association between PM2.5 and U5MR, with an embedding dimension of 5 and 7, and nonlinear values θ of 4 and 6, respectively. CONCLUSION: China exhibited a downward trend in U5MR from 1999 to 2012, with spatial heterogeneity observed across the country. Our analysis reveals a positive association between PM2.5 and U5MR, which may support a causal relationship.

Warning criteria for intraoperative neurophysiologic monitoring.

PURPOSE OF REVIEW: Intraoperative changes in somatosensory (SEP) and motor evoked potentials (MEPs) may indicate potential injury to the spinal cord and will require timely intervention to prevent permanent damage. This review focuses on the validity of currently recommended warning criteria for intraoperative evoked potential monitoring. RECENT FINDINGS: Current guideline recommends a decrease in SEP amplitude by 50% and MEP amplitude by 50-100% as warning signals for injury to the ascending sensory and descending motor pathway, respectively. On the basis of cohort studies, the diagnostic accuracy of SEP and MEP to predict postoperative neurologic deficits was variable. Importantly, 0.1-4.1% of monitored patients suffered postoperative neurologic deficit despite apparently normal SEP and MEP recordings (i.e. false negative events). These data suggested that the true warning criteria may be lower than previously acknowledged. A systematic review of studies that reported changes in SEP or MEP monitoring and postoperative neurological outcome showed an association between changes in monitoring signals and postoperative neurological deficits. However, the confidence intervals were wide and it is not possible to determine a threshold value in SEP or MEP amplitude beyond which may indicate neurologic deficit. SUMMARY: Current recommendations for warning criteria during intraoperative evoked potential monitoring are empirically derived. Until a threshold that predicts spinal cord injury can be accurately determined, it remains difficult to define the clinical utility of intraoperative neurophysiologic monitoring.

Efgartigimod for generalized myasthenia gravis: A multicenter real-world cohort study in China.

OBJECTIVE: Efgartigimod, a neonatal Fc receptor antagonist, facilitates antibody degradation including pathogenic IgGs. The ADAPT study demonstrated the tolerability and efficacy of efgartigimod in the treatment of generalized myasthenia gravis (gMG). However, very limited evidence is available for the Chinese population, and it remains inconclusive about which kind of patients are selected to preferentially receive efgartigimod in real-world settings. METHODS: This multicenter cohort study included gMG patients treated at 14 neuromuscular reference centers in China. The Myasthenia Gravis Activities of Daily Living (MG-ADL) score, immunosuppressants, and the incidence of treatment-emergent adverse events (TEAEs) were prospectively collected. RESULTS: Of the 1640 gMG admitted between September and December 2023, 61 (3.7%) received efgartigimod for at least one treatment cycle. Among them, 56 cases (92%) were anti-AChR antibody-positive, 4 were anti-MuSK antibody-positive, and 1 was seronegative. Thymoma-associated myasthenia gravis accounted for most cases (44%, 27 out of 61). The principal causes of efgartigimod initiation included MG acute exacerbation (MGAE) (48%, 29 out of 61) and myasthenic crisis (MC) (15%, 9 out of 61). Clinically meaningful improvement was rapidly achieved in 97% (58 out of 61) of patients at 1.3 ± 0.7 weeks. By week 12, the MG-ADL score reduced to 3.8 ± 4.1 (baseline:10.5 ± 5.2) for all participants, while it reduced to 4.0 ± 4.7 for MGAE and 3.8 ± 4.2 for MC, respectively. All but one TMG patient required no additional rescue therapies after efgartigimod initiation. 11.5% (7 out of 61) reported ≥1 TEAEs. INTERPRETATION: This multicenter cohort study demonstrated the efficacy of efgartigimod in rapid control of gMG. Patients with MGAE or MC would benefit from efgartigimod treatment.

The effects of smoke-free legislation on acute myocardial infarction: a systematic review and meta-analysis.

BACKGROUND: Comprehensive smoke-free legislation has been implemented in many countries. The current study quantitatively examined the reduction in risk of acute myocardial infarction (MI) occurrence following the legislations and the relationship with the corresponding smoking prevalence decrease. METHODS: PubMed, EMBASE, and Google Scholar databases and bibliographies of relevant studies and reviews were searched for potential original studies published from January 1, 2004, through October 31, 2011. Meta-analysis was performed using a random effect model to estimate the overall effects of the smoking-free legislations. Meta-regression was used to investigate possible causes of heterogeneity in risk estimates. RESULTS: A total of 18 eligible studies with 44 estimates of effect size were used in this study. Meta-analysis produced a pooled estimate of the relative risk of 0.87 (95% confidence interval (CI): 0.84 to 0.91). There was significant heterogeneity in the risk estimates (overall I² = 96.03%, p<0.001). In meta-regression analysis, studies with greater smoking prevalence decrease produced larger relative risk (adjusted coefficient -0.027, 95% CI: -0.049 to -0.006, p=0.014). CONCLUSION: Smoke-free legislations in public and work places were associated with significant reduction in acute MI risk, which might be partly attributable to reduced smoking prevalence.

Anti-rituximab antibodies in patients with refractory autoimmune nodopathy with anti-neurofascin-155 antibody.

Background: Recent studies have reported that similar to other IgG4 autoimmune diseases, such as muscle-specific kinase antibody-associated myasthenia gravis, most anti-neurofascin-155 (anti-NF155) nodopathies respond well to rituximab treatment, regardless of the dosage. However, there are still a few patients for which rituximab is ineffective for unknown reasons. Currently, there are no studies on the mechanism of ineffective treatment with rituximab. Methods: A 33-year-old Chinese man presenting with numbness, tremor, and muscle weakness for 4 years was recruited for this study. Anti-NF155 antibodies were identified by cell-based assay and confirmed by immunofluorescence assay on teased fibers. The anti-NF155 immunoglobulin (IgG) subclasses were also detected by immunofluorescence assay. Anti-rituximab antibodies (ARAs) were quantitatively analyzed using enzyme-linked immunosorbent assay (ELISA), and peripheral B cell counts were determined by flow cytometry. Results: The patient exhibited anti-NF155 IgG4-antibody positivity. After the first round of rituximab infusion, the patient showed stratified outcomes with improvements in numbness, muscle weakness and ambulation. However, after three rounds of rituximab infusion, the patient's symptoms deteriorated, and the numbness, tremor and muscle weakness returned. No obvious improvement was found after plasma exchange and another round of rituximab treatment. 14 days after the last treatment with rituximab, ARAs were detected. And the titers gradually decreased on day 28 and 60 but remained higher than normal. Peripheral CD19+ B cell counts were less than 1% within the 2-month period following the final rituximab administration. Conclusions: In this study, ARAs presented in a patient with anti-NF155 nodopathy undergoing rituximab treatment and showed an unfavorable impact on rituximab efficacy. This is the first case to report the occurrence of ARAs in patients with anti-NF155 antibodies. We suggest that ARAs should be tested early during the initial intervention, especially in patients who respond poorly to rituximab treatment. In addition, we believe it is necessary to investigate the association between ARAs and B cell counts, their effect on clinical efficacy, and their potential adverse reactions in a larger cohort of patients with anti-NF155 nodopathy.

Metabolic disorder and intestinal microflora dysbiosis in chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVE: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare acquired immune-mediated neuropathy. Although microbial infection is potentially a contributing factor, a causative link between CIDP and microbial infection remains unclear. There is also no definitive biomarker for CIDP diagnostics and therapies. The present study aimed to characterize the serum metabolic profile and gut microbiome structure in CIDP. METHODS: Targeted metabolomics profiling of serum, using liquid chromatography-mass spectrometry, and metagenomics sequencing of stool samples from a cohort of CIDP and non-CIDP subjects were performed to evaluate serum metabolic profiles and gut microbiome structure in CIDP subjects relative to healthy controls. RESULTS: Metabolome data revealed that the bile acids profile was perturbed in CIDP with bile acids and arachidonic acid enriched significantly in CIDP versus non-CIDP controls. Metagenome data revealed that opportunistic pathogens, such as Klebsiella pneumonia and Megamonas funiformis, and genes involved in bacterial infection were notably more abundant in CIDP subjects, while gut microbes related to biotransformation of secondary bile acids were abnormal in CIDP versus non-CIDP subjects. Correlation analysis revealed that changes in secondary bile acids were associated with altered gut microbes, including Bacteroides ovatus, Bacteroides caccae, and Ruminococcus gnavus. CONCLUSION: Bile acids and arachidonic acid metabolism were disturbed in CIDP subjects and might be affected by the dysbiosis of gut microbial flora. These findings suggest that the combination of bile acids and arachidonic acid could be used as a CIDP biomarker and that modulation of gut microbiota might impact the clinical course of CIDP.

Clinical and diagnostic features of anti-neurofascin-155 antibody-positive neuropathy in Han Chinese.

OBJECTIVE: To investigate the clinical features of Han Chinese patients with anti-neurofascin-155 (NF155) antibody-positive neuropathy. METHODS: We screened 194 patients with peripheral neuropathy for NF155 antibodies using a cell-based assay (CBA) and teased-fiber immunofluorescence assay. We summarized the clinical findings of seropositive patients. RESULTS: The sera from 17 patients reacted to human embryonic kidney 293 cells transfected with NF155. Eleven of these patients had the immunoglobulin G (IgG) 4 isotype, a younger onset age, tremor, higher levels of cerebrospinal fluid protein, a larger diameter of the lumbosacral nerve root on magnetic resonance imaging, and the distal demyelinating symmetric phenotype. Most patients responded to steroids and rituximab. For the remaining six seropositive patients in CBA, the predominant antibody isotype was IgG3, IgG1, or undetectable, and only one patient with IgG3 showed a positive result in the teased-fiber immunofluorescence assay. These patients did not share the typical features displayed by patients with the IgG4 isotype. INTERPRETATION: In the Han Chinese population, a significant proportion of patients who fulfilled the criteria for chronic inflammatory demyelinating polyradiculoneuropathy diagnosis had anti-NF155 IgG4 antibody-positive neuropathy and displayed specific phenotypes. Ambiguous staining patterns may appear, and the potential for false positivity should be considered. For patients who presented with specific phenotypes, identifying antibodies and subtypes involved a significant laboratory workup.

Effect of low-dose rituximab treatment on autoimmune nodopathy with anti-contactin 1 antibody.

Background: Autoimmune nodopathy with anti-contactin-1 (CNTN1) responds well to rituximab instead of traditional therapies. Although a low-dose rituximab regimen was administered to patients with other autoimmune diseases, such as myasthenia gravis and neuromyelitis optica spectrum disorders, and satisfactory outcomes were obtained, this low-dose rituximab regimen has not been trialed in anti-CNTN1-positive patients. Methods: Anti-CNTN1 nodopathy patients were enrolled in this prospective, open-label, self-controlled pilot study. A cell-based assay was used to detect anti-CNTN1 antibodies and their subclasses in both serum and cerebrospinal fluid. Clinical features were evaluated at baseline, 2 days, 14 days, and 6 months after single low-dose rituximab treatment (600 mg). The titers of the subclasses of anti-CNTN1 antibody and peripheral B cells were also evaluated at baseline, 2 days, and 6 months after the rituximab regimen. Results: Two patients with anti-CNTN1 antibodies were enrolled. Both patients had neurological symptoms including muscle weakness, tremor, sensory ataxia, numbness and mild nephrotic symptoms. In the field of neurological symptoms, sensory ataxia markedly improved, and the titer of anti-CNTN1 antibody as well as CD19+ B cells decreased only two days following low-dose rituximab treatment. Other neurological symptoms improved within two weeks of rituximab treatment. At the 6-month follow-up, all neurological symptoms steadily improved with steroid reduction, and both the anti-CNTN1 antibody titer and CD19+ B cells steadily decreased. No adverse events were observed after this single low-dose rituximab treatment. Conclusions: We confirmed the clinical efficacy of low-dose rituximab by B cell depletion in autoimmune nodopathy with anti-CNTN1 antibody. This rapid and long-lasting response suggests that low-dose rituximab is a promising option for anti-CNTN1 nodopathy.

Juvenile idiopathic inflammatory myopathies with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase antibodies in a Chinese cohort.

AIMS: To characterize the clinical and histopathological characteristics and treatment outcomes of juvenile idiopathic inflammatory myopathies (JIIMs) with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies in a Chinese cohort. METHODS: We detected anti-HMGCR antibodies in a series of Chinese JIIM by ELISA and indirect immunofluorescence assay on HEK293 cells, and summarized the clinical findings of these anti-HMGCR antibody-positive patients. RESULTS: Of 32 JIIM patients, 5 (15.63%) were found to be anti-HMGCR antibody-positive. The disease duration was 1.20 ± 0.45 months. Statin exposure was not found. Four patients had skin lesions, while typical pathological features of dermatomyositis such as perifascicular atrophy or myxovirus resistance protein A expression were not found. The mean creatine kinase level was 16771.60 U/L. Among the four patients who received long-term (10.46 ± 1.42 years) follow-up, three exhibited favorable outcomes with prednisone and additional immunosuppressants. CONCLUSIONS: Our study indicates that anti-HMGCR antibodies may not be rare in Chinese JIIM. These anti-HMGCR-positive JIIMs were characterized by acute onset, substantially elevated creatine kinase level, and skin lesions without perifascicular changes in muscle pathology. The treatment outcome is generally favorable with the combination of steroid and immunosuppressant.

Reversible Neuropsychiatric Disturbances Caused by Nitrous Oxide Toxicity: Clinical, Imaging and Electrophysiological Profiles of 21 Patients with 6-12 Months Follow-up.

PURPOSE: Nitrous oxide (N2O) abuse has become an increasingly severe problem in China. The aim of the study was to summarize the features of N2O-induced neurology and enhance the awareness of this disease among physicians. PATIENTS AND METHODS: We retrospectively reviewed the clinical, imaging, electrophysiological characteristics and the prognosis of patients with N2O neurotoxicity in our hospital from January 2016 to August 2019. RESULTS: Twenty-one patients (average age: 22.6±4.6 years) were collected. Eighty-six percent (18/21) patients presented with acute or subacute neurological disorders as their initial symptoms. The remaining fourteen percent (3/21) had psychiatric symptoms as the earliest symptoms. With progression, movement dysfunction appeared in ninety percent (19/21) of the patients with fifty-three percent (10/19) presented with weakness limited to both lower extremities. Sixty-two percent (13/21) of the patients presented with subjective sensory deficit. Seventy-one percent (15/21) had vibration sense impairment and positive Romberg's sign. Sixty-seven percent of the patients had hyporeflexia or areflexia. Fourteen percent (3/21) showed positive Babinski's sign. Seventy-eight percent (14/18) showed significantly increased homocysteine (HCY) level and only seventeen percent (3/18) showed decreased serum vitamin B12 level. T2 hyperintensity involving the posterior columns and lateral columns with inverted V sign in cervical spinal MRI had been observed in forty-seven percent (8/17) of the patients. Axonal peripheral neuropathy occurred in eighty-five percent (17/20) of the patients. The level of serum vitamin B12 and HCY, as well as imaging findings, were rapidly recovered after supplementation of Vitamin B12. CONCLUSION: The N2O-induced neuropsychiatric disturbances mainly occurred in the young groups and should be recognized by clinicians. The prognosis of N2O intoxication is relatively good.

Berberine downregulates CDC6 and inhibits proliferation via targeting JAK-STAT3 signaling in keratinocytes.

Psoriasis is a chronic skin disease characterized by hyperproliferation and impaired differentiation of epidermal keratinocytes accompanied by increased inflammation, suggesting that molecules with antiproliferation and anti-inflammatory abilities may be effective for its treatment. One of the key steps in regulating cell proliferation is DNA replication initiation, which relies on prereplication complex (pre-RC) assembly on chromatin. CDC6 is an essential regulator of pre-RC assembly and DNA replication in eukaryotic cells, but its role in proliferation of keratinocytes and psoriasis is unknown. Here we examined CDC6 expression in psoriatic skin and evaluated its function in the proliferation of human keratinocytes. CDC6 expression is upregulated in epidermal cells in psoriatic lesions and it could be induced by IL-22/STAT3 signaling, a key signaling pathway involved in the pathogenesis of psoriasis, in keratinocytes. Depletion of CDC6 leads to decreased proliferation of keratinocytes. We also revealed that berberine (BBR) could inhibit CDK4/6-RB-CDC6 signaling in keratinocytes, leading to reduced proliferation of keratinocytes. The mechanism of antiproliferation effects of BBR is through the repression of JAK1, JAK2, and TYK2, which in turn inhibits activation of STAT3. Finally, we demonstrated that BBR could inhibit imiquimod-induced psoriasis-like skin lesions and upregulation of CDC6 and p-STAT3 in mice. Collectively, our findings indicate that BBR inhibits CDC6 expression and proliferation in human keratinocytes by interfering the JAK-STAT3 signaling pathway. Thus, BBR may serve as a potential therapeutic option for patients with psoriasis.

Hypertension modifies the short-term effects of temperature on morbidity of hemorrhagic stroke.

BACKGROUND: This study estimated the effects of ambient temperature on hospital admissions for hemorrhagic stroke during 2004-2009 in Jinan, China, and the effect modification of hypertension status. METHODS: The exposure-response relationship between temperature and hemorrhagic stroke was firstly examined, and then the association between daily mean temperature and hemorrhagic stroke was investigated using a generalized additive model. Stratified analyses were conducted to examine the potential effect modification of hypertension. RESULTS: A total of 1577 hemorrhagic stroke cases were observed between 2004 and 2009, among which, 1058 were hypertensive and 519 were non-hypertensive. We found an approximately linear relationship between ambient temperature and hemorrhagic stroke. Each 1°C decrease in the current day's temperature was associated with 1.63% (95% CI: 0.33%, 2.95%) increase in daily hemorrhagic stroke. The stratified analyses observed that the association was significant among hypertensive hemorrhagic stroke, each 1°C decrease in the current day's temperature was associated with 2.26% (95% CI: 0.57%, 3.98%) increase in daily hypertensive hemorrhagic stroke. While no significant effect was observed for non-hypertensive hemorrhagic stroke. CONCLUSIONS: Low temperature might be one risk factor for hemorrhagic stroke and hypertension may be one effect modifier of this association in Jinan, China.

Protective effects of nimodipine on cerebrovascular function in chronic alcoholic encephalopathy.

In the present study, we used chronic gavage administration of alcohol with gradual increases in alcohol concentration and volume to generate a rat model of chronic alcohol intoxication. We measured the changes in biological, behavioral, pathological and vascular injury-related molecular biological markers, and explored the effects of nimodipine intervention on alcohol intoxication. We found that chronic alcohol consumption induced a variety of behavioral abnormalities, accompanied by severe pathological changes in cerebral arterioles, prefrontal cortex and cerebellar tissue, as well as an upregulation of vascular endothelial growth factor (VEGF), leptin receptor (ob-R) and endothelin-1 (ET-1). Treatment with mimodipine for 15 days significantly improved behavioral abnormalities, alleviated the pathological changes in blood vessels and brain tissues, increased VEGF expression, decreased ob-R expression, reduced plasma ET-1 leakage and protected vascular and neuronal functions.

Short-term effect of El Niño-Southern Oscillation on pediatric hand, foot and mouth disease in Shenzhen, China.

Hand, foot and mouth disease (HFMD) was an emerging viral infectious disease in recent years in Shenzhen. The underlying risk factors have not yet been systematically examined. This study analyzed the short-term effect of El Niño-Southern Oscillation on pediatric HFMD in Shenzhen, China. Daily count of HFMD among children aged below 15 years old, Southern Oscillation Index (SOI), and weather variables were collected to construct the time series. A distributed lag non-linear model was applied to investigate the effect of daily SOI on pediatric HFMD occurrence during 2008-2010. We observed an acute effect of SOI variation on HFMD occurrence. The extremely high SOI (SOI = 45, with 0 as reference) was associated with increased HFMD, with the relative risk (RR) being 1.66 (95% Confidence Interval [CI]: 1.34-2.04). Further analyses of the association between HFMD and daily mean temperature and relative humidity supported the correlation between pediatric HFMD and SOI. Meteorological factors might be important predictors of pediatric HFMD occurrence in Shenzhen.

Ischemic stroke hospital admission associated with ambient temperature in Jinan, China.

BACKGROUND: This study estimated the effects of ambient temperature and relative humidity on hospital admissions for ischemic stroke during 1990-2009 in Jinan, China. METHODS: To account for possible delayed effects and harvesting effect, we examined the impact of meteorological factors up to 30 days before each admission using a distributed lag non-linear model; we controlled for season, long-term trend, day of week and public holidays in the analysis. Stratified analyses were also done for summer and winter. RESULTS: A total of 1,908 ischemic stroke hospital admissions were observed between 1990 and 2009. We found a strong non-linear acute effect of daily temperatures on ischemic stroke hospital admission. With the mean temperature 15°C as the reference, the relative risk (RR) was 1.43 (95% confidence interval (CI): 1.10-1.85) for 0°C daily temperature on the same day, and 0.43 (95% CI: 0.31-0.59) for 30°C daily temperature on the same day, respectively. The effect of ambient temperature was similar in summer and winter. No significant association was observed between relative humidity and ischemic stroke hospitalization. CONCLUSIONS: Low temperature might be a risk factor for ischemic stroke, and high temperature might be protective factor of ischemic stroke occurrence in Jinan, China.