Serum myoglobin as predictor of acute kidney injury and 90-day mortality in patients with rhabdomyolysis after exertional heatstroke: an over 10-year intensive care survey.

OBJECTIVE: Rhabdomyolysis (RM) in exertional heatstroke (EHS) often leads to multiple organ dysfunction including acute kidney injury (AKI). Studies have shown that serum creatine kinase (CK) >1000 U/L as a serological diagnostic criterion for RM does not reflect the risk of AKI or mortality. METHODS: This longitudinal cohort study included all patients with EHS who were admitted to intensive care unit between January 2008 and June 2019. Serum myoglobin (sMb) was studied as the serological marker of RM and compared with CK. Outcome events were AKI and 90-day mortality. RESULTS: A total of 161 patients were enrolled, of whom 52 (32.3%) had sMb ≥1000 ng/mL. Patients with sMb ≥1000 ng/mL had higher SOFA score, higher APACHE II score, lower GCS score, and higher incidence of disseminated intravascular coagulation, acute myocardial injury, acute liver injury, AKI, and 90-day mortality than patients with sMb <1000 ng/mL. Lymphocytes, neutrophils, D-Dimer were risk factors for AKI in patients with sMb ≥1000 ng/mL. Curve fitting showed a curved relationship between sMb and EHS-induced AKI but not CK. sMb ≥1000 ng/mL showed better predictive ability for AKI (area under curve: 0.786). APACHE II, SOFA, and GCS scores were risk factors for 90-day mortality in patients with sMb ≥1000 ng/mL. CONCLUSION: Serum myoglobin is a better predictor of AKI and 90-day mortality than CK in patients with RM after EHS.

Severe COVID-19-associated sepsis is different from classical sepsis induced by pulmonary infection with carbapenem-resistant klebsiella pneumonia (CrKP).

PURPOSE: COVID-19 is also referred to as a typical viral septic pulmonary infection by 2019-nCoV. However, little is known regarding its characteristics in terms of systemic inflammation and organ injury, especially compared with classical bacterial sepsis. This article aims to investigate the clinical characteristics and prognosis between COVID-19-associated sepsis and classic bacterial-induced sepsis. METHODS: In this retrospective cohort study, septic patients with COVID-19 in the intensive care unit (ICU) of a government-designed therapy center in Shenzhen, China between January 14, 2020 and March 10, 2020, and septic patients induced by carbapenem-resistant klebsiella pneumonia (CrKP) admitted to the ICU of the Second People's Hospital of Shenzhen, China between January 1, 2014 and October 30, 2019 were enrolled. Demographic and clinical parameters including comorbidities, critical illness scores, treatment, and laboratory data, as well as prognosis were compared between the two groups. Risk factors for mortality and survival rate were analyzed using multivariable logistic regression and survival curve, respectively. RESULTS: A total of 107 patients with COVID-19 and 63 patients with CrKP were enrolled. A direct comparison between the two groups demonstrated more serious degrees of primary lung injury following 2019-nCoV infection (indicated by lower PaO2/FiO2), but milder systemic inflammatory response, lower sequential organ failure assessment score and better functions of the organs like heart, liver, kidney, coagulation, and circulation. However, the acquired immunosuppression presented in COVID-19 patients was more severe, which presented as lower lymphocyte counts (0.8×109/L vs. 0.9×109/L). Moreover, the proportion of COVID-19 patients treated with corticosteroid therapy and extracorporeal membrane oxygenation was larger compared with CrKP patients (78.5% vs. 38.1% and 6.5% vs. 0, respectively) who required less invasive mechanical ventilation (31.6% vs. 54.0%). The incidence of hospitalized mortality and length of ICU stay and total hospital stay were also lower or shorter in viral sepsis (12.1% vs. 39.7%, 6.5 days vs. 23.0 days and 21.0 days vs. 33.0 days, respectively) (all p < 0.001). Similar results were obtained after being adjusted by age, gender, comorbidity and PaO2/FiO2. Lymphocytopenia and high acute physiology and chronic health evaluation II scores were common risk factors for in-hospital death. While the death cases of COVID-19 sepsis mostly occurred at the later stages of patients' hospital stay. CONCLUSION: Critical COVID-19 shares clinical characteristics with classical bacterial sepsis, but the degree of systemic inflammatory response, secondary organ damage and mortality rate are less severe. However, following 2019-nCoV infection, the level of immunosuppression may be increased and thus induce in more death at the later stage of patients' hospitalstay.

Risk factors for mortality in critically ill patients with COVID-19: a multicenter retrospective case-control study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has spread around the world, until now, the number of positive and death cases is still increasing. Therefore, it remains important to identify risk factors for death in critically patients. METHODS: We collected demographic and clinical data on all severe inpatients with COVID-19. We used univariable and multivariable Cox regression methods to determine the independent risk factors related to likelihood of 28-day and 60-day survival, performing survival curve analysis. RESULTS: Of 325 patients enrolled in the study, Multi-factor Cox analysis showed increasing odds of in-hospital death associated with basic illness (hazard ratio [HR] 6.455, 95% Confidence Interval [CI] 1.658-25.139, P = 0.007), lymphopenia (HR 0.373, 95% CI 0.148-0.944, P = 0.037), higher Sequential Organ Failure Assessment (SOFA) score on admission (HR 1.171, 95% CI 1.013-1.354, P = 0.033) and being critically ill (HR 0.191, 95% CI 0.053-0.687, P = 0.011). Increasing 28-day and 60-day mortality, declining survival time and more serious inflammation and organ failure were associated with lymphocyte count < 0.8 × 109/L, SOFA score > 3, Acute Physiology and Chronic Health Evaluation II (APACHE II) score > 7, PaO2/FiO2 < 200 mmHg, IL-6 > 120 pg/ml, and CRP > 52 mg/L. CONCLUSIONS: Being critically ill and lymphocyte count, SOFA score, APACHE II score, PaO2/FiO2, IL-6, and CRP on admission were associated with poor prognosis in COVID-19 patients.

Clinical characteristics and risk factors of male exertional heatstroke in patients with myocardial injury: an over 10-year retrospective cohort study.

BACKGROUND: Heatstrokes are a serious threat to human health, particularly the cardiovascular system. Understanding the clinical features and risk factors related to death in patients with myocardial injury (MI) complicated by heat stroke is crucial. METHOD: This study included the baseline data of all patients with severe heatstroke between October 2008 and May 2019. RESULTS: Of the 162 patients enrolled, 75 (46.3%) were in the MI group and 87 (53.7%) were in the non-MI group. A significant difference was noted in 90-day survival between the two groups even after correction for Age, Acute Physiology, and Chronic Health Evaluation II (APACHE II) scores, Sequential Organ Failure Assessment (SOFA) scores, Glasgow Coma Score (GCS), and activated partial thromboplastin time (before correction (p < .001; after correction, p = .023). Survival analysis showed that the 90-day survival time of patients with MI was shorter than that of patients without MI (p < .001). The area under the receiver operating characteristic (ROC) curve for predicting mortality based on the SOFA score was 92.8% (95% CI 0.847-1.000, p < .001), the optimal cutoff value was 7.5, the sensitivity was 91.7%, and the specificity was 94.6%. CONCLUSION: Patients with heatstroke having MI had more severe clinical conditions, 90-day mortality was significantly increased, and the survival time was shortened. A high SOFA score is an independent risk factor for death in patients with heatstroke having MI, with an optimal cutoff value of 7.5, sensitivity of 91.7%, and specificity of 94.6%.

Association of D-dimer and acute kidney injury associated with rhabdomyolysis in patients with exertional heatstroke: an over 10-year intensive care survey.

Patients with rhabdomyolysis (RM) following exertional heatstroke (EHS) are often accompanied by dysfunction of coagulation and acute kidney injury (AKI). The purpose of this study was to investigate the relationship between D-dimer and AKI in patients with RM following EHS. A retrospective study was performed on patients with EHS admitted to the intensive care unit over 10-year. Data including baseline clinical information at admission, vital organ dysfunction, and 90-day mortality were collected. A total of 84 patients were finally included, of whom 41 (48.8%) had AKI. AKI patients had more severe organ injury and higher 90-day mortality (34.1 vs.0.0%, p < 0.001) than non-AKI patients. Multivariate logistic analysis showed that D-dimer (OR 1.3, 95% CI 1.1-1.7, p = 0.018) was an independent risk factor for AKI with RM following EHS. Curve fitting showed a curve relationship between D-dimer and AKI. Two-piecewise linear regression showed that D-dimer was associated with AKI in all populations (OR 1.3, 95% CI 1.2-1.5, p < 0.001) when D-dimer <10.0 mg/L, in RM group (OR 1.3, 95% CI 1.1-1.5, p < 0.001) when D-dimer >0.4 mg/L, in the non-RM group (OR 6.4, 95% CI 1.7-23.9, p = 0.005) when D-dimer <1.3 mg/L and D-dimer did not increase the incidence of AKI in the non-RM group when D-dimer >1.3 mg/L. AKI is a life-threatening complication of RM following EHS. D-dimer is associated with AKI in critically ill patients with EHS. The relationship between D-dimer and AKI depends on whether RM is present or not.

Epidemiologic characteristics of traumatic fractures in elderly patients during the outbreak of coronavirus disease 2019 in China.

PURPOSE: This study aimed to describe the epidemiologic characteristics of fracture in the elderly during the COVID-19. METHODS: This was a retrospective multi-centre study, which included patients who sustained fractures between 20 January and 19 February 2020. The collected data included patients' demographics (age and gender), injury-related (injury type, fracture location, injury mechanism, places where fracture occurred), and treatment modality. SPSS 23.0 was used to describe the data and perform some analysis. RESULTS: A total of 436 patients with 453 fractures were included; there were 153 males and 283 females, with an average age of 76.2 years (standard deviation, SD, 7.7 years; 65 to 105). For either males or females, 70-74 years was the most commonly involved age group. A total of 317 (72.7%) patients had their fractures occurring at home. Among 453 fractures, there were 264 (58.3%) hip fractures, accounting for 58.3%. Fall from standing height was the most common cause of fracture, making a proportion of 89.4% (405/453). Most fractures (95.8%, 434/453) were treated surgically, and 4.2% (19/453) were treated by plaster fixation or traction. Open reduction and internal fixation (ORIF) was the most used surgical method, taking a proportion of 49.2% (223/453). CONCLUSION: These findings highlighted the importance of primary prevention (home prevention) measures and could be used for references for individuals, health care providers, or health administrative department during the global pandemic of COVID-19.

Sex Differences in Clinical Characteristics and 2-Year Prognosis of Patients with Heart Failure Grouped by Left Ventricular Ejection Fraction Status.

After the new left ventricular ejection fraction (LVEF) classification criteria emerged, many studies have focused on the differences between heart failure (HF) with reduced EF (HFrEF), HF with midrange EF (HFmrEF), and HF with preserved EF (HFpEF). However, the lack of consensus on sex-related differences in prognosis within the new standard remains. We aimed to explore sex differences in the clinical characteristics and prognoses of Chinese inpatients with HF defined according to the new standard.From March 2014 to February 2016, 2284 patients with symptomatic HF were consecutively recruited to this prospective research. Case data and 2-year follow-up observations were used to identify sex differences in clinical characteristics and prognoses.When comparing men and women with HFrEF, HFmrEF, and HFpEF, women were older, were more likely to be hospitalized for the first diagnosis of HF, and had lower mean LVEF. Women had a higher tendency of all-cause mortality than did men at 3, 12, and 24 months following HF. After multivariate adjustment, the hazard ratios (HRs) for 24-month all-cause mortality for HFrEF, HFmrEF, and HFpEF were 1.113 (0.728, 1.704), P = 0.620; 1.063 (0.730, 1.548), P = 0.750; and 0.619 (0.240, 1.593), P = 0.320, for men versus women, respectively.There were some sex differences in the clinical characteristics of patients with symptomatic HF in HFrEF, HFmrEF, and HFpEF, but women and men had comparable outcomes over the 2-year period following hospitalization.

Serum procalcitonin levels are associated with rhabdomyolysis following exertional heatstroke: an over 10-year intensive care survey.

BACKGROUND: Heatstroke has become a common emergency event in hospitals. Procalcitonin (PCT) is used as a biomarker of infection in the emergency department (ED), but its role in rhabdomyolysis (RM) following exertional heatstroke (EHS) remains unclear. METHODS: A retrospective cohort study enrolled patients with EHS from the intensive care unit (ICU). We collected RM biomarkers, inflammation markers, critical disease scores at admission, 24 h, 48 h, and discharge, and 90-day mortality. Correlation analysis, linear regression and curve fitting were used to identify the relationship between PCT and RM. RESULTS: A total of 162 patients were recruited and divided into RM (n=56) and non-RM (n=106) groups. PCT was positively correlated with myoglobin (Mb), acute hepatic injury, disseminated intravascular coagulation (DIC), Sequential Organ Failure Assessment (SOFA) score, and Acute Physiology and Chronic Health Evaluation II (APACHE II) score, with correlation coefficients of 0.214, 0.237, 0.285, 0.454, and 0.368, respectively (all P<0.05). Interestingly, the results of curve fitting revealed a nonlinear relationship between PCT and RM, and a two-piecewise linear regression model showed that PCT was related to RM with an odds ratio of 1.3 and a cut-off of <4.6 ng/mL. Survival analysis revealed that RM was associated with higher mortality compared to non-RM cases (P=0.0093). CONCLUSION: High serum PCT concentrations are associated with RM after EHS in critically ill patients. Elevated PCT concentrations should be interpreted cautiously in patients with EHS in the ED.

Genetic causal association between varicella-zoster virus infection and psychiatric disorders: A 2-sample Mendelian randomization study.

BACKGROUND: Psychiatric disorders, such as schizophrenia (SCZ), major depressive (MDD), and bipolar disorder (BD) have a profound impact on millions of individuals worldwide. The critical step toward developing effective preventive and treatment strategies lies in comprehending the causal mechanisms behind these diseases and identifying modifiable risk factors associated with them. METHODS: In this study, we conducted a 2-sample Mendelian randomization analysis to explore the potential links between chickenpox(varicella-zoster virus infection) and three major psychiatric disorders(SCZ, MDD, BD). RESULTS: In our MR study, among the three major psychiatric disorders, chickenpox was shown to be causally related to BD, indicating that infection with chickenpox may increase the risk of developing BD (IVW: OR = 1.064, 95% CI =1.025-1.104, P=0.001; RAPS: OR=1.066, 95% CI=1.024-1.110, P=0.002), while there was no causal relationship between SCZ and MDD. Similar estimated causal effects were observed consistently across the various MR models. The robustness of the identified causal relationship between chickenpox and BD holds true regardless of the statistical methods employed, as confirmed by extensive sensitivity analyses that address violations in model assumptions. The MR-Egger regression test failed to reveal any signs of directional pleiotropy (intercept = -0.042, standard error (SE) = 0.029, p = 0.236). Similarly, the MR-PRESSO analysis revealed no evidence of directional pleiotropy or outliers among the chickenpox-related instrumental variables (global test p = 0.653). Furthermore, a leave-one-out sensitivity analysis yielded consistent results, further underscoring the credibility and stability of the causal relationship. CONCLUSIONS: Our findings provide compelling evidence of a causal effect of chickenpox on the risk of BD. To gain a more comprehensive understanding of this association and its underlying mechanisms, additional research is needed. Such investigations are pivotal in identifying effective interventions for promoting BD prevention.

Identification of toll-like receptor 2 as a key regulator of neuronal apoptosis in vascular dementia by bioinformatics analysis and experimental validation.

BACKGROUND: Vascular dementia (VaD), the second most prevalent type of dementia, lacks a well-defined cause and effective treatment. Our objective was to utilize bioinformatics analysis to discover the fundamental disease-causing genes and pathological mechanisms in individuals diagnosed with VaD. METHODS: To identify potential pathogenic genes associated with VaD, we conducted weighted gene co-expression network analysis (WGCNA), differential expression analysis, and protein-protein interaction (PPI) analysis. The exploration of potential biological mechanisms involved the utilization of Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis. Moreover, a bilateral common carotid artery stenosis (BCAS) mouse model of VaD was established, and the expression of the hub gene, its relationship with cognitive function and its potential pathogenic mechanism were verified by cognitive behavior tests, cerebral blood flow measurement, Western blotting, and immunofluorescence experiments. RESULTS: This study identified 293 DEGs from the brain cortex of VaD patients and healthy controls, among these genes, the Toll-like receptor 2 (TLR2) gene was identified as hub gene, and it was associated with the apoptosis-related pathway PI3K/AKT.The BCAS model demonstrated that the use of TLR2 inhibitors greatly enhanced the cognitive function of the mice (p < 0.05). Additionally, there was a notable decrease in the number of apoptotic cells in the brain cortex of the mice (p < 0.01). Moreover, significant alterations in the levels of proteins related to the PI3K/AKT pathway and cleaved-caspase3 proteins were detected (p < 0.05). CONCLUSIONS: TLR2 plays a role in the pathophysiology of VaD by enhancing the neuronal apoptotic pathway, suggesting it could be a promising therapeutic target.

CSF1R blockade slows progression of cerebral hemorrhage by reducing microglial proliferation and increasing infiltration of CD8 + CD122+ T cells into the brain.

Microglia play a pivotal role in the neuroinflammatory response after brain injury, and their proliferation is dependent on colony-stimulating factors. In the present study, we investigated the effect of inhibiting microglia proliferation on neurological damage post intracerebral hemorrhage (ICH) in a mouse model, an aspect that has never been studied before. Using a colony-stimulating factor-1 receptor antagonist (GW2580), we observed that inhibition of microglia proliferation significantly ameliorated neurobehavioral deficits, attenuated cerebral edema, and reduced hematoma volume after ICH. This intervention was associated with a decrease in pro-inflammatory factors in microglia and an increased infiltration of peripheral regulatory CD8 + CD122+ T cells into the injured brain tissue. The CXCR3/CXCL10 axis is the mechanism of brain homing of regulatory CD8 + CD122+ T cells, and the high expression of IL-10 is the hallmark of their synergistic anti-inflammatory effect with microglia. And activated astrocytes around the insult site are a prominent source of CXCL10. Thus, inhibition of microglial proliferation offers a new perspective for clinical translation. The cross-talk between multiple cells involved in the regulation of the inflammatory response highlights the comprehensive nature of neuroimmunomodulation.

Telomeres: Dysfunction, Maintenance, Aging and Cancer.

Aging has emerged at the forefront of scientific research due to the growing social and economic costs associated with the growing aging global population. The defining features of aging involve a variety of molecular processes and cellular systems, which are interconnected and collaboratively contribute to the aging process. Herein, we analyze how telomere dysfunction potentially amplifies or accelerates the molecular and biochemical mechanisms underpinning each feature of aging and contributes to the emergence of age-associated illnesses, including cancer and neurodegeneration, via the perspective of telomere biology. Furthermore, the recently identified novel mechanistic actions for telomere maintenance offer a fresh viewpoint and approach to the management of telomeres and associated disorders. Telomeres and the defining features of aging are intimately related, which has implications for therapeutic and preventive approaches to slow aging and reduce the prevalence of age-related disorders.

Relationship between BUN/Cr and Prognosis of HF Across the Full Spectrum of Ejection Fraction. / Relação entre a Razão Nitrogênio Ureico/Creatinina e Prognóstico de Insuficiência Cardíaca em Todo o Espectro da Fração de Ejeção.

BACKGROUND: In patients with heart failure (HF), due to the relative deficiency of blood volume, neurohormone system activation leads to renal vasoconstriction, which affects the content of blood urea nitrogen (BUN) and creatinine (Cr) in the body, while BUN and Cr are easily affected by other factors. Therefore, BUN/Cr can be used as another marker for the prognosis of HF. OBJECTIVE: Explore the prognosis of adverse outcome of HF in the high BUN/Cr group compared with the low BUN/Cr group across the full spectrum of ejection fraction. METHODS: From 2014 to 2016, symptomatic hospitalized HF patients were recruited and followed up to observe adverse cardiovascular outcomes. Logistic analysis and COX analysis were performed to determine significance. p-values <0.05 were considered statistically significant. RESULTS: In the univariate logistic regression analysis, the high BUN/Cr group had a higher risk of adverse outcome in heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Multivariate logistic regression analysis showed that the risk of cardiac death in the HFrEF group was higher than that in the low BUN/Cr group, while the risk of all-cause death was significant only in 3 months (p<0.05) (Central Illustration). The risk of all-cause death in the high BUN/Cr in the HFpEF group was significantly higher than that in the low BUN/Cr group at two years. CONCLUSION: The high BUN/Cr group is related to the risk of poor prognosis of HFpEF, and is not lower than the predictive value of left ventricular ejection fraction (LVEF).

FUNDAMENTO: Em pacientes com insuficiência cardíaca (IC), devido à relativa deficiência do volume sanguíneo, a ativação do sistema neuro-hormonal leva à vasoconstrição renal, que afeta o teor de nitrogênio ureico (NU) e creatinina (C) no organismo, sendo que NU e C são facilmente afetados por outros fatores. Portanto, a razão NU/C pode ser utilizada como mais um marcador para o prognóstico da IC. OBJETIVO: Explorar o prognóstico do desfecho adverso da IC no grupo NU/C alta em comparação com o grupo NU/C baixa em todo o espectro da fração de ejeção. MÉTODOS: De 2014 a 2016, pacientes sintomáticos hospitalizados com IC foram recrutados e acompanhados para observar desfechos cardiovasculares adversos. Foram realizadas análise logística e a análise COX para determinar a significância. Valores de p<0,05 foram considerados estatisticamente significativos. RESULTADOS: Na análise de regressão logística univariada, o grupo NU/C alta apresentou maior risco de desfecho adverso na insuficiência cardíaca com fração de ejeção reduzida (ICFEr) e insuficiência cardíaca com fração de ejeção preservada (ICFEp). A análise de regressão logística multivariada mostrou que o risco de morte cardíaca no grupo ICFEr foi maior do que no grupo NU/C baixa, enquanto o risco de morte por todas as causas foi significativo apenas em 3 meses (p<0,05) (Ilustração Central). O risco de morte por todas as causas no grupo NU/C alta no grupo ICFEP foi significativamente maior do que no grupo NU/C baixa em dois anos. CONCLUSÃO: O grupo NU/C alta está relacionado ao risco de mau prognóstico da ICFEP, não sendo inferior ao valor preditivo da fração de ejeção do ventrículo esquerdo (FEVE).

Serum myoglobin modulates kidney injury via inducing ferroptosis after exertional heatstroke.

Background and Objectives: Myoglobin released by rhabdomyolysis (RM) is considered to be involved in pathogenesis of kidney disease caused by crush injury, but whether high level of serum myoglobin predisposes patients to acute kidney injury (AKI) and its molecular mechanisms are still unclear in exertional heatstroke (EHS). We aimed to determine the association and potential mechanism of myoglobin and AKI, and further investigate the targeted therapeutic agents for myoglobinemia. Methods: Serum myoglobin concentrations in patients with EHS were measured at admission, 24 h and 48 h after admission and discharge. The risk of AKI at 48 h was the primary outcome; the secondary outcome was composite outcome events with myoglobin levels and AKI at discharge and death at 90 days. In experimental studies, we further investigated the mechanisms of human kidney proximal tubular (HK-2) cells that were exposed to human myoglobin under heat stress conditions and the effect of baicalein. Results: Our measurements showed that the highest myoglobin quartile (vs. the lowest) had an adjusted odds ratio (OR) of 18.95 (95% confidence interval [CI], 6.00-59.83) for AKI and that the OR (vs. quartile 2) was 7.92 (95% CI, 1.62-38.89) for the secondary outcome. The survival rate of HK-2 cells treated with myoglobin under heat stress was significantly decreased, and the production of Fe2+ and reactive oxygen species (ROS) was markedly increased, accompanied by changes in ferroptosis proteins, including increased p53, decreased SLC7A11 and GPX4, and alterations in endoplasmic reticulum stress (ERS) marker proteins. Treatment with baicalein attenuated HK-2 cell ferroptosis induced by myoglobin under heat stress through inhibition of ERS. Conclusions: High myoglobin was associated with AKI in the EHS, and its mechanisms involved ERS-associated ferroptosis. Baicalein may be a potential therapeutic drug for the treatment of AKI in patients with high myoglobin induced by rhabdomyolysis following EHS.

CoMFA Directed Molecular Design for Significantly Improving Fungicidal Activity of Novel [1,2,4]-Triazolo-[3,4-b][1,3,4]-thiadizoles.

Target based molecular design via the aid of computation is one of the most efficient methods in the discovery of novel pesticides. Here, a combination of the comparative molecular field analysis (CoMFA) and molecular docking was applied for discovery of potent fungicidal [1,2,4]-triazolo-[3,4-b][1,3,4]-thiadiazoles. Bioassay results indicated that the synthesized target compounds 3a, 3b, and 3c exhibited good activity against Alternaria solani, Botrytis cinerea, Cercospora arachidicola, Fusarium graminearum, Physalospora piricola, Rhizoctonia solani, and Sclerotinia sclerotiorum with an EC50 value falling between 0.64 and 16.10 µg/mL. Specially, 3c displayed excellent fungicidal activity against C. arachidicola and R. solani, which was 5 times more potent than the lead YZK-C22. The enzymatic inhibition assay and fluorescence quenching analysis with R. solani pyruvate kinase (RsPK) showed a weaker binding affinity between RsPK and 3a, 3b, or 3c. Transcriptomic analyses showed that 3c exerted its fungicidal activity by disrupting steroid biosynthesis and ribosome biogenesis in eukaryotes. These findings support that 3c is a promising fungicide candidate, and a fine modification from a lead may lead to a totally different mode of action.

Intranasal Delivery of Gene-Edited Microglial Exosomes Improves Neurological Outcomes after Intracerebral Hemorrhage by Regulating Neuroinflammation.

Neural inflammatory response is a crucial pathological change in intracerebral hemorrhage (ICH) which accelerates the formation of perihematomal edema and aggravates neural cell death. Although surgical and drug treatments for ICH have advanced rapidly in recent years, therapeutic strategies that target and control neuroinflammation are still limited. Exosomes are important carriers for information transfer among cells. They have also been regarded as a promising therapeutic tool in translational medicine, with low immunogenicity, high penetration through the blood-brain barrier, and ease of modification. In our previous research, we have found that exogenous administration of miRNA-124-overexpressed microglial exosomes (Exo-124) are effective in improving post-injury cognitive impairment. From this, we evaluated the potential therapeutic effects of miRNA-124-enriched microglial exosomes on the ICH mice in the present study. We found that the gene-edited exosomes could attenuate neuro-deficits and brain edema, improve blood-brain barrier integrity, and reduce neural cell death. Moreover, the protective effect of Exo-124 was abolished in mice depleted of Gr-1+ myeloid cells. It suggested that the exosomes exerted their functions by limiting the infiltration of leukocyte into the brain, thus controlling neuroinflammation following the onset of ICH. In conclusion, our findings provided a promising therapeutic strategy for improving neuroinflammation in ICH. It also opens a new avenue for intranasal delivery of exosome therapy using miRNA-edited microglial exosomes.

Immune Cells Characteristics and Their Prognostic Effects in Exertional Heatstroke Patients: A Retrospective Cohort Study.

Background: Exertional heatstroke (EHS) remains a major problem for those who take strenuous physical activity. Inflammation and immune dysfunction were thought to be crucial to the pathophysiological process of heatstroke. The present study was aimed to investigate the dynamic changes of the immune cells in patients with EHS and determine their prognostic effects to provide the clinical evidence of the above process. Methods: This single-center retrospective cohort study collected all patients with EHS admitted to the intensive care unit (ICU) of the General Hospital of Southern Theater Command of PLA from October 2008 to May 2019. The dynamic changes of the main immune cell count and ratio were collected, including white blood cell (WBC), neutrophil, monocyte, and lymphocyte. The neutrophil-to-lymphocyte ratios (NLR) were calculated by the neutrophil count/lymphocyte count × 100%. The main outcome was 90-day mortality. Results: A total of 189 patients were enrolled. For survivors, after 24 h, the WBC and neutrophil counts began to decrease, and they were back to normal in 72 h. In addition, the lymphocyte counts were within normal limits all the time. For non-survivors, the WBC and neutrophil counts were continuous over the normal range, while the lymphocyte count and the ratio began to decrease after 24 h and were continuously low in the following days. Receiver operating characteristic (ROC) curves analysis showed that increased neutrophils and decreased lymphocytes were associated with the poor prognosis of the patients. A prediction model based on immune cell counts and ratios was constructed, and the lymphocyte count was accounted for the maximum weight. Conclusions: In patients with EHS, increased neutrophils and decreased lymphocytes were associated with the poor prognosis. The lymphocyte count at 72 h after admission was the most important prognostic factor.

Analysis of Clinical Symptoms of Guillain-Barré Syndrome Induced by Heat Stroke: Three Case Reports and Literature Review.

Background: Heat stroke is a potentially fatal condition that is caused by elevated core temperature. Guillain-Barré syndrome (GBS) induced by heat stroke is extremely rare and has only been reported in few case reports. The purpose of this case study was to evaluate the clinical symptoms, neuroelectrophysiological and imageological features of GBS after heat stroke. Methods: We reviewed our hospital records and previously published reports to find the cases of GBS after heat stroke. The clinical, imageological, and electrophysiological profiles, treatment and prognosis were presented and analyzed. Results: We retrieved three cases of GBS induced by heat stroke from our hospital, which presented as lesions on multiple cranial and peripheral nerves and albuminocytologic dissociation in the cerebrospinal fluid. All of these patients had disorders of consciousness at the early stage of heat stroke and a "pseudo-recovery period" after they recovered from coma after heat stroke. After immunoglobulin administration and immunoregulation therapy, these patients' neurological deficiencies were relieved significantly. But there are still disabilities and almost totally reliant on others. Conclusions: The number of the cases of GBS induced by HS reported in this study has been the most in the recent 5 years. Clinicians should pay attention to patients with heat stroke with sustained coma and the sudden quadriplegia. Early, exact and timely diagnosis and treatment of GBS need to be performed, to accelerate recovery and improve prognosis.

Modafinil Reduces Neuronal Pyroptosis and Cognitive Decline After Sleep Deprivation.

Sleep deprivation (SD) induces systemic inflammation that promotes neuronal pyroptosis. The purpose of this study was to investigate the effect of an antioxidant modafinil on neuronal pyroptosis and cognitive decline following SD. Using a mouse model of SD, we found that modafinil improved learning and memory, reduced proinflammatory factor (IL-1ß, TNF-α, and IL-6) production, and increased the expression of anti-inflammatory factors (IL-10). Modafinil treatment attenuated inflammasome activity and reduced neuronal pyroptosis involving the NLRP3/NLRP1/NLRC4-caspase-1-IL-1ß pathway. In addition, modafinil induced an upregulation of brain-derived neurotrophic factor (BDNF) and synaptic activity. These results suggest that modafinil reduces neuronal pyroptosis and cognitive decline following SD. These effects should be further investigated in future studies to benefit patients with sleep disorders.

Sequential Organ Failure Assessment Score for Prediction of Mortality of Patients With Rhabdomyolysis Following Exertional Heatstroke: A Longitudinal Cohort Study in Southern China.

Background: Heatstroke is a medical emergency that causes multi-organ injury and death without intervention, but limited data are available on the illness scores in predicting the outcomes of exertional heat stroke (EHS) with rhabdomyolysis (RM). The aim of our study was to investigate the Sequential Organ Failure Assessment (SOFA) score in predicting mortality of patients with RM after EHS. Methods: A retrospective cohort study was performed, which included all patients with EHS admitted into the intensive care unit (ICU) of General Hospital of Southern Theater Command of Peoples Liberation Army from January 2008 to June 2019. RM was defined as creatine kinase (CK) > 1,000 U/L. Data, including the baseline data at admission, vital organ function indicators, and 90-day mortality, were reviewed. Results: A total of 176 patients were enrolled; among them, 85 (48.3%) had RM. Patients with RM had a significantly higher SOFA score (4.0 vs. 3.0, p = 0.021), higher occurrence rates of disseminated intravascular coagulation (DIC) (53.1 vs. 18.3%, p < 0.001) and acute liver injury (ALI) (21.4 vs. 5.5%, p = 0.002) than patients with non-RM. RM was positively correlated with ALI and DIC, and the correlation coefficients were 0.236 and 0.365, respectively (both p-values <0.01). Multivariate logistics analysis showed that the SOFA score [odds ratio (OR) 1.7, 95% CI 1.1-2.6, p = 0.024] was the risk factor for 90-day mortality in patients with RM after EHS, with the area under the curve (AUC) 0.958 (95% CI 0.908-1.000, p < 0.001) and the optimal cutoff 7.5 points. Conclusions: Patients with RM after EHS have severe clinical conditions, which are often accompanied by DIC or ALI. The SOFA score could predict the prognosis of patients with RM with EHS. Early treatment strategies based on decreasing the SOFA score at admission may be pivotal to reduce the 90-day mortality of patients with EHS.