Neurometabolite levels in the brains of patients with autism spectrum disorders: A meta-analysis of proton magnetic resonance spectroscopy studies (N = 1501).

Evidence suggests that neurometabolite alterations may be involved in the pathophysiology of autism spectrum disorders (ASDs). We performed a meta-analysis of proton magnetic resonance spectroscopy (1H-MRS) studies to examine the neurometabolite levels in the brains of patients with ASD. A systematic search of PubMed and Web of Science identified 54 studies for the meta-analysis. A random-effects meta-analysis demonstrated that compared with the healthy controls, patients with ASD had lower N-acetyl-aspartate-containing compound (NAA) and choline-containing compound (Cho) levels and NAA/(creatine-containing compound) Cr ratios in the gray matter and lower NAA and glutamate + glutamine (Glx) levels in the white matter. Furthermore, NAA and gamma-aminobutyric acid (GABA) levels, NAA/Cr ratios, and GABA/Cr ratios were significantly decreased in the frontal cortex of patients with ASD, whereas glutamate (Glu) levels were increased in the prefrontal cortex. Additionally, low NAA levels and GABA/Cr ratios in the temporal cortex, low NAA levels and NAA/Cr ratios in the parietal and dorsolateral prefrontal cortices, and low NAA levels in the cerebellum and occipital cortex were observed in patients with ASD. Meta-regression analysis revealed that age was positively associated with effect size in studies analyzing the levels of gray matter NAA and white matter Glx. Taken together, these results provide strong clinical evidence that neurometabolite alterations in specific brain regions are associated with ASD and age is a confounding factor for certain neurometabolite levels in patients with ASD.

Comparison of metagenomic next-generation sequencing and conventional culture for the diagnostic performance in febrile patients with suspected infections.

BACKGROUND: Timely and accurate identification of pathogens is crucial for appropriate treatment and prognosis of infectious diseases. As an increasingly popular pathogen detection method, the performance of metagenomic next-generation sequencing (mNGS) in detecting pathogens in febrile patients with suspected infection requires further exploration. METHODS: This study included 368 febrile patients with suspected infections who were admitted to the Infectious Disease Department of Qilu Hospital, Shandong University between January 5, 2021 and April 14, 2023. Both mNGS testing and conventional culture were performed in all patients. Clinical data of enrolled patients were collected, and the diagnostic performances of mNGS and culture were compared. RESULTS: Of the 368 enrolled patients, 231 were finally diagnosed with infection and 137 were with diseases other than infection. The sensitivity (58.01% vs. 21.65%, p < 0.001) and negative predictive value (54.67% vs. 42.9%) of mNGS were superior to those of culture. In contrast, the culture exhibited higher specificity (99.27% vs. 85.40%, p < 0.001) and positive predictive value (98.84% vs. 87.01%) than mNGS. Among infected patients with positive mNGS results, 64 received adjusted antibiotic therapy including treatment transitions, antibiotic downgrading, and combination therapy. Among them, 9 had additional antifungal drugs and 21 patients had a treatment turning point based on the mNGS results and these patients recovered and discharged due to timely antibiotic adjustment. Both positive rates of puncture fluid mNGS and tissue mNGS were higher than those of culture in the patients who had prior antibiotic use, and this difference was statistically significant (p = 0.000). CONCLUSION: mNGS is more sensitive and accurate than traditional culture, making it ideal for identifying pathogens and screening infectious diseases, especially for those with uncultivated or difficult-to-cultivate species. Early diagnosis allows for prompt treatment with targeted antibiotics, and mNGS is recommended when samples are limited.

Systemic inflammation indicators and risk of incident arrhythmias in 478,524 individuals: evidence from the UK Biobank cohort.

BACKGROUND: The role of systemic inflammation in promoting cardiovascular diseases has attracted attention, but its correlation with various arrhythmias remains to be clarified. We aimed to comprehensively assess the association between various indicators of systemic inflammation and atrial fibrillation/flutter (AF), ventricular arrhythmia (VA), and bradyarrhythmia in the UK Biobank cohort. METHODS: After excluding ineligible participants, a total of 478,524 eligible individuals (46.75% male, aged 40-69 years) were enrolled in the study to assess the association between systemic inflammatory indicators and each type of arrhythmia. RESULTS: After covariates were fully adjusted, CRP levels were found to have an essentially linear positive correlation with the risk of various arrhythmias; neutrophil count, monocyte count, and NLR showed a non-linear positive correlation; and lymphocyte count, SII, PLR, and LMR showed a U-shaped association. VA showed the strongest association with systemic inflammation indicators, and it was followed sequentially by AF and bradyarrhythmia. CONCLUSIONS: Multiple systemic inflammatory indicators showed strong associations with the onset of AF, VA, and bradyarrhythmia, of which the latter two have been rarely studied. Active systemic inflammation management might have favorable effects in reducing the arrhythmia burden and further randomized controlled studies are needed.

Bullatine A exerts anti-inflammatory effects by inhibiting the ROS/JNK/NF-κB pathway and attenuating systemic inflammatory responses in mice.

CONTEXT: Aconiti brachypodi Radix (Xue-shang-yi-zhi-hao) is a traditional Chinese herbal medicine that is capable of anti-analgesic and anti-inflammatory effects. Bullatine A (BA) is one of the major active ingredients of this plant, and most of the previous studies reported that it has anti-analgesic effects. However, the mechanism of BA anti-inflammatory remains unclear. OBJECTIVE: This study investigates the anti-inflammatory activities of BA, both in vitro and in vivo, and elucidates its mechanism. MATERIALS AND METHODS: In vitro, BA (10, 20, 40 and 80 µM) was added to 1 µg/mL of lipopolysaccharide (LPS)-activated microglia BV2 cells and immortalized murine bone marrow-derived macrophages, respectively. After 6 h, the mRNA and protein levels of inflammatory factors were determined by real-time quantitative PCR and western blotting. In vivo, C57BL/6 mice were randomly divided into control, model (5 mg/kg dose of LPS) and treated groups (LPS with 5, 10 or 20 mg/kg dose of BA) to evaluate the anti-inflammatory efficacy of BA. RESULTS: BA significantly inhibited LPS-induced expression of inflammatory factors, such as IL-1ß, IL-6, TNF-α, inducible nitric oxide synthase (iNOS) and COX-2. Further investigations showed that BA reduced the translocation of NF-κB p65 (38.5%, p < 0.01). BA also reduced the phosphorylation of c-Jun N-terminal kinase (JNK) (11.2%, p < 0.05) and reactive oxygen species (ROS) generation (24.2%, p < 0.01). Furthermore, BA treatment attenuated the LPS-primed inflammatory response and liver and lung damage in vivo. CONCLUSIONS: BA can inhibit the inflammatory response in part through the ROS/JNK/NF-κB signalling pathway, providing a theoretical basis for the clinical application of BA in the treatment of periphery inflammatory diseases.

11-watt single-frequency 1342-nm laser based on multi-segmented Nd:YVO4 crystal.

High power continuous-wave (CW) single-frequency 1342 nm lasers are of interest for fundamental research, particularly, for laser cooling of lithium atoms. Using the popular Nd:YVO4 laser crystal requires careful heat management, because strong thermal effects in the gain medium are the most severe limitations of output power. Here, we present a multi-segmented Nd:YVO4 crystal design that consists of three segments with successive doping concentrations, optimized using a theoretical model. In order to quantify the optimization, we measured the thermal lens power of conventional crystal designs and compare them to our multi-segmented design. The optimized design displays a two times lower thermal lens dioptric power for the same amount of absorbed pump power in the non-lasing case. Using the optimized design, we demonstrate a high power all-solid-state laser emitting 10.0 W single-frequency radiation at 1342 nm when operating the laser crystal at room temperature. Further integration of the laser allows us to operate the laser crystal below room temperature for improving output power up to 11.4 W at 8°C. This is explained by the reduction of energy-transfer upconversion and excited-state absorption effects. Stable free-running operation at the low temperature of 8 °C is achieved with the power stability of ± 0.42 % by peak-to-peak fluctuation and frequency peak-to-peak fluctuation of ± 72 MHz in three hours.

High-power 671 nm laser by second-harmonic generation with 93% efficiency in an external ring cavity.

Second-harmonic generation (SHG) is useful for obtaining single-frequency continuous-wave laser sources at various wavelengths for applications ranging from biology to fundamental physics. Using an external power-enhancement cavity is an effective approach to improve the frequency conversion efficiency. However, thermal effects limit the efficiency, particularly, in high-power operation. Therefore, reducing thermal effects is important when designing a cavity. This Letter reports the use of an external ring cavity for SHG, yielding a 5.2 W, 671 nm laser light with a conversion efficiency of 93.8±0.8% which, to the best of our knowledge, is a new record of conversion efficiency for an external ring cavity. It is achieved using a 10 mm length periodically poled potassium titanyl phosphate crystal and a 65 µm radius beam waist in the cavity so as to minimize thermal dephasing and thermal lensing. Furthermore, a method is developed to determine a conversion efficiency more accurately based on measuring the pump depletion using a photodiode detector and a maximum pump depletion up to 97% is recorded. In this method, the uncertainty is much less than that achieved in a common method by direct measuring with a power meter.

Bergapten alleviates depression-like behavior by inhibiting cyclooxygenase 2 activity and NF-κB/MAPK signaling pathway in microglia.

Major depressive disorder (MDD) is a common psychiatric disorder that severely affects human life and health. However, the pathological mechanism of MDD is unclear, and effective treatment strategies are urgently needed. Microglia-mediated neuroinflammation is closely associated with the pathophysiology of depression. Bergapten (BG) is a natural pharmaceutical monomer with anti-inflammatory effects; however, its role in neuroinflammation and depression remains unclear. In this study, we employed a lipopolysaccharide (LPS) injection-induced acute depression mouse model, and found that treatment with BG significantly alleviated LPS-induced depression-like behavior in mice. BG administration largely decreased the increase in microglial numbers and rescued the microglial morphological changes induced by LPS injection. Furthermore, transcriptomic changes revealed a protective role of BG in the hippocampus of mice. Mechanistically, we found that BG directly inhibited cyclooxygenase 2 (COX2) activity, and suppressed nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways in microglia. Together, these results highlight the important role of BG in microglial activation, neuroinflammation, and depression-like behavior, thus providing a new candidate drug for depression treatment.

Metagenomic next-generation sequencing-guided antimicrobial treatment versus conventional antimicrobial treatment in early severe community-acquired pneumonia among immunocompromised patients (MATESHIP): A study protocol.

Background: Severe community-acquired pneumonia (SCAP) is the main cause of mortality in immunocompromised patients. Compared with conventional microbiological tests (CMT), metagenomic next-generation sequencing (mNGS) can quickly and simultaneously detect a wide array of bacteria, viruses, and fungi in an unbiased manner. It is increasingly used for severe respiratory infectious diseases, especially for immunocompromised patients. However, the effects of mNGS-based antimicrobial treatment procedures on clinical outcomes in immunocompromised patients with SCAP have not been evaluated. Methods/Design: The MATESHIP study is a prospective, multicenter, parallel-group, open-label, randomized controlled trial from 20 ICUs in university hospitals and academic teaching hospitals across Shandong Province, China. We will enroll 342 immunocompromised patients with early onset SCAP who are admitted to an intensive care unit (ICU). Participants will be randomly allocated to an mNGS-guided treatment group or a conventional treatment group (guided by CMT), according to centrally computer-based block randomization stratified by participating centers. Participants will undergo CMT tests using appropriate lower respiratory tract (LRT) and other necessary specimens, with or without mNGS tests using LRT specimens. The primary outcomes will be: (1) The relative change in Sequential Organ Failure Assessment (SOFA) score from randomization to day 5, day 7, day 10, or the day of ICU discharge/death; and (2) the consumption of antimicrobial agents during ICU stay (expressed as defined daily doses). The secondary outcome measures will be: days from randomization to initiation of definitive antimicrobial treatment; overall antimicrobial agent use and cost; total cost of hospitalization; length of ICU stay; 28- and 90-day mortality; and clinical cure rate. This study hypothesizes that mNGS-guided treatment will decrease the degree of organ dysfunction/failure, the consumption of antimicrobial agents, and mortality, while the cure rate will be increased, and the time to initiation of appropriate therapy will be advanced. Discussion: The MATESHIP study will evaluate for the first time whether mNGS-guided antimicrobial therapy improves the outcomes of SCAP in an immunocompromised population, and provide high-level evidence on the application of mNGS in the management of this population. Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT05290454].

Factors associated with the decision to administer ß-lactams via prolonged infusion in patients with sepsis: a prospective observational cohort study.

OBJECTIVE: ß-lactams are the most widely used antibiotics in sepsis. We aimed to explore the factors that drive physicians to choose prolonged infusion (PI) of ß-lactams in septic patients. METHODS: This prospective observational national cohort study was conducted in 40 ICUs at the teaching hospitals of 31 provinces in China between August 20, 2021 and September 20, 2021. RESULTS: Of the 441 enrolled patients, 265 (60.09%) received PI therapy. Multivariate analysis showed that multidrug-resistant bacterial infection and septic shock were independent factors associated with PI. However, our data showed that the survival benefit of PI use was evident in subgroups with less severe sepsis, including those with lower Charlson comorbidity index values (<2), those without septic shock, and those with lower acute physiology and chronic health evaluation II scores (<15). Univariate and multivariate Cox regression indicated that PI was an independent protective factor of 28d mortality, even after adjusting the variables associated with disease severity. CONCLUSIONS: PI for administering ß-lactams was not a commonly applied strategy in sepsis and was more likely to be used in severely ill patients. However, PI had a survival benefit independent of disease severity.

Mangiferin Alleviates Postpartum Depression-Like Behaviors by Inhibiting MAPK Signaling in Microglia.

Postpartum depression (PPD), a severe mental health disorder, is closely associated with decreased gonadal hormone levels during the postpartum period. Mangiferin (MGF) possesses a wide range of pharmacological activities, including anti-inflammation. Growing evidence has suggested that neuroinflammation is involved in the development of depression. However, the role of MGF in the development of PPD is largely unknown. In the present study, by establishing a hormone-simulated pregnancy PPD mouse model, we found that the administration of MGF significantly alleviated PPD-like behaviors. Mechanistically, MGF treatment inhibited microglial activation and neuroinflammation. Moreover, we found that MGF treatment inhibited mitogen-activated protein kinase (MAPK) signaling in vivo and in vitro. Together, these results highlight an important role of MGF in microglial activation and thus give insights into the potential therapeutic strategy for PPD treatment.

Large Screening Identifies ACE2 Positively Correlates With NF-κB Signaling Activity and Targeting NF-κB Signaling Drugs Suppress ACE2 Levels.

Coronaviruses SARS-CoV-2 infected more than 156 million people and caused over 3 million death in the whole world, therefore a better understanding of the underlying pathogenic mechanism and the searching for more effective treatments were urgently needed. Angiotensin-converting enzyme 2 (ACE2) was the receptor for SARS-CoV-2 infection. In this study, we found that ACE2 was an interferon-stimulated gene (ISG) in human cell lines. By performing an ISG library screening, we found that ACE2 levels were positively regulated by multiple ISGs. Interestingly, ACE2 levels were highly correlated with ISGs-induced NF-κB activities, but not IFNß levels. Furthermore, using an approved clinical durgs library, we found two clinical drugs, Cepharanthine and Glucosamine, significantly inhibited ACE2 level, IFNß level, and NF-κB signaling downstream TNFα and IL6 levels. Our finding suggested the possible inhibitory effects of Cepharanthine and Glucosamine during SARS-CoV-2 infection and the subsequent inflammatory cytokine storm.

Dlg1 Knockout Inhibits Microglial Activation and Alleviates Lipopolysaccharide-Induced Depression-Like Behavior in Mice.

Microglia-mediated neuroinflammation is widely perceived as a contributor to numerous neurological diseases and mental disorders including depression. Discs large homolog 1 (Dlg1), an adaptor protein, regulates cell polarization and the function of K+ channels, which are reported to regulate the activation of microglia. However, little is known about the role of Dlg1 in microglia and the maintenance of central nervous system homeostasis. In this study, we found that Dlg1 knockdown suppressed lipopolysaccharide (LPS)-induced inflammation by down-regulating the activation of nuclear factor-κB signaling and the mitogen-activated protein kinase pathway in microglia. Moreover, using an inducible Dlg1 microglia-specific knockout (Dlg1flox/flox; CX3CR1CreER) mouse line, we found that microglial Dlg1 knockout reduced the activation of microglia and alleviated the LPS-induced depression-like behavior. In summary, our results demonstrated that Dlg1 plays a critical role in microglial activation and thus provides a potential therapeutic target for the clinical treatment of depression.

Time-Variant Reliability Analysis for Rubber O-Ring Seal Considering Both Material Degradation and Random Load.

Due to the increase in working hours, the reliability of rubber O-ring seals used in hydraulic systems of transfer machines will change. While traditional methods can only analyze one of the material properties or seal properties, the failure of the O-ring is caused by these two factors together. In this paper, two factors are mainly analyzed: the degradation of material properties and load randomization by processing technology. Firstly, the two factors are defined in terms of material failure and seal failure, before the experimental methods of rubber materials are studied. Following this, the time-variant material properties through experiments and load distribution by monitoring the processing can be obtained. Thirdly, compressive stress and contact stress have been calculated, which was combined with the reliability model to acquire the time-variant reliability for the O-ring. Finally, the life prediction and effect of oil pressure were discussed, then compared with the actual situation. The results show a lifetime of 12 months for the O-ring calculated in this paper, and compared with the replacement records from the maintenance workshop, the result is credible.

Traffic congestion and the lifetime of networks with moving nodes.

For many power-limited networks, such as wireless sensor networks and mobile ad hoc networks, maximizing the network lifetime is the first concern in the related designing and maintaining activities. We study the network lifetime from the perspective of network science. In our model, nodes are initially assigned a fixed amount of energy moving in a square area and consume the energy when delivering packets. We obtain four different traffic regimes: no, slow, fast, and absolute congestion regimes, which are basically dependent on the packet generation rate. We derive the network lifetime by considering the specific regime of the traffic flow. We find that traffic congestion inversely affects network lifetime in the sense that high traffic congestion results in short network lifetime. We also discuss the impacts of factors such as communication radius, node moving speed, routing strategy, etc., on network lifetime and traffic congestion.