Gut microbiota and sepsis and sepsis-related death: a Mendelian randomization investigation.

Background: It is unclear what the causal relationship is between the gut microbiota and sepsis. Therefore, we employed Mendelian randomization (MR) to determine whether a causal link exists between the two. Methods: This study used publicly available genome-wide association studies (GWAS) summary data of gut microbiota, sepsis, sepsis (critical care), and sepsis (28-day death in critical care) to perform a two-sample MR analysis. To ensure the robustness of the results, we also conducted a sensitivity analysis. Results: For sepsis susceptibility, inverse variance weighted (IVW) estimates revealed that Victivallales (OR = 0.86, 95% CI, 0.78-0.94, p = 0.0017) was protective against sepsis, while Lentisphaerae (OR = 0.89, 95% CI, 0.80-0.99), Gammaproteobacteria (OR = 1.37, 95% CI, 1.08-1.73), Clostridiaceae1 (OR = 1.21, 95% CI, 1.04-1.40), RuminococcaceaeUCG011 (OR = 1.10, 95% CI, 1.01-1.20), Dialister (OR = 0.85, 95% CI, 0.74-0.97), and Coprococcus2 (OR = 0.81, 95% CI, 0.69-0.94) presented a suggestive association with the development of sepsis (all p < 0.05). For sepsis (critical care), IVW estimates indicated that Lentisphaerae (OR = 0.70, 95% CI, 0.53-0.93), Victivallales (OR = 0.67, 95% CI, 0.50-0.91), Anaerostipes (OR = 0.49, 95% CI, 0.31-0.76), LachnospiraceaeUCG004 (OR = 0.51, 95% CI, 0.34-0.77), and Coprococcus1 (OR = 0.66, 95% CI, 0.44-0.99) showed a suggestive negative correlation with sepsis (critical care) (all p < 0.05). For sepsis (28-day death in critical care), IVW estimates suggested that four bacterial taxa had a normally significant negative correlation with the risk of sepsis-related death, including Victivallales (OR = 0.54, 95% CI, 0.30-0.95), Coprococcus2 (OR = 0.34, 95% CI, 0.14-0.83), Ruminiclostridium6 (OR = 0.43, 95% CI, 0.22-0.83), and Coprococcus1 (OR = 0.45, 95% CI, 0.21-0.97), while two bacterial taxa were normally significantly positively linked to the risk of sepsis-related death, namely, Mollicutes (OR = 2.03, 95% CI, 1.01-4.08) and Bacteroidales (OR = 2.65, 95% CI, 1.18-5.96) (all p < 0.05). The robustness of the above correlations was verified by additional sensitivity analyses. Conclusion: This MR research found that several gut microbiota taxa were causally linked to the risk of sepsis, sepsis in critical care, and sepsis-related 28-day mortality in critical care.

Anti-CD20 treatment attenuates Th2 cell responses: implications for the role of lung follicular mature B cells in the asthmatic mice.

BACKGROUND: B cells were believed to act as antigen-presenting cells (APCs) to promote T helper type 2 (Th2) cell responses. However, the role of lung B cells and its subpopulations in Th2 cell responses in asthma remains unclear. OBJECTIVE: We leveraged an anti-CD20 monoclonal antibody (mAb) treatment that has been shown to selectively deplete B cells in mice and investigated whether this treatment modulates Th2 cell responses and this modulation is related to lung follicular mature (FM) B cells in a murine model of asthma. METHODS AND RESULTS: We used a house dust mite (HDM)-induced asthma mouse model and found that anti-CD20 mAb treatment attenuates Th2 cell responses. Meanwhile, anti-CD20 mAb treatment did dramatically reduce the number of B cells, especially FM B cells in the lungs, but did not impact the frequency of other immune cell types, including lung T cells, dendritic cells, natural killer cells, and regulatory T cells in wild-type mice. Moreover, we found that the suppressive effect of anti-CD20 mAb treatment on Th2 cell responses could be reversed upon adoptive transfer of lung FM B cells, but not lung CD19+ B cells without FM B cells in asthmatic mice. CONCLUSIONS: These findings reveal that anti-CD20 mAb treatment alleviates Th2 cell responses, possibly by depleting lung FM B cells in a Th2-driven asthma model. This implies a potential therapeutic approach for asthma treatment through the targeting of lung FM B cells.

Age-related differences in long-term potentiation-like plasticity and short-latency afferent inhibition and their association with cognitive function.

Background: The neurophysiological differences in cortical plasticity and cholinergic system function due to ageing and their correlation with cognitive function remain poorly understood. Aims: To reveal the differences in long-term potentiation (LTP)-like plasticity and short-latency afferent inhibition (SAI) between older and younger individuals, alongside their correlation with cognitive function using transcranial magnetic stimulation (TMS). Methods: The cross-sectional study involved 31 younger adults aged 18-30 and 46 older adults aged 60-80. All participants underwent comprehensive cognitive assessments and a neurophysiological evaluation based on TMS. Cognitive function assessments included evaluations of global cognitive function, language, memory and executive function. The neurophysiological assessment included LTP-like plasticity and SAI. Results: The findings of this study revealed a decline in LTP among the older adults compared with the younger adults (wald χ2=3.98, p=0.046). Subgroup analysis further demonstrated a significant reduction in SAI level among individuals aged 70-80 years in comparison to both the younger adults (SAI(N20): (t=-3.37, p=0.018); SAI(N20+4): (t=-3.13, p=0.038)) and those aged 60-70 (SAI(N20): (t=-3.26, p=0.025); SAI(N20+4): (t=-3.69, p=0.006)). Conversely, there was no notable difference in SAI level between those aged 60-70 years and the younger group. Furthermore, after employing the Bonferroni correction, the correlation analysis revealed that only the positive correlation between LTP-like plasticity and language function (r=0.61, p<0.001) in the younger group remained statistically significant. Conclusions: During the normal ageing process, a decline in synaptic plasticity may precede cholinergic system dysfunction. In individuals over 60 years of age, there is a reduction in LTP-like plasticity, while a decline in cholinergic system function is observed in those over 70. Thus, the cholinergic system may play a vital role in preventing cognitive decline during normal ageing. In younger individuals, LTP-like plasticity might represent a potential neurophysiological marker for language function.

Neural correlates of impaired learning and recognition of novel faces in mild cognitive impairment.

OBJECTIVE: Face memory impairment significantly affects social interactions and daily functioning in individuals with mild cognitive impairment (MCI). While deficits in recognizing familiar faces among individuals with MCI have been reported, their ability to learn and recognize unfamiliar faces remains unclear. This study examined the behavioral performance and event-related potentials (ERPs) of unfamiliar face memorization and recognition in MCI. METHODS: Fifteen individuals with MCI and 15 healthy controls learned and recognized 90 unfamiliar neutral faces. Their performance accuracy and cortical ERPs were compared between the two groups across the learning and recognition phases. RESULTS: Individuals with MCI had lower accuracy in identifying newly learned faces than healthy controls. Moreover, individuals with MCI had reduced occipitotemporal N170 and central vertex positive potential responses during both the learning and recognition phases, suggesting impaired initial face processing and attentional resources allocation. Also, individuals with MCI had reduced central N200 and frontal P300 responses during the recognition phase, suggesting impaired later-stage face recognition and attention engagement. CONCLUSION: These findings provide neurobehavioral evidence for impaired learning and recognition of unfamiliar faces in individuals with MCI. SIGNIFICANCE: Individuals with MCI may have face memory deficits in both early-stage face processing and later-stage recognition .

Effects of robot-assisted gait training on cardiopulmonary function and lower extremity strength in individuals with spinal cord injury: A systematic review and meta-analysis.

CONTEXT: Robot-assisted gait training (RAGT) has been increasingly adopted in many rehabilitation facilities for walking function and activity in individuals with spinal cord injury (SCI). However, the effectiveness of RAGT on lower extremity strength and cardiopulmonary function, especially static pulmonary function, have not been clearly outlined. OBJECTIVE: Determine the effect of RAGT on cardiopulmonary function and lower extremity strength in SCI survivors. METHODS: Eight databases were systematically searched for randomized controlled trials comparing RAGT with conventional physical therapy or other non-robotic therapies for survivors with SCI. Study selection required lower extremity strength decline after SCI at baseline. The overall effects of RAGT were calculated using a meta-analytic method. Begg's test was used to assess the risk of publication bias. RESULTS: The pooled analysis demonstrated that RAGT may have a positive effect for individuals with SCI on lower extremity strength enhancing (n = 408; standardized mean difference [SMD] = 0.81; 95% confidence interval [CI] = 0.14-1.48) and cardiopulmonary endurance(n = 104; standardized mean difference [SMD] = 2.24; 95% confidence interval [CI] = 0.28-4.19). However, no significant effect was established on static pulmonary function. No publication bias was observed according to the Begg's test. CONCLUSIONS: RAGT may be a useful technique for improving lower limb strength and cardiovascular endurance in SCI survivors. The usefulness of RAGT in enhancing static pulmonary function was not demonstrated by the study. However, these results should be interpreted with caution, given the low number of selected studies and subjects. Clinical studies with large sample sizes will be necessary in the future.

Thymopentin plays a key role in restoring the function of macrophages to alleviate the sepsis process.

Immune dysfunction is one of the leading causes of death of sepsis. How to regulate host immune functions to improve prognoses of septic patients has always been a clinical focus. Here we elaborate on the efficacy and potential mechanism of a classical drug, thymopentin (TP5). TP5 could decrease peritoneal bacterial load, and reduce inflammatory cytokine levels both in the peritoneal lavage fluid (PLF) and serum, alleviate pathological injuries in tissue and organ, coaxed by cecal ligation and perforation (CLP) in mice, ultimately improve the prognosis of septic mice. Regarding the mechanism, using RNA-seq and flow cytometry, we found that TP5 induced peptidoglycan recognition protein 1 (PGLYRP1) expression, increased phagocytosis and restored TNF-α expression of small peritoneal macrophage (SPM) in the septic mice. This may be increased SPM's ability to clear peritoneal bacteria, thereby attenuates the inflammatory response both in the peritoneal cavity and the serum. It was shown that TP5 plays a key role in restoring the function of peritoneal macrophages to alleviate the sepsis process. We reckon that this is closely relevant to SPM phagocytosis, which might involve increased PGLYRP1 expression and restored TNF-α secretion.

Human blood metabolites and risk of sepsis: A Mendelian randomization investigation.

BACKGROUND: Evidence supports the observational correlations between human blood metabolites and sepsis. However, whether these associations represent a causal relationship is unknown. In this study, we applied two-sample Mendelian randomization (MR) analyses to examine causality between genetically proxied 486 blood metabolites and sepsis risk. METHODS: We used summary data from genome-wide association studies (GWAS) on 486 metabolites involving 7824 individuals as exposure and a sepsis GWAS including 11,643 cases and 474,841 controls as the outcome. The inverse-variance weighted (IVW) was the primary method to estimate the causal relationship between exposure and outcome, with MR-Egger and weighted median serving as supplements. Sensitivity analyses were implemented with Cochrane's Q test, MR-Egger intercept, MR-PRESSO and leave-one-out analysis. In addition, we performed replication MR, meta-analysis, Steiger test, linkage disequilibrium score (LDSC) regression and multivariable MR (MVMR) to thoroughly verify the causation. RESULTS: We identified that genetically determined high levels of 1-oleoylglycerophosphoethanolamine (odds ratio (OR) = .52, 95% confidence interval (CI): .31-.87, p = .0122), alpha-glutamyltyrosine (OR = .75, 95% CI: .60-.93, p = .0102), heptanoate (7:0) (OR = .51, 95% CI: .33-.81, p = .0041) and saccharin (OR = .84, 95% CI: .74-.94, p = .0036) were causally associated with a lower risk of sepsis. MVMR analysis demonstrated the independent causal effect of these metabolites on sepsis. CONCLUSIONS: These findings indicated that four blood metabolites have a protective impact on sepsis, thus providing novel perspectives into the metabolite-mediated development mechanism of sepsis by combining genomics and metabolomics.

An embedded obstacle type micromixer-concentration gradient generator based on capillary driven.

An embedded obstacle-type micromixer-concentration gradient generator based on capillary self-driven is proposed and studied. Herringbone structure (HS) for mixing and palisade-shape small channels at the outlet are designed in the device (named HS). Simulation and experimentation are done to study the liquid mixing efficiency in the small channels and concentration gradient at the outlet, and the experimental results agree with the simulation results. For three cases of liquid dripping (sequential, reverse, and delayed drippings), mixing analysis shows that the mixing efficiency increases along both mixing channel and palisade length, and is high in the middle small channel of the palisade-shape area and low on both sides. An obvious concentration gradient at the outlet can form compared with the device without the palisade-shape area. Finally, water pH value detection is done as one of the applications of HS. This study can provide guidance for the application of HS in biochemical detection, cell research, drug screening, etc. based on the capillary-driven effect.

Association of autoimmune diseases with the occurrence and 28-day mortality of sepsis: an observational and Mendelian randomization study.

BACKGROUND: Observational studies have indicated a potential association between autoimmune diseases and the occurrence of sepsis, with an increased risk of mortality among affected patients. However, whether a causal relationship exists between the two remains unknown. METHODS: In the Mendelian randomization (MR) study, we accessed exposure Genome-wide association study (GWAS) data from both the MRC Integrative Epidemiology Unit (MRC-IEU) and the FinnGen consortium. GWAS data for sepsis and its 28-day mortality were obtained from MRC-IEU. We employed univariable, multivariable, and reverse MR analyses to explore potential associations between autoimmune disorders and sepsis and its 28-day mortality. Additionally, a two-step mediation MR analysis was performed to investigate indirect factors possibly influencing the relationship between autoimmune disorders and sepsis. Afterward, we conducted an observational analysis to further explore the relationship between autoimmune disease and occurrence as well as 28-day mortality of sepsis using a real-world database (the MIMIC-IV database). A cohort of 2537 patients diagnosed with autoimmune disease were extracted from the database for analysis. Multivariable logistic regression models were used to confirm the association between autoimmune diseases and the occurrence of sepsis, as well as the 28-day mortality associated with sepsis. RESULTS: In univariable MR analysis, there appeared to be causal relationships between genetically predicted type 1 diabetes (OR = 1.036, 95% CI = 1.023-1.048, p = 9.130E-09), rheumatoid arthritis (OR = 1.077, 95% CI = 1.058-1.097, p = 1.00E-15) and sepsis, while a potential causal link was observed between celiac disease and sepsis (OR = 1.013, 95% CI = 1.002-1.024, p = 0.026). In a subsequent multivariable MR analysis, only rheumatoid arthritis was found to be independently associated with the risk of sepsis (OR = 1.138, 95% CI = 1.044-1.240, p = 3.36E-03). Furthermore, there was no causal link between autoimmune disorders and 28-day mortality from sepsis. In reverse MR analysis, sepsis was suggested to potentially trigger the onset of psoriasis (OR = 1.084, 95% CI = 1.040-1.131, p = 1.488E-04). In the real-world observational study, adjusting for multiple confounders, rheumatoid arthritis (OR = 1.34, 95% CI = 1.11-1.64, p = 0.003) and multiple sclerosis (OR = 1.31, 95% CI = 1.03-1.68, p = 0.02) were associated with a higher risk of sepsis. In addition, we did not find that autoimmune diseases were associated with 28-day mortality from sepsis. CONCLUSION: Both in observational and MR analysis, only rheumatoid arthritis is highly correlated with occurrence of sepsis. However, autoimmune disease was not associated with an increased 28-day mortality in patient with sepsis. Sepsis may increase the risk of developing psoriasis.

Effects of repetitive transcranial magnetic stimulation on episodic memory in patients with subjective cognitive decline: study protocol for a randomized clinical trial.

Introduction: Early decline of episodic memory is detectable in subjective cognitive decline (SCD). The left dorsolateral prefrontal cortex (DLPFC) is associated with encoding episodic memories. Repetitive transcranial magnetic stimulation (rTMS) is a novel and viable tool to improve cognitive function in Alzheimer's disease (AD) and mild cognitive impairment, but the treatment effect in SCD has not been studied. We aim to investigate the efficacy of rTMS on episodic memory in individuals with SCD, and to explore the potential mechanisms of neural plasticity. Methods: In our randomized, sham-controlled trial, patients (n = 60) with SCD will receive 20 sessions (5 consecutive days per week for 4 weeks) of real rTMS (n = 30) or sham rTMS (n = 30) over the left DLPFC. The primary outcome is the Auditory Verbal Learning Test-Huashan version (AVLT-H). Other neuropsychological examinations and the long-term potentiation (LTP)-like cortical plasticity evaluation serve as the secondary outcomes. These outcomes will be assessed before and at the end of the intervention. Discussion: If the episodic memory of SCD improve after the intervention, the study will confirm that rTMS is a promising intervention for cognitive function improvement on the early stage of dementia. This study will also provide important clinical evidence for early intervention in AD and emphasizes the significance that impaired LTP-like cortical plasticity may be a potential biomarker of AD prognosis by demonstrating the predictive role of LTP on cognitive improvement in SCD. Ethics and dissemination: The study was approved by the Human Research Ethics Committee of the hospital (No. 2023-002-01). The results will be published in peer-review publications. Clinical trial registration: https://www.chictr.org.cn/, identifier ChiCTR2300075517.

Bisphenol AF Induces Prostatic Dorsal Lobe Hyperplasia in Rats through Activation of the NF-κB Signaling Pathway.

Bisphenol AF (BPAF) represents a common environmental estrogenic compound renowned for its capacity to induce endocrine disruptions. Notably, BPAF exhibits an enhanced binding affinity to estrogen receptors, which may have more potent estrogenic activity compared with its precursor bisphenol A (BPA). Notwithstanding, the existing studies on BPAF-induced prostate toxicity remain limited, with related toxicological research residing in the preliminary stage. Our previous studies have confirmed the role of BPAF in the induction of ventral prostatic hyperplasia, but its role in the dorsal lobe is not clear. In this study, BPAF (10, 90 µg/kg) and the inhibitor of nuclear transcription factor-κB (NF-κB), pyrrolidinedithiocarbamate (PDTC, 100 mg/kg), were administered intragastrically in rats for four weeks. Through comprehensive anatomical and pathological observations, as well as the assessment of PCNA over-expression, we asserted that BPAF at lower doses may foster dorsal prostatic hyperplasia in rats. The results of IHC and ELISA indicated that BPAF induced hyperplastic responses in the dorsal lobe of the prostate by interfering with a series of biomarkers in NF-κB signaling pathways, containing NF-κB p65, COX-2, TNF-α, and EGFR. These findings confirm the toxic effect of BPAF on prostate health and emphasize the potential corresponding mechanisms.

Beyond Fear: Unveiling the Relationship Between Fear of Childbirth and Pharmacological Pain Relief.

BACKGROUND: Pharmacological analgesia is the dominant method for pain relief in labor. Fear of childbirth (FOC) may significantly affect women's preferences for and usage of pharmacological analgesia. AIM: This study aimed to investigate the relationship between FOC in late pregnancy and preferences for, as well as actual use of, pharmacological analgesia among nulliparous and multiparous women, accounting for confounding factors. METHODS: A total of 1,300 women participated in the study, completing questionnaires assessing preferences for pharmacological analgesia, FOC, perception of labor pain, social support, coping styles, and demographic variables. The actual use of pharmacological analgesia was followed up. The data were analyzed using univariate and multivariate regression analyses. RESULTS: Univariate analysis revealed that women with moderate to severe FOC had a stronger preference for pharmacological analgesia compared to those with none to mild FOC. However, multivariate analysis showed no direct association between FOC and actual usage of pharmacological analgesia. Instead, a stronger preference for pharmacological analgesia increased the likelihood of its actual usage during labor. CONCLUSIONS: Our study underscores the effect of FOC on preferences for pharmacological analgesia and its potential influence on actual usage during labor. Healthcare providers should consider women's FOC and preferences when evaluating pain management options. Targeted interventions focusing on promoting non-pharmacological techniques should be implemented to optimize labor pain management for women, particularly nulliparous women.

The Natural Product Oridonin as an Anticancer Agent: Current Achievements and Problems.

Oridonin, an active diterpenoid isolated from traditional Chinese herbal medicine, has received a rising attention for its remarkable roles in cancer therapy. In recent years, increasing evidence have revealed that oridonin inhibits the occurrence and development of tumor cells through multiple mechanisms, including induction of apoptosis and autophagy, cell cycle arrest, and inhibition of angiogenesis as well as migration and invasion. In addition, several molecular signal targets have been identified, including ROS, EGFR, NF-κB, PI3K/Akt, and MAPK. In this paper, we review considerable knowledge about the molecular mechanisms and signal targets of oridonin, which has been studied in recent years. It is expected that oridonin may be developed as a novel anti-tumor herbal medicine in human cancer treatment.

Predictive factors and clinicopathological characteristics of outcome in poorly differentiated thyroid carcinoma: a single-institution study.

Objective: To elucidate the clinicopathological characteristics and prognostic factors of poorly differentiated thyroid carcinoma. Method: A total of 24912 thyroid carcinoma patients admitted to the First Medical Center of Chinese People's Liberation Army General Hospital from 2005 to 2020 were retrospectively reviewed. A total of 94 patients (39 males and 55 females, a male-female ratio of 1:1.4) fulfilled the selection criteria. Of these, 73 patients had undergone surgery. The clinical and pathological data were collected from each enrolled patient. Univariate and multivariate Cox regression analyses were performed to determine independent prognostic factors. All analyses were performed with the SPSS version 26.0 and R version 1.2.5033 in the R Studio environment. Results: The specimens included 20 cases of poorly differentiated thyroid carcinoma complicated with papillary thyroid carcinoma, 17 cases complicated with follicular thyroid carcinoma, 34 cases complicated with other pathological types and 23 with a separate entity. The patient demonstrated a large age span, median age was 57 years (range 8-85 years, average 55.20 ± 15.74 years). The survival time of the 94 cases was calculated, and the mean Overall survival time was 33 (range, 1-170) months, and the mean Recurrence-free survival time was 14 (range, 1-90) months. Recurrence-free mortality is related to the age at diagnosis, extrathyroidal extension and Associated thyroid cancer (p<0.05). In contrast, overall mortality is related to the age at diagnosis, sex, extrathyroidal extension, T stage (AJCC 8th), surgery and radiation (p<0.05). Conclusion: Middle-aged and elderly patients are still at high risk for poorly differentiated thyroid carcinoma. The pathologic results of poorly differentiated thyroid carcinoma are varied, and reasonable treatment has an important impact on the prognosis of poorly differentiated thyroid carcinoma.

Association of gut microbiota with COVID-19 susceptibility and severity: A two-sample Mendelian randomization study.

Evidence supports the observational associations of gut microbiota with the risk of COVID-19; however, it is unclear whether these associations reflect a causal relationship. This study investigated the association of gut microbiota with COVID-19 susceptibility and severity. Data were obtained from a large-scale gut microbiota data set (n = 18 340) and the COVID-19 Host Genetics Initiative (n = 2 942 817). Causal effects were estimated with inverse variance weighted (IVW), MR-Egger, and weighted median, and sensitivity analyses were implemented with Cochran's Q test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots. For COVID-19 susceptibility, IVW estimates suggested that Gammaproteobacteria (odds ratio [OR] = 0.94, 95% confidence interval [CI], 0.89-0.99, p = 0.0295] and Streptococcaceae (OR = 0.95, 95% CI, 0.92-1.00, p = 0.0287) had a reduced risk, while Negativicutes (OR = 1.05, 95% CI, 1.01-1.10, p = 0.0302), Selenomonadales (OR = 1.05, 95% CI, 1.01-1.10, p = 0.0302), Bacteroides (OR = 1.06, 95% CI, 1.01-1.12, p = 0.0283), and Bacteroidaceae (OR = 1.06, 95% CI, 1.01-1.12, p = 0.0283) were associated with an increased risk (all p < 0.05, nominally significant). For COVID-19 severity, Subdoligranulum (OR = 0.80, 95% CI, 0.69-0.92, p = 0.0018), Cyanobacteria (OR = 0.85, 95% CI, 0.76-0.96, p = 0.0062), Lactobacillales (OR = 0.87, 95% CI, 0.76-0.98, p = 0.0260), Christensenellaceae (OR = 0.87, 95% CI, 0.77-0.99, p = 0.0384), Tyzzerella3 (OR = 0.89, 95% CI, 0.81-0.97, p = 0.0070), and RuminococcaceaeUCG011 (OR = 0.91, 95% CI, 0.83-0.99, p = 0.0247) exhibited negative correlations, while RikenellaceaeRC9 (OR = 1.09, 95% CI, 1.01-1.17, p = 0.0277), LachnospiraceaeUCG008 (OR = 1.12, 95% CI, 1.00-1.26, p = 0.0432), and MollicutesRF9 (OR = 1.14, 95% CI, 1.01-1.29, p = 0.0354) exhibited positive correlations (all p < 0.05, nominally significant). Sensitivity analyses validated the robustness of the above associations. These findings suggest that gut microbiota might influence the susceptibility and severity of COVID-19 in a causal way, thus providing novel insights into the gut microbiota-mediated development mechanism of COVID-19.

Development of an icIEF assay for monitoring AAV capsid proteins and application to gene therapy products.

Adeno-associated virus (AAV) gene therapy vectors, which contain a DNA transgene packaged into a protein capsid, have shown tremendous therapeutic potential in recent years. Methods traditionally used in quality control labs, such as high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE), do not provide a complete understanding of capsid viral protein (VP) charge heterogeneity. In the present study, we developed simple, one-step sample preparation and charge-based VP separation using imaged capillary isoelectric focusing (icIEF) for monitoring AAV products. The robustness of the method was confirmed through a design of experiments (DoE) exercise. An orthogonal reverse-phase (RP) HPLC method coupled with mass spectrometry was developed to separate and identify charge species. Additionally, capsid point mutants demonstrate the capability of the method to resolve deamidation at a single site on the viral proteins. Finally, case studies using two different AAV serotype vectors establish the icIEF method as stability indicating and demonstrate that increases in acidic species measured by icIEF correlate with increased deamidation, which, we show, results in decreased transduction efficiency. The addition of a rapid and robust icIEF method to the AAV capsid analytical toolkit enables development and consistent manufacturing of well-characterized gene therapy products.

Application of Neuromuscular Blockers in Patients with ARDS in ICU: A Retrospective Study Based on the MIMIC-III Database.

BACKGROUND: Although neuromuscular blocker agents (NMBAs) are recommended by guidelines as a treatment for ARDS patients, the efficacy of NMBAs is still controversial. Our study aimed to investigate the association between cisatracurium infusion and the medium- and long-term outcomes of critically ill patients with moderate and severe ARDS. METHODS: We performed a single-center, retrospective study of 485 critically ill adult patients with ARDS based on the Medical Information Mart for Intensive Care III (MIMIC-III) database. Propensity score matching (PSM) was used to match patients receiving NMBA administration with those not receiving NMBAs. The Cox proportional hazards model, Kaplan-Meier method, and subgroup analysis were used to evaluate the relationship between NMBA therapy and 28-day mortality. RESULTS: A total of 485 moderate and severe patients with ARDS were reviewed and 86 pairs of patients were matched after PSM. NMBAs were not associated with reduced 28-day mortality (hazard ratio (HR) 1.44; 95% CI: 0.85~2.46; p = 0.20), 90-day mortality (HR = 1.49; 95% CI: 0.92~2.41; p = 0.10), 1-year mortality (HR = 1.34; 95% CI: 0.86~2.09; p = 0.20), or hospital mortality (HR = 1.34; 95% CI: 0.81~2.24; p = 0.30). However, NMBAs were associated with a prolonged duration of ventilation and the length of ICU stay. CONCLUSIONS: NMBAs were not associated with improved medium- and long-term survival and may result in some adverse clinical outcomes.

Development and application of a new biological nano-selenium fermentation broth based on Bacillus subtilis SE201412.

In order to improve the functionality and additional value of agricultural products, this study developing nano-selenium fermentation broth and established a new application strategy of bio-nano-selenium by screening and identifying selenium-rich microorganisms. We isolated a new strain from tobacco waste and named it Bacillus subtilis SE201412 (GenBank accession no. OP854680), which could aerobically grow under the condition of 66,000 mg L-1 selenite concentration, and could convert 99.19% of selenite into biological nano-selenium (BioSeNPs) within 18 h. Using strain SE201412, we industrially produced the different concentrations of fermentation broth containing 5000-3000 mg L-1 pure selenium for commercial use. The synthesized selenium nanoparticles (SeNPs) were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and nanoparticle tracking analysis (NTA). TEM and SEM results showed that SeNPs were distributed outside cells. NTA assay of fermentation broth indicated that the nanoparticles were spherical with an average particle size of 126 ± 0.5 nm. Toxicity test revealed that the median lethal dose (LD50) of the fermentation broth to mice was 2710 mg kg-1, indicating its low toxicity and high safety. In addition, we applied BioSeNP fermentation broth to rice and wheat through field experiments. The results showed that the application of fermentation broth significantly increased the total selenium content and organic selenium percentage in rice and wheat grains. Our findings provide valuable reference for the development of BioSeNPs with extensive application prospects.

Combining Preoperative Clinical and Imaging Characteristics to Predict MVI in Hepatitis B Virus-Related Combined Hepatocellular Carcinoma and Cholangiocarcinoma.

BACKGROUND: Combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CCA) is a rare form of primary liver malignancy. Microvascular invasion (MVI) indicates poor postsurgical prognosis in cHCC-CCA. The objective of this study was to investigate preoperative predictors of MVI in hepatitis B virus (HBV) -related cHCC-CCA patients. METHODS: A total of 69 HBV-infected patients with pathologically confirmed cHCC-CCA who underwent hepatectomy were included. Univariate and multivariate analyses were conducted to determine independent risk factors that were then incorporated into the predictive model associated with MVI. Receiver operating characteristic analysis was used to assess the predictive performance of the new model. RESULTS: For the multivariate analysis, γ-glutamyl transpeptidase (OR, 3.69; p = 0.034), multiple nodules (OR, 4.41; p = 0.042) and peritumoral enhancement (OR, 6.16; p = 0.004) were independently associated with MVI. Active replication of HBV indicated by positive HBeAg showed no differences between MVI-positive and MVI-negative patients. The prediction score using the independent predictors achieved an area under the curve of 0.813 (95% CI 0.717-0.908). A significantly lower recurrence-free survival was observed in the high-risk group with a score of ≥1 (p < 0.001). CONCLUSION: γ-glutamyl transpeptidase, peritumoral enhancement and multiple nodules were independent preoperative predictors of MVI in HBV-related cHCC-CCA patients. The established prediction score demonstrated satisfactory performance in predicting MVI pre-operatively and may facilitate prognostic stratification.

Efficacy and safety of Paxlovid in severe adult patients with SARS-Cov-2 infection: a multicenter randomized controlled study.

Background: Nirmatrelvir plus ritonavir (Paxlovid) reduced the risk of hospitalization or death by 89% in high-risk, ambulatory adults with COVID-19. We aimed at studying the efficacy and safety of Paxlovid in hospitalized adult patients with SARS-Cov-2 (Omicron BA.2.2 variant) infection and severe comorbidities. Methods: We conducted an open-label, multicenter, randomized controlled trial in which hospitalized adult patients with severe comorbidities were eligible and assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 h for 5 days with standard treatment or only standard treatment. All-cause mortality on day 28, the duration of SARS-CoV-2 RNA clearance, and safety were evaluated. Findings: 264 patients (mean age, 70.35 years; 122 [46.21%] female) who met the criteria were enrolled at 5 sites in Shanghai from April 10 to May 19 in 2022. After randomization, a total of 132 patients were assigned to receive Paxlovid treatment plus standard treatment, and 132 patients were assigned to receive only standard treatment. The overall 28-day mortality was 4.92%, 8 patients died in the standard treatment group and 5 died in the Paxlovid plus standard treatment group. There was no significant difference in mortality from any cause at 28 days between the Paxlovid plus standard treatment group and the standard treatment group (absolute risk difference [ARD], 2.27; 95% CI -2.94 to 7.49, P = 0.39). There was no significant difference in the duration of SARS-CoV-2 RNA clearance among the two groups (mean days, 10 in Paxlovid plus standard treatment group and 10.50 in the standard treatment group; ARD, -0.62; 95% CI -2.29 to 1.05, P = 0.42). The incidence of adverse events that occurred during the treatment period was similar in the two groups (any adverse event, 10.61% with Paxlovid plus standard treatment vs. 7.58% with the standard, P = 0.39; serious adverse events, 4.55% vs. 3.788%, P = 0.76). Interpretation: Paxlovid showed no significant reduction in the risk of all-cause mortality on day 28 and the duration of SARS-CoV-2 RNA clearance in hospitalized adult COVID-19 patients with severe comorbidities. Funding: National Natural Science Foundation of China (grant number: 82172152, 81873944).