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The European Larynx Organ Preservation Study (ELOS; NCT06137378) is a prospective, randomized, open-label, two-armed parallel group controlled, phase II multicenter larynx organ preservation (LOP) trial in locoregionally advanced (LA) stage III, IVA/B head and neck squamous cell carcinoma of the larynx or hypopharynx (LHSCC) amenable for total laryngectomy (TL) with PD-L1 expression within tumor tissue biopsy, calculated as CPS ≥ 1. Induction chemotherapy (IC) with docetaxel and cisplatin (TP) followed by radiation will be compared to TP plus PD-1 inhibition by pembrolizumab (MK-3475; 200 mg i.v. starting day 1 q3w for 17 cycles). After a short induction early response evaluation (ERE) 21 ± 3 days after the first cycle of IC (IC-1), responders achieving endoscopic estimated tumor surface shrinkage (ETSS) ≥30% will get an additional two cycles of IC followed by intensity-modulated radiotherapy 70-72 Gy (EQD2/α/ß = 10) aiming at LOP. Nonresponders (ETSS < 30% or progressing disease) will receive TL and bilateral neck dissection followed by postoperative radiation or chemoradiation as recommended by the clinic's multidisciplinary tumor board. Pembrolizumab treatment will be continued in the intervention arm regardless of ETSS status after IC-1 in both responders and laryngectomized nonresponders, independent of subsequent decisions on adjuvant therapy after TL. Clinical Trial Registration: clinicaltrials.gov, identifier NCT06137378.

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OBJECTIVE: Acetaminophen (APAP), an antipyretic and analgesic commonly used during pregnancy, has been recognized as a novel environmental contaminant. Preliminary evidence suggests that prenatal acetaminophen exposure (PAcE) could adversely affect offspring's gonadal and neurologic development, but there is no systematic investigation on the characteristics of APAP's fetal developmental toxicity. METHODS: Pregnant mice were treated with 100 or 400 mg/kg∙d APAP in the second-trimester, or 400 mg/kg∙d APAP in the second- or third-trimester, or different courses (single or multiple) of APAP, based on clinical regimen. The effects of PAcE on pregnancy outcomes, maternal/fetal blood phenotypes, and multi-organ morphological and functional development of fetal mice were analyzed. RESULTS: PAcE increased the incidence of adverse pregnancy outcomes and altered blood phenotypes including aminotransferases, lipids, and sex hormones in dams and fetuses. The expression of key functional genes in fetal organs indicated that PAcE inhibited hippocampal synaptic development, sex hormone synthesis, and osteogenic and chondrogenic development, but enhanced hepatic lipid synthesis and uptake, renal inflammatory hyperplasia, and adrenal steroid hormone synthesis. PAcE also induced marked pathological alterations in the fetal hippocampus, bone, kidney, and cartilage. The sensitivity rankings of fetal organs to PAcE might be hippocampus/bone > kidney > cartilage > liver > gonad > adrenal gland. Notably, PAcE-induced multi-organ developmental toxicity was more considerable under high-dose, second-trimester, and multi-course exposure and in male fetuses. CONCLUSION: This study confirmed PAcE-induced alterations in multi-organ development and function in fetal mice and elucidated its characteristics, which deepens the comprehensive understanding of APAP's developmental toxicity.

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BACKGROUND: TRILUMINATE Pivotal is a prospective, randomized, controlled study of patients with severe tricuspid regurgitation (TR). Venous congestion due to TR may lead to end-organ dysfunction and failure. The potential to reverse or stop further deterioration in end-organ function is an important goal of treatment. OBJECTIVES: Examine changes in end-organ function after tricuspid transcatheter edge-to-edge repair (TEER) and assess the association of baseline end-organ function with heart failure (HF) hospitalizations and mortality. METHODS: Subjects were randomized 1:1 to either the TEER group (TriClip™ System + medical therapy) or Control group (medical therapy alone). Laboratory assessments and TR grading were performed at baseline and at all follow-up visits (discharge, 30 days, 6 months, and 12 months). An independent echocardiography core laboratory assessed TR severity and an independent clinical events committee adjudicated adverse events. RESULTS: 572 subjects were enrolled and randomized (285 TEER, 287 Control). Patients with moderate to severe end-organ impairment (eGFR <45 ml/min/1.73m2 or MELD-XI >15) at baseline had increased incidence of HF hospitalization and death through 12 months, regardless of treatment. There were no statistically significant differences between TEER and Control in eGFR or MELD-XI at 12 months. In subgroup analyses examining only successful TEER patients (moderate or less TR at discharge) compared to control patients, as well as when censoring patients with normal baseline values, both eGFR (+3.55 ± 1.04 vs 0.07 ± 1.10 , p=0.022) and MELD-XI (-0.52 ± 0.18 vs 0.34 ± 0.18, p=0.0007) improved. CONCLUSIONS: Baseline end-organ function were associated with HF hospitalization and death in patients with severe TR. At 12 months, eGFR and MELD-XI scores were not statistically significantly different between the overall TEER and Control groups. In patients who had successful TEER, statistically significant, yet small, favorable changes occurred for both eGFR and MELD-XI. Further investigation is needed to assess whether these changes in end-organ function after successful TEER are clinically meaningful and reduce HF hospitalization or death.

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Disseminated intravascular coagulation (DIC) poses a high mortality risk, yet its exact impact remains contentious. This study investigates DIC's association with mortality in individuals with sepsis, emphasizing multiple organ function. Using data from the Peking University People's Hospital Investigation on Sepsis-Induced Coagulopathy database, we categorized patients into DIC and non-DIC groups based on DIC scores within 24 h of ICU admission (< 5 cutoff). ICU mortality was the main outcome. Initial data comparison preceded logistic regression analysis of mortality factors post-propensity score matching (PSM). Employing mediation analysis estimated direct and indirect associations. Of 549 participants, 131 were in the DIC group, with the remaining 418 in the non-DIC group. Following baseline characteristic presentation, PSM was conducted, revealing significantly higher nonplatelet sequential organ failure assessment (nonplt-SOFA) scores (6.3 ± 2.7 vs 5.0 ± 2.5, P < 0.001) and in-hospital mortality rates (47.3% vs 29.5%, P = 0.003) in the DIC group. A significant correlation between DIC and in-hospital mortality persisted (OR 2.15, 95% CI 1.29-3.59, P = 0.003), with nonplt-SOFA scores (OR 1.16, 95% CI 1.05-1.28, P = 0.004) and hemorrhage (OR 2.33, 95% CI 1.08-5.03, P = 0.032) as predictors. The overall effect size was 0.1786 (95% CI 0.0542-0.2886), comprising a direct effect size of 0.1423 (95% CI 0.0153-0.2551) and an indirect effect size of 0.0363 (95% CI 0.0034-0.0739), with approximately 20.3% of effects mediated. These findings underscore DIC's association with increased mortality risk in patients with sepsis, urging anticoagulation focus over bleeding management, with organ dysfunction assessment recommended for anticoagulant treatment efficacy.

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Spontaneous filling and voiding cycles represent a key dynamical feature of the healthy lower urinary tract. Some urinary tract dysfunctions, such as over-flow incontinence, may alter the natural occurrence of these cycles. As the function of the lower urinary tract arises from the interplay of a multitude of factors, it is difficult to determine which of them can be modulated to regain spontaneous cycles. In this study, we develop a mathematical model of the lower urinary tract that can capture filling and voiding cycles in the form of periodic solutions of a system of ordinary differential equations. After experimental validation, we utilize this model to study the effect that several physiological quantities have on the onset of cycles. We find that some parameters have an associated numerical threshold that determines whether the system exhibits healthy cycles or settles in a state of constant overflow.

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BACKGROUND: Previous meta-analyses have systematically assessed the therapeutic effect of continuous blood purification (CBP) in adult patients with sepsis. Considering infection etiology and host response of sepsis is different in children, this systematic review and meta-analysis aims to evaluate the clinical efficacy of CBP in children with sepsis. METHODS: Studies were searched from the Pubmed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), WanFang, and VIP databases. Outcomes included vital signs, coagulation markers, organ function markers, immune markers, inflammatory markers, and prognostic markers. Heterogeneity was evaluated by the I-square statistic (I2), and sensitivity analysis was performed. RESULTS: 24 studies were included in this meta-analysis. Pooled results showed that CBP decreased levels of alanine transaminase (ALT) (weighted mean difference [WMD] = -44.867, 95%CI: 64.809 to -24.926), aspartate aminotransferase (AST) (WMD = -55.373, 95%CI: 73.286 to -37.460), blood urea nitrogen (BUN) (WMD = -2.581, 95%CI: 4.539 to -0.622), and serum creatinine (Scr) (WMD = -11.567, 95%CI: 19.509 to -3.625). The percentage of CD3+ cells (WMD = 8.242, 95%CI: 3.339 to 13.144) and CD4+ cells (WMD = 4.278, 95%CI: 3.252 to 5.303, I2 = 3.1 %) were increased in the CBP group. C-reaction protein (CRP) (WMD = -20.699, 95%CI: 34.740 to -6.657) and tumor necrosis factor-α (TNF-α) (WMD = -19.185, 95%CI: 34.133 to -4.237) were reduced after CBP treatment. Pediatric critical illness score (PCIS) was increased (WMD = 7.916, 95%CI: 4.317 to 11.516) and the risk of 28-day mortality (risk ratio [RR] = 0.781, 95%CI: 0.632 to 0.965) was lower in the CBP group. CONCLUSIONS: CBP reduced the level of inflammatory markers, increased the level of immune markers, and improved organ function and prognosis, which may provide evidence for the use of CBP in sepsis children patients.

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Purpose: Cold seawater immersion aggravates hemorrhagic shock-induced homeostasis imbalance and organ dysfunction, leading to increased mortality. Previous studies have shown that treatments targeting oxidative stress and mitochondrial dysfunction have limited efficacy for cold seawater immersion combined with hemorrhagic shock (SIHS). Thus, the mechanisms responsible for SIHS need further investigation. Methods and Results: Data from the hemorrhagic shock transcriptome and cold seawater immersion targets used for bioinformatics analysis revealed the involvement of endoplasmic reticulum stress (ERS) in SIHS occurrence and progression. Based on these findings, the effects and possible mechanism of inhibiting ERS in SIHS rats were investigated. SIHS causes a lethal triad and impairment of vital organ function, leading to death. Compared to lactated Ringer's solution, the ERS inhibitor 4-phenylbutyric acid (PBA)significantly ameliorated acidosis and coagulopathy and protected vital organ function while prolonging survival and the golden treatment time. Through target screening and validation, 7 targets were identified for the ERS inhibitor PBA for the treatment of SIHS, among which S1PR1, MMP8 and CFTR may play more important roles. Conclusion: ERS plays a crucial role in the progression of SIHS. Inhibition of ERS caused by SIHS alleviates the lethal triad, protects organ function, and prolongs survival and the golden treatment time. The ERS inhibitor PBA may be an effective therapeutic measure for treating SIHS.

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BACKGROUND: Acute type A aortic dissection (ATAAD) complicated by mesenteric malperfusion is a critical and complicated condition. The optimal treatment strategy remains controversial, debate exists as to whether aortic dissection or mesenteric malperfusion should be addressed first, and the exact time window for mesenteric ischemia intervention is still unclear. To solve this problem, we developed a new concept based on the pathophysiological mechanism of mesenteric ischemia, using a 6-hour time window to divide newly admitted patients by the time from onset to admission, applying different treatment protocols to improve the clinical outcomes of patients with ATAAD complicated by mesenteric malperfusion. METHODS: This was a retrospective study that covered a five-year period. From July 2018 to December 2020(phase I), all patients underwent emergency open surgery. From January 2021 to June 2023(phase II), patients with an onset within 6 h all underwent open surgical repair, followed by immediately postoperative examination if the malperfusion is suspected, while the restoration of mesenteric perfusion and visceral organ function was performed first, followed by open repair, in patients with an onset beyond 6 h. RESULTS: There were no significant differences in baseline and surgical data. In phase I, eleven patients with mesenteric malperfusion underwent open surgery, while in phase II, our novel strategy was applied, with sixteen patients with an onset greater than 6 h and eleven patients with an onset less than 6 h. During the waiting period, none died of aortic rupture, but four patients died of organ failure, twelve patients had organ function improvement and underwent surgery successfully survived. The overall mortality rate decreased with the use of this novel strategy (54.55% vs. 18.52%, p = 0.047). Furthermore, the surgical mortality rate between the two periods showed even stronger statistical significance (54.55% vs. 4.35%, p = 0.022). Moreover, the proportions of patients with sepsis and multiorgan failure also showed differences. CONCLUSIONS: Our novel strategy for patients with ATAAD complicated by mesenteric malperfusion not only improves the surgical success rate but also reduces the overall mortality rate.

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Gut microbes supporting body growth are known but the mechanisms are less well documented. Using the microbial tryptophan metabolite indole, known to regulate prokaryotic cell division and metabolic stress conditions, we mono-colonized germ-free (GF) mice with indole-producing wild-type Escherichia coli (E. coli) or tryptophanase-encoding tnaA knockout mutant indole-non-producing E. coli. Indole mutant E. coli mice showed multiorgan growth retardation and lower levels of glycogen, cholesterol, triglycerides, and glucose, resulting in an energy deficiency despite increased food intake. Detailed analysis revealed a malfunctioning intestine, enlarged cecum, and reduced numbers of enterochromaffin cells, correlating with a metabolic phenotype consisting of impaired gut motility, diminished digestion, and lower energy harvest. Furthermore, indole mutant mice displayed reduction in serum levels of tricarboxylic acid (TCA) cycle intermediates and lipids. In stark contrast, a massive increase in serum melatonin was observed-frequently associated with accelerated oxidative stress and mitochondrial dysfunction. This observational report discloses functional roles of microbe-derived indoles regulating multiple organ functions and extends our previous report of indole-linked regulation of adult neurogenesis. Since indoles decline by age, these results imply a correlation with age-linked organ decline and levels of indoles. Interestingly, increased levels of indole-3-acetic acid, a known indole metabolite, have been shown to correlate with younger biological age, further supporting a link between biological age and levels of microbe-derived indole metabolites. The results presented in this resource paper will be useful for the future design of food intervention studies to reduce accelerated age-linked organ decline.

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Dexamethasone is widely used in pregnant women at risk of preterm birth to reduce the occurrence of neonatal respiratory distress syndrome and subsequently reduce neonatal mortality. Studies have suggested that dexamethasone has developmental toxicity, but there is a notable absence of systematic investigations about its characteristics. In this study, we examined the effects of prenatal dexamethasone exposure (PDE) on mother/fetal mice at different doses (0.2, 0.4, or 0.8 mg/kg b.i.d), stages (gestational day 14-15 or 16-17) and courses (single- or double-course) based on the clinical practice. Results showed that PDE increased intrauterine growth retardation rate, and disordered the serum glucose, lipid and cholesterol metabolic phenotypes, and sex hormone level of mother/fetal mice. PDE was further discovered to interfere with the development of fetal lung, hippocampus and bone, inhibits steroid synthesis in adrenal and testis, and promotes steroid synthesis in the ovary and lipid synthesis in the liver, with significant effects observed at high dose, early stage and double course. The order of severity might be: ovary > lung > hippocampus/bone > others. Correlation analysis revealed that the decreased serum corticosterone and insulin-like growth factor 1 (IGF1) levels were closely related to PDE-induced low birth weight and abnormal multi-organ development in offspring. In conclusion, this study systematically confirmed PDE-induced multi-organ developmental toxicity, elucidated its characteristics, and proposed the potential "glucocorticoid (GC)-IGF1" axis programming mechanism. This research provided an experimental foundation for a comprehensive understanding of the effect and characteristics of dexamethasone on fetal multi-organ development, thereby guiding the application of "precision medicine" during pregnancy.

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BACKGROUND: Sepsis, the life-threatening host response to infection, is a major cause of mortality. Obesity increases vulnerability to sepsis; however, some degree of obesity may be protective, called the "obesity paradox". This scoping review systematically maps the literature on outcomes associated with diet-induced obesity and sepsis-induced organ injury, focusing on non-transgenic murine models. METHODS: A literature search of primary articles was conducted from database inception to June 2023. Eligible articles compared diet-induced obesity to non-obese mice in sepsis models involving live pathogens. Two reviewers screened articles and extracted data on obesogenic and sepsis models utilized, and organ injury outcomes, including physiological dysfunction, histological alterations, and biochemical changes. RESULTS: Seventeen studies met eligibility criteria; 82% used male C57BL/6 mice, and 88% used cecal ligation and puncture to induce sepsis. Most studies used 60% high-fat diets compared to 10-16% fat in controls. Seven (64%) studies reported increased mortality in obese septic mice, one (9%) observed a decrease, and three (37%) found no significant difference. The liver, lungs, and kidneys were the most studied organs. Alanine transaminase results were inconclusive. Myeloperoxidase levels were increased in the livers of two studies and inconclusive in the lungs of obese septic mice. Creatinine and neutrophil gelatinase-associated lipocalin were elevated in obese septic mice. CONCLUSIONS: There is variability in the methodology and measured outcomes in murine models of diet-induced obesity and sepsis and a lack of studies in female mice. The absence of standardized models has produced conflicting findings on the impact of obesity on sepsis outcomes.

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Lung cancer is a prevalent and highly lethal disease often complicated by lower respiratory tract infections. Microbial patterns in these infections vary based on treatment modalities. The present study explored the impact of lung cancer treatments on pathogens and clinical characteristics in the presence of lower respiratory tract infections to inform antimicrobial drug selection. A retrospective analysis was performed that included data from 93 patients diagnosed with advanced lung cancer and lower respiratory tract infections between January 2019 and December 2021. Patients were divided into the targeted therapy and chemoradiotherapy groups. Clinical, nutritional, biochemical, infection and pathogenetic indicators were compared. Of the 93 cases, 24 were in the targeted therapy group and 69 were in the chemoradiotherapy group. Pathological type and hospitalization duration differed significantly (P<0.05), but age, sex, smoking history, alcohol consumption and underlying diseases did not (P>0.05). Lymphocyte counts differed (P<0.05), while body mass index, albumin, hemoglobin, alanine aminotransferase and creatinine levels, erythrocyte sedimentation rate, hypersensitive C-reactive protein and procalcitonin levels, and the percentage of neutrophils did not (P>0.05). Pathogenetic testing was negative in 15 patients and positive in 78 patients, with Gram-negative bacteria (61.77%), fungi (17.65%) and viruses (11.76%) predominant in the targeted therapy group. In the chemoradiotherapy group, Gram-negative bacteria (47.46%), fungi (28.81%) and viruses (16.95%) were also more prevalent. Candida albicans was the most frequent fungal infection in both groups, and mixed infections were common (50% in targeted therapy and 73.92% in chemoradiotherapy). The chemoradiotherapy group had significantly more mixed infections (P<0.05). Overall, common pathogens in both groups included Gram-negative bacteria, fungi and viruses. Chemoradiotherapy patients experienced longer hospital stays and a higher incidence of mixed infections, predominantly involving Gram-negative bacteria and fungi. The results provide valuable insights into the rational selection of empirical antibiotics and antifungals for critically ill patients with lung cancer and lower respiratory tract infections in targeted therapy or chemoradiotherapy.

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Mitigating sepsis-induced severe organ dysfunction with magnetic nanoparticles has shown remarkable advances in extracorporeal blood treatment. Nevertheless, treating large septic animals remains challenging due to insufficient magnetic separation at rapid blood flow rates (>6 L h-1) and limited incubation time in an extracorporeal circuit. Herein, superparamagnetic nanoclusters (SPNCs) coated with red blood cell (RBC) membranes are developed, which promptly capture and magnetically separate a wide range of pathogens at high blood flow rates in a swine sepsis model. The SPNCs exhibited an ultranarrow size distribution of clustered iron oxide nanocrystals and exceptionally high saturation magnetization (≈ 90 emu g-1) close to that of bulk magnetite. It is also revealed that CD47 on the RBCs allows the RBC-SPNCs to remain at a consistent concentration in the blood by evading innate immunity. The uniform size distribution of the RBC-SPNCs greatly enhances their effectiveness in eradicating various pathogenic materials in extracorporeal blood. The use of RBC-SPNCs for extracorporeal treatment of swine infected with multidrug-resistant E. coli is validated and found that severe bacteremic sepsis-induced organ dysfunction is significantly mitigated after 12 h. The findings highlight the potential application of RBC-SPNCs for extracorporeal therapy of severe sepsis in large animal models and potentially humans.

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Background: This study aims to analyze the changes and significance of organ function indices in patients with severe Coronavirus Disease 2019 (COVID-19) pneumonia for prediction of major organ damages and guiding treatment schemes. Methods: 63 patients with severe COVID-19 pneumonia were selected as the severe group and 73 patients with mild syndromes were selected as the mild group. SAS9.4 software was used for statistical analysis of the data. Results: Levels of ALT, AST, cTnI, Cr, PT, APTT and Ddimer of the severe group were significantly higher while PLT was lower than those of the mild group. The data of all quantitative variables were converted into categorical variables. Significantly higher levels of AST, ALB, D-dimer and higher proportion of bilateral lung involvement were observed from the severe group comparing to those in the mild group, while the difference in the other indices between the two groups was insignificant in statistical perspective. Conclusions: There are significant differences in the levels of multiple organ function indices between the severe group and the mild group of patients with COVID-19 pneumonia infection. Through examining the relevant indices, conditions of patients' multiple organ function damage could be predicted and used as guidance of treatment.

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INTRODUCTION: Hematopoietic stem cell transplant (HSCT) is the only readily available curative option for sickle cell disease (SCD). Cure rates following human leukocyte antigen (HLA)-matched related donor HSCT with myeloablative or non-myeloablative conditioning are >90%. Alternative donor sources, including haploidentical donor and autologous with gene therapy, expand donor options but are limited by inferior outcomes, limited data, and/or shorter follow-up and therefore remain experimental. AREAS COVERED: Outcomes are improving with time, with donor type and conditioning regimens having the greatest impact on long-term complications. Patients with stable donor engraftment do not experience SCD-related symptoms and have stabilization or improvement of end-organ pathology; however, the long-term effects of curative strategies remain to be fully established and have significant implications in a patient's decision to seek therapy. This review covers currently published literature on HSCT outcomes, including organ-specific outcomes implicated in SCD, as well as long-term effects. EXPERT OPINION: HSCT, both allogeneic and autologous gene therapy, in the SCD population reverses the sickle phenotype, prevents further organ damage, can resolve prior organ dysfunction in both pediatric and adult patients. Data support greater success with HSCT at a younger age, thus, curative therapies should be discussed early in the patient's life.

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OBJECTIVES: To focus on evaluating the clinical influence of metoprolol on sepsis-induced cardiomyopathy (SICM). METHODS: A total of 90 patients with SICM was enrolled from December 2018 to February 2021 and divided into 2 groups according to the use of metoprolol during hospitalization in Suzhou Municipal Hospital in Suzhou, China. We compared them with the cardiac function, sequential organ failure assessment score, and clinical outcomes. RESULTS: Between the 2 groups, the oxygenation indices and Glasgow coma scale in the metoprolol group were higher on the first day of treatment, with Glasgow coma scale higher on the third day of treatment. However, the doses of norepinephrine in patients with metoprolol showed no significant differences with the control group. The all-causemortality at 28 days in the metoprolol group was lower, and the time of removing from ventilator support as well as the number of failured organs also significantly differed between the 2 groups. CONCLUSION: Metoprolol can reduce the 28-day mortality and shorten the duration of mechanical ventilation in SICM. It can also reduce the number of organ failures and improve the oxygenation index and Glasgow coma scale of these patients. Meanwhile, metoprolol did not affect the norepinephrine dose in patients with SICM.

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Introduction: The recent discovery of TAK981(Subasumstat), the first-in-class selective inhibitor of SUMOylation, enables new immune treatments. TAK981 is already in clinical trials to potentiate immunotherapy in metastatic tumors and hematologic malignancies. Cancer patients have more than ten times higher risk of infections, but the effects of TAK981 in sepsis are unknown and previous studies on SUMO in infections are conflicting. Methods: We used TAK981 in two sepsis models; polymicrobial peritonitis (CLP) and LPS endotoxemia. Splenectomy was done in both models to study the role of spleen. Western blotting of SUMO-conjugated proteins in spleen lysates was done. Global SUMO1 and SUMO3 knockout mice were used to study the specific SUMO regulation of inflammation in LPS endotoxemia. Splenocytes adoptive transfer was done from SUMO knockouts to wild type mice to study the role of spleen SUMOylation in experimental sepsis. Results and discussion: Here, we report that inhibition of SUMOylation with TAK981 improved survival in mild polymicrobial peritonitis by enhancing innate immune responses and peritoneal bacterial clearance. Thus, we focused on the effects of TAK981 on the immune responses to bacterial endotoxin, showing that TAK981 enhanced early TNFα production but did not affect the resolution of inflammation. Splenectomy decreased serum TNFα levels by nearly 60% and TAK981-induced TNFα responses. In the spleen, endotoxemia induced a distinct temporal and substrate specificity for SUMO1 and SUMO2/3, and both were inhibited by TAK981. Global genetic depletion of SUMO1, but not SUMO3, enhanced TNFα production and metabolic acidosis. The transfer of SUMO1-null, but not wild-type, splenocytes into splenectomized wild-type mice exacerbated TNFα production and metabolic acidosis in endotoxemia. Conclusion: These results suggest that specific regulation of splenic SUMO1 can modulate immune and metabolic responses to bacterial infection.

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AIMS: Azithromycin is widely used in clinical practice for treating maternal infections during pregnancy. Meanwhile, azithromycin, as an "emerging pollutant", is increasingly polluting the environment due to the rapidly increasing usage (especially after the COVID-19). Previous studies have suggested a possible teratogenic risk of prenatal azithromycin exposure (PAzE), but its effects on fetal multi-organ development are still unclear. This study aimed to explore the potential impacts of PAzE. MATERIALS AND METHODS: We focused on pregnancy outcomes, maternal/fetal serum phenotypes, and fetal multiple organ development in mice at different doses (50/200 mg/kg·d) during late pregnancy or at 200 mg/kg·d during different stages (mid-/late-pregnancy) and courses (single-/multi-course). KEY FINDINGS: The results showed PAzE increased the rate of the absorbed fetus during mid-pregnancy and increased the intrauterine growth retardation rate (IUGR) during late pregnancy. PAzE caused multiple blood phenotypic changes in maternal and fetal mice, among which the number and degree of changes in fetal blood indicators were more significant. Moreover, PAzE inhibited long bone/cartilage development and adrenal steroid synthesis, promoting hepatic lipid production and ovarian steroid synthesis in varying degrees. The order of severity might be bone/cartilage > liver > gonads > other organs. PAzE-induced multi-organ alterations differed in stages, courses doses and fetal sex. The most apparent changes might be in high-dose, mid-pregnancy, multi-course, and female, while there was no typical rule for a dose-response relationship. SIGNIFICANCE: This study confirmed PAzE could cause fetal developmental abnormalities and multi-organ functional alterations, which deepens the comprehensive understanding of azithromycin's fetal developmental toxicity.

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Today, fertility preservation is receiving more attention than ever. Cryopreservation, which preserves ovarian tissue to preserve fertility in young women and reduce the risk of infertility, is currently the most widely practiced. Transplantation, however, is less feasible for women with blood-borne leukemia or cancers with a high risk of ovarian metastasis because of the risk of cancer recurrence. In addition to cryopreservation and re-implantation of embryos, in vitro ovarian organ reconstruction techniques have been considered as an alternative strategy for fertility preservation. In vitro culture of oocytes in vitro Culture, female germ cells induction from pluripotent stem cells (PSC) in vitro, artificial ovary construction, and ovaria-related organoids construction have provided new solutions for fertility preservation, which will therefore maximize the potential for all patients undergoing fertility preservation. In this review, we discussed and thought about the latest ovarian organ function reconstruction techniques in vitro to provide new ideas for future ovarian disease research and fertility preservation of patients with cancer and premature ovarian failure.

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The prevalence and severity of high-altitude sickness increases with increasing altitude. Prevention of hypoxia caused by high-altitude sickness is an urgent problem. As a novel oxygen-carrying fluid, modified hemoglobin can carry oxygen in a full oxygen partial pressure environment and release oxygen in a low oxygen partial pressure environment. It is unclear whether modified hemoglobin can improve hypoxic injury on a plateau. Using hypobaric chamber rabbit (5000 m) and plateau goat (3600 m) models, general behavioral scores and vital signs, hemodynamic, vital organ functions, and blood gas are measured. The results show that the general behavioral scores and vital signs decrease significantly in the hypobaric chamber or plateau, and the modified hemoglobin can effectively improve the general behavioral scores and vital signs in rabbits and goats, and reduce the degree of damage to vital organs. Further studies reveal that arterial partial pressure of oxygen (PaO2 ) and arterial oxygen saturation (SaO2 ) on the plateau decrease rapidly, and the modified hemoglobin could increase PaO2 and SaO2 ; thus, increasing the oxygen-carrying capacity. Moreover, modified hemoglobin has few side effects on hemodynamics and kidney injury. These results indicate that modified hemoglobin has a protective effect against high-altitude sickness.

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