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Abstract Background Sepsis-associated acute kidney injury (SA-AKI) is common and associated with poor outcomes in critically ill patients. Acetaminophen is often used as an antipyretic and analgesic drug, but the association of acetaminophen use with mortality and recovery of renal function in SA-AKI patients remain unclear. We aimed to investigate the association between acetaminophen use and outcomes in SA-AKI patients. Methods This is a retrospective cohort study based on the MIMIC-IV database. Adult patients with SA-AKI were included in the analysis. The exposure was acetaminophen use within 7 days after the onset of SA-AKI. The primary outcome was 28-day mortality. Secondary outcomes included ICU mortality, in-hospital mortality, 90-day mortality, 1-year mortality, and renal recovery. Cox proportional hazards regression models were used to estimate the hazard ratio (HR) with 95% confidence interval (CI) for mortality. Logistic regression models were used to estimate the odd ratio (OR) with 95% CI for renal recovery. Results 6752 patients with SA-AKI were included, and 3892 (57.6%) patients received acetaminophen. Acetaminophen use was associated with decreased 28-day mortality (HR 0.69, 95% CI 0.63–0.75), ICU mortality (HR 0.56, 95% CI 0.50–0.63), in-hospital mortality (HR 0.62, 95% CI 0.57–0.69), 90-day mortality (HR 0.73, 95% CI 0.68–0.79), and 1-year mortality (HR 0.62, 95% CI 0.57–0.69). Acetaminophen use also was associated with improved renal recovery (OR 1.15, 95% CI 1.04–1.28). Conclusions Acetaminophen use is associated with decreased mortality and improved renal recovery in SA-AKI patients.

Abstract Background Although ROX index is frequently used to assess the efficacy of high-flow nasal cannula treatment in acute hypoxemic respiratory failure (AHRF) patients, the relationship between the ROX index and the mortality remains unclear. Therefore, a retrospective cohort study was conducted to evaluate the ability of the ROX index to predict mortality risk in patients with AHRF. Method Patients diagnosed with AHRF were extracted from the MIMIC-IV database and divided into four groups based on the ROX index quartiles. The primary outcome was 28-day mortality, while in-hospital mortality and follow-up mortality were secondary outcomes. To investigate the association between ROX index and mortality in AHRF patients, restricted cubic spline curve and COX proportional risk regression were utilized. Result A non-linear association (L-shaped) has been observed between the ROX index and mortality rate. When the ROX index is below 8.28, there is a notable decline in the 28-day mortality risk of patients as the ROX index increases (HR per SD, 0.858 [95%CI 0.794–0.928] P

BackgroundSeveral studies have confirmed the direct relationship between extracellular acidification and the occurrence of pain. As an effective pain management approach, the mechanism of electroacupuncture (EA) treatment of acidification-induced pain is not fully understood. The purpose of this study was to assess the analgesic effect of EA in this type of pain and to explore the underlying mechanism(s).MethodsWe used plantar injection of the acidified phosphate-buffered saline (PBS; pH 6.0) to trigger thermal hyperalgesia in male Sprague–Dawley (SD) rats aged 6–8 weeks. The value of thermal withdrawal latency (TWL) was quantified after applying EA stimulation to the ST36 acupoint and/or chemogenetic control of astrocytes in the hindlimb somatosensory cortex.ResultsBoth EA and chemogenetic astrocyte activation suppressed the acid-induced thermal hyperalgesia in the rat paw, whereas inhibition of astrocyte activation did not influence the hyperalgesia. At the same time, EA-induced analgesia was blocked by chemogenetic inhibition of astrocytes.ConclusionThe present results suggest that EA-activated astrocytes in the hindlimb somatosensory cortex exert an analgesic effect on acid-induced pain, although these astrocytes might only moderately regulate acid-induced pain in the absence of EA. Our results imply a novel mode of action of astrocytes involved in EA analgesia.

Abstract Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed drugs for mental disorders in critically ill patients. We performed a retrospective cohort study to investigate the association between pre-ICU use of SSRIs and mortality in critically ill adults with mental disorders. We identified critically ill adults with mental disorders based on the Medical Information Mart in Intensive Care-IV database. The exposure was the use of SSRIs during the period after hospital admission and before ICU admission. The outcome was in-hospital mortality. Time-dependent Cox proportional hazards regression models were used to estimate the adjusted hazard ratio (aHR) with 95% confidence interval (CI). To further test the robustness of the results, we performed propensity score matching and marginal structural Cox model estimated by inverse probability of treatment weighting. The original cohort identified 16601 patients. Of those, 2232 (13.4%) received pre-ICU SSRIs, and 14369 (86.6%) did not. Matched cohort obtained 4406 patients, with 2203 patients in each group (SSRIs users vs. non-users). In the original cohort, pre-ICU use of SSRIs was associated with a 24% increase in the hazard for in-hospital mortality (aHR, 1.24; 95% CI, 1.05–1.46; P = 0.010). The results were robust in the matched cohort (aHR, 1.26; 95% CI, 1.02–1.57; P = 0.032) and the weighted cohort (aHR, 1.43; 95% CI, 1.32–1.54; P

We used low and high molecular weight fluorescence tracers to investigate the entry of foreign solutes into the brain parenchyma and their exit from it by the glymphatic system, during experimentally induced depressive-like behavior in rats. The tail suspension test (TST), as an acute stressor, is known to induce such a type of behavior, considered to model the human major depressive disorder (MDD). Electroacupuncture (EAP) relieves both depressive-like behavior in rodents and the symptoms of MDD in humans. Here we report that 180 min after the intracisternal injection of the low molecular weight tracer Fluorescein-5-Isothiocianate Conjugated Dextran (FITC-d3), a 15-min duration TST tended to increase the control fluorescence in the brain of rats. Both EAP and sham EAP decreased the fluorescence of FITC-d3 in comparison with the TST, but not the control value. In addition, EAP and sham EAP counteracted the effects of TST. The high molecular weight tracer Ovalbumin Alexa Fluor 555 Conjugate (OA-45) failed to enter the brain parenchyma and accumulated at more superficial sites; however, EAP or sham EAP modified the distribution of fluorescence under TST application in a similar manner as that observed during the use of FITC-d3. It is concluded that EAP is possibly a valid treatment to slow down the entry of foreign solutes into the brain; in view of the comparable effects of EAP on FITC-d3 and OA-45 distribution, EAP seems to act before FITC-d3 passes the astroglial aquaporin-4 water channels, which are a critical constituent of the glymphatic system.

Abstract Background Numerous studies have investigated the mean arterial pressure in patients with sepsis, and many meaningful results have been obtained. However, few studies have measured the systolic blood pressure (SBP) multiple times and established trajectory models for patients with sepsis with different SBP trajectories. Methods Data from patients with sepsis were extracted from the Medical Information Mart for Intensive Care-III database for inclusion in a retrospective cohort study. Ten SBP values within 10 h after hospitalization were extracted, and the interval between each SBP value was 1 h. The SBP measured ten times after admission was analyzed using latent growth mixture modeling to construct a trajectory model. The outcome was in-hospital mortality. The survival probability of different trajectory groups was investigated using Kaplan-Meier (K-M) analysis, and the relationship between different SBP trajectories and in-hospital mortality risk was investigated using Cox proportional-hazards regression model. Results This study included 3034 patients with sepsis. The median survival time was 67 years (interquartile range: 56–77 years). Seven different SBP trajectories were identified based on model-fit criteria. The in-hospital mortality rates of the patients in trajectory classes 1–7 were 25.5%, 40.5%, 11.8%, 18.3%, 23.5%, 13.8%, and 10.5%, respectively. The K-M analysis indicated that patients in class 2 had the lowest probability of survival. Univariate and multivariate Cox regression analysis indicated that, with class 1 as a reference, patients in class 2 had the highest in-hospital mortality risk (P

Abstract Background Previous studies have indicated that the ratio of lactate/albumin (L/A) has predictive value for the prognosis of critically ill patients with heart failure. Some studies have also indicated that a low serum bicarbonate concentration is inversely related to the mortality risk of patients with cardiogenic shock. However, the value of bicarbonate and the L/A ratio for predicting the mortality risk of patients with acute myocardial infarction (AMI) is still unclear. We therefore conducted a retrospective study to research this problem. Methods The subjects of this study were patients with AMI, and the data source was the Medical Information Mart for Intensive Care III database. The primary endpoint was 30-day all-cause mortality after admission. The Receiver operating characteristic (ROC) curve was used to compare the predictive value of L/A ratio, lactate and albumin for end-point events. The effects of different L/A ratio levels and different bicarbonate concentrations on 7-day and 30-day all-cause mortality were compared using Kaplan–Meier (K-M) curves. Hazard ratios for different L/A ratio and different bicarbonate concentrations were investigated using COX proportional hazards models. Results The Area Under Curve (AUC) of L/A ratio, lactate, and albumin were 0.736, 0.718, and 0.620, respectively. (1) L/A ratio: The patients were divided into three groups according to their L/A ratio: tertile T1 (L/A ratio ≤ 0.47), tertile T2 (L/A ratio ≤ 0.97), and tertile T3 (L/A ratio > 0.97). The T2 and T3 groups had higher 30-day all-cause mortality risks than the T1 group. The restricted cubic spline (RCS) model indicated that there was a nonlinear relationship between L/A ratio and 30-day mortality (P 27 mmol/L). The G2 and G3 groups had higher 30-day all-cause mortality risks than the G1 group. The RCS model indicated that there was a nonlinear relationship between bicarbonate concentration and 30-day mortality (P

Background: Ventricular septal defect is a common congenital heart disease. As the disease progresses, the likelihood of lung infection and heart failure increases, leading to prolonged hospital stays and an increased likelihood of complications such as nosocomial infections. We aimed to develop a nomogram for predicting hospital stays over 14 days in pediatric patients with ventricular septal defect and to evaluate the predictive power of the nomogram. We hope that nomogram can provide clinicians with more information to identify high-risk groups as soon as possible and give early treatment to reduce hospital stay and complications.Methods: The population of this study was pediatric patients with ventricular septal defect, and data were obtained from the Pediatric Intensive Care Database. The resulting event was a hospital stay longer than 14 days. Variables with a variance inflation factor (VIF) greater than 5 were excluded. Variables were selected using the least absolute shrinkage and selection operator (Lasso), and the selected variables were incorporated into logistic regression to construct a nomogram. The performance of the nomogram was assessed by using the area under the receiver operating characteristic curve (AUC), Decision Curve Analysis (DCA) and calibration curve. Finally, the importance of variables in the model is calculated based on the XGboost method.Results: A total of 705 patients with ventricular septal defect were included in the study. After screening with VIF and Lasso, the variables finally included in the statistical analysis include: Brain Natriuretic Peptide, bicarbonate, fibrinogen, urea, alanine aminotransferase, blood oxygen saturation, systolic blood pressure, respiratory rate, heart rate. The AUC values of nomogram in the training cohort and validation cohort were 0.812 and 0.736, respectively. The results of the calibration curve and DCA also indicated that the nomogram had good performance and good clinical application value.Conclusion: The nomogram established by BNP, bicarbonate, fibrinogen, urea, alanine aminotransferase, blood oxygen saturation, systolic blood pressure, respiratory rate, heart rate has good predictive performance and clinical applicability. The nomogram can effectively identify specific populations at risk for adverse outcomes.

Silage can be contaminated with mycotoxins and accidental fungi after aerobic exposure. The study assessed the effects of bunker silos (BS), round bales (RB), and silage bags (SB) on the nutritional characteristics, fermentation quality, aerobic stability, mycotoxin levels and microbial communities of whole-plant corn silage (WPCS). After 90 days of fermentation, silages were opened and sampled at 0, 1, 3, 5, 7, and 9 days of exposure. SB group conserved higher lactic acid and dry matter contents and a lower pH value than other groups after 9 days of exposure (p

Background: Heart failure (HF) is the terminal stage of various heart diseases. Conventional treatments have poor efficacy, and diuretic resistance can present. Previous studies have found that the use of glucocorticoids can enhance the diuretic effect of patients with heart failure and reduce heart failure symptoms. However, the relationship between glucocorticoid use and mortality in patients with heart failure in intensive care units is unclear.Objectives: The aim of this study was to determine the association between glucocorticoid use and all-cause mortality in critically ill patients with heart failure. Methods: The information on patients with heart failure in this study was extracted from the MIMIC-III (Medical Information Mart for Intensive Care-III) database. Patients in the glucocorticoid and non-glucocorticoid groups were matched using propensity scores. The Kaplan-Meier method was used to explore the difference in survival probability between the two groups. A Cox proportional-hazards regression model was used to analyze the hazard ratios (HRs) for the two patient groups. Subgroup analyses were performed with prespecified stratification variables to demonstrate the robustness of the results.Results: The study included 9,482 patients: 2,099 in the glucocorticoid group and 7,383 in the non-glucocorticoid group. There were 2,055 patients in each group after propensity-score matching. The results indicated that the non-glucocorticoid group was not significantly associated with reduced mortality in patients with heart failure during the 14-day follow-up period [HRs = .901, 95% confidence interval (CI) = .767–1.059]. During the follow-up periods of 15–30 and 15–90 days, the mortality risk was significantly lower in the non-glucocorticoid group than in the glucocorticoid group (HRs = .497 and 95% CI = .370–.668, and HRs = .400 and 95% CI = .310–.517, respectively). Subgroup analyses indicated no interaction among each stratification variable and glucocorticoid use.Conclusion: Glucocorticoid use was associated with an increased mortality risk in critically ill patients with heart failure.

There is ongoing dispute on the question whether CNS neurons possess ATP-sensitive P2X7 receptors (Rs) or whether only non-neuronal cells bear this receptor-type and indirectly signal to the neighboring neurons. We genetically deleted P2X7Rs specifically in astrocytes, oligodendrocytes and microglia, and then recorded current responses in neurons to the prototypic agonist of this receptor, dibenzoyl-ATP (Bz-ATP). These experiments were made in brain slice preparations taken from the indicated variants of the P2X7R KO animals. In hippocampal CA3, but not CA1 pyramidal neurons, the deletion of oligodendrocytic (NG2 glial) P2X7Rs abolished the Bz-ATP-induced current responses. In contrast to the Bz-ATP-induced currents in CA3 pyramidal neurons, current amplitudes evoked by the ionotropic glutamate/GABAAR agonists AMPA/muscimol were not inhibited at all. Whereas in the CA3 area NG2 glia appeared to mediate the P2X7R-mediated stimulation of pyramidal neurons, in the CA1 area, astrocytic P2X7Rs had a somewhat similar effect. This was shown by recording the frequencies and amplitudes of spontaneous excitatory currents (sPSCs) in brain slice preparations. Bz-ATP increased the sPSC frequency in CA1, but not CA3 pyramidal neurons without altering the amplitude, indicating a P2X7R-mediated increase of the neuronal input. Micro-injection of the selective astrocytic toxin L-α-aminoadipate into both hippocampi, or the in vitro application of the GABAAR antagonistic gabazine, completely blocked the frequency increases of sPSCs. Hence, CA1 and CA3 pyramidal neurons of the mouse did not possess P2X7Rs, but were indirectly modulated by astrocytic and oligodendrocytic P2X7Rs, respectively.

Objective: The objective of the study was to explore the research status and hot topics that are most studied about in Tai Chi Chuan (TCC) analgesia through a metrical and visualization analysis of the literature and provide some references for the experimental research on the analgesic effect of TCC and its clinical applications. Methods: The literature on TCC analgesia was collected from the Web of Science database, and the metrical and visualization analysis was performed using the CiteSpace. 5.6.R4 software in terms of publication outputs, countries, institutions, keywords, highly cited articles, and highly cited journals. Results: The number of annual publications gradually increased over time. The five research groups presented stable cooperative relationships and more publications. The authors ranked as top 1 were from America rather than China, which has more publications. The most common keywords were Tai Chi, randomized controlled trial, older adults, exercise, pain, low back pain, quality of life, management, etc. The literature on knee osteoarthritis and fibromyalgia had the highest citation frequency. The journals with high citation frequency included Cochrane Database System Review, Pain, and Plos One. Conclusions: Increasing attention has been paid to TCC analgesia. Randomized controlled trials, older adults, low back pain, and quality of life were found to be most studied in this field. Investigating clinical efficacy and conducting meta-analyses could be a promising direction in the future. The international cooperation and literature quality of TCC analgesia should be further strengthened.

Purinergic P2X7 receptor, a nonselective cation channel, is highly expressed in immune cells as well as cardiac smooth muscle cells and endothelial cells. Its activation exhibits to mediate nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome activation, resulting in the release of interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), and pyroptosis, thus triggering inflammatory response. These pathological mechanisms lead to the deterioration of various cardiovascular diseases, including atherosclerosis, arrhythmia, myocardial infarction, pulmonary vascular remodeling, and cardiac fibrosis. All these worsening cardiac phenotypes are proven to be attenuated after the P2X7 receptor inhibition in experimental studies. The present review aimed to summarize key aspects of P2X7 receptor–mediated inflammation and pyroptosis in cardiovascular diseases. The main focus is on the evidence addressing the involvement of the P2X7 receptor in the inflammatory responses to the occurrence and development of cardiovascular disease and therapeutic interventions.

Background: The prognostic factors for efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors in ovarian cancer remain unknown. The purpose of this study is to evaluate the efficacy of PARP inhibitors and to explore their prognostic factors in ovarian cancer.Methods: PubMed, Embase, and conference databases were searched for relevant prospective clinical trials. The primary outcomes included overall survival (OS), progression-free survival (PFS), and their prognostic factors. Secondary outcomes included PFS2, time to first subsequent therapy (TFST), time to second subsequent therapy (TSST), chemotherapy-free interval (CFI), and their prognostic factors. Hazard ratio (HR) with a 95% confidence interval (CI) was used as an effect measure.Results: PARP inhibitors significantly prolonged PFS in patients with ovarian cancer regardless of their BRCA and HRD status (HR = 0.44, 95% CI = 0.36–0.55). BRCA mutation, HRD-positive status, and sensitivity to platinum represented effective prognostic factors for PFS (Pinteraction < 0.01 and within-trial interaction HR < 1). Other clinicopathological factors did not predict the benefit of PFS (Pinteraction > 0.10). Moreover, PARP inhibitors significantly increased PFS2, TFST, TSST, and CFI, with significant BRCA-related differences. However, HRD-related differences could not be evaluated due to the lack of eligible studies. Furthermore, PARP inhibitors did not translate into prolonged OS, although there was a benefit associated with OS (HR = 0.84, 95% CI = 0.70–1.02). PARP inhibitors used as maintenance therapy after first or subsequent line therapy improved OS (HR = 0.77, 95% CI = 0.63–0.93).Conclusions: PARP inhibitors can significantly prolong PFS, PFS2, TFST, TSST, and CFI in ovarian cancer patients. BRCA mutation, HRD-positive status, and sensitivity to platinum are effective prognostic factors for the efficacy of PARP inhibitors. However, despite the PFS improvement, this does not translate into prolonged OS for patients.

Background: Tai Chi Chuan(TCC), as a mind-body exercise, may have a positive impact on physical function and psychological well-being in breast cancer patients. The latest systematic review and meta-analysis of TCC for breast cancer was made 4 years ago and some new clinical trials about it were published. We remade a systematic review and meta-analysis to evaluate the effect of TCC in breast cancer patients.Methods: In this systematic review and meta-analysis, we searched MEDLINE (via PubMed), EMBASE (via embase.com), CENTRAL, CNKI, COVIP, Wanfang, Chaoxing, CiNii, J-SSTAGE, DBpia, and ThaiJO with no language restrictions from inception to December 31, 2018 (updated on February 16, 2020), for randomized clinical trials comparing TCC with non-exercised therapy in breast cancer patients. The primary outcome was quality of life in patients with breast cancer and data pooled by a random-effects model. Subgroup analyses were conducted to estimate the effect of different durations of TCC for breast cancer patients. This study was registered in PROSPERO, number CRD 4201810326.Results: Fifteen articles involving a total of 885 breast cancer participants were included in this review. Compared with non-exercised therapy, TCC had a significant effect on quality of life in breast cancer patients (SMD = 0.37, 95% CI 0.15–0.59, p = 0.001), and subgroup analysis found that TCC showed beneficial effect in 12 weeks and 25 weeks (12 weeks: SMD = 0.40, 95% CI 0.19–0.62, p = 0.0003; 25 weeks: SMD = 0.38, 95% CI 0.15–0.62, p = 0.002). Meta-analyses of secondary outcomes showed that 3 weeks TCC increased shoulder function (SMD = 1.08, 95% CI 0.28–1.87, p = 0.008), 12 weeks TCC improved pain (SMD = 0.30, 95% CI 0.08–0.51, p = 0.007), shoulder function (SMD = 1.34, 95% CI 0.43–2.25, p = 0.004), strength of arm (SMD = 0.44, 95% CI 0.20–0.68, p = 0.0004), and anxiety (MD = −4.90, 95% CI −7.83 to −1.98, p = 0.001) in breast cancer patients compared with the control group.Conclusions: TCC appears to be effective on some physical and psychological symptoms and improves the quality of life in patients with breast cancer. Additional randomized controlled trials with a rigorous methodology and low risk of bias are needed to provide more reliable evidence.

Abstract Background Conventional moxibustion is a representative non-drug intervention in traditional Chinese medicine, and it has been reported to produce encouraging results and benefits in relieving symptoms and improving the quality of life for patients with knee osteoarthritis (KOA) in previous clinical trials and systematic reviews. Given that increasing concerns on the safety of generated smoke from conventional moxibustion have received much attention, smoke-free moxibustion is regarded as a potential alternative. However, whether smoke-free moxibustion would display a similar efficacy to that of conventional moxibustion still remains unclear. Therefore, this randomized controlled trial attempts to investigate the difference of efficacy between conventional moxibustion and smoke-free moxibustion in patients with KOA. Methods/design This is a multicenter, randomized, single-blinded, parallel-group clinical trial. A total of 138 eligible participants with KOA will be randomly allocated to two groups (conventional moxibustion group and smoke-free moxibustion group) in seven hospitals in China. Participants will receive 12 sessions of moxibustion treatment at three acupoints (EX-LE4, ST35, and ST36) over a period of 4 weeks (3 sessions per week). A smoke-removing device is placed at the top of the moxibustion device for the smoke-free moxibustion group (n = 69), while the conventional moxibustion group (n = 69) is treated with traditional moxibustion. The primary outcome measure will be the change of the global scale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) from the baseline to 4 weeks. Secondary outcomes include the visual analog scale VASand Patient Global Assessment scores. Follow-up measurements will be performed on the 8th and 12th weeks after random allocation. Discussion This study will contribute to providing a solid foundation for the selection of moxibustion in clinical application as well as future research in moxibustion therapy. Trial registration ClinicalTrials.gov, NCT02772055 . Registered on 12 May 2016.

Background: Rhein is considered to have beneficial influence on diabetic nephropathy. Animal experiments suggested that the mechanisms of rhein against diabetic nephropathy may involve many processes, but the credibility of the evidence is unclear. Therefore, we conducted systematic review and meta-analysis of pre-clinical animal data to assess the current evidence for rhein effects and mechanisms in treating diabetic nephropathy.Methods: The databases of PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure, VIP information database, Wanfang Data Information Site, and Chinese Biomedical Literature were searched for this review. SYRCLE’s risk of bias tool for animal studies was applied to assess the methodological quality of studies. A meta-analysis was performed according to the Cochrane Handbook for Systematic Reviews of Interventions by using RevMan 5.3 and STATA/SE 12.0 software. This study was registered with PROSPERO, number CRD42018105220.Results: Twenty-five studies involving 537 animals were included. There was significant association of rhein with levels of blood glucose (P < 0.05), serum creatinine (Scr) (P < 0.05), urine protein (P < 0.05), kidney tubules injury index (P < 0.05), relative area of kidney collagen (P < 0.05), transforming growth factor-β1 (P < 0.05), malondialdehyde (P < 0.05), and superoxide dismutase (P < 0.05) compared with that in the control group. No significant association between rhein and endothelin (P > 0.05) was found. Subgroup analysis showed that the hypoglycemic effect of rhein on type 2 diabetic nephropathy was better than on type 1 diabetic nephropathy (P < 0.05).Conclusions: These findings suggested that rhein has beneficial effects on animal models of diabetic nephropathy, and that the mechanisms are mostly involved with ameliorating levels of TGF-β1, renal fibrosis, metabolism, and oxidative stress status. However, some factors such as possible publication bias, methodological quality, and sample size may affect the accuracy of positive findings. These limitations suggested that a cautious interpretation of the positive results of this systematic review and meta-analysis is necessary. Therefore, high methodological quality and well-reported animal experiments are needed in future research.

TRPC6 (transient receptor potential cation channels; canonical subfamily C, member 6) is widespread localized in mammalian tissues like kidney and lung and associated with progressive proteinuria and pathophysiological pulmonary alterations, e.g., reperfusion edema or lung fibrosis. However, the understanding of TRPC6 channelopathies is still at the beginning stages. Recently, by chemical diversification of (+)-larixol originating from Larix decidua resin traditionally used for inhalation, its methylcarbamate congener, named SH045, was obtained and identified in functional assays as a highly potent, subtype-selective inhibitor of TRPC6. To pave the way for use of SH045 in animal disease models, this study aimed at developing a capable bioanalytical method and to provide exploratory pharmacokinetic data for this promising derivative. According to international guidelines, a robust and selective LC-MS/MS method based on MRM detection in positive ion mode was established and validated for quantification of SH045 in mice plasma, whereby linearity and accuracy were demonstrated for the range of 2–1600 ng/mL. Applying this method, the plasma concentration time course of SH045 following single intraperitoneal administration (20 mg/kg body weight) revealed a short half-life of 1.3 h. However, the pharmacological profile of SH045 is promising, as five hours after administration, plasma levels still remained sufficiently higher than published low nanomolar IC50 values. Summarizing, the LC-MS/MS method and exploratory pharmacokinetic data provide essential prerequisites for experimental pharmacological TRPC6 modulation and translational treatment of TRPC6 channelopathies.

Background: Ventricular septal defect is a common congenital heart disease. As the disease progresses, the likelihood of lung infection and heart failure increases, leading to prolonged hospital stays and an increased likelihood of complications such as nosocomial infections. We aimed to develop a nomogram for predicting hospital stays over 14 days in pediatric patients with ventricular septal defect and to evaluate the predictive power of the nomogram. We hope that nomogram can provide clinicians with more information to identify high-risk groups as soon as possible and give early treatment to reduce hospital stay and complications. Methods: The population of this study was pediatric patients with ventricular septal defect, and data were obtained from the Pediatric Intensive Care Database. The resulting event was a hospital stay longer than 14 days. Variables with a variance inflation factor (VIF) greater than 5 were excluded. Variables were selected using the least absolute shrinkage and selection operator (Lasso), and the selected variables were incorporated into logistic regression to construct a nomogram. The performance of the nomogram was assessed by using the area under the receiver operating characteristic curve (AUC), Decision Curve Analysis (DCA) and calibration curve. Finally, the importance of variables in the model is calculated based on the XGboost method. Results: A total of 705 patients with ventricular septal defect were included in the study. After screening with VIF and Lasso, the variables finally included in the statistical analysis include: Brain Natriuretic Peptide, bicarbonate, fibrinogen, urea, alanine aminotransferase, blood oxygen saturation, systolic blood pressure, respiratory rate, heart rate. The AUC values of nomogram in the trainingcohort and validation cohort were 0.812 and 0.736, respectively. The results of the calibration curve and DCA also indicated that the nomogram had good performance and good clinical application value. Conclusion: The nomogram established by BNP, bicarbonate, fibrinogen, urea, alanine aminotransferase, blood oxygen saturation, systolic blood pressure, respiratory rate, heart rate has good predictive performance and clinical applicability. The nomogram can effectively identify specific populations at risk for adverse outcomes. [ABSTRACT FROM AUTHOR]