A pharmacovigilance study of FDA adverse events for sugammadex.

BACKGROUND: Sugammadex, a selective steroidal neuromuscular blocking agent reversal agent, is increasingly employed for the rapid restoration of neuromuscular function. This study aimed to conduct a comprehensive evaluation of sugammadex's safety profile. METHODS: Adverse events (AEs) related to sugammadex reported in the FDA Adverse Event Reporting System (FAERS) database from January 2009 to September 2023 were extracted. Disproportionality analysis with four measures: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) were employed to detect significant AEs. We also inspected for unexpected AEs absent from the sugammadex FDA approval documentation and categorized AEs based on the latest version (26.1) of 'Important Medical Event Terms List (IME list)' developed by the EudraVigilance Expert Working Group. RESULTS: A total of 1452 reports were linked to sugammadex. At the preferred terms (PTs) levels, 98 sugammadex-related AEs were identified, including "anaphylactic reaction", "bradycardia", "bronchospasm" and "cardiac arrest". Among them, 37 representing unexpected events were absent from official FDA labeling, and 50 AEs were recognized as IME warranting observation. Notably, 19 PTs denoted serious AEs were absent from labeling yet needing IME surveillance, including: "Kounis syndrome", "angioedema", "pulseless electrical activity" and "laryngeal edema". CONCLUSION: The study identified unexpected and potentially life-threatening AEs associated with sugammadex, a valuable agent for rapidly reversing neuromuscular blockade. Clinicians are advised to be mindful of these potential risks, particularly in patients with allergies or existing cardiovascular or respiratory conditions.

Identifying Novel Proteins for Chronic Pain: Integration of Human Brain Proteomes and Genome-Wide Association Data.

Numerous genome-wide association studies have identified risk genes for chronic pain, yet the mechanisms by which genetic variants modify susceptibility have remained elusive. We sought to identify key genes modulating chronic pain risk by regulating brain protein expression. We integrated brain proteomic data with the largest genome-wide dataset for multisite chronic pain (N=387,649) in a proteome-wide association study (PWAS) using discovery and confirmatory proteomic datasets (N=376 and 152) from the dorsolateral prefrontal cortex (dPFC). Leveraging summary data-based Mendelian randomization (SMR) and Bayesian colocalization analysis (COLOC), we pinpointed potential causal genes, while a transcriptome-wide association study (TWAS) integrating 452 human brain transcriptomes investigated whether cis-effects on protein abundance extended to the transcriptome. Single-cell RNA sequencing data and single-nucleus transcriptomic data revealed cell-type specific expression patterns for identified causal genes in the dPFC and dorsal root ganglia (DRG), complemented by RNA microarray analysis of expression profiles in other pain-related brain regions. Of the 22 genes cis-regulating protein abundance identified by the discovery PWAS, 18 (82%) were deemed causal by SMR or COLOC analyses, with 7 of these 18 genes (39%) replicating in the confirmatory PWAS, including GMPPB, which also associated at the transcriptome level. Several causal genes exhibited selective expression in excitatory neurons, inhibitory neurons, oligodendrocytes, and astrocytes, while most identified genes were expressed across additional pain-related brain regions. This integrative proteogenomic approach identified 18 high-confidence causal genes for chronic pain, regulated by cis-effects on brain protein levels, suggesting promising avenues for treatment research and indicating a contributory role for the DRG. PERSPECTIVE: The current post-GWAS analyses identified 18 high-confidence causal genes regulating chronic pain risk via cis-modulation of brain protein abundance, suggesting promising avenues for future chronic pain therapies. Additionally, the significant expression of these genes in the DRG indicated a potential contributory role, warranting further investigation.

Pore-Engineered Hydrogen-Bonded Supramolecular Fluorosensor for Ultrasensitive Determination of Copper Ions.

The selective quantification of copper ions (Cu2+ ) in biosamples holds great importance for disease diagnosis, treatment, and prognosis since the Cu2+ level is closely associated with the physiological state of the human body. While it remains a long-term challenge due to the extremely low level of free Cu2+ and the potential interference by the complex matrices. Here, a pore-engineered hydrogen-bonded organic framework (HOF) fluorosensor is constructed enabling the ultrasensitive and highly selective detection of free Cu2+ . Attributing to atomically precise functionalization of active amino "arm" within the HOF pores and the periodic π-conjugated skeleton, this porous HOF fluorosensor affords high affinity toward Cu2+ through double copper-nitrogen (Cu─N) coordination interactions, resulting in specific fluorescence quenching of the HOF as compared with a series of substances ranging from other metal ions, metabolites, amino acids to proteins. Such superior fluorescence quenching effect endows the Cu2+ quantification by this new HOF sensor with a wide linearity of 50-20 000 nm, a low detection limit of 10 nm, and good recoveries (89.5%-115%) in human serum matrices, outperforming most of the reported approaches. This work highlights the practicability of hydrogen-bonded supramolecular engineering for designing facile and ultrasensitive biosensors for clinical free Cu2+ determination.

Preoperative flurbiprofen diminishes the rate of reoperation after free flap reconstruction: A retrospective study.

This study aimed to evaluate the association between preoperative flurbiprofen, a non-selective COX inhibitor, and reoperation for flap crisis after free flap reconstruction. In this retrospective study, patients who underwent head and neck surgery with free flap reconstructions were collected. To identify risk factors for reoperation from demographic features and perioperative variables, univariate and multivariate logistic analyses were conducted. After propensity score matching (PSM), univariate and adjusted multivariate analyses were employed to explore the impact of preoperative flurbiprofen on reoperation after free flap reconstruction. This study comprised 437 patients, 33 of whom underwent reoperations for flap crisis. After multivariate analysis, radiotherapy history (P = 0.005; odds ratio [OR] = 0.225; 95% CI, 0.080-0.636) and preoperative flurbiprofen (P = 0.038; OR = 5.059; 95% CI, 1.094-23.386) were identified as independent factors for reoperation. PSM was achieved, and preoperative flurbiprofen was found to diminish the reoperation rate (P = 0.046; OR = 4.765; 95% CI, 1.029-22.202) without increasing bleeding complications. Within the limitations of the study, flurbiprofen should be administered preoperatively to reduce the rate of reoperations for flap crisis whenever appropriate.

THE EFFECTS OF EARLY-PHASE FUROSEMIDE USE ON THE PROGRESSION OF OLIGURIC ACUTE KIDNEY INJURY ACROSS DIFFERENT CENTRAL VENOUS PRESSURE: A RETROSPECTIVE ANALYSIS.

ABSTRACT: Background: Furosemide is a commonly used loop diuretic in critical care. However, its effect on the progression of oliguric acute kidney injury across different central venous pressure (CVP) remains unknown. This study therefore aims to investigate the association between furosemide 6-12h (defined as the use of furosemide within 6 h after the diagnosis of AKI according to the urine output [UO] criteria set by the Kidney Disease: Improving Global Outcomes [KDIGO] guidelines) and the progression of AKI across different CVP 6-12h (defined as CVP within 6 h after the diagnosis of AKI by the KDIGO UO criteria) levels. Methods: Patients involved in this study were identified from the Medical Information Mart for Intensive Care IV database with the following criteria: (i) adults with UO <0.5 mL/kg per hour for the first 6 h upon admission to the intensive care unit (ICU) (meeting stage 1 AKI by UO) and (ii) CVP 6-12h ranging from 0 to 30 mm Hg. From there on, the target primary outcome would be progression to stage 3 AKI by UO among these chosen patients. The secondary outcome was 28-d mortality since ICU admission. The risks of severe-stage AKI progression and 28-d mortality were respectively examined against furosemide 6-12h (vs. without furosemide 6-12h ) within the full cohort and across different subgroups of CVP 6-12h , using multivariate adjusted logistic regression and inverse probability treatment weighting (IPTW). Sensitivity analyses were performed to assess the robustness of our findings. Results: One thousand one hundred eighty patients were ultimately selected for this study, of whom 643 (54.5%) progressed to stage 3 AKI from stage 1 based on the UO criteria by KDIGO. Multivariate analysis showed that furosemide 6-12h is significantly associated with this severe-stage progression within the full cohort (odds ratio [OR] was 0.62 at 95% confidence interval [CI] of 0.43-0.90, P = 0.011). After dividing the patients into CVP 6-12h subgroups according to their CVP during the early phases, lower risk of AKI progression was observed only in furosemide 6-12h application at CVP 6-12h of ≥12 mm Hg (adjusted OR was 0.40 at 95% CI of 0.25-0.65, P < 0.001), as confirmed by the IPTW analysis (OR was 0.47 at 95% CI of 0.29-0.76, P = 0.002). The robustness of these findings was confirmed by sensitivity analyses. In addition, for patients with CVP 6-12h ≥12 mm Hg, furosemide 6-12h is also significantly associated with lower risk of 28-d mortality (adjusted OR was 0.47 at 95% CI of 0.25-0.92, P = 0.026) in the multivariate logistic regression analysis, and there was a similar trend in the IPTW analysis (adjusted OR was 0.55 at 95% CI of 0.28-1.10, P = 0.092). Conclusions: Among the identified early-stage AKI patients in critical care, the use of furosemide was associated only with lower risk of oliguric AKI progression and 28-d mortality within the high CVP group. These findings suggest the potential of CVP as a guidance or reference point in the usage of furosemide among early-stage oliguric AKI patients in the ICU.

Perioperative Risk Factors Associated With Unplanned Reoperation Following Vascularized Free Flaps Reconstruction of the Oral Squamous Cell Carcinoma.

OBJECTIVES: To find out the occurrence rate and risk factors of unplanned reoperation (any unscheduled surgery within 30 d after the initial surgery) in patients who have received oral squamous cell carcinoma (OSCC) surgery and vascularized free flap reconstruction. PATIENTS AND METHODS: We organized a retrospective study of 1058 patients who underwent OSCC resection and reconstruction with vascularized free flaps from 2011 to 2019. Clinical characteristics, reasons for unplanned reoperation, flap types, and previous treatment were compared between the unplanned reoperation group and the control group. Univariate and multivariate analyses were performed to identify perioperative risk factors for unplanned reoperation. The related perioperative factors that may influence perioperative infusion were included in propensity score matching to investigate the independent contribution of intraoperative colloid infusion on unplanned reoperation. RESULTS: The overall rate of unplanned reoperation in OSCC patients was 11% (n=115). Flap necrosis and bleeding were the most common causes. Higher American Society of Anesthesiologists (ASA) grade [odds ratio (OR)=1.709, P=0.009], postoperative anemia (OR=0.983, P=0.011) and excessive intraoperative colloid input (OR=1.55, P=0.037) were identified as risk factors for unplanned reoperation. Propensity score matching was applied, and the difference of unplanned reoperation incidence between the matched groups was statistically significant (14.59% versus 8.54%; P=0.025). The multivariate analyses after propensity score matching confirmed that the intraoperative rate of colloid infusion of more than 2.3 mL/kg/h (OR=1.756, P=0.042) and prior radiotherapy (OR=2.78, P=0.001) are independent risk factors for unplanned reoperation. CONCLUSION: High intraoperative colloid infusion rate and prior radiotherapy may increase the risk of unplanned reoperation in patients who underwent OSCC surgery and vascularized free flap reconstruction.

Early-Phase Urine Output and Severe-Stage Progression of Oliguric Acute Kidney Injury in Critical Care.

Background: The relationship between urine output (UO) and severe-stage progression in the early phase of acute kidney injury (AKI) remains unclear. This study aimed to investigate the relationship between early-phase UO6-12h [UO within 6 h after diagnosis of stage 1 AKI by Kidney Disease: Improving Global Outcomes (KDIGO) UO criteria] and severe-stage progression of AKI and to identify a reference value of early-phase UO6-12h for guiding initial therapy in critical care. Methods: Adult patients with UO < 0.5 ml/kg/h for the first 6 h after intensive care unit (ICU) admission (meeting stage 1 AKI by UO) and UO6-12h ≥ 0.5 ml/kg/h were identified from the Medical Information Mart for Intensive Care (MIMIC) III database. The primary outcome was progression to stage 2/3 AKI by UO. After other variables were adjusted through multivariate analysis, generalized additive model (GAM) was used to visualize the relationship between early-phase UO6-12h and progression to stage 2/3 AKI by UO. A two-piecewise linear regression model was employed to identify the inflection point of early-phase UO6-12h above which progression risk significantly leveled off. Sensitivity and subgroup analyses were performed to assess the robustness of our findings. Results: Of 2,984 individuals, 1,870 (62.7%) with KDIGO stage 1 UO criteria progressed to stage 2/3 AKI. In the multivariate analysis, early-phase UO6-12h showed a significant association with progression to stage 2/3 AKI by UO (odds ratio, 0.40; 95% confidence interval, 0.34-0.46; p < 0.001). There was a non-linear relationship between early-phase UO6-12h and progression of AKI. Early-phase UO6-12h of 1.1 ml/kg/h was identified as the inflection point, above which progression risk significantly leveled off (p = 0.780). Patients with early-phase UO6-12h ≥ 1.1 ml/kg/h had significantly shorter length of ICU stay (3.82 vs. 4.17 days, p < 0.001) and hospital stay (9.28 vs. 10.43 days, p < 0.001) and lower 30-day mortality (11.05 vs. 18.42%, p < 0.001). The robustness of our findings was confirmed by sensitivity and subgroup analyses. Conclusions: Among early-stage AKI patients in critical care, there was a non-linear relationship between early-phase UO6-12h and progression of AKI. Early-phase UO6-12h of 1.1 ml/kg/h was the inflection point above which progression risk significantly leveled off.

Nomogram for predicting mandatory ICU admission after gastrectomy for gastric cancer.

BACKGROUND: This study aimed to identify risk factors that were associated with mandatory intensive care unit (ICU) admission after gastrectomy for gastric cancer. We then employed these risk factors to construct and validate a nomogram for predicting mandatory ICU admission after gastrectomy, which may identify those who require ICU indeed and improve ICU utilization. METHODS: A number of 999 gastric cancer patients undergoing gastrectomy from January 2010 to June 2019 were included in the retrospective study. Forty-three patients were classified into mandatory ICU admission groups, and the remaining 956 patients were allocated into the no need for ICU admission group. The candidate variables, including patient demographic characteristics, preoperative laboratory tests and surgical variables, were compared between the two groups. We then carried out univariate and multivariate logistic regression analyses to find out risk factors for mandatory ICU admission. In order to develop the predictive model, we used Akaike information criterion (AIC) to select risk factors via a step-down backward process from the multivariate regression model. RESULTS: A number of risk factors for mandatory ICU admission were identified and subsequently used to build the nomogram: age [odds ratio (OR), 1.03; 95% CI, 1.00-1.07; P=0.031], ASA status (III-IV vs. I-II: OR,1.74; 95% CI, 0.88-3.46; P=0.114), tumor size (OR, 1.28; 95% CI, 1.08-1.51; P=0.004), estimated blood loss (OR, 1.001; 95% CI, 1.000-1.001; P=0.082) as well as intraoperative transfusion (Yes vs. No: OR, 3.82; 95% CI, 1.87-7.82; P<0.001). C-index of the nomogram was 0.800, indicating good discrimination. Both Calibration curve and Hosmer-Lemeshow goodness-of-fit tests (P=0.128) showed that there was a high degree of agreement between the prediction and actual outcome. CONCLUSIONS: A nomogram to predict mandatory ICU admission after gastrectomy for gastric cancer was constructed and validated. Clinicians could apply this predictive model to improve usage of limited ICU resources effectively.

Nomogram based on albumin and neutrophil-to-lymphocyte ratio for predicting postoperative complications after pancreaticoduodenectomy.

BACKGROUND: The aim of this study was to identify a preoperative inflammatory marker with the most predictive value for postoperative complications after pancreaticoduodenectomy (PD). We then combined it with other perioperative variables to construct and validate a nomogram for complications after PD. METHODS: A total of 223 patients who received PD from January 2014 to July 2019 at a high-volume (>60 PDs/year) pancreatic centers in China were included in this retrospective study. All of the PDs were performed by the same surgeon who is beyond the learning curve with more than 100 PDs over the previous 3 years before 2014. 15 preoperative inflammatory markers were collected, including neutrophils, lymphocytes, high-sensitivity C-reactive protein and lactic dehydrogenase. The inflammatory markers' predicting abilities for complications were analyzed by calculating the values of an area under the curve (AUC). The complications included surgical complications (such as pancreatic fistula, delayed gastric emptying and bile leakage) and medical complications (such as sepsis, pneumonia, urinary tract infection, acute heart failure and acute liver failure) in this study. Univariable and multivariable logistic regression analyses were performed to investigate the perioperative features for independent risk factors for complications after PD. Nomograms with or without the most predictive inflammatory for complications were subsequently developed based on multivariable logistic regression using Akaike information criterion. Nomograms' performance was quantified and compared in terms of calibration and discrimination. We studied the utility of the nomograms using decision curve analysis. RESULTS: The albumin/ NLR score (ANS) exhibited the highest AUC value (0.616) for predicting postoperative complications. ANS and approach method were identified as independent risk factors for complications. The nomogram with ANS had higher C-index (0.725) and better calibration. The NRI compared between nomograms was 0.160 (95% CI: 0.023-0.296; P=0.022). By decision curve analysis, the model with ANS had higher clinical value. CONCLUSIONS: The ANS is a useful predictor and an independent risk factor for postoperative complications after PD. The nomogram with ANS was constructed with better performance and more clinical benefit for predicting postoperative complications.

Development and validation of a nomogram to predict intraoperative blood transfusion for gastric cancer surgery.

OBJECTIVE: To construct and validate a nomogram composed of preoperative variables to predict intraoperative blood transfusion for gastric cancer surgery. BACKGROUND: Intraoperative transfusion for gastric cancer surgery is a common medical procedure that is associated with increased postoperative complications. METHODS: A total of 999 patients who underwent gastrectomy between January 2010 and June 2019 were randomly allocated into the primary and validation cohorts in a 2:1 ratio. In the primary cohort, logistic analyses were performed to identify independent predictors for transfusion. Using the Akaike information criterion, selected variables were incorporated to construct a nomogram. Validations of the nomogram were performed in the primary and validation cohorts. The discrimination ability of the nomogram was assessed by the concordance index (C-index), and calibration was assessed by calibration curves and the Hosmer-Lemeshow goodness-of-fit test. RESULTS: The following risk factors for transfusion were identified and used to construct the nomogram: ASA status (III-IV vs I-II: odds ratio [OR] 1.74), comorbidities (yes vs no: OR 1.57), tumour location (diffuse vs lower: OR 4.05), cTNM stage (III vs I: OR 1.95), and a preoperative haemoglobin level less than 80 g/L (vs over 120 g/L: OR 35.30). The C-index was 0.859 and 0.850 in the primary and validation cohorts, respectively, which both indicated good discrimination of the nomogram. Additionally, both calibration curves and Hosmer-Lemeshow tests (p-value 0.184 and 0.887, respectively) demonstrated high agreement between the predictions and actual outcomes. CONCLUSION: A nomogram composed of preoperative variables to predict blood transfusion for gastric cancer surgery was effectively developed and validated. This nomogram could be used to improve the utilisation of red blood cells for gastrectomy.

Development and validation of a nomogram incorporating selected systemic inflammation-based prognostic marker for complication prediction after vascularized fibula flap reconstruction.

OBJECTIVE: To develop and validate a nomogram incorporating systemic inflammatory markers (the Albumin/NLR Score [ANS]) to predict postoperative complications after vascularized fibula flap reconstruction. PATIENTS AND METHODS: A total of 238 patients who underwent vascularized fibula flap reconstruction between March 2012 and December 2016 were collected as the primary cohort. Univariable and multivariable analysis were performed to identify independent risk factors for postoperative complications. Backward stepwise logistic regression analysis was then applied with and without the ANS; and nomograms were established based on these criteria. Independent validation of these nomograms was carried out in an independent validation cohort including 106 consecutive patients from December 2016 and January 2018. RESULTS: Radiotherapy history (odds ratio [OR] = 0.336; 95% CI, 0.157-0.717; P = 0.005), the ANS (OR = 0.248; 95% CI, 0.093-0.661; P = 0.005) and fluid infusion rate over 24 h (OR = 0.671; 95% CI, 0.479-0.94; P = 0.02) were identified as independent risk factors for postoperative complications. A higher C-index was found in both the primary (0.759; 95% CI, 0.719-0.739) and validation cohort (0.704; 95% CI, 0.613-0.659) for the nomogram incorporating the ANS, and NRI was 0.496 (95% CI, 0.072-0.920; P = 0.022) comparing of these nomograms. Furthermore, a wider threshold probability (0.2-0.9) and superior clinical value were observed in the nomogram incorporating the ANS on the decision curve. CONCLUSION: The ANS was an independent risk factor for postoperative complications associated with vascularized fibula flap reconstruction. The nomogram incorporating the ANS was established with better accuracy and showed more potential clinical benefit for the estimation of postoperative complications.

Mouse embryonic fibroblast (MEF)/BMP4-conditioned medium enhanced multipotency of human dental pulp cells.

Dental pulp cells (DPCs) are valuable cell source for dental regeneration, albeit their application is restricted by limited pluripotency due to current culture condition. Mouse embryonic fibroblasts (MEFs) are served as feeder layer to maintain undifferentiated state of iPSCs and ESCs with long-term in vitro culture. Bone morphogenetic protein 4 (BMP4) plays an important role in the regulation of undifferentiated state and lineage commitment of cells through modulation of microenvironment. However, so far little was known how micro environment affect the multipotency of dental derived cells. To demonstrate the effect of optimized culture condition on multipotency of DPCs, cell proliferation and senescence of DPCs with MEF and/or rhBMP4-CM were examined by CCK8, telomerase activity and flow cytometry. Multilineage differentiation was detected by immunofluorescent staining, Real-time PCR and western blot. Expression of BMP4/NFATc1/LIF in the co-culture medium was evaluated by ELISA and expression of Oct-4/Sox2/c-Myc/NFATc1 in co-cultured DPCs was detected by Real-time PCR. NFATc1 inhibitor INCA-6 was applied to DPCs with MEF and/or rhBMP4-CM, expression of NFATc1/Oct-4/Sox2/c-Myc was examined by Realtime PCR and western blot. Our results demonstrated that DPCs cultured with MEF and/or rhBMP4-CM showed increased cell proliferation, telomerase rate and multilineage differentiation capability. MEF-CM enhanced expression of Oct-4/Sox2/c-Myc/NFATc1 in co-cultured DPCs through secretion of BMP4/NFATc1 in the culture medium. INCA-6 effectively restrained the MEF/BMP4-CM induced upregulation of Oct-4/Sox2/c-Myc/NFATc1 in DPCs. These resuts indicate that both MEF-CM and BMP4-CM provided similar efficient culture system to improve the multipotency of DPCs, which might contribute to the application of DPCs in dental regeneration.

Luteolin and apigenin activate the Oct-4/Sox2 signal via NFATc1 in human periodontal ligament cells.

Identifying small molecules to activate the Oct-4/Sox2-derived pluripotency network represents a hopeful and safe method to pluripotency without genetic manipulation. Luteolin and apigenin, two major bioactive flavonoids, enhance reprogramming efficiency and increase expression of Oct-4/Sox2/c-Myc, albeit the detailed mechanism regulating pluripotency in dental-derived cells remains unknown. In the present study, to elucidate the effect of luteolin/apigenin on pluripotency of periodontal ligament cells (PDLCs) through interaction with downstream signals, we examined cell cycle, proliferation, apoptosis, expression of Oct-4/Sox2/c-Myc, and multilineage differentiation of PDLCs with luteolin/apigenin treatment. Moreover, we profiled the differentially expressed pluripotency genes by PCR arrays. Our results demonstrated that luteolin/apigenin restrained cell proliferation, increased apoptosis, and arrested PDLCs in G2/M and S phase. Luteolin and apigenin activated expression of Oct-4, Sox2, and c-Myc in a time- and dose-dependent pattern, and repressed lineage-specific differentiation. PCR arrays profiled multiple signals in PDLCs with luteolin/apigenin treatment, among which NFATc1 was the major upregulated gene. Notably, blocking of the NFATc1 signal with INCA-6 significantly decreased mRNA and protein expression of Oct-4, Sox2, and c-Myc in PDLCs with luteolin/apigenin treatment, indicating that NFATc1 may act as an upstream modulator of Oct-4/Sox2 signal. Taken together, this study showed that luteolin and apigenin effectively maintain pluripotency of PDLCs through activation of Oct-4/Sox2 signal via NFATc1.