A review on reactive oxygen species-induced mechanism pathways of pharmaceutical waste degradation: Acetaminophen as a drug waste model.

Innately designed to induce physiological changes, pharmaceuticals are foreknowingly hazardous to the ecosystem. Advanced oxidation processes (AOPs) are recognized as a set of contemporary and highly efficient methods being used as a contrivance for the removal of pharmaceutical residues. Since reactive oxygen species (ROS) are formed in these processes to interact and contribute directly toward the oxidation of target contaminant(s), a profound insight regarding the mechanisms of ROS leading to the degradation of pharmaceuticals is fundamentally significant. The conceptualization of some specific reaction mechanisms allows the design of an effective and safe degradation process that can empirically reduce the environmental impact of the micropollutants. This review mainly deliberates the mechanistic reaction pathways for ROS-mediated degradation of pharmaceuticals often leading to complete mineralization, with a focus on acetaminophen as a drug waste model.

Efficacy of intravenous acetaminophen on postoperative shivering: A meta-analysis of randomized controlled trials.

PURPOSE: Postoperative shivering (POS) is a common and vital complication after anesthesia, which may result in serious consequences and uncomfortable experiences. Acetaminophen has been used to treat fever and mild to moderate pain. However, there is not enough evidence to prove its advantage for POS. This meta-analysis aimed to explore the prophylactic use of acetaminophen as a valid agent for POS. METHODS: Two researchers independently searched PubMed, the Cochrane Library, and Embase for controlled clinical trials. The meta-analysis of randomized controlled trials (RCTs) was performed by Review Manager. RESULTS: Nine trials with 856 patients were included in our meta-analysis. Acetaminophen significantly reduced POS compared with placebo (pooled risk ratio [RR]: 0.43, 95% confidence interval [CI]: 0.35-0.52). What is more, not only 15 mg/kg but also 1000 mg intravenous acetaminophen could reduce the incidence of shivering compared with placebo. CONCLUSION: Our present meta-analysis demonstrates that the intravenous prophylactic infusion of acetaminophen may prevent POS, and the results may provide new evidence to expand the clinical value of acetaminophen in addition to its routine usage.

GPR116 alleviates acetaminophen-induced liver injury in mice by inhibiting endoplasmic reticulum stress.

BACKGROUND: Acetaminophen (APAP) overdose is a significant contributor to drug-induced liver injury worldwide. G-protein-coupled receptor 116 (GPR116) is an important homeostatic maintenance molecule in the body, but little is known about its role in APAP-induced liver injury (AILI). METHODS: GPR116 expression was determined in both human and mouse AILI models. Hepatic function and damage response were analyzed in hepatocyte-specific GPR116 deletion (GPR116△HC) mice undergoing APAP challenge. RNA-sequencing, immunofluorescence confocal, and co-immunoprecipitation (CO-IP) were employed to elucidate the impact and underlying mechanisms of GPR116 in AILI. RESULTS: Intrahepatic GPR116 was upregulated in human and mice with AILI. GPR116△HC mice were vulnerable to AILI compared to wild-type mice. Overexpression of GPR116 effectively mitigated AILI in wild-type mice and counteracted the heightened susceptibility of GPR116△HC mice to APAP. Mechanistically, GPR116 inhibits the binding immunoglobulin protein (BiP), a critical regulator of ER function, through its interaction with ß-arrestin1, thereby mitigating ER stress during the early stage of AILI. Additionally, the activation of GPR116 by ligand FNDC4 has been shown to confer a protective effect against early hepatotoxicity caused by APAP in murine model. CONCLUSIONS: Upregulation of GPR116 on hepatocytes inhibits ER stress by binding to ß-arrestin1, protecting mice from APAP-induced hepatotoxicity. GPR116 may serve as a promising therapeutic target for AILI.

Identification and validation of cuproptosis-related genes in acetaminophen-induced liver injury using bioinformatics analysis and machine learning.

Background: Acetaminophen (APAP) is commonly used as an antipyretic analgesic. However, acetaminophen overdose may contribute to liver injury and even liver failure. Acetaminophen-induced liver injury (AILI) is closely related to mitochondrial oxidative stress and dysfunction, which play critical roles in cuproptosis. Here, we explored the potential role of cuproptosis-related genes (CRGs) in AILI. Methods: The gene expression profiles were obtained from the Gene Expression Omnibus database. The differential expression of CRGs was determined between the AILI and control samples. Protein protein interaction, correlation, and functional enrichment analyses were performed. Machine learning was used to identify hub genes. Immune infiltration was evaluated. The AILI mouse model was established by intraperitoneal injection of APAP solution. Quantitative real-time PCR and western blotting were used to validate hub gene expression in the AILI mouse model. The copper content in the mouse liver samples and AML12 cells were quantified using a colorimetric assay kit. Ammonium tetrathiomolybdate (ATTM), was administered to mouse models and AML12 cells in order to investigate the effects of copper chelator on AILI. Results: The analysis identified 7,809 differentially expressed genes, 4,245 of which were downregulated and 3,564 of which were upregulated. Four optimal feature genes (OFGs; SDHB, PDHA1, NDUFB2, and NDUFB6) were identified through the intersection of two machine learning algorithms. Further nomogram, decision curve, and calibration curve analyses confirmed the diagnostic predictive efficacy of the four OFGs. Enrichment analysis indicated that the OFGs were involved in multiple pathways, such as IL-17 pathway and chemokine signaling pathway, that are related to AILI progression. Immune infiltration analysis revealed that macrophages were more abundant in AILI than in control samples, whereas eosinophils and endothelial cells were less abundant. Subsequently, the AILI mouse model was successfully established, and histopathological analysis using hematoxylin-eosin staining along with liver function tests revealed a significant induction of liver injury in the APAP group. Consistent with expectations, both mRNA and protein levels of the four OFGs exhibited a substantial decrease. The administration of ATTAM effectively mitigates copper elevation induced by APAP in both mouse model and AML12 cells. However, systemic administration of ATTM did not significantly alleviate AILI in the mouse model. Conclusion: This study first revealed the potential role of CRGs in the pathological process of AILI and offered novel insights into its underlying pathogenesis.

Prepacked Take-Home Analgesia in Outpatient Hand Surgery Reduces Opioid Dispensation.

BACKGROUND: Adequate postoperative pain treatment is important for quality of life, patient satisfaction, rehabilitation, function, and total opioid consumption, and might lower both the risk of chronic postoperative pain and the costs for society. Prolonged opioid consumption is a well-known risk factor for addiction. Previous studies in upper extremity surgery have shown that total opioid consumption is a third of the amount prescribed, which can be explained by package size. The aim of this study was to examine whether implementation of prepacked takehome analgesia bags reduced the quantity of prescribed and dispensed opioids. MATERIAL AND METHODS: We introduced prepacked take-home analgesia bags for postoperative pain treatment in outpatient surgery. The bags came in two sizes, each containing paracetamol, etoricoxib, and oxycodone. The first 147 patients who received the prepacked analgesia bags were included in the study, and received a questionnaire one month after surgery covering self-assessed pain (visual analog scale of 0-10) and satisfaction (0-5), as well as opioid consumption. Prescription data after introducing the analgesia bags were compared with data before the bags were introduced. RESULTS: Of the 147 patients included in the study, 58 responded. Compared to standard prescription (small bag group: 14 oxycodone immediate release capsules (5 mg), large bag group: additional 28 oxycodone extended release tablets (5 mg), based on the smallest available package), the patients in the small analgesia bag group received 50% less oxycodone and 67% less for the large bag group. Patients with small bags consumed a median of 0.0 mg oxycodone and those with large bags consumed a median of 25.0 mg oxycodone. The median satisfaction was 5.0 (range: 2-5) and the median pain score was acceptable at the first postoperative day. Prescription data showed a significant reduction of 60.0% in the total amount of prescribed opioids after the introduction of prepacked analgesia bags. CONCLUSIONS: The introduction of prepacked analgesia bags dramatically reduced the quantity of opioids prescribed after outpatient hand surgery. Patient satisfaction was high and the postoperative pain level was acceptable. KEY WORDS: analgesia, hand surgery, opioids, outpatint surgery, wrist surgery.

Comparison of analgesic effectiveness between nefopam and propacetamol in living kidney donors following rectus sheath block after hand-assisted living donor nephrectomy: a prospective, randomized controlled trial.

BACKGROUND: Nefopam and propacetamol are the most commonly used analgesics in postoperative multimodal analgesic regimens. Distinct mechanisms are involved in each drug's anti-nociceptive effects. No studies have compared pain relief efficacy between the two drugs in patients undergoing transplantation surgery. Here, we investigated whether the administration of nefopam or propacetamol to healthy living kidney donors who underwent rectus sheath block (RSB) for parietal pain could reduce the subsequent opioid dose necessary to produce adequate analgesia. METHODS: This prospective, randomized controlled trial included 72 donors undergoing elective hand-assisted living donor nephrectomy into two groups: propacetamol (n = 36) and nefopam (n = 36). Intraoperative RSB was performed in all enrolled donors. The primary outcome was the total volume of intravenous opioid-based patient-controlled analgesia (PCA) used on postoperative day 1 (POD 1). Additionally, the Numeric Rating Scale scores for flank (visceral) and umbilicus (parietal) pain at rest and during coughing were compared, and the Korean adaptation of the Quality of Recovery-15 Questionnaire (QoR-15 K) was evaluated on POD 1. RESULTS: Both groups had similar preoperative and intraoperative characteristics. On POD 1, the total amount of PCA infusion was significantly lower in the nefopam group than in the propacetamol group (44.5 ± 19.3 mL vs. 70.2 ± 29.0 mL; p < 0.001). This group also reported lower pain scores at the flank and umbilical sites and required fewer rescue doses of fentanyl in the post-anesthesia care unit. However, pain scores and fentanyl consumption in the ward were comparable between groups. The QoR-15 K scores were similar between groups; there were substantial improvements in breathing, pain severity, and anxiety/depression levels in the nefopam group. The incidences of postoperative complications, including sweating and tachycardia, were similar between groups. CONCLUSION: Compared with propacetamol, nefopam provides a greater analgesic effect for visceral pain and enhances the effects of blocks that reduce the opioid requirement in living kidney donors with parietal pain managed by RSB. TRIAL REGISTRATION: The trial was registered prior to patient enrollment in the clinical trial database using the Clinical Research Information Service (registration no. KCT0007351 , Date of registration 03/06/2022).

Identification of Proteomic Biomarkers of Acetaminophen-Induced Hepatotoxicity Using Stable Isotope Labeling.

Quantitative proteomics approaches based on stable isotopic labeling and mass spectrometry have been widely applied to disease research, drug target discovery, biomarker identification, and systems biology. One of the notable stable isotopic labeling approaches is trypsin-catalyzed 18O/16O labeling, which has its own advantages of low sample consumption, simple labeling procedure, cost-effectiveness, and absence of chemical reactions that potentially generate by-products. In this chapter, a protocol for 18O/16O labeling-based quantitative proteomics approach is described with an application to the identification of proteomic biomarkers of acetaminophen (APAP)-induced hepatotoxicity in rats. The protocol involves first the extraction of proteins from liver tissues of control and APAP-treated rats and digestion into peptides by trypsin. After cleaning of the peptides by solid-phase extraction, equal amounts of peptides from the APAP treatment and the control groups are then subject to trypsin-catalyzed 18O/16O labeling. The labeled peptides are combined and fractionated by off-line strong cation exchange liquid chromatography (SCXLC), and each fraction is then analyzed by nanoflow reversed-phase LC coupled online with tandem mass spectrometry (RPLC-MS/MS) for identification and quantification of differential protein expression between APAP-treated rats and controls. The protocol is applicable to quantitative proteomic analysis for a variety of biological samples.

Christensenella minuta Alleviates Acetaminophen-Induced Hepatotoxicity by Regulating Phenylalanine Metabolism.

Acetaminophen (APAP)-induced liver injury (AILI), even liver failure, is a significant challenge due to the limited availability of therapeutic medicine. Christensenella minuta (C. minuta), as a probiotic therapy, has shown promising prospects in metabolism and inflammatory diseases. Our research aimed to examine the influence of C. minuta on AILI and explore the molecular pathways underlying it. We found that administration of C. minuta remarkably alleviated AILI in a mouse model, as evidenced by decreased levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) and improvements in the histopathological features of liver sections. Additionally, there was a notable decrease in malondialdehyde (MDA), accompanied by restoration of the reduced glutathione/oxidized glutathione (GSH/GSSG) balance, and superoxide dismutase (SOD) activity. Furthermore, there was a significant reduction in inflammatory markers (IL6, IL1ß, TNF-α). C. minuta regulated phenylalanine metabolism. No significant difference in intestinal permeability was observed in either the model group or the treatment group. High levels of phenylalanine aggravated liver damage, which may be linked to phenylalanine-induced dysbiosis and dysregulation in cytochrome P450 metabolism, sphingolipid metabolism, the PI3K-AKT pathway, and the Integrin pathway. Furthermore, C. minuta restored the diversity of the microbiota, modulated metabolic pathways and MAPK pathway. Overall, this research demonstrates that supplementing with C. minuta offers both preventive and remedial benefits against AILI by modulating the gut microbiota, phenylalanine metabolism, oxidative stress, and the MAPK pathway, with high phenylalanine supplementation being identified as a risk factor exacerbating liver injury.

Unused, leftover and expired medicine and disposal practices among health sciences faculty students in Burdur, Turkey.

Objective: To evaluate the opinions of university-level Health Sciences students about unused, leftover and expired medicine, as well as their disposal practices, and to classify the medicines. METHODS: The cross-sectional study was conducted from April 1 to May 31, 2023, at the Faculty of Health Sciences, Burdur Mehmet Akif Ersoy University, Turkey, and comprised those studying at the Nursing, Nutrition Dietetics and Physical Therapy and Rehabilitation departments. Data was collected using Google Forms. The Anatomical Therapeutic Chemical classification was used for classifying pharmaceutical active ingredients. Data was analysed using SPSS 24. RESULTS: Of the 373 participants, 272(73%) were females and 101(27%) were males. The overall mean age was 20.8±2.8 years. There were 348(93.3%) subejcts who reported having a total of 845 boxes of leftover and unused medicines in their homes (2.3±1.9 per capita), while 25(6.7%) participants had none. The medicines were stored in the kitchen 261(61.5%) as the storage area, and in the refrigerator 181(40.2%) as the storage unit. The expired medicine was disposed of in the garbage in 328(86.1%) cases. Self-medication was prevalent in 325(87.1%) cases. Anatomical Therapeutic Chemical classification analysis showed that paracetamol, acetylsalicylic acid, paracetamol+caffeine and metamizole sodium was the most common group of leftover and unused medicines 283(81.3%). Conclusion: High prevalence of unused and leftover medicine, disposal of medicine in household garbage, and selfmedication behaviour indicated a serious public health and environmental problem.

Phytolacca Dodecandra (L' Herit) (Phytolaccaceae) Methanol Root Extract Protects Liver from Acetaminophen-Induced Injury in Rats.

Phytolacca dodecandra (L' Herit), or 'Endod', is one of the widely known medicinal plants in Ethiopia. Berries of the endod have been used as a detergent for centuries. The present study was aimed to test the hepatoprotective effects of the plant against acetaminophen (APAP)-induced liver injury in rats. Mice of either sex were used for oral acute toxicity tests and APAP-induced lethality tests. Hepatoprotective experiments were done on male rats using 2 g/kg of APAP to induce liver damage. Liver enzymes, total bilirubin (TB), and lipid profile were determined. Liver tissues were also examined histopathologically to see a morphologic change in the control and experiment groups. The protective effect of the plant extract was also tested through sodium pentobarbital (SPB)-induced sleeping time. A significant increase in serum levels of liver enzymes, TB, low-density lipoprotein (LDL), and triglycerides (TGs) was seen from oral administration of 2 g/kg APAP. Total cholesterol (TC) and high-density lipoprotein (HDL) levels were decreased. Serum levels of all parameters were reversed to normal after administration of silymarin 100 mg/kg and, 100, 200, and 400 mg/kg doses of the extract. A significant dose-dependent hepatoprotective effect of Phytolacca dodecandra Methanol Root Extract (PDME) was seen in terms of LDL. Histopathological investigations and SPB-induced sleeping time confirmed the findings of biochemical analysis. The findings of the present study indicate that PDME protected the liver from APAP injury.

Effect of ferroptosis inhibitors in a murine model of acetaminophen-induced liver injury.

Liver injury caused by acetaminophen (APAP) overdose is the leading cause of acute liver failure in western countries. The mode of APAP-induced cell death has been controversially discussed with ferroptosis emerging as a more recent hypothesis. Ferroptosis is characterized by ferrous iron-catalyzed lipid peroxidation (LPO) causing cell death, which can be prevented by the lipophilic antioxidants ferrostatin-1 and UAMC-3203. To assess the efficacy of these ferroptosis inhibitors, we used two murine models of APAP hepatotoxicity, APAP overdose alone or in combination with FeSO4 in fasted male C57BL/6J mice. APAP triggered severe liver injury in the absence of LPO measured as hepatic malondialdehyde (MDA) levels. In contrast, ferrous iron co-treatment aggravated APAP-induced liver injury and caused extensive LPO. Standard doses of ferrostatin-1 did not affect MDA levels or the injury in both models. In contrast, UAMC-3203 partially protected in both models and reduced LPO in the presence of ferrous iron. However, UAMC-3203 attenuated the translocation of phospho-JNK through downregulation of the mitochondrial anchor protein Sab resulting in reduced mitochondrial dysfunction and liver injury. Thus, APAP toxicity does not involve ferroptosis under normal conditions. The lack of effects of ferroptosis inhibitors in the pathophysiology indicates that ferroptosis signaling pathways are not relevant therapeutic targets.

Outcomes after hip fracture surgery in patients receiving non-steroidal anti-inflammatory drugs alone, acetaminophen alone, or both.

Aims: The use of multimodal non-opioid analgesia in hip fractures, specifically acetaminophen combined with non-steroidal anti-inflammatory drugs (NSAIDs), has been increasing. However, the effectiveness and safety of this approach remain unclear. This study aimed to compare postoperative outcomes among patients with hip fractures who preoperatively received either acetaminophen combined with NSAIDs, NSAIDs alone, or acetaminophen alone. Methods: This nationwide retrospective cohort study used data from the Diagnosis Procedure Combination database. We included patients aged ≥ 18 years who underwent surgery for hip fractures and received acetaminophen combined with NSAIDs (combination group), NSAIDs alone (NSAIDs group), or acetaminophen alone (acetaminophen group) preoperatively, between April 2010 and March 2022. Primary outcomes were in-hospital mortality and complications. Secondary outcomes were opioid use postoperatively; readmission within 90 days, one year, and two years; and total hospitalization costs. We used propensity score overlap weighting models, with the acetaminophen group as the reference group. Results: We identified 93,018 eligible patients, including 13,068 in the combination group, 29,203 in the NSAIDs group, and 50,474 in the acetaminophen group. Propensity score overlap weighting successfully balanced patient characteristics among the three groups, with no significant difference in in-hospital mortality rates observed among the groups (combination group risk difference 0.0% (95% CI -0.5 to 0.4%); NSAIDs group risk difference -0.2% (95% CI -0.5 to 0.2%)). However, the combination group exhibited a significantly lower risk of in-hospital complications than the acetaminophen group (risk difference -1.9% (95% CI -3.2 to -0.6%)) as well as a significantly lower risk of deep vein thrombosis (risk difference -1.4% (95% CI -2.2 to -0.7%)). Furthermore, total hospitalization costs were higher in the NSAIDs group than in the acetaminophen group (difference USD $438 (95% CI 249 to 630); p < 0.001). No significant differences in other secondary outcomes were observed among the three groups. Conclusion: The combination of acetaminophen with NSAIDs appears to be safe and advantageous in terms of reducing in-hospital complications.

Sustainable removal of tetracycline and paracetamol from water using magnetic activated carbon derived from pine fruit waste.

This work presents highly porous magnetic activated carbon nanoparticles (MPFRC-A) derived from pine fruit residue. The MPFRC-A were produced through a three-step process: physical activation (carbonization temperature: 110-550 °C), chemical activation (H2SO4 (0.1 N, 96%)), and co-precipitation. These nanoparticles were then used to remove tetracycline (TC) and paracetamol (PC) from water. Functionalization with Fe3O4 nanoparticles on the surface of the pine fruit residue-derived activated carbon (PFRC-A) resulted in high saturation magnetization, allowing for separation from aqueous solution using an external magnet. The MPFRC-A adsorbent was characterized by Brunauer-Emmett-Teller (BET) analysis, Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffraction (XRD), and Energy-dispersive X-ray spectroscopy (EDX) analyses, In the experimental section, the effects of various factors on the adsorption process were investigated, including pH, contact time, initial pollutant concentrations, adsorbent dosage, and temperature. Based on these investigations, adsorption isotherm models and kinetics were studied and determined. The results showed that MPFRC-A exhibited a large specific surface area (182.5 m2/g) and a high total pore volume (0.33 cm3/g). The maximum adsorption capacity was achieved at pH 6 and 5 for PC and TC drugs with an adsorbent dose of 400 mg and an initial concentration of 20 mg/L at 25 °C. The study revealed that the experimental data were well-fitted by the Langmuir isotherm model (R2 > 0.98), with maximum uptake capacities of 43.75 mg/g for TC and 41.7 mg/g for PC. Outcomes of the adsorption thermodynamics shows non-spontaneity of the reaction and the adsorption process by all adsorbents was endothermic.

Acetaminophen for Patent Ductus Arteriosus and Risk of Mortality and Pulmonary Morbidity.

OBJECTIVE: Emerging data indicate that acetaminophen may adversely affect lung health. We examined whether acetaminophen compared with cyclooxygenase (COX) inhibitor alone for patent ductus arteriosus (PDA) is associated with mortality or respiratory morbidity in extremely preterm infants. METHODS: This is a retrospective cohort study using data from the National Institute of Child Health and Human Development Neonatal Research Network. Infants were born at 22 to 28 weeks' gestation or weighing 401 to 1000 g between 2016 and 2020 and received acetaminophen, ibuprofen, and/or indomethacin for PDA closure. The primary outcome was death or grade 2 to 3 bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age. Secondary outcomes included predischarge mortality and respiratory morbidities. Risk ratios were adjusted for baseline and early postnatal factors. Additional exploratory analyses were adjusted for later postnatal covariates. RESULTS: Of 1921 infants, 627 (32.6%) received acetaminophen and 1294 (67.3%) received COX inhibitor only. Multidrug therapy (42.9% vs 4.7%) and surgical or catheter PDA closure (26.5% vs 19.9%) were more common among acetaminophen-exposed infants. Death or grade 2 to 3 BPD at 36 weeks' postmenstrual age was similar between infants treated with acetaminophen versus COX inhibitor only (57.1% vs 58.3%; adjusted relative risk [aRR] 0.96, 95% confidence interval [CI] 0.87-1.06). Acetaminophen was associated with increased risk of predischarge mortality (13.3% vs 10.0%) when adjusting for perinatal and early postnatal factors (aRR 1.42, 95% CI 1.02-1.93), but not in exploratory analyses that included later postnatal factors (aRR 1.28, 95% CI 0.91-1.82). CONCLUSIONS: Treatment with acetaminophen versus COX inhibitor alone for PDA was not associated with the composite outcome of death or BPD in extremely preterm infants. Our results support further evaluation of whether acetaminophen for PDA increases mortality.

Fracture pain in children in the emergency department: the impact of a new pain management procedure.

PURPOSE: To compare compliance with the French national guidelines before and after the implementation (in 2018) of a new protocol on acute fracture pain management in the pediatric emergency department of a French university medical center. METHODS: We conducted a retrospective, before-after study in patients aged below 16 years presenting at the pediatric emergency department with a fracture. We compared pain management before (in 2017) and after (in 2019 and 2020) implementation of the new procedure. The primary endpoint was appropriate pain management, defined as (i) an appropriate initial assessment of pain, (ii) appropriate treatment with analgesic drugs (acetaminophen for mild pain, acetaminophen and ibuprofen for moderate pain, ibuprofen and morphine for severe pain) and (iii) reassessment of the pain intensity. RESULTS: 572 patients were included (mean age: 6.5 years; male: 60%). 190 in 2017 and 382 in 2019-2020. Pain management was appropriate for 40% of the patients in 2017 and 52% in 2019-2020 (p = 0.004). Pain was rated for 98% of patients in 2017 vs. 100% in 2019-2020 (p = 0.04). The frequency of appropriate treatment for mild pain and moderate pain increased significantly from 52 to 76% and from 0 to 44%, respectively. The administration of ibuprofen increased by 26% points (from 3 to 20 patients treated) and the administration of morphine increased by 29% points (from 1 to 17 patients treated). Pain reassessment rose significantly from 21 to 43%. Levels of compliance with the guidelines were similar in 2019 and 2020. Analgesia was significantly more effective in 2019-2020 than in 2017 (in 20% vs. 14% of the patients, respectively; p = 0.005). CONCLUSION: After the implementation of a new protocol for the management of acute fracture pain, we observed an increase in compliance with the guidelines. Although the use of ibuprofen and morphine rose significantly as did the frequency of pain reassessment, further improvements are required.

Opioid free analgesia after return home in ambulatory colonic surgery patients: a single-center observational study.

BACKGROUND: Because of the adverse effects of morphine and its derivatives, non-opioid analgesia procedures are proposed after outpatient surgery. Without opioids, the ability to provide quality analgesia after the patient returns home may be questioned. We examined whether an opioid-free strategy could ensure satisfactory analgesia after ambulatory laparoscopic colectomy. METHODS: We performed a retrospective observational single-center study (of prospective collected database) including all patients eligible for scheduled outpatient colectomy. Postoperative analgesia was provided by paracetamol and nefopam. Postoperative follow-up included pain at mobilization (assessed by a numerical rating scale, NRS), hemodynamic variables, temperature, resumption of transit and biological markers of postoperative inflammation. The primary outcome was the proportion of patients with moderate to severe pain (NRS > 4) the day after surgery. RESULTS: Data from 144 patients were analyzed. The majority were men aged 59 ± 12 years with a mean BMI of 27 [25-30] kg/m2. ASA scores were 1 for 14%, 2 for 59% and 3 for 27% of patients. Forty-seven patients (33%) underwent surgery for cancer, 94 for sigmoiditis (65%) and 3 (2%) for another colonic pathology. Postoperative pain was affected by time since surgery (Q3 = 52.4,p < 0.001) and decreased significantly from day to day. The incidence of moderate to severe pain at mobilization (NRS > 4) on the first day after surgery was (0.19; 95% CI, 0.13-0.27). CONCLUSION: Non-opioid analgesia after ambulatory laparoscopic colectomy seems efficient to ensure adequate analgesia. This therapeutic strategy makes it possible to avoid the adverse effects of opioids. TRIAL REGISTRATION: The study was retrospectively registered and approved by the relevant institutional review board (CERAR) reference IRB 00010254-2018 - 188). All patients gave written informed consent for analysis of their data. The anonymous database was declared to the French Data Protection Authority (CNIL) (reference 221 2976 v0 of April 12, 2019).

Adenosine kinase protects against acetaminophen-induced acute liver injury by activating autophagy in hepatocytes.

Acute liver injury (ALI) is a common life-threatening condition with a high mortality rate due to liver disease-related death. However, current therapeutic interventions for ALI remain ineffective, and the development of effective novel therapies is urgently needed. Liver samples from patients with drug-induced ALI were collected to detect adenosine kinase (ADK) expression. Male C57BL/6 J mice, hepatocyte-specific ADK knockout (ADKHKO) mice, and their controls (ADKf/f) were exposed to acetaminophen (APAP) and other treatments to investigate the mechanisms of APAP-related ALI. ADK expression was significantly decreased in APAP-injured livers. Hepatocyte-specific ADK deficiency exacerbated APAP-induced ALI, while a gain-of-function approach delivering AAV-ADK, markedly alleviated APAP-induced ALI, as indicated by changes in alanine aminotransferases (ALT) levels, aspartate aminotransferase (AST) levels, neutrophil infiltration and hepatocyte death. This study showed that ADK played a critical role in ALI by activating autophagy through two signaling pathways, the adenosine monophosphate-activated protein kinase (AMPK)-mTOR pathway and the adenosine receptor A1 (ADORA1)-Akt-mTOR pathway. Furthermore, we found that metformin upregulated ADK expression in hepatocytes and protected against APAP-induced ALI. These results demonstrate that ADK is critical in protecting against APAP-induced ALI and that developing therapeutics targeting ADK-adenosine-ADORA1 is a new approach for ALI treatment. Metformin is a potential candidate for preventing ALI by upregulating ADK.

Continuous stationary phase gradient preparation on planar chromatographic media using vapor phase deposition of silane.

A new, versatile, and straightforward vapor phase deposition (VPD) approach was used to prepare continuous stationary phase gradients (cSPGs) on silica thin-layer chromatography (TLC) plates using phenyldimethylchlorosilane (PDCS) as a precursor. A mixture of paraffin oil and PDCS was placed at the bottom of an open-ended rectangular chamber, allowing the reactive silanes to evaporate and freely diffuse under a controlled atmosphere. As the volatile silane diffused across the length of the TLC plate, it reacted with the surface silanol groups thus functionalizing the surface in a gradient fashion. Characterization of the gradient TLC plates was done through UV visualization and diffuse reflectance spectroscopy (DRS). Visualizing the fluorescent gradient plates under UV radiation shows the clear presence of a gradient with the side closest to the vapor source undergoing the most modification. More quantitative characterization of the shape of the gradient was provided by DRS. The DRS showed that the degree of modification and shape of the gradient was dependent on the concentration of silane, VPD time, and relative humidity. To evaluate the chromatographic performance, a mixture of three aromatic compounds (acetaminophen (A), aspirin (As), and 3-hydroxy-2-naphthoic acid (3H)) was spotted on the high (GHP) and low phenyl (GLP) ends of the gradient TLC plates and the results compared to the separations carried out on unmodified and uniformly modified plates. The GHP TLC plates showed retention factors (Rf) of 0.060 ± 0.006, 0.391 ± 0.006, and 0.544 ± 0.006, whereas the unmodified plate displayed Rf values of 0.059 ± 0.006, 0.092 ± 0.003, and 0.037 ± 0.002 for the analytes A, As, and 3H, respectively. From the Rf values, it was observed that each modified plate exhibited different selectivity for the analytes. The GHP TLC plates exhibited better separation performance, and improved resolution compared to the GLP, unmodified, and uniformly modified plates. Overall, VPD is a new, cost-effective method for creating a gradient on the stationary phase which has the potential to advance chromatographic separation capabilities.