Acetaminophen influences musculoskeletal signaling but not adaptations to endurance exercise training.

Acetaminophen (ACE) is a widely used analgesic and antipyretic drug with various applications, from pain relief to fever reduction. Recent studies have reported equivocal effects of habitual ACE intake on exercise performance, muscle growth, and risks to bone health. Thus, this study aimed to assess the impact of a 6-week, low-dose ACE regimen on muscle and bone adaptations in exercising and non-exercising rats. Nine-week-old Wistar rats (n = 40) were randomized to an exercise or control (no exercise) condition with ACE or without (placebo). For the exercise condition, rats ran 5 days per week for 6 weeks at a 5% incline for 2 min at 15 cm/s, 2 min at 20 cm/s, and 26 min at 25 cm/s. A human equivalent dose of ACE was administered (379 mg/kg body weight) in drinking water and adjusted each week based on body weight. Food, water intake, and body weight were measured daily. At the beginning of week 6, animals in the exercise group completed a maximal treadmill test. At the end of week 6, rats were euthanized, and muscle cross-sectional area (CSA), fiber type, and signaling pathways were measured. Additionally, three-point bending and microcomputer tomography were measured in the femur. Follow-up experiments in human primary muscle cells were used to explore supra-physiological effects of ACE. Data were analyzed using a two-way ANOVA for treatment (ACE or placebo) and condition (exercise or non-exercise) for all animal outcomes. Data for cell culture experiments were analyzed via ANOVA. If omnibus significance was found in either ANOVA, a post hoc analysis was completed, and a Tukey's adjustment was used. ACE did not alter body weight, water intake, food intake, or treadmill performance (p > .05). There was a treatment-by-condition effect for Young's Modulus where placebo exercise was significantly lower than placebo control (p < .05). There was no treatment by condition effects for microCT measures, muscle CSA, fiber type, or mRNA expression. Phosphorylated-AMPK was significantly increased with exercise (p < .05) and this was attenuated with ACE treatment. Furthermore, phospho-4EBP1 was depressed in the exercise group compared to the control (p < .05) and increased in the ACE control and ACE exercise group compared to placebo exercise (p < .05). A low dose of ACE did not influence chronic musculoskeletal adaptations in exercising rodents but acutely attenuated AMPK phosphorylation and 4EBP1 dephosphorylation post-exercise.

Use of metamizole and other non-opioid analgesics in Switzerland between 2014 and 2019: an observational study using a large health insurance claims database.

OBJECTIVE: To investigate claims patterns for metamizole and other non-opioid analgesics in Switzerland. To characterise users of these non-opioid analgesics regarding sex, age, comedications and canton of residence. METHODS: We conducted a retrospective descriptive study using administrative claims data of outpatient prescribed non-opioid analgesics of the Swiss health insurance company Helsana between January 2014 and December 2019. First, we evaluated the number of claims and defined daily doses  per year of metamizole, ibuprofen, diclofenac and paracetamol in adults aged 18 years or over. Second, we characterised new users of these non-opioid analgesics in terms of sex, age, claimed comedications and canton of residence. RESULTS: From 2014 to 2019, among the investigated non-opioid analgesics, metamizole showed the highest increase in claims (+9545 claims, +50%) and defined daily doses (+86,869 defined daily doses, +84%) per 100,000 adults. Metamizole users had the highest median age (62 years [IQR: 44-77]) compared to ibuprofen (47 years [IQR: 33-62]), diclofenac (57 years [IQR: 43-71]) and paracetamol (58 years [IQR: 39-75]) users. Metamizole users also more frequently claimed proton pump inhibitors, anticoagulants, platelet aggregation inhibitors and antihypertensive drugs than users of other non-opioid analgesics. While metamizole was most frequently claimed in German-speaking regions of Switzerland, ibuprofen and paracetamol were most frequently claimed in the French-speaking regions and diclofenac in German- and Italian-speaking regions. CONCLUSION: In Switzerland, metamizole was increasingly claimed between 2014 and 2019. Metamizole was most frequently claimed by older adults and patients with comedications suggestive of underlying conditions, which can be worsened or caused by use of nonsteroidal anti-inflammatory drugs. The lack of studies regarding the effectiveness and safety of metamizole in this population warrants further investigation.

Acute liver failure.

ABSTRACT: Acute liver failure, commonly caused by acetaminophen overdose, is associated with numerous systemic complications including cerebral edema, hypotension, acute kidney injury, and infection. Management is primarily supportive, with an emphasis on excellent neurocritical care. Although some antidotes and targeted treatments exist, the only definitive treatment remains orthotopic liver transplant.

Evaluation of capillary miR-122 as a prognostic biomarker of paracetamol-induced liver toxicity.

INTRODUCTION: Paracetamol (acetaminophen) overdose is a leading cause of acute liver failure in many Western countries. Diagnostic tools for this poisoning may be suboptimal in some cases and new biomarkers have been investigated. We investigated the role of capillary microRNA-122 (miR-122) as a prognostic biomarker of liver injury in the clinical management of patients with paracetamol overdose. METHODS: In a paracetamol overdose patient cohort, miR-122 was measured by quantitative polymerase chain reaction in a blood drop obtained by a finger prick at the end of an antidote cycle treatment with N-acetylcysteine treatment (12 h). Liver injury was defined as serum alanine aminotransferase (ALT) activity > 100 IU/L collected at 10 or 20 h after the start of treatment. Pearson's correlation analyses were performed. RESULTS: In patients with paracetamol overdose, capillary miR-122 was positively correlated with ALT measured at 10 h and at 20 h (r = 0.83, P < 0.0001; r = 0.96, P < 0.0001, respectively). CONCLUSION: This work supports the potential use of capillary miR-122 as a prognostic biomarker of liver injury throughout clinical management of patients with paracetamol overdose. Capillary miR-122 can be measured in a blood drop collected by a finger prick, a minimally invasive diagnostic test for patient stratification.

Evaluation of Postoperative Pain After Cardiothoracic Surgery in Patients With and Without Significant Preoperative Anxiety: A Prospective Observational Study.

BACKGROUND AND AIMS: Anxiety plays a distressing role in cardiothoracic operations. It may trigger hemodynamic instability, increased morbidity, and very crucially, postoperative pain and analgesic use. Our aim is to look at the association between anxiety, postoperative pain, and analgesic use. MATERIALS AND METHODS: One hundred and twenty-two patients scheduled for cardiothoracic surgeries were asked questions according to the Amsterdam Preoperative Anxiety and Information Scale (APAIS), the evening prior to the surgery. Different factors that could affect anxiety perioperatively were recorded through the patient's hospital records. The visual analog score (VAS) was recorded at arrival in the ICU after surgery. Paracetamol (1 g) and Inj Tramadol (1 mg/kg) were administered as postoperative analgesia. Additional fentanyl boluses (1 mcg/kg) were administered whenever the VAS exceeded 4. Analgesic doses were documented. All the data were then analyzed statistically. RESULTS: Preoperative anxiety was recorded in 63.9% of the 122 subjects included in the study, with younger patients and patients with very low socioeconomic status being the majority. VAS, at 20 and 24 hrs of assessment, was higher in both groups, and there was a statistically significant difference, with patients that were preoperatively anxious, recording higher VAS scores. Postoperative analgesic doses were also significantly higher for patients with anxiety. CONCLUSIONS: This clinical trial demonstrated that greater than 60% of the participants presented with preoperative anxiety, the majority being young participants. Lower socioeconomic status is also a risk factor for preoperative anxiety. Patients who suffered from preoperative anxiety are more likely to have greater pain scores and analgesic needs during postsurgical assessment.

Indole-3-carboxaldehyde alleviates acetaminophen-induced liver injury via inhibition of oxidative stress and apoptosis.

Drug-induced liver injury (DILI) occurs frequently and can be life-threatening. Increasing researches suggest that acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury. Indole-3-carboxaldehyde (I3A) alleviates hepatic inflammation, fibrosis and atherosclerosis, suggesting a potential role in different disease development. However, the question of whether and how I3A protects against acetaminophen-induced liver injury remains unanswered. In this study, we demonstrated that I3A treatment effectively mitigates acetaminophen-induced liver injury. Serum alanine/aspartate aminotransferases (ALT/AST), liver malondialdehyde (MDA) activity, liver glutathione (GSH), and superoxide dismutase (SOD) levels confirmed the protective effect of I3A against APAP-induced liver injury. Liver histological examination provided further evidence of I3A-induced protection. Mechanistically, I3A reduced the expression of apoptosis-related factors and oxidative stress, alleviating disease symptoms. Finally, I3A treatment improved survival in mice receiving a lethal dose of APAP. In conclusion, our study demonstrates that I3A modulates hepatotoxicity and can be used as a potential therapeutic agent for DILI.

Chronic Low Back Pain in Adults: Evaluation and Management.

Chronic low back pain, defined as lumbar pain persisting for 12 weeks or more, occurs in about 13% of U.S. adults. Patients with chronic low back pain should have a history and physical examination to identify red flags that may indicate serious conditions that warrant immediate intervention or yellow flags (i.e., psychological, environmental, and social factors) that indicate risk of disability. The examination should include an evaluation for radicular symptoms. Routine imaging is not recommended but is indicated when red flags are present, there is a neuromuscular deficit, or if pain does not resolve with conservative therapy. Patients should avoid bed rest. Nonpharmacologic treatment is first-line management and may include therapies with varying evidence of support, such as counseling, exercise therapy, spinal manipulation, massage, heat, dry needling, acupuncture, transcutaneous electrical nerve stimulation, and physical therapy. Pharmacologic interventions are second-line treatment. Nonsteroidal anti-inflammatory drugs are the initial medication of choice; duloxetine may also be beneficial. Evidence is inconclusive to recommend the use of benzodiazepines, muscle relaxants, antidepressants, corticosteroids, insomnia agents, anticonvulsants, cannabis, acetaminophen, or long-term opioids. Epidural corticosteroid injections are not recommended except for short-term symptom relief in patients with radicular pain. Most patients with chronic low back pain will not require surgery; evaluation for surgery may be considered in those with persistent functional disabilities and pain from progressive spinal stenosis, worsening spondylolisthesis, or herniated disk. Physicians should consider prevention of chronic low back pain when patients present with acute back pain. Screening tools are available to predict the progression from acute to chronic low back pain, and targeted treatment strategies are beneficial for preventing progression.

Autonomous circadian rhythms in the human hepatocyte regulate hepatic drug metabolism and inflammatory responses.

Critical aspects of physiology and cell function exhibit self-sustained ~24-hour variations termed circadian rhythms. In the liver, circadian rhythms play fundamental roles in maintaining organ homeostasis. Here, we established and characterized an in vitro liver experimental system in which primary human hepatocytes display self-sustained oscillations. By generating gene expression profiles of these hepatocytes over time, we demonstrated that their transcriptional state is dynamic across 24 hours and identified a set of cycling genes with functions related to inflammation, drug metabolism, and energy homeostasis. We designed and tested a treatment protocol to minimize atorvastatin- and acetaminophen-induced hepatotoxicity. Last, we documented circadian-dependent induction of pro-inflammatory cytokines when triggered by LPS, IFN-ß, or Plasmodium infection in human hepatocytes. Collectively, our findings emphasize that the phase of the circadian cycle has a robust impact on the efficacy and toxicity of drugs, and we provide a test bed to study the timing and magnitude of inflammatory responses over the course of infection in human liver.

Capacitive biophysical stimulation improves the healing of vertebral fragility fractures: a prospective multicentre randomized controlled trial.

BACKGROUND: Capacitively coupling electric fields (CCEF) is a method of non-invasive biophysical stimulation that enhances fracture repair and spinal fusion. This multicentre randomized controlled trial aimed to further examine the roles of CCEF in (1) the resolution of vertebral bone marrow oedema (VBME) using a follow-up MRI study and (2) pain relief, analgesic drug consumption and quality of life improvement in stimulated patients who were referred with acute vertebral fragility fractures (VFFs) compared to non-stimulated patients. METHODS: Between September 2016 and December 2019, patients who were referred to the spine centres that participated in this multicentre randomized clinical study with acute VFFs of type OF1 or OF2 were included in the present study. All the VFFs were conservatively managed according to Good Clinical Practice. Moreover, the patients were randomized into two groups: the CCEF group received, as an adjunct to the clinical study protocol, biophysical stimulation with a CCEF device (Osteospine, IGEA) for 8 h per day for 60 days, whereas the control group was treated according to the clinical study protocol. At baseline (T0), the 30-day follow-up (T1), the 60-day follow-up (T2), and the 6-month follow-up (T3), each patient underwent clinical evaluation using the Visual Analogue Scale (VAS) for Pain and the Oswestry Disability Index (ODI). Analgesic therapy with paracetamol 1000 mg tablets for 7 days-or longer, depending on the pain intensity-was performed; patients were required to report their paracetamol consumption on a specific sheet between study day 8 to 180 days of follow-up. MRI studies of the thoracolumbar spine were performed at 0 (T0), 30 (T1) and 60 days of follow-up (T2) using a 1.5-T MRI system in all of the centres that took part in the study. For each VBME area examined via MRI, the vertebral body geometry (i.e. anterior wall height/posterior wall height and vertebral kyphosis) were assessed. RESULTS: A total of 66 patients (male: 9, 13.63%; mean age: 73.15 years old) with 69 VFFs were included in the present study and randomized as follows: 33 patients were included in the control group and the remaining 33 patients were randomized into the CCEF group. In the CCEF group, good compliance with CCEF therapy was observed (adherence = 94%), and no adverse effects were recorded. In the stimulated patients, faster VBME resolution and significantly less vertebral body collapse during follow-up were observed compared to the control patients. Moreover, in the active group, faster pain reduction and improvement in the ODI mean score were observed. Stimulated patients also reported a significantly lower paracetamol consumption rate from the third follow-up after treatment until the 6-month follow-up. In terms of sex-related differences, in the CCEF group, VBME showed a faster resolution in male patients compared with females. CONCLUSION: Biophysical stimulation with CCEF, as an adjunct to traditional conservative treatment, is a useful tool to hasten the VBME resolution process and prevent vertebral body deformation. These MRI findings also correlate with faster back pain resolution and quality of life improvement. From the third follow-up after treatment until the 6-month follow-up, stimulated patients reported a significantly lower paracetamol consumption than control patients, even though back pain and quality of life showed no significant differences between the two groups. LEVEL OF EVIDENCE: II. Trial Registration Register: ClinicalTrials.gov, number: NCT05803681.

Association of acetaminophen use with perinatal outcomes among pregnant women: a retrospective cohort study with propensity score matching.

BACKGROUND: Although acetaminophen is widely used in women during pregnancy, its safety has not been clearly stated. The study aimed to investigate the association between acetaminophen use and adverse pregnancy outcomes in pregnant women in China. METHODS: We conducted a retrospective cohort study by collecting data on pregnant women who delivered in the Beijing Obstetrics and Gynecology Hospital from January 2018 to September 2023. An acetaminophen use group and a control group were formed based on prenatal exposure to acetaminophen. The pregnancy outcomes that we focused on were stillbirth, miscarriage, preterm birth, APGAR score, birth weight, and congenital disabilities. Pregnant women exposed to acetaminophen were matched to unexposed in a 1:1 ratio with propensity score matching, using the greedy matching macro. SPSS software was used for statistical analysis. Multivariable logistics regression was used to assess the association between acetaminophen use during pregnancy and adverse pregnancy outcomes. RESULTS: A total of 41,440 pregnant women were included, of whom 501 were exposed to acetaminophen during pregnancy, and 40,939 were not exposed. After the propensity score matching, the acetaminophen use and control groups consisted of 501 pregnant women each. The primary analysis showed that acetaminophen exposure during pregnancy was associated with an increased risk of stillbirth (adjusted OR (aOR) = 2.29, 95% CI, 1.19-4.43), APGAR score < 7 at 1 min (aOR = 3.28, 95% CI, 1.73-6.21), APGAR score < 7 at 5 min (aOR = 3.54, 95% CI, 1.74-7.20), APGAR score < 7 at 10 min (aOR = 3.18, 95% CI, 1.58-6.41), and high birth weight (HBW) (aOR = 1.75, 95% CI, 1.05-2.92). Drug exposure during the first and second trimesters increased the odds of stillbirth, miscarriage, APGAR < 7, and the occurrence of at least one adverse pregnancy outcome. In addition, the frequency of drug use more than two times was associated with a higher risk of preterm birth and APGAR score < 7. CONCLUSIONS: Exposure to acetaminophen during pregnancy was significantly associated with the occurrence of adverse pregnancy outcomes, particularly exposure in the first and second trimesters and frequency of use more than twice. It is suggested that acetaminophen should be prescribed with caution in pregnant women.

Pharmacokinetic profile of oral and subcutaneous administration of paracetamol in the koala (Phascolarctos cinereus) and prediction of its analgesic efficacy.

The pharmacokinetic profile of paracetamol in koalas is described when administered orally at 15 mg/kg; followed by the same dose, administered every 12 hours (hrs), repeated five times. After the initial oral administration, the median (range) maximal plasma concentration (Cmax), the time Cmax was reached (Tmax) and elimination half-life (t1/2) were 16.93 µg/mL (13.66 to 20.25 µg/mL); 4 hrs (4 to 8 hrs) and 5.54 hrs (4.66 to 7.67 hrs), respectively. When paracetamol was administered orally at 15 mg/mL every 12 hrs, the trough total plasma concentration range remained comparable to the therapeutic range in humans i.e. 4 to 20 µg/mL that is known to provide some analgesia. However, there is a smaller proportion of free drug (i.e. not bound to plasma proteins; and the active form) available in koala plasma (approximately 40% unbound) compared to human plasma (approximately 80% unbound). Consequently, even when there are similar total drug plasma concentrations in both koala and human plasma, the therapeutic efficacy may be reduced in koalas compared to humans. The initial oral dose and subsequent twice daily doses resulted in no obvious adverse effects in any koala. Haematology, plasma electrolyte and biochemical analyte values remained within their reference ranges eight hrs after the last dose but there was a significant change in alanine transaminase (ALT) levels (an increase), and in total protein (a decrease) (both p = 0.03). A dose of 15 mg/kg was also administered as a subcutaneous injection, diluted 50:50 with saline, to two koalas. As the oral formulation and the subcutaneous administration resulted in comparable absorption, the study focused on the oral profile. Based on these results there is an argument to recommend a slight increase in the oral paracetamol dose for the koala, however further investigation is required to confirm whether repeated administration of a slightly higher dose may be associated with more severe or additional significant changes in haematology, electrolytes or biochemical analytes. However, a preferable recommendation would be to administer this dosage of paracetamol in combination with another analgesic such as tramadol, as a subcutaneous injection, to improve efficacy.

Ameliorative effects of berberine and selenium against paracetamol-induced hepatic toxicity in rats.

Background: Paracetamol (PCM) overdosing induces hepatotoxicity, which can result in death if the dose is high enough and the patients are not given N-acetyl cysteine. Berberine (BBR) has a variety of biological proprieties including anti-inflammatory and antioxidant activities. Aim: Assessment of the potential effect of BBR and selenium when used alone or together on the PCM-induced acute hepatic toxicity in rats. Methods: This research involved 40 clinically healthy mature adult male albino rats, their weights ranged from 150 to 200 g and housed in standard conditions. Our study involved evaluating the potential effect of BBR and selenium when used alone or together on the PCM-induced acute hepatic toxicity via estimation of the liver function tests, determination of the antioxidant enzyme activities, lipid peroxidation markers, immune-modulatory effects, liver histopathological, and immunohistochemical studies. Results: Co-treatment of BBR (150 mg/kg BW) with selenium (5 mg/kg BW) showed significant improvement in the liver function parameters, the antioxidant enzyme activities, reduction in the nitric oxide (NO), lysozyme, malondialdehyde (MDA), TNF-α, and TGF-ß1 levels, and marked elevation in the IgM levels. Conclusion: Altogether, BBR, selenium, or both augment antioxidant activity and alleviate PCM-induced hepatic toxicity.

Effect of the long-term use of a NOAEL dose of acetaminophen (paracetamol) on hepatic, renal, and neural tissues of aged albino rats.

Background: Paracetamol is one of the most popular drugs; it is used daily by many people especially the elderly, without a limitation on the length of the period allowed for continuous use. Harms from long-term use are less clear, particularly in extrahepatic regions. Aim: This study aimed to investigate whether using paracetamol at a non-observable adverse effect level dose, known not to cause toxic effects, for a long period can induce toxicity in aged male albino rats. Methods: A daily dose of 500 mg per kg body weight of paracetamol was given to adult male albino rats for 12 weeks. During this period, rats were sacrificed at 4, 6, 8, 10, and 12 weeks to evaluate the toxic changes at several time intervals. Results: Chemical analysis revealed elevated serum alanine transaminase, aspartate transaminase, alkaline phosphatase, urea, creatinine, and declined level of total protein in N-acetyl-p-aminophenol (APAP)-treated group; it also caused oxidative stress, as shown by decreased glutathione, superoxide dismutase, and elevated malondialdehyde in the liver, kidney, and brain. Histopathological examination demonstrated cytoplasmic vacuolation and sinusoidal congestion with the development of single-cell necrosis in the liver. Renal tubular necrosis, glomerular atrophy, and ischemic neuronal injury, especially in the hippocampus were observed. the deleterious effects of APAP were increased in severity with increasing the period of treatment. Conclusion: Our results suggest that acetaminophen in a subtoxic dose for a long period could result in mild toxic effects on the liver but more serious lesions in the kidney and brain.

Swept-source Raman spectroscopy of chemical and biological materials.

Significance: Raman spectroscopy has been used as a powerful tool for chemical analysis, enabling the noninvasive acquisition of molecular fingerprints from various samples. Raman spectroscopy has proven to be valuable in numerous fields, including pharmaceutical, materials science, and biomedicine. Active research and development efforts are currently underway to bring this analytical instrument into the field, enabling in situ Raman measurements for a wider range of applications. Dispersive Raman spectroscopy using a fixed, narrowband source is a common method for acquiring Raman spectra. However, dispersive Raman spectroscopy requires a bulky spectrometer, which limits its field applicability. Therefore, there has been a tremendous need to develop a portable and sensitive Raman system. Aim: We developed a compact swept-source Raman (SS-Raman) spectroscopy system and proposed a signal processing method to mitigate hardware limitations. We demonstrated the capabilities of the SS-Raman spectroscopy by acquiring Raman spectra from both chemical and biological samples. These spectra were then compared with Raman spectra obtained using a conventional dispersive Raman spectroscopy system. Approach: The SS-Raman spectroscopy system used a wavelength-swept source laser (822 to 842 nm), a bandpass filter with a bandwidth of 1.5 nm, and a low-noise silicon photoreceiver. Raman spectra were acquired from various chemical samples, including phenylalanine, hydroxyapatite, glucose, and acetaminophen. A comparative analysis with the conventional dispersive Raman spectroscopy was conducted by calculating the correlation coefficients between the spectra from the SS-Raman spectroscopy and those from the conventional system. Furthermore, Raman mapping was obtained from cross-sections of swine tissue, demonstrating the applicability of the SS-Raman spectroscopy in biological samples. Results: We developed a compact SS-Raman system and validated its performance by acquiring Raman spectra from both chemical and biological materials. Our straightforward signal processing method enhanced the quality of the Raman spectra without incurring high costs. Raman spectra in the range of 900 to 1200 cm-1 were observed for phenylalanine, hydroxyapatite, glucose, and acetaminophen. The results were validated with correlation coefficients of 0.88, 0.84, 0.87, and 0.73, respectively, compared with those obtained from dispersive Raman spectroscopy. Furthermore, we performed scans across the cross-section of swine tissue to generate a biological tissue mapping plot, providing information about the composition of swine tissue. Conclusions: We demonstrate the capabilities of the proposed compact SS-Raman spectroscopy system by obtaining Raman spectra of chemical and biological materials, utilizing straightforward signal processing. We anticipate that the SS-Raman spectroscopy will be utilized in various fields, including biomedical and chemical applications.

Physical-chemical Stability of the Extemporaneous Paracetamol Oral Suspension in Puccini Base.

This study describes a new method for the preparation of extemporaneous paracetamol-based suspensions for pediatric and adult patients. This method allows the preparation of extemporaneous suspensions up to concentrations of 50 mg/mL by using a liquid base, named "Puccini". A high-pressure liquid chromatographic method was developed and validated for the determination of chemical stability of paracetamol when the formulations were stored at 4°C and 25°C. The chemical stability of the active pharmaceutical ingredient in the base was demonstrated for more than 90 days. Visual analyses of the formulations showed a phenomenon of precipitation at both storage temperatures, but the simple agitation of the formulations before its use re-established the formation of homogeneous suspensions.

Acetaminophen Use During Pregnancy and Children's Risk of Autism, ADHD, and Intellectual Disability.

Importance: Several studies suggest that acetaminophen (paracetamol) use during pregnancy may increase risk of neurodevelopmental disorders in children. If true, this would have substantial implications for management of pain and fever during pregnancy. Objective: To examine the associations of acetaminophen use during pregnancy with children's risk of autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability. Design, Setting, and Participants: This nationwide cohort study with sibling control analysis included a population-based sample of 2 480 797 children born in 1995 to 2019 in Sweden, with follow-up through December 31, 2021. Exposure: Use of acetaminophen during pregnancy prospectively recorded from antenatal and prescription records. Main Outcomes and Measures: Autism, ADHD, and intellectual disability based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes in health registers. Results: In total, 185 909 children (7.49%) were exposed to acetaminophen during pregnancy. Crude absolute risks at 10 years of age for those not exposed vs those exposed to acetaminophen were 1.33% vs 1.53% for autism, 2.46% vs 2.87% for ADHD, and 0.70% vs 0.82% for intellectual disability. In models without sibling control, ever-use vs no use of acetaminophen during pregnancy was associated with marginally increased risk of autism (hazard ratio [HR], 1.05 [95% CI, 1.02-1.08]; risk difference [RD] at 10 years of age, 0.09% [95% CI, -0.01% to 0.20%]), ADHD (HR, 1.07 [95% CI, 1.05-1.10]; RD, 0.21% [95% CI, 0.08%-0.34%]), and intellectual disability (HR, 1.05 [95% CI, 1.00-1.10]; RD, 0.04% [95% CI, -0.04% to 0.12%]). To address unobserved confounding, matched full sibling pairs were also analyzed. Sibling control analyses found no evidence that acetaminophen use during pregnancy was associated with autism (HR, 0.98 [95% CI, 0.93-1.04]; RD, 0.02% [95% CI, -0.14% to 0.18%]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]; RD, -0.02% [95% CI, -0.21% to 0.15%]), or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]; RD, 0% [95% CI, -0.10% to 0.13%]). Similarly, there was no evidence of a dose-response pattern in sibling control analyses. For example, for autism, compared with no use of acetaminophen, persons with low (<25th percentile), medium (25th-75th percentile), and high (>75th percentile) mean daily acetaminophen use had HRs of 0.85, 0.96, and 0.88, respectively. Conclusions and Relevance: Acetaminophen use during pregnancy was not associated with children's risk of autism, ADHD, or intellectual disability in sibling control analysis. This suggests that associations observed in other models may have been attributable to familial confounding.

Monitoring Pharmaceuticals and Personal Care Products in Healthcare Effluent Wastewater Samples and the Effectiveness of Drug Removal in Wastewater Treatment Plants Using the UHPLC-MS/MS Method.

A multi-residue UHPLC-MS/MS analytical method, previously developed for monitoring 52 pharmaceuticals in drinking water, was used to analyse these pharmaceuticals in wastewater originating from healthcare facilities in the Czech Republic. Furthermore, the methodology was expanded to include the evaluation of the effectiveness of drug removal in Czech wastewater treatment plants (WWTPs). Of the 18 wastewater samples analysed by the validated UHPLC-MS/MS, each sample contained at least one quantifiable analyte. This study reveals the prevalence of several different drugs; mean concentrations of 702 µg L-1 of iomeprol, 48.8 µg L-1 of iopromide, 29.9 µg L-1 of gabapentin, 42.0 µg L-1 of caffeine and 82.5 µg L-1 of paracetamol were present. An analysis of 20 samples from ten WWTPs revealed different removal efficiencies for different analytes. Paracetamol was present in the inflow samples of all ten WWTPs and its removal efficiency was 100%. Analytes such as caffeine, ketoprofen, naproxen or atenolol showed high removal efficiencies exceeding 80%. On the other hand, pharmaceuticals like furosemide, metoprolol, iomeprol, zolpidem and tramadol showed lower removal efficiencies. Four pharmaceuticals exhibited higher concentrations in WWTP effluents than in the influents, resulting in negative removal efficiencies: warfarin at -9.5%, indomethacin at -53%, trimethoprim at -54% and metronidazole at -110%. These comprehensive findings contribute valuable insights to the pharmaceutical landscape of wastewater from healthcare facilities and the varied removal efficiencies of Czech WWTPs, which together with the already published literature, gives a more complete picture of the burden on the aquatic environment.

Shoulder pain management strategies and early functional outcome after arthroscopic rotator cuff tear repair. A randomized controlled study.

BACKGROUND: The management of acute postoperative pain after rotator cuff surgery can be challenging. To our knowledge, there are no data available in the literature correlating satisfactory pain control with improvement in terms of function. The purposes of the present study were to evaluate: 1) pain pattern after arthroscopic rotator cuff repair in patients operated with two different techniques (transosseous vs transosseous equivalent); 2) safety/efficacy of three different pharmacological pain control strategies; 3) possible relationship between a correct shoulder pain management protocol in the early post-operative period and patients' functional improvement. METHODS: 114 patients underwent rotator cuff tear repair, either with a Transosseus or a Transosseus equivalent technique. 62 (54%) were male and 52 (46%) were female. The average age was 59 ± 9 years. They were randomly assigned into three different pain management protocols: Paracetamol as needed (max 3 tablets/day) for 1 week (Protocol A), Paracetamol + Codein 1 tablet three times per day for 7 days (Protocol B), or Paracetamol + Ibuprofen 1 tablet two times per day for 7 days (Protocol C). Immediate passive mobilization of the operated shoulder was allowed. VAS and Passive Flexion values were recorded at 7 (T1), 15 (T2) and 30 (T3) days post-surgery. DASH values were recorded at 90 days post-surgery. All patients were asked to register any kind of signs/symptoms that may appear during drug assumption according to each pain management protocols. RESULTS: All the pain management protocols administered were well tolerated by all the study population, and no adverse signs/symptoms were highlighted during drug assumption. Pain pattern: in both surgical techniques, patients within Protocol A were associated with worst results in terms of mean VAS at each time point examined when compared to Protocol B and C (p < 0,05). In patients within Protocol A, no statistically significant differences were found at each point time examined comparing the two surgical techniques, with the exception of T2, where the TO was associated with an higher VAS value than TOE (p < 0.05). No differences were highlighted in Protocol B and C when comparing the values between two surgical techniques. ROM: in both surgical techniques, patients within Protocol A were associated with worst results in terms of mean PROM at each time point examined when compared to Protocol B and C (p < 0,05). In the TO group, patients within Protocol B had better PROM values at T1 (p < 0,05) and T2 (p < 0,05) compared to Protocol C, but no differences were highlighted at T3. In the TOE group, no statistically significant differences were found between patients within Protocol B and C at each time point examined. DASH: In the TO group, no statistically significant differences were found regarding the DASH values comparing Protocol B vs Protocol C, but they were highlighted comparing the values between Protocol A and Protocol B (p < 0,05), and between Protocol A and Protocol C (p < 0,05). Similar results were recorded in the TOE group. CONCLUSION: Post-operative pain is influenced by the surgical technique used being transosseous more painful in the first 15 days after surgery. Oral anti-inflammatory drugs are a feasible strategy to appropriately control post-operative pain. An association between Paracetamol and either Codein or Ibuprofen can lead to better outcomes in terms of VAS reduction and early recovery of passive ROM.

Pain management after tonsil surgery in children and adults-A national survey related to pain outcome measures from the Swedish Quality Register for tonsil surgery.

OBJECTIVE: The primary aim of this study was to describe the current practice regarding pain management in relation to tonsil surgery among Ear Nose and Throat (ENT) clinics in Sweden. The secondary aim was to determine the impact of the provider's regime of rescue analgesics on the pain related Patient Reported Outcome Measures (pain-PROMs) from the Swedish Quality Register for Tonsil Surgery (SQTS). MATERIALS & METHODS: A descriptive cross-sectional study originating from a validated web-based questionnaire. The survey enrolled one respondent from each ENT clinic (47/48 participated) nationally. Pain-PROMs from the SQTS, recorded from October 2019 to October 2022, were included (8163 tonsil surgeries). RESULTS: Paracetamol was used by all enrolled ENT clinics as preemptive analgesia. The addition of COX inhibitors was used in 40% of the clinics. Betamethasone was usually administered, to prevent pain and nausea (92%). All clinics gave postdischarge instructions on multimodal analgesia with COX inhibitors and paracetamol. Rescue analgesics were prescribed after tonsillectomy for 77% of adults, 62% of older children, 43% of young children and less often after tonsillotomy. The most frequently prescribed rescue analgesic was clonidine in children (55%) and oxycodone in adults (72%). A high proportion of patients reported contact with health care services due to postoperative pain (pain-PROMs/ SQTS). Tonsillectomy procedures were associated with the highest rates of contacts (children/adolescents 13-15%; adults 26%), while tonsillotomy were associated with lower rates, (5-7% of children/adolescents). There was no significant difference in the frequency of health care contacts due to pain regarding whether clinics routinely prescribed rescue analgesics or not after tonsillectomy. CONCLUSION: The Swedish analgesic regimen after tonsil surgery is good overall. Nevertheless, there is a need for increased awareness and knowledge to achieve optimal patient recovery. Pain-PROM data demonstrate the call for improvement in pain management after tonsil surgery.

Deficiency of ASGR1 promotes liver injury by increasing GP73-mediated hepatic endoplasmic reticulum stress.

Liver injury is a core pathological process in the majority of liver diseases, yet the genetic factors predisposing individuals to its initiation and progression remain poorly understood. Here we show that asialoglycoprotein receptor 1 (ASGR1), a lectin specifically expressed in the liver, is downregulated in patients with liver fibrosis or cirrhosis and male mice with liver injury. ASGR1 deficiency exacerbates while its overexpression mitigates acetaminophen-induced acute and CCl4-induced chronic liver injuries in male mice. Mechanistically, ASGR1 binds to an endoplasmic reticulum stress mediator GP73 and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73 levels and promotes the interaction between GP73 and BIP to activate endoplasmic reticulum stress, leading to liver injury. Neutralization of GP73 not only attenuates ASGR1 deficiency-induced liver injuries but also improves survival in mice received a lethal dose of acetaminophen. Collectively, these findings identify ASGR1 as a potential genetic determinant of susceptibility to liver injury and propose it as a therapeutic target for the treatment of liver injury.