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Background: Chat Generative Pre-trained Transformer (ChatGPT) is a language model that may have the potential to revolutionize health care. The study purpose was to test whether ChatGPT could be used to create educational brochures about kidney transplant tailored for three target audiences: caregivers, teens and children., Methods: Using a list of 25 educational topics, standardized prompts were employed to ensure content consistency in ChatGPT generation. An expert panel assessed the accuracy of the content by rating agreement on a Likert scale (1 = <25 % agreement; and 5 = 100 % agreement). The understandability, actionability and readability of the brochures were assessed using the Patient Education Materials Assessment Tool for printable materials (PEMAT-P) and standard readability scales. A caregiver and patient reviewed and provided written feedback., Results: We found mean understandability scores of 69 %, 66 %, and 73 % for caregiver, teen, and child brochures respectively, with 90.7 % of the ChatGPT generated brochures scoring 40 % on the actionability scale. Generated caregiver and teen materials achieved readability levels of grades 9-14, while child-specific brochures achieved readability levels of grades 6-11. Brochures were formatted appropriately but lacked depth., Conclusion: ChatGPT demonstrates potential for rapidly generating patient education materials; however, challenges remain in ensuring content specificity. We share the lessons learned to assist other healthcare providers with using this technology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: There are increasing concerns regarding pharmaceutical opioid harms including overdose and dependence, with an associated increase in treatment demand. People dependent on pharmaceutical opioids appear to differ in important ways from people who use heroin, yet most opioid agonist treatment research has been conducted in people who use heroin., Objectives: To assess the effects of maintenance agonist pharmacotherapy for the treatment of pharmaceutical opioid dependence., Search Methods: The search included the Cochrane Drugs and Alcohol Group's Specialised Register of Trials; the Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 5); PubMed (January 1966 to May 2015); EMBASE (Ovid) (January 1974 to May 2015); CINAHL (EBSCOhost) (1982 to May 2015); ISI Web of Science (to May 2014); and PsycINFO (Ovid) (1806 to May 2014)., Selection Criteria: We included randomised controlled trials examining maintenance opioid agonist treatments that made the following two comparisons:1. full opioid agonists (methadone, morphine, oxycodone, levo-alpha-acetylmethadol (LAAM), or codeine) versus different full opioid agonists or partial opioid agonists (buprenorphine) for maintenance treatment and2. full or partial opioid agonist maintenance versus placebo, detoxification only, or psychological treatment (without opioid agonist treatment)., Data Collection and Analysis: We used standard Cochrane methodological procedures., Main Results: We identified six randomised controlled trials that met inclusion criteria (607 participants).We found moderate quality evidence from two studies of no difference between methadone and buprenorphine in self reported opioid use (risk ratio (RR) 0.37, 95% confidence interval (CI) 0.08 to 1.63) or opioid positive urine drug tests (RR 0.81, 95% CI 0.56 to 1.18). There was low quality evidence from three studies of no difference in retention between buprenorphine and methadone maintenance treatment (RR 0.69, 95% CI 0.39 to 1.22). There was moderate quality evidence from two studies of no difference between methadone and buprenorphine on adverse events (RR 1.10, 95% CI 0.64 to 1.91).We found low quality evidence from three studies favouring maintenance buprenorphine treatment over detoxification or psychological treatment in terms of fewer opioid positive urine drug tests (RR 0.63, 95% CI 0.43 to 0.91) and self reported opioid use in the past 30 days (RR 0.54, 95% CI 0.31 to 0.93). There was no difference on days of unsanctioned opioid use (standardised mean difference (SMD) -0.31, 95% CI -0.66 to 0.04). There was moderate quality evidence favouring buprenorphine maintenance over detoxification or psychological treatment on retention in treatment (RR 0.33, 95% CI 0.23 to 0.47). There was moderate quality evidence favouring buprenorphine maintenance over detoxification or psychological treatment on adverse events (RR 0.19, 95% CI 0.06 to 0.57).The main weaknesses in the quality of the data was the use of open-label study designs., Authors' Conclusions: There was low to moderate quality evidence supporting the use of maintenance agonist pharmacotherapy for pharmaceutical opioid dependence. Methadone or buprenorphine appeared equally effective. Maintenance treatment with buprenorphine appeared more effective than detoxification or psychological treatments.Due to the overall low to moderate quality of the evidence and small sample sizes, there is the possibility that the further research may change these findings.

Background: Internationally, there is concern about the increased prescribing of pharmaceutical opioids for chronic non-cancer pain (CNCP). In part, this is related to limited knowledge about the long-term benefits and outcomes of opioid use for CNCP. There has also been increased injection of some pharmaceutical opioids by people who inject drugs, and for some patients, the development of problematic and/or dependent use. To date, much of the research on the use of pharmaceutical opioids among people with CNCP, have been clinical trials that have excluded patients with complex needs, and have been of limited duration (i.e. fewer than 12 weeks). The Pain and Opioids In Treatment (POINT) study is unique study that aims to: 1) examine patterns of opioid use in a cohort of patients prescribed opioids for CNCP; 2) examine demographic and clinical predictors of adverse events, including opioid abuse or dependence, medication diversion, other drug use, and overdose; and 3) identify factors predicting poor pain relief and other outcomes., Methods/design: The POINT cohort comprises around 1,500 people across Australia prescribed pharmaceutical opioids for CNCP. Participants will be followed-up at four time points over a two year period. POINT will collect information on demographics, physical and medication use history, pain, mental health, drug and alcohol use, non-adherence, medication diversion, sleep, and quality of life. Data linkage will provide information on medications and services from Medicare (Australia's national health care scheme). Data on those who receive opioid substitution therapy, and on mortality, will be linked., Discussion: This study will rigorously examine prescription opioid use among CNCP patients, and examine its relationship to important health outcomes. The extent to which opioids for chronic pain is associated with pain reduction, quality of life, mental and physical health, aberrant medication behavior and substance use disorders will be extensively examined. Improved understanding of the longer-term outcomes of chronic opioid therapy will direct community-based interventions and health policy in Australia and internationally. The results of this study will assist clinicians to better identify those patients who are at risk of adverse outcomes and who therefore require alternative treatment strategies.

Cells of the innate immune system play important roles in the progression of prion disease after peripheral infection. It has been found in vivo and in vitro that the expression of the cellular prion protein (PrP(c)) is up-regulated on stimulation of immune cells, also indicating the functional importance of PrP(c) in the immune system. The aim of our study was to investigate the impact of cytosine-phosphate-guanosine- and lipopolysaccharide-induced PrP(c) up-regulation on the uptake and processing of the pathological prion protein (PrP(Sc)) in phagocytic innate immune cells. For this purpose, we challenged the macrophage cell line J774, the microglial cell line BV-2 and primary bone marrow-derived macrophages in a resting or stimulated state with various prion strains, and monitored the uptake and clearance of PrP(Sc). Interestingly, stimulation led either to a transient increase in the level of PrP(Sc) relative to unstimulated cells or to a decelerated degradation of PrP(Sc). These features were dependent on cell type and prion strain. Our data indicate that the stimulation of innate immune cells may be able to support transient prion propagation, possibly explained by an increased PrP(c) cell surface expression in stimulated cells. We suggest that stimulation of innate immune cells can lead to an imbalance between the propagation and degradation of PrP(Sc).

Prion diseases are rare and obligatory fatal neurodegenerative disorders caused by the accumulation of a misfolded isoform (PrPSc) of the host-encoded prion protein (PrPc). Prophylactic and therapeutic regimens against prion diseases are very limited. To extend such strategies we selected peptide aptamers binding to PrP from a combinatorial peptide library presented on the Escherichia coli thioredoxin A (trxA) protein as a scaffold. In a yeast two-hybrid screen employing full-length murine PrP (aa 23-231) as a bait we identified three peptide aptamers that reproducibly bind to PrP. Treatment of prion-infected cells with recombinantly expressed aptamers added to the culture medium abolished PrPSc conversion with an IC50 between 350 and 700 nM. For expression in eukaryotic cells, peptide aptamers were fused to an N-terminal signal peptide for entry of the secretory pathway. The C terminus was modified by a glycosyl-phosphatidyl-inositol-(GPI) anchoring signal, a KDEL retention motif and the transmembrane and cytosolic domain of LAMP-I, respectively. These peptide aptamers retained their binding properties to PrPc and, depending on peptide sequence and C-terminal modification, interfered with endogenous PrPSc conversion upon expression in prion-infected cells. Notably, infection of cell cultures could be prevented by expression of KDEL peptide aptamers. For the first time, we show that trxA-based peptide aptamers can be targeted to the secretory pathway, thereby not losing the affinity for their target protein. Beside their inhibitory effect on prion conversion, these molecules could be used as fundament for rational drug design.

The cellular prion protein PrP(c) is attached to the plasma membrane by a glycosyl-phosphatidyl-inositol (GPI-) anchor and is localized in lipid rafts, membrane microdomains characterized by a high content of sphingolipids and cholesterol. Previous studies revealed that perturbation of cholesterol synthesis prevents prion conversion, explained by redistribution of PrP(c) at the plasma membrane. We investigated the influence of inhibition of cholesterol synthesis by the HMG-CoA-reductase inhibitor mevinolin on the trafficking of PrP(c) in neuronal cells. Treatment with mevinolin significantly reduces the amount of surface PrP(c) and leads to its accumulation in the Golgi compartment. Analysis of mutant PrPs highlights the importance of the GPI-anchor for raft localization and provides information about domains implicated in lipid raft association of PrP in the secretory pathway. Our data show that cholesterol is essential for the cell surface localization of PrP(c), known to be necessary for prion conversion.

The conversion of the cellular prion protein (PrPc) into a pathogenic isoform (PrP(Sc)) is one of the underlying events in the pathogenesis of the fatal transmissible spongiform encephalopathies (TSEs). Numerous compounds have been described to inhibit prion replication and PrP(Sc) accumulation in cell culture. Among these, the drug suramin induces aggregation and re-targeting of PrPc to endocytic compartments. Plasma membrane and sites of conversion into PrP(Sc) are thereby bypassed. In the present study, a library of suramin analogues was tested as a potential class of new anti-prion compounds and the molecular mechanisms underlying these effects were analysed. Treatment of prion-infected neuroblastoma cells with compounds containing symmetrical aromatic sulfonic acid substitutions inhibited de novo synthesis of PrP(Sc) and induced aggregation and reduction of the half-life of PrPc without downregulating PrPc cell surface expression. Half-molecule compounds lacking the symmetrical bipolar structure or the anionic groups had no effect on PrP(Sc) synthesis or PrPc solubility. Cell surface expression of PrPc was necessary for the activity of effective compounds. Suramin derivatives did not induce aggregation of PrPc when transport along the secretory pathway was compromised, suggesting that their effects occur at a post trans-Golgi network (TGN) site, possibly close to the compartment of conversion into PrP(Sc). In vitro studies with recombinant PrP demonstrated that the inhibitory effect correlated with direct binding to PrP and induction of insoluble PrP aggregates. Our data reveal an anti-prion effect that differs from those characterising other sulphated polyanions and is dependent on the presence of the symmetrical anionic structure of these molecules.

Background: Cardiac beta receptor down-regulation is associated with a reduction of tissue cyclic adenosine monophosphate (AMP) content. Milrinone exerts its effects by inhibiting the metabolism of existing cyclic AMP. The purpose of this study was to evaluate the effect of reduced myocardial cyclic AMP content on the pharmacologic action of milrinone., Methods: A reduction of myocardial cyclic AMP content was produced by creating catecholamine depletion in the hearts of adult guinea pigs with intraperitoneal reserpine. Control animals received the reserpine vehicle. Isolated heart perfusion was maintained with modified Krebs buffer, and hearts were paced at 270 beats/min. A latex balloon and transducer-tipped catheter were inserted into the left ventricle. Isovolemic work was maintained at a constant balloon volume. Hearts from control and reserpine treated animals were perfused for 20 minutes with buffer containing either no milrinone, 1.7 x 10(-6), or 1.0 x 10(-4) mol/L milrinone (n = 12 for each dose). Maximal positive and negative dP/dt were assessed. The hearts were then frozen and cyclic AMP was measured., Results: Cyclic AMP content was significantly lower in the reserpine-treated hearts at each milrinone concentration (0.33 +/- 0.01 vs 0.46 +/- 0.01; 0.33 +/- 0.01 vs 0.53 +/- 0.01; 0.30 +/- 0.01 vs 0.61 +/- 0.02 pmol/mg wet weight, p < 0.05). Milrinone significantly increased positive and negative dP/dtmax (p < 0.05), but no difference was observed between control and reserpine-treated hearts., Conclusions: Endogenous catecholamine depletion reduces myocardial cyclic AMP content but does not attenuate the response to milrinone in the isolated heart.

This study was designed to determine the extent by which mild or moderate hyperthermia attenuates the triggering of malignant hypothermia (MH) induced by the combined administration of halothane and succinylcholine. Sixteen susceptible swine were initially anesthetized with nontriggering drugs and then either kept normothermic (approximately equal to 38 degrees C, n = 6) or cooled to induce mild (approximately equal to 35 degrees C, n = 6), or moderate (approximately equal to 33 degrees C, n = 4) hypothermia. Next, after a 30-min control period, the normothermic and mildly hypothermic animals were administered 1 minimum alveolar anesthetic concentration (MAC) halothane followed by a bolus dose of succinylcholine (2 mg/kg). Within 10 min all normothermic animals developed fulminant MH, whereas the onset of MH was slowed or was absent in the mildly hypothermic group. To test whether moderate hypothermia could more effectively minimize the signs of a MH episode, this group of animals was exposed to 1.5 MAC halothane followed 10 min later by a 3-mg/kg bolus of succinylcholine. MH was not induced and anesthesia was then changed to nontriggering drugs (ketamine and pancuronium). The animals were then aggressively rewarmed to 38 degrees C: a slight increase in the ETCO2 was detected, but MH episodes did not spontaneously occur. Subsequently, the readministration of halothane and succinylcholine rapidly provoked fulminant MH. We concluded that the induction of mild hypothermia impairs triggering and reduces the progression of MH induced by the combined administration of halothane and succinylcholine, whereas moderate hypothermia was completely protective and thus could be considered for prophylaxis.

This study was designed to evaluate how vital organ and skin-surface temperatures correlate with other clinical signs of a malignant hyperthermia (MH) episode. Six susceptible swine were anesthetized with thiopental and nitrous oxide and kept normothermic (approximately equal to 38 degrees C). After a 30-min control period, halothane (1 minimum alveolar anesthetic concentration) was administered, followed in 5 min by a bolus of succinylcholine (2 mg/kg intravenously). Monitoring included: 1) ETCO2; 2)PaO2, PaCO2, pHa; 3) cardiovascular function; 4) core temperatures (esophagus, pulmonary artery, and rectum); 5) organ temperatures (brain, kidney, liver, and four skeletal muscles); and 6) skin temperatures (forehead, neck, and axilla). Within 10 min after exposure to halothane and succinylcholine, all animals developed fulminant MH. Kidney, liver, and brain temperatures increased more rapidly than pulmonary artery temperature with the onset of MH. Temperatures significantly increased in the visceral organs prior to the detection of contractures within skeletal muscles. The masseter, longissimus dorsi, quadriceps, deltoid, and extensor digiti II intramuscular temperatures were 1-2 degrees C less than pulmonary artery and esophageal temperatures during the episodes, whereas those of the kidney, liver, and brain were the same or slightly greater. When it occurs, core hyperthermia during acute MH results largely from heat produced in central organs, not in skeletal muscle per se. In these swine, changes in axilla skin surface temperatures correlated well with core temperature trends, whereas those of the neck and forehead did not. Unless a skin-surface probe can be placed in close proximity to a major vessel, cutaneous temperatures should not be substituted for measurements at an appropriate core site.

The study was undertaken to define a dose-response relationship for clonidine in prolonging canine tetracaine spinal anesthesia. Using a randomized blind cross-over design, six mongrel dogs were given subarachnoid injections (1 ml) of the following solutions over an 8-week period: tetracaine 4 mg (control), or tetracaine 4 mg with clonidine in doses of 10, 25, 50, 100, 150, 200, and 300 micrograms. With clonidine doses equal to or exceeding 50 micrograms/ml, motor and sensory blockade were significantly (P less than 0.01) prolonged, when compared to the control times. Analysis of data by second order polynomial regression analysis produced a relationship defined by Y = 23.241 + 1.104(x) - 0.0023(x2) with r2 = 0.92 and P less than 0.001 for sensory blockade and Y = 38.7072 + 1.64425(x) - 0.004125(x2) with r2 = 0.90 and P less than 0.005 for motor blockade. From these curves, a plateau in clonidine dose-response for both sensory blockade and motor blockade occurred at 150 micrograms. The increase in duration of spinal anesthesia with clonidine may be related to a direct post-synaptic alpha 2 adrenoceptor arteriolar effect, a spinal cord pre- or post-synaptic alpha 2 antinociceptive action or supraspinal alpha 2 modulation of nociception. No animals showed evidence of neurologic dysfunction during the study. The authors conclude that a well-defined dose-response relationship exists for clonidine in canine tetracaine spinal anesthesia.