Orthopedic postoperative infection profile and antibiotic sensitivity of 2038 patients across 24 countries - Call for region and institution specific surgical antimicrobial prophylaxis.

Purpose: Improper utilization of surgical antimicrobial prophylaxis frequently leads to increased risks of morbidity and mortality.This study aims to understand the common causative organism of postoperative orthopedic infection and document the surgical antimicrobial prophylaxis protocol across various institutions in to order to strengthen surgical antimicrobial prophylaxis practice and provide higher-quality surgical care. Methods: This multicentric multinational retrospective study, includes 24 countries from five different regions (Asia Pacific, South Eastern Africa, Western Africa, Latin America, and Middle East). Patients who developed orthopedic surgical site infection between January 2021 and December 2022 were included. Demographic details, bacterial profile of surgical site infection, and antibiotic sensitivity pattern were documented. Results: 2038 patients from 24 countries were included. Among them 69.7 % were male patients and 64.1 % were between 20 and 60 years. 70.3 % patients underwent trauma surgery and instrumentation was used in 93.5 %. Ceftriaxone was the most common preferred in 53.4 %. Early SSI was seen in 55.2 % and deep SSI in 59.7 %. Western Africa (76 %) and Asia-Pacific (52.8 %) reported a higher number of gram-negative infections whereas gram-positive organisms were predominant in other regions. Most common gram positive organism was Staphylococcus aureus (35 %) and gram-negative was Klebsiella (17.2 %). Majority of the organisms showed variable sensitivity to broad-spectrum antibiotics. Conclusion: Our study strongly proves that every institution has to analyse their surgical site infection microbiological profile and antibiotic sensitivity of the organisms and plan their surgical antimicrobial prophylaxis accordingly. This will help to decrease the rate of surgical site infection, prevent the emergence of multidrug resistance and reduce the economic burden of treatment.

Development, reliability, validity, and acceptability of the remote administration of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS).

BACKGROUND: ALS clinical care and research has changed dramatically since the COVID-19 pandemic, accelerating the need for cognitive assessments to be adapted for remote use. OBJECTIVES: To develop the remote administration method of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), and determine its reliability and validity. Methods: The validation process consisted of: (1) Two versions of the ECAS (A and B) were administered, one in-person and one remotely via video call in a randomized order to 27 people without ALS; (2) The ECAS was administered remotely to 24 pwALS, with a second rater independently scoring performance; and (3) Acceptability was assessed by gathering feedback from 17 pwALS and 19 clinicians and researchers about their experience of using the ECAS remotely. RESULTS: In the group without ALS, the remote and in-person ECAS total scores were found to be equivalent, and a Bland-Altman plot showed good agreement between the two administration methods. In pwALS, there was excellent agreement between two raters (ICC = 0.99). Positive feedback was gained from pwALS, researchers and clinicians with regards to ease of process, convenience, time, and the environment. CONCLUSIONS: These findings provide evidence of the reliability and validity of the remote administration of the ECAS for pwALS, with clinicians, researchers and pwALS viewing it as a good alternative to face-to-face administration.

Circular External Fixator Removal in the Outpatient Clinic Using Regional Anaesthesia: A Pilot Study of a Novel Approach.

Introduction: External fixator (EF) devices are commonly used in the management of complex skeletal trauma, as well as in elective limb reconstruction surgery for the management of congenital and acquired pathology. The subsequent removal of an EF is commonly performed under general anaesthesia in an operating theatre. This practice is resource-intensive and limits the amount of time available for other surgical cases in the operating theatre. We aimed to assess the use of regional anaesthesia as an alternative method of analgesia to facilitate the EF removal in an outpatient setting. Design and methods: This prospective case series evaluated the first 50 consecutive cases of EF removal in the outpatient clinic between 10/06/22 and 03/02/23. Regional anaesthesia using ultrasound-guided blockade of peripheral nerves was administered using 1% lidocaine due to its rapid onset and short half-life. Patients were assessed for additional analgesia requirements and then were asked to evaluate their experience and perceived pain using the visual analogue scale (VAS). Results: Fifty patients were included in the study. The mean age was 46.8 years (range 21-85 years). About 54% of the patients were male patients (N = 27). Post-procedure, all patients indicated positive satisfaction ratings, each participant responded as either 'satisfied' (N = 6), 'very satisfied' (N = 24) or 'highly satisfied' (N = 20). In addition, 90% of the participants reported that they would opt for this method of EF removal again in future. The VAS for pain immediately following completion of the procedure was low, with a mean score of 0.36 (range 0-4), where a score of 0 = 'No pain', and 10 = 'worst pain possible'. The median score was 0. Conclusion: We present the first description of outpatient EF removal using regional anaesthesia, with a prospective case series of 50 fully conscious patients from whom the EF was removed. This novel technique is likely to be cost-effective, reproducible, and safe. This technique reduces the burden of EF removal from an operating list and also improves the patient's experience when compared with other forms of conscious sedation. By eliminating the use of Entonox and methoxyflurane for sedation and analgesia, this technique also demonstrates a method of improving environmental sustainability. How to cite this article: Williams LM, Stamps G, Peak H, et al. Circular External Fixator Removal in the Outpatient Clinic Using Regional Anaesthesia: A Pilot Study of A Novel Approach. Strategies Trauma Limb Reconstr 2023;18(1):7-11.

Optimizing CRE and PhiC31 mediated recombination in Aedes aegypti.

Introduction: Genetic manipulation of Aedes aegypti is key to developing a deeper understanding of this insects' biology, vector-virus interactions and makes future genetic control strategies possible. Despite some advances, this process remains laborious and requires highly skilled researchers and specialist equipment. Methods: Here we present two improved methods for genetic manipulation in this species. Use of transgenic lines which express Cre recombinase and a plasmid-based method for expressing PhiC31 when injected into early embryos. Results: Use of transgenic lines which express Cre recombinase allowed, by simple crossing schemes, germline or somatic recombination of transgenes, which could be utilized for numerous genetic manipulations. PhiC31 integrase based methods for site-specific integration of genetic elements was also improved, by developing a plasmid which expresses PhiC31 when injected into early embryos, eliminating the need to use costly and unstable mRNA as is the current standard. Discussion: Here we have expanded the toolbox for synthetic biology in Ae. aegypti. These methods can be easily transferred into other mosquito and even insect species by identifying appropriate promoter sequences. This advances the ability to manipulate these insects for fundamental studies, and for more applied approaches for pest control.

Decolonising food regulatory frameworks: importance of recognising traditional culture when assessing dietary safety of traditional foods.

As interest in Australian native products continues to grow worldwide, Aboriginal and Torres Strait Islander peoples (First Peoples) are striving to be industry leaders in the production of their traditional foods that are being developed for commercial markets. To successfully gain market approval both within Australia and globally, food regulatory authorities require at least a documented history of safe use to indicate dietary safety. Moreover, many countries also require compositional analysis and safety data to further support their safe human consumption. However, safety data are lacking for many of these traditional food items and the history that surrounds their safe use has rarely been recorded in written form, but rather passed on through cultural practices and language. This review evaluates the suitability of current frameworks for assessing the dietary safety of traditional foods and highlights the food-safety regulatory hurdles currently felt by First Peoples and their businesses attempting to enter the Australian native foods industry. These issues also extend to the requirements of food regulatory authorities around the world, when assessing the market eligibility of traditional food items. Potential solutions to these problems are discussed, including new proposed processes that can be incorporated into the current food regulatory frameworks. Importantly, these proposed processes would allow the dietary risk assessment of traditional foods to be completed in a manner that better accommodates the stories, traditional knowledge and interests of First Peoples, while also meeting the safety data requirements set out by regulatory bodies both within Australia and around the world.

Sternal fractures and thoracic injury: an analysis of 288 sternal fractures attending a major trauma centre.

INTRODUCTION: Sternal fractures (SF) are uncommon injuries usually associated with a significant mechanism of injury. Concomitant injury is likely, and a risk of mortality is substantial. AIM: Our aim in this study was to identify the risk factors for mortality in patients who had sustained sternal fractures. METHODS: We conducted a single centre retrospective review of the trust's Trauma Audit and Research Network Database, from May 2014 to July 2021. Our inclusion criteria were any patients who had sustained a sternal fracture. The regions of injury were defined using the Abbreviated Injury Score. Pearson Chi-Squared, Fisher Exact tests and multivariate regression analyses were performed using IBM SPSS. RESULTS: A total of 249 patients were identified to have sustained a SF. There were 19 patients (7.63%) who had died. The most common concomitant injuries with SF were Rib fractures (56%), Lung Contusions (31.15%) and Haemothorax (21.88%). There was a significant increase in age (59.93 vs 70.06, p = .037) and admission troponin (36.34 vs. 100.50, p = .003) in those who died. There was a significantly lower GCS in those who died (10.05 vs. 14.01, p < .001). On multi regression analysis, bilateral rib injury (p = 0.037, OR 1.104) was the only nominal variable which showed significance in mortality. CONCLUSION: Sternal Fractures are uncommon but serious injuries. Our review has identified that bilateral rib injuries, increase in age, low GCS, and high admission troponin in the context of SF, were associated with mortality.

Enolate SNAr of unactivated arenes via [(η6-arene)RuCp]+ intermediates.

A series of complexes of the general formula [(η6-arene)RuCp][PF6] (where arene = aryl halides or nitroarenes) were synthesised and the arene ring was found to be reactive towards an intermolecular nucleophilic aromatic substitution (SNAr) reaction with a series of cyclic 1,3-diones. Competition experiments indicated that leaving group ability of the aryl halides and nitroarenes went in the order of F ≫ NO2 > Cl > Br. Following SNAr, the arene rings were liberated quantitatively via a rapid photolysis reaction (<15 min).

Safety, tolerability, pharmacokinetics, and subjective effects of 50, 75, and 100 µg LSD in healthy participants within a novel intervention paradigm: A proof-of-concept study.

BACKGROUND: Classic psychedelics hold promise as therapeutics for psychiatric disorders, but require scalable intervention protocols. This proof-of-concept study evaluated the safety, tolerability, pharmacokinetics, and subjective effects of 50, 75, and 100 µg lysergic acid diethylamide (LSD) in healthy adults within a novel intervention paradigm. METHODS: Up to three participants were administered LSD on the same day in separate rooms, each with a single attendant, after 1 day of preparation. An open-label design and a double-blind placebo-controlled design were used. RESULTS: Ninety-one percent of participants completed the study. Thirty-two adults (mean age = 28.8 years) received 50 (n = 3), 75 (n = 7), 100 (n = 3) LSD, 50 µg followed by 75 µg LSD (n = 9) 1 week apart, or placebo followed by a 75 µg LSD (n = 10) 1 week apart. There were no serious adverse events. Twenty-eight percent of participants experienced at least one expected mild adverse event, with one expected moderate adverse event. The maximum blood plasma levels occurred between 1.2 and 2 h post-administration, with an apparent half-life between 2.8 and 4.3 h. LSD largely induced greater subjective effects versus placebo. CONCLUSION: In the current novel intervention paradigm, 50, 75, and 100 µg LSD are tolerable with favourable safety profiles in healthy adults, only mild adverse events during the day of drug administration, and mystical-type subjective experiences. Future studies are needed to evaluate safety, tolerability, subjective effects, and cost-effectiveness in clinical populations.

Perceptions of safety, subjective effects, and beliefs about the clinical utility of lysergic acid diethylamide in healthy participants within a novel intervention paradigm: Qualitative results from a proof-of-concept study.

BACKGROUND: Classic psychedelics show promise in the treatment of mental health conditions; however, more scalable intervention protocols are needed to maximize access to these novel therapeutics. In this proof-of-concept study, perceptions of safety, subjective effects, and beliefs about the clinical utility of lysergic acid diethylamide (LSD) were evaluated among healthy participants (N = 31) administered 50 to 100 µg LSD in a treatment paradigm conceptualized as more scalable than traditional approaches to administering classic psychedelics. METHODS: Semi-structured interviews assessed participants' expectations, experience, and thoughts on the safety and efficacy of the study design. These interviews were transcribed for thematic analysis relating to perceptions of safety, subjective effects, and beliefs about the clinical utility of LSD. RESULTS: Most participants felt safe throughout the study, with a minority reporting concerns related to having a challenging experience that diminished over time. Participants attributed their feelings of safety to the study structure and support of their attendants, which allowed them to "let go" and immerse themselves in the experience without pre-occupation. Furthermore, participants reported transcendent, mystical-type experiences characteristic of classic psychedelics, with almost half highlighting the prominent role played by music during the acute period of drug action. Finally, participants endorsed support for the clinical utility of LSD in controlled environments, expressing the belief that LSD is safe and has the potential to help others. CONCLUSION: Findings provide preliminary support for the feasibility of this scalable interventional paradigm and set the stage for future critical research with clinical populations.

Clinical outcomes, Kadish-INSICA staging and therapeutic targeting of somatostatin receptor 2 in olfactory neuroblastoma.

INTRODUCTION: Olfactory neuroblastoma (ONB) is a rare cancer of the sinonasal region. We provide a comprehensive analysis of this malignancy with molecular and clinical trial data on a subset of our cohort to report on the potential efficacy of somatostatin receptor 2 (SSTR2)-targeting imaging and therapy. METHODS: We conducted a retrospective analysis of 404 primary, locally recurrent, and metastatic olfactory neuroblastoma (ONB) patients from 12 institutions in the United States of America, United Kingdom and Europe. Clinicopathological characteristics and treatment approach were evaluated. SSTR2 expression, SSTR2-targeted imaging and the efficacy of peptide receptor radionuclide therapy [PRRT](177Lu-DOTATATE) were reported in a subset of our cohort (LUTHREE trial; NCT03454763). RESULTS: Dural infiltration at presentation was a significant predictor of overall survival (OS) and disease-free survival (DFS) in primary cases (n = 278). Kadish-Morita staging and Dulguerov T-stage both had limitations regarding their prognostic value. Multivariable survival analysis demonstrated improved outcomes with lower stage and receipt of adjuvant radiotherapy. Prophylactic neck irradiation significantly reduces the rate of nodal recurrence. 82.4% of the cohort were positive for SSTR2; treatment of three metastatic cases with SSTR2-targeted peptide-radionuclide receptor therapy (PRRT) in the LUTHREE trial was well-tolerated and resulted in stable disease (SD). CONCLUSIONS: This study presents pertinent clinical data from the largest dataset, to date, on ONB. We identify key prognostic markers and integrate these into an updated staging system, highlight the importance of adjuvant radiotherapy across all disease stages, the utility of prophylactic neck irradiation and the potential efficacy of targeting SSTR2 to manage disease.

Novel strategy for improved outcomes of extra-corporeal membrane oxygenation as a treatment for refractory post cardiotomy cardiogenic shock in the current era: a refreshing new perspective.

OBJECTIVES: Post-cardiotomy cardiogenic shock is an infrequent but important cause of death following cardiac surgery. Extra-corporeal membrane oxygenation offers the opportunity for temporary cardiovascular support and myocardial rest, with a view to recovery. We examine our results with our recently-implemented management algorithm. METHODS: We report our series of 15 consecutive patients out of 357 patients [4.2%] who required institution of veno-arterial extra-corporeal membrane oxygenation system support as treatment for Post-cardiotomy cardiogenic shock in the current era [January-2017 to January-2020]. RESULTS: The mean age was 64.3 ± 11.6 years (range: 40-82 years); there were 13 males (86.7%). Duration of veno-arterial extra-corporeal membrane oxygenation support was 6.7 ± 1.9 days. Duration of stay on intensive care unit [ICU] was 18.9 ± 17.1 days. Duration of hospital-stay was 28.3 ± 20.8 days. Survival to discharge and at 2.2 ± 0.9 years was 67%. CONCLUSIONS: We have shown clearly that veno-arterial extra-corporeal membrane oxygenation is an important rescue option for patients who develop refractory post-cardiotomy cardiogenic shock, with improved survival of 67% at 2.2 ± 0.9 years in those placed on post-cardiotomy veno-arterial extra corporeal membrane oxygenation support, which is superior to that reported hitherto in literature. We have sought to highlight the successes of post cardiotomy veno-arterial extra corporeal membrane oxygenation support, with improved results, based on careful patient selection, as well as diligent management of these critically-ill patients in the postoperative period, prior to establishment of irreversible end-organ dysfunction. Our strategy has also helped us rationalize and optimize the use of this expensive treatment modality.

Biological variation of cardiac myosin-binding protein C in healthy individuals.

OBJECTIVES: Cardiac myosin-binding protein C (cMyC) is a novel biomarker of myocardial injury, with a promising role in the triage and risk stratification of patients presenting with acute cardiac disease. In this study, we assess the weekly biological variation of cMyC, to examine its potential in monitoring chronic myocardial injury, and to suggest analytical quality specification for routine use of the test in clinical practice. METHODS: Thirty healthy volunteers were included. Non-fasting samples were obtained once a week for ten consecutive weeks. Samples were tested in duplicate on the Erenna® platform by EMD Millipore Corporation. Outlying measurements and subjects were identified and excluded systematically, and homogeneity of analytical and within-subject variances was achieved before calculating the biological variability (CVI and CVG), reference change values (RCV) and index of individuality (II). RESULTS: Mean age was 38 (range, 21-64) years, and 16 participants were women (53%). The biological variation, RCV and II with 95% confidence interval (CI) were: CVA (%) 19.5 (17.8-21.6), CVI (%) 17.8 (14.8-21.0), CVG (%) 66.9 (50.4-109.9), RCV (%) 106.7 (96.6-120.1)/-51.6 (-54.6 to -49.1) and II 0.42 (0.29-0.56). There was a trend for women to have lower CVG. The calculated RCVs were comparable between genders. CONCLUSIONS: cMyC exhibits acceptable RCV and low II suggesting that it could be suitable for disease monitoring, risk stratification and prognostication if measured serially. Analytical quality specifications based on biological variation are similar to those for cardiac troponin and should be achievable at clinically relevant concentrations.

Novel ruthenium complexes bearing bipyridine-based and N-heterocyclic carbene-supported pyridine (NCN) ligands: the influence of ligands on catalytic transfer hydrogenation of ketones.

Transfer hydrogenation (TH) is a powerful synthetic tool in the production of secondary alcohols from ketones by using a non-H2 hydrogen source along with metal catalysts. Among homogeneous catalysts, Ru(II) complexes are the most efficient catalysts. In our research, six novel ruthenium(II) complexes bearing bipyridine-based ligands [Ru(L1)Cl2] (1), [Ru(L1)(PPh3)Cl]Cl (2) and [Ru(L2)Cl2] (3) and N-heterocyclic carbene-supported pyridine (NCN) ligands [RuCp(L3)]PF6 (4), [RuCp*(L3)]PF6 (5), and [Ru(p-cymene)(L3)Cl]PF6 (6) (where L1 = 6,6'-bis(aminomethyl)-2,2'-bipyridine, L2 = 6,6'-bis(dimethylaminomethyl)-2,2'-bipyridine and L3 = 1,3-bis(2-methylpyridyl)imidazolium bromide) were synthesised and characterised by NMR spectroscopy, HRMS, and X-ray crystallography. The catalytic transfer hydrogenation of 28 ketones in 2-propanol at 80 °C in the presence of KOtBu (5 mol%) was demonstrated and the effect of ligands is highlighted. The results show that catalyst 1 exhibits improved TH efficiency compared to the commercially available Milstein catalyst and displays higher catalytic activity than 2 due to the steric effect from PPh3. From a combination of kinetic data and Eyring analysis, a zero-order dependence on the acetophenone substrate is observed, implying a rate-limiting hydride transfer step, leading to the proposed inner-sphere hydride transfer mechanism.

The plastic Trojan horse: Biofilms increase microplastic uptake in marine filter feeders impacting microbial transfer and organism health.

Microplastic pollution has become a major source of concern, with a large body of literature surrounding the impacts of microplastic ingestion by biota. However, many of these studies utilise virgin microbeads, which are not reflective of environmental microplastics that are rapidly colonised with microbial communities (plastisphere) in marine ecosystems. It is a concern therefore that current evidence of the impacts of microplastics on biota are unrepresentative of the environmental microplastic pollution. In this study, uptake and bioaccumulation of both virgin and Escherichia coli coated microplastics, by European native oysters (Ostrea edulis) were compared, and the physiological responses of oysters to the exposure were investigated. The uptake of E. coli coated microplastics was found to be significantly higher than the uptake of virgin microplastics, with average concentrations of 42.3 ± 23.5 no. g-1 and 11.4 ± 0.6 no. g-1 microbeads found in oysters exposed to coated and virgin microplastics, respectively. This suggests that environmental microplastic uptake into the marine trophic web by benthic filter feeders may be greater than previously thought. The oxygen consumption and respiration rate of oysters exposed to E. coli coated microplastics increased significantly over time, whilst virgin microplastics did not produce any measurable significant physiological responses. However, less than 0.5% of the total amount of administered microbeads were retained by all oysters, suggesting a limited residence time within the organisms. Although microplastics did not bioaccumulate in oyster tissues in the short-term, microorganisms assimilated by the ingestion of coated microplastics may be transferred to higher trophic levels. This poses a risk, not only for wildlife, but also for food safety and human health. The capacity to carry pathogens and expose a wide range of organisms to them means microplastics may have an important role as vectors for disease.

Optimization of Benzothiazole and Thiazole Hydrazones as Inhibitors of Schistosome BCL-2.

Limited therapeutic options are available for the treatment of human schistosomiasis caused by the parasitic Schistosoma flatworm. The B cell lymphoma-2 (BCL-2)-regulated apoptotic cell death pathway in schistosomes was recently characterized and shown to share similarities with the intrinsic apoptosis pathway in humans. Here, we exploit structural differences in the human and schistosome BCL-2 (sBCL-2) pro-survival proteins toward a novel treatment strategy for schistosomiasis. The benzothiazole hydrazone scaffold previously employed to target human BCL-XL was repurposed as a starting point to target sBCL-2. We utilized X-ray structural data to inform optimization and then applied a scaffold-hop strategy to identify the 5-carboxamide thiazole hydrazone scaffold (43) with potent sBCL-2 activity (IC50 30 nM). Human BCL-XL potency (IC50 13 nM) was inadvertently preserved during the optimization process. The lead analogues from this study exhibit on-target activity in model fibroblast cell lines dependent on either sBCL-2 or human BCL-XL for survival. Further optimization of the thiazole hydrazone class is required to exhibit activity in schistosomes and enhance the potential of this strategy for treating schistosomiasis.

As Nice as π: Aromatic Reactions Activated by π-Coordination to Transition Metals.

π-Coordination of aromatic molecules to metals dramatically alters their reactivity. For example, coordinated carbons become more electrophilic and C-H bonds of coordinated rings become more acidic. For many years, this change in reactivity has been used to trigger reactions that would not take place for uncoordinated arenes, however, there has been a recent resurgence in use of this technique, in part due to the development of catalytic reactions in which π-coordination is transient. In this Minireview, we describe the key reaction chemistry of arenes coordinated to a range of transition metals, including stereoselective reactions and industrially relevant syntheses. We also summarise outstanding examples of catalytic processes. Finally, we give perspectives on the future direction of the field, with respect to both reactions that are stoichiometric in activating metals and those employing catalytic metal.

Synthesis of Biologically Active Heterospirocycles through Iterative 1,3-Dipolar Cycloaddition Pathways.

We demonstrate the novel spiroannulation of exo-imines with 1,3-dipoles, for the first time, leading to 3D spirocycles with a secondary amine (NH) in the spiro-ring. The synthetic method described herein allows access to these previously unexplored heterospirocyclic cores that have application in the discovery of functional molecules for medicinal and materials science. This was demonstrated by discovering an unprecedented class of heterospirocycles with antimalarial activity against the human protozoan P. falciparum.

Correction to: The effects of microdose LSD on time perception: a randomised, double-blind, placebo-controlled trial.

The manufacturer of the drug product was Onyx Scientific Limited UK, to cGMP standards.

Uniportal subxiphoid bilateral removal of self-introduced thoracic foreign bodies.

This is a report of a 31-year-old male refugee, who was admitted to Intensive Therapy Unit after being found in severe chest pain after escaping extreme torture from his home country. He was found to have four nails in his thorax. These were removed using a subxiphoid video-assisted thorascopic surgery (VATS) technique. This technique allowed excellent visualization of the right, left and anterior mediastinal part of the chest and therefore preventing damage or injury to surrounding structures. This was particularly useful in a complex case such as this. By avoiding an intercoastal incision and intercostal manipulation, our patient had limited pain post-procedure facilitating an earlier aggressive mobilization program with potential benefit in terms of improved lung expansion, reduction of atelectasis and lung infections. With the right training, the technical challenges of using the technique should be overcome and thus the benefits of subxiphoid VATS will be offered to a larger portion of thoracic surgical patients.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers.

Research has shown that psychedelics, such as lysergic acid diethylamide (LSD), have profound anti-inflammatory properties mediated by 5-HT2A receptor signaling, supporting their evaluation as a therapeutic for neuroinflammation associated with neurodegenerative disease. OBJECTIVE: This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of orally repeated administration of 5 µg, 10 µg, and 20 µg LSD in older healthy individuals. In the current paper, we present safety, tolerability, pharmacokinetics, and pharmacodynamic measures that relate to safety, tolerability, and dose response. METHODS: This was a phase 1 double-blind, placebo-controlled, randomized study. Volunteers were randomly assigned to 1 of 4 dose groups (5 µg, 10 µg, 20 µg LSD, and placebo), and received their assigned dose on six occasions (i.e., every 4 days). RESULTS: Forty-eight older healthy volunteers (mean age = 62.9 years) received placebo (n = 12), 5 µg (n = 12), 10 µg (n = 12), or 20 µg (n = 12) LSD. LSD plasma levels were undetectable for the 5 µg group and peak blood plasma levels for the 10 µg and 20 µg groups occurred at 30 min. LSD was well tolerated, and the frequency of adverse events was no higher than for placebo. Assessments of cognition, balance, and proprioception revealed no impairment. CONCLUSIONS: Our results suggest safety and tolerability of orally administered 5 µg, 10 µg, and 20 µg LSD every fourth day over a 21-day period and support further clinical development of LSD for the treatment and prevention of Alzheimer's disease (AD).