Anaerobic Lactate Production Is Associated With Decreased Microcirculatory Blood Flow and Decreased Mitochondrial Respiration Following Cardiovascular Surgery With Cardiopulmonary Bypass.

OBJECTIVES: Quantify the relationship between perioperative anaerobic lactate production, microcirculatory blood flow, and mitochondrial respiration in patients after cardiovascular surgery with cardiopulmonary bypass. DESIGN: Serial measurements of lactate-pyruvate ratio (LPR), microcirculatory blood flow, plasma tricarboxylic acid cycle cycle intermediates, and mitochondrial respiration were compared between patients with a normal peak lactate (≤ 2 mmol/L) and a high peak lactate (≥ 4 mmol/L) in the first 6 hours after surgery. Regression analysis was performed to quantify the relationship between clinically relevant hemodynamic variables, lactate, LPR, and microcirculatory blood flow. SETTING: This was a single-center, prospective observational study conducted in an academic cardiovascular ICU. PATIENTS: One hundred thirty-two patients undergoing elective cardiovascular surgery with cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients with a high postoperative lactate were found to have a higher LPR compared with patients with a normal postoperative lactate (14.4 ± 2.5 vs. 11.7 ± 3.4; p = 0.005). Linear regression analysis found a significant, negative relationship between LPR and microcirculatory flow index (r = -0.225; ß = -0.037; p = 0.001 and proportion of perfused vessels: r = -0.17; ß = -0.468; p = 0.009). There was not a significant relationship between absolute plasma lactate and microcirculation variables. Last, mitochondrial complex I and complex II oxidative phosphorylation were reduced in patients with high postoperative lactate levels compared with patients with normal lactate (22.6 ± 6.2 vs. 14.5 ± 7.4 pmol O2/s/106 cells; p = 0.002). CONCLUSIONS: Increased anaerobic lactate production, estimated by LPR, has a negative relationship with microcirculatory blood flow after cardiovascular surgery. This relationship does not persist when measuring lactate alone. In addition, decreased mitochondrial respiration is associated with increased lactate after cardiovascular surgery. These findings suggest that high lactate levels after cardiovascular surgery, even in the setting of normal hemodynamics, are not simply a type B phenomenon as previously suggested.

Combination of Physicochemical Tropism and Affinity Moiety Targeting of Lipid Nanoparticles Enhances Organ Targeting.

Two camps have emerged for targeting nanoparticles to specific organs and cell types: affinity moiety targeting and physicochemical tropism. Here we directly compare and combine both using intravenous (IV) lipid nanoparticles (LNPs) designed to target the lungs. We utilized PECAM antibodies as affinity moieties and cationic lipids for physicochemical tropism. These methods yield nearly identical lung uptake, but aPECAM LNPs show higher endothelial specificity. LNPs combining these targeting methods had >2-fold higher lung uptake than either method alone and markedly enhanced epithelial uptake. To determine if lung uptake is because the lungs are the first organ downstream of IV injection, we compared IV vs intra-arterial (IA) injection into the carotid artery, finding that IA combined-targeting LNPs achieve 35% of the injected dose per gram (%ID/g) in the first-pass organ, the brain, among the highest reported. Thus, combining the affinity moiety and physicochemical strategies provides benefits that neither targeting method achieves alone.

Development of the Squaramide Scaffold for High Potential and Multielectron Catholytes for Use in Redox Flow Batteries.

Nonaqueous organic redox flow batteries (N-ORFBs) are a promising technology for grid-scale storage of energy generated from intermittent renewable sources. Their primary benefit over traditional aqueous RFBs is the wide electrochemical stability window of organic solvents, but the design of catholyte materials, which can exploit the upper range of this window, has proven challenging. We report herein a new class of N-ORFB catholytes in the form of squaric acid quinoxaline (SQX) and squaric acid amide (SQA) materials. Mechanistic investigation of decomposition in battery-relevant conditions via NMR, HRMS, and electrochemical methods enabled a rational design approach to optimizing these scaffolds. Three lead compounds were developed: a highly stable one-electron SQX material with an oxidation potential of 0.51 V vs Fc/Fc+ that maintained 99% of peak capacity after 102 cycles (51 h) when incorporated into a 1.58 V flow battery; a high-potential one-electron SQA material with an oxidation potential of 0.81 V vs Fc/Fc+ that demonstrated negligible loss of redox active material as measured by pre- and postcycling CV peak currents when incorporated in a 1.63 V flow battery for 110 cycles over 29 h; and a proof-of-concept two-electron SQA catholyte material with oxidation potentials of 0.48 and 0.85 V vs Fc/Fc+ that demonstrated a capacity fade of just 0.56% per hour during static H-cell cycling. These findings expand the previously reported space of high-potential catholyte materials and showcase the power of mechanistically informed synthetic design for N-ORFB materials development.

IL-18-secreting multi-antigen targeting CAR T-cells eliminate antigen-low myeloma in an immunocompetent mouse model.

Multiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T-cells in leukemia and lymphoma, CAR T-cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to low expression of BCMA on myeloma cells, suggesting that novel approaches to better address antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the pro-inflammatory cytokine interleukin-18 (IL-18) and multi-antigen targeting could improve CAR T-cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T-cells targeting the myeloma-associated antigens BCMA and B-cell activating factor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed, whereas IL-18-secreting CAR T-cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T-cells developed an effector-like T-cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type I/II interferon signaling, and activated macrophages to mediate anti-myeloma activity. Simultaneous targeting of weakly expressed BCMA and BAFF-R with dual-CAR T-cells enhanced T-cell:target cell avidity, increased overall CAR signal strength, and stimulated anti-myeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. Our results demonstrate that combination of engineered IL-18 secretion and multi-antigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.

Readability of Online Patient Education Materials for Shoulder Instability Surgery in English and Spanish.

BACKGROUND: Online patient education materials exist to inform patient medical decisions, yet the average adult in the United States reads at an eighth-grade level and 50% of Medicaid patients read at or below a fifth-grade level. To appropriately meet U.S. health literacy needs, the American Medical Association and National Institutes of Health recommend that patient education materials not exceed a sixth-grade level. The purpose of this study was to assess and compare the readability of English and Spanish online patient education materials pertaining to shoulder instability surgery. METHODS: Google searches of the terms "shoulder instability surgery" and "cirugía de inestabilidad de hombro'' were conducted to include 25 eligible OPEMs per language. English OPEM readability was calculated using Flesch-Kincaid Grade Level, Flesch Reading Ease, Flesch Reading Ease Grade Level, Gunning-Fog Index, Coleman-Liau Index, and Simple Measure of Gobbledygook. Spanish OPEM readability was assessed using Fernandez-Huerta Index (the Spanish equivalent of Flesch Reading Ease), Fernandez-Huerta Index Grade Level, Gutiérrez de Polini's Fórmula de comprensibilidad, and INFLESZ. RESULTS: Readability index analysis revealed that the mean Flesch Reading Ease of English online patient education materials was significantly lower than the mean Fernandez-Huerta Index of Spanish online patient education materials. English materials were also found to be written at a significantly higher grade level than Spanish materials. CONCLUSIONS: Shoulder instability surgery online patient education materials in both English and Spanish are written at higher reading levels than recommended by the AMA and NIH, though Spanish online patient education materials were more readable on average.

Strategies to Improve Drug Delivery Across the Blood-Brain Barrier for Glioblastoma.

PURPOSE OF REVIEW: Glioblastoma remains resistant to most conventional treatments. Despite scientific advances in the past three decades, there has been a dearth of effective new treatments. New approaches to drug delivery and clinical trial design are needed. RECENT FINDINGS: We discuss how the blood-brain barrier and tumor microenvironment pose challenges for development of effective therapies for glioblastoma. Next, we discuss treatments in development that aim to overcome these barriers, including novel drug designs such as nanoparticles and antibody-drug conjugates, novel methods of drug delivery, including convection-enhanced and intra-arterial delivery, and novel methods to enhance drug penetration, such as blood-brain barrier disruption by focused ultrasound and laser interstitial thermal therapy. Lastly, we address future opportunities, positing combination therapy as the best strategy for effective treatment, neoadjuvant and window-of-opportunity approaches to simultaneously enhance therapeutic effectiveness with interrogation of on-treatment biologic endpoints, and adaptive platform and basket trials as imperative for future trial design. New approaches to GBM treatment should account for the blood-brain barrier and immunosuppression by improving drug delivery, combining treatments, and integrating novel clinical trial designs.

A Robust and Efficient Method to Purify DNA-Scaffolded Nanostructures by Gravity-Driven Size Exclusion Chromatography.

In recent decades, nucleic acid self-assemblies have emerged as popular nanomaterials due to their programmable and robust assembly, prescribed geometry, and versatile functionality. However, it remains a challenge to purify large quantities of DNA nanostructures or DNA-templated nanocomplexes for various applications. Commonly used purification methods are either limited by a small scale or incompatible with functionalized structures. To address this unmet need, we present a robust and scalable method of purifying DNA nanostructures by Sepharose resin-based size exclusion. The resin column can be manually packed in-house with reusability. The separation is driven by a low-pressure gravity flow in which large DNA nanostructures are eluted first followed by smaller impurities of ssDNA and proteins. We demonstrated the efficiency of the method for purifying DNA origami assemblies and protein-immobilized DNA nanostructures. Compared to routine agarose gel electrophoresis that yields 1 µg or less of purified products, this method can purify ∼100-1000 µg of DNA nanostructures in less than 30 min, with the overall collection yield of 50-70% of crude preparation mixture. The purified nanocomplexes showed more precise activity in evaluating enzyme functions and antibody-triggered activation of complement protein reactions.

Stereoretentive enantioconvergent reactions.

Enantioconvergent reactions are pre-eminent in contemporary asymmetric synthesis as they convert both enantiomers of a racemic starting material into a single enantioenriched product, thus avoiding the maximum 50% yield associated with resolutions. All currently known enantioconvergent processes necessitate the loss or partial loss of the racemic substrate's stereochemical information, thus limiting the potential substrate scope to molecules that contain labile stereogenic units. Here we present an alternative approach to enantioconvergent reactions that can proceed with full retention of the racemic substrate's configuration. This uniquely stereo-economic approach is possible if the two enantiomers of a racemic starting material are joined together to form one enantiomer of a non-meso product. Experimental validation of this concept is presented using two distinct strategies: (1) a direct asymmetric coupling approach, and (2) a multicomponent approach, which exhibits statistical amplification of enantiopurity. Thus, the established dogma that enantioconvergent reactions require substrates that contain labile stereogenic units is shown to be incorrect.

Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape Without Side Effects.

Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, based on their success in the COVID-19 vaccines and late-stage clinical studies in other indications. However, we and others have shown that LNPs induce severe inflammation, and massively aggravate pre-existing inflammation. Here, using structure-function screening of lipids and analyses of signaling pathways, we elucidate the mechanisms of LNP-associated inflammation and demonstrate solutions. We show that LNPs' hallmark feature, endosomal escape, which is necessary for RNA expression, also directly triggers inflammation by causing endosomal membrane damage. Large, irreparable, endosomal holes are recognized by cytosolic proteins called galectins, which bind to sugars on the inner endosomal membrane and then regulate downstream inflammation. We find that inhibition of galectins abrogates LNP-associated inflammation, both in vitro and in vivo . We show that rapidly biodegradable ionizable lipids can preferentially create endosomal holes that are smaller in size and reparable by the endosomal sorting complex required for transport (ESCRT) pathway. Ionizable lipids producing such ESCRT-recruiting endosomal holes can produce high expression from cargo mRNA with minimal inflammation. Finally, we show that both routes to non-inflammatory LNPs, either galectin inhibition or ESCRT-recruiting ionizable lipids, are compatible with therapeutic mRNAs that ameliorate inflammation in disease models. LNPs without galectin inhibition or biodegradable ionizable lipids lead to severe exacerbation of inflammation in these models. In summary, endosomal escape induces endosomal membrane damage that can lead to inflammation. However, the inflammation can be controlled by inhibiting galectins (large hole detectors) or by using biodegradable lipids, which create smaller holes that are reparable by the ESCRT pathway. These strategies should lead to generally safer LNPs that can be used to treat inflammatory diseases.

Retrograde Solubility of Methylammonium Lead Iodide in γ-Butyrolactone Does Not Enhance the Uniformity of Continuously Coated Films.

Halide perovskite thin films can be the centerpiece of high-performance solar cells, light-emitting diodes, and other optoelectronic devices if the films are of high uniformity and relatively free of pinholes and other defects. A common strategy to form dense films from solution has been to generate a high density of nuclei by rapidly increasing supersaturation, for example, by timely application of an antisolvent or forced convection. In this work, we examine the role of retrograde solubility, wherein solubility decreases with increasing temperature, as a means of increasing the nucleation density and film coverage of slot-die-coated methylammonium lead iodide (MAPbI3) from γ-butyrolactone (GBL) solution. Coverage was investigated as a function of the substrate temperature and the presence and temperature of an air knife. Results were considered within the framework of the dimensionless modified Biot number, which quantifies the interplay between evaporation and horizontal diffusion. Moderate temperatures and a heated air knife improved film coverage and morphology by enhanced nucleation up to ∼80 °C. However, despite the dense nucleation enabled by retrograde solubility, slow evaporation as a result of the low vapor pressure of GBL, combined with Ostwald ripening at high temperatures, prevented the deposition of void-free, device-quality films. This work has provided a more detailed understanding of the interplay between perovskite processing, solvent parameters, and film morphology and ultimately indicates the obstacles to forming dense, uniform films from solvents with high boiling points even in the presence of rapid nucleation.

First-in-Human Clinical Series of a Novel Conformable Large-Lattice Pulsed Field Ablation Catheter for Pulmonary Vein Isolation.

BACKGROUND/AIMS: Pulsed field ablation (PFA) has significant advantages over conventional thermal ablation of atrial fibrillation (AF). This first-in-human, single-arm trial to treat paroxysmal AF (PAF) assessed the efficiency, safety, pulmonary vein isolation (PVI) durability and one-year clinical effectiveness of an 8-Fr, large-lattice, conformable single-shot PFA catheter together with a dedicated electroanatomical mapping system. METHODS: After rendering the PV anatomy, the PFA catheter delivered monopolar, biphasic pulse trains (5-6 secs per application; ∼4 applications per PV). Three waveforms were tested: PULSE1, PULSE2 and PULSE3. Follow-up included ECGs, Holters at 6 and 12 months, and symptomatic and scheduled transtelephonic monitoring. The primary and secondary efficacy endpoints were acute PVI and post-blanking atrial arrhythmia recurrence, respectively. Invasive remapping was conducted ∼75 days post-ablation. RESULTS: At three centers, PVI was performed by five operators in 85 patients using PULSE1 (n=30), PULSE2 (n=20), and PULSE3 (n=35). Acute PVI was achieved in 100% of PVs using 3.9±1.4 PFA applications per PV. Overall procedure, transpired ablation, PFA catheter dwell and fluoroscopy times were 56.5±21.6, 10.0 ± 6.0, 19.1±9.3 and 5.7±3.9 min, respectively. No pre-defined primary safety events occurred. Upon remapping, PVI durability was 90% and 99% on a per vein basis for the total and PULSE3 cohort, respectively. The Kaplan-Meier estimate of one-year freedom from atrial arrhythmias was 81.8% (95% CI 70.2-89.2%) for the total, and 100% (95% CI 80.6-100%) for the PULSE3 cohort. CONCLUSION: PVI utilizing a conformable single-shot PFA catheter to treat PAF was efficient, safe, and effective, with durable lesions demonstrated upon remapping.

Incontinence Is an Independent Risk Factor for Total Hip and Knee Arthroplasty.

Background: Urinary incontinence has been linked to worse postoperative pain, decreased physical function, and reduced quality of life in patients following total joint arthroplasty. The purpose of this study was to analyze whether incontinence is associated with increased postoperative medical and joint complications following primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). Methods: A retrospective cohort study was conducted using a national insurance database. Thirty-two thousand eight hundred eleven patients with incontinence who underwent primary THA were identified and matched 1:4 with 129,073 patients without incontinence. Ninety-one thousand nine hundred thirty-five patients with incontinence who underwent primary TKA were matched 1:4 with 367,285 patients without incontinence. Medical and joint complication rates at 90 days and 2 years, respectively, were then compared for patient cohorts using multivariable logistic regressions. Results: Patients who underwent primary THA with incontinence had statistically higher rates of dislocation, periprosthetic fracture, aseptic revisions, and overall joint complications compared to controls. Patients who underwent primary TKA with incontinence had higher rates of mechanical failure, aseptic revision, and all-cause revision compared to controls. Conclusions: This study demonstrated an association between patients with incontinence and higher rates of dislocation, periprosthetic fractures, aseptic revisions, and overall joint complications following primary THA compared to controls. Patients with incontinence experience higher rates of mechanical failure, aseptic revision, and all-cause revision following TKA compared to controls. As such, perioperative management of urinary incontinence may help mitigate the risk of postoperative complications.

Association of Smokeless Tobacco and Complications Following Ankle and Hindfoot Arthrodesis.

BACKGROUND: The purpose of this study was to (1) evaluate the rates of postoperative complications following ankle or hindfoot arthrodesis among current smokeless tobacco users and people who smoke compared to matched controls, and (2) compare rates of postoperative complications in current smokeless tobacco users vs people who smoke tobacco cigarettes. METHODS: A retrospective cohort study was conducted using a large national database. For patients who underwent ankle or hindfoot arthrodesis, smokeless tobacco users (n = 131) and people who smoke (n = 1948) were matched 1:4 with controls, and smokeless tobacco users (n = 131) were matched 1:4 with people who smoke tobacco cigarettes (n = 524). Orthopaedic complications within 90 days, 1 year, and 2 years were compared using multivariable logistic regressions. RESULTS: Within 90 days of ankle or hindfoot arthrodesis, smokeless tobacco users demonstrated significantly higher rates of hardware removal (odds ratio [OR] 5.01, 95% CI 1.65-15.20), wound disruption or dehiscence (OR 3.00, 95% CI 1.21-7.44), and pooled complications (16.0% vs 5.9%, OR 2.84, 95% CI 1.50-5.38) compared with tobacco-naïve controls. The rates of hardware removal, wound disruption and dehiscence, and pooled complications remained significant in the smokeless tobacco cohort at 1 and 2 years. At 2 years following ankle or hindfoot arthrodesis, smokeless tobacco users additionally demonstrated significantly higher rates of infection (OR 6.08, 95% CI 1.15-32.05) and nonunion (OR 2.35, 95% CI 1.31-4.20) compared with tobacco-naïve controls. Within 90 days of ankle or hindfoot arthrodesis, smokeless tobacco users demonstrated significantly lower rates of malunion or nonunion than patients who smoke tobacco cigarettes (OR 0.34, 95% CI 0.12-0.97), whereas all other complications were not significantly different. CONCLUSION: Smokeless tobacco use is associated with higher rates of complications following ankle or hindfoot arthrodesis compared with tobacco-naïve controls, and physicians should screen for smokeless tobacco use specifically and encourage cessation before operating electively. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Does Scheduled Low-Dose Short-Term NSAID (Ketorolac) Modulate Cytokine Levels Following Orthopaedic Polytrauma? A Secondary Analysis of a Randomized Clinical Trial.

OBJECTIVES: To determine whether scheduled low-dose, short-term ketorolac modulates cytokine concentrations in orthopaedic polytrauma patients. DESIGN: Secondary analysis of a double-blinded, randomized controlled trial. SETTING: Single Level I trauma center from August 2018 to October 2022. PATIENT SELECTION CRITERIA: Orthopaedic polytrauma patients between 18-75 years with a New Injury Severity Score greater than 9 were enrolled. Participants were randomized to receive 15 mg of intravenous (IV) ketorolac every 6 hours for up to 5 inpatient days or 2 mL of IV saline similarly. OUTCOME MEASURES AND COMPARISONS: Daily concentrations of prostaglandin E2 (PGE2), interleukin (IL)-1a, IL-1b, IL-6, and IL-10. Clinical outcomes included hospital and intensive care unit (ICU) length of stay (LOS), pulmonary complications, and acute kidney injury (AKI). RESULTS: Seventy orthopaedic polytrauma patients were enrolled, with 35 participants randomized to the ketorolac group and 35 to the placebo group. The overall IL-10 trend over time was significantly different in the ketorolac group (p = 0.043). IL-6 was 65.8% higher at enrollment compared to Day 3 (p < 0.001) when aggregated over both groups. There was no significant treatment effect for PGE2, IL-1a, or IL-1b (p > 0.05). There were no significant differences in clinical outcomes between groups (p > 0.05). CONCLUSIONS: Scheduled low-dose, short-term, IV ketorolac was associated with significantly different mean trends in IL-10 concentration in orthopaedic polytrauma patients with no significant differences in PGE2, IL-1a, IL-1b, or IL-6 levels between groups. The treatment did not have an impact on clinical outcomes of hospital or ICU LOS, pulmonary complications, or AKI. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

The Influence of Cold Therapy on the Physical Working Capacity at the Electromyographic Threshold for Consecutive Exercise Sessions.

BACKGROUND: The purpose of this study was to determine whether cold therapy after the first exercise test influences the physical working capacity at the fatigue threshold (PWCFT) during the second exercise test. We hypothesized that cold therapy would delay the onset of PWCFT for the second exercise test relative to the control visit (i.e., no cold therapy). METHODS: Eight healthy college-aged men volunteered for the present study. For each of the two visits, subjects performed incremental, single-leg, knee-extensor ergometer, followed by either resting for 30 min (control visit) or having a cold pack applied for 15 min and then resting for 15 min (experimental visit). Then, the same exercise test was performed. The order of visits (control vs. experimental) was randomized for each subject. The exercise indices and PWCFT were determined for each of the two visits and statistically analyzed using two-way repeated measures analysis of variance. RESULTS: The results indicate no significant (p > 0.05) mean differences for maximal power output, heart rate at end-exercise, and PWCFT between the control and cold therapy visits. Moreover, there were no significant (p > 0.05) mean differences between the first and second exercise workbout within each visit. CONCLUSIONS: The findings of this study suggest that cold therapy did not influence neuromuscular fatigue.

Targeting lipid nanoparticles to the blood-brain barrier to ameliorate acute ischemic stroke.

Effective delivery of mRNA or small molecule drugs to the brain is a significant challenge in developing treatment for acute ischemic stroke (AIS). To address the problem, we have developed targeted nanomedicine to increase drug concentrations in endothelial cells of the blood-brain barrier (BBB) of the injured brain. Inflammation during ischemic stroke causes continuous neuronal death and an increase in the infarct volume. To enable targeted delivery to the inflamed BBB, we conjugated lipid nanocarriers (NCs) with antibodies that bind cell adhesion molecules expressed at the BBB. In the transient middle cerebral artery occlusion mouse model, NCs targeted to vascular cellular adhesion molecule-1 (VCAM) achieved the highest level of brain delivery, nearly two orders of magnitude higher than untargeted ones. VCAM-targeted lipid nanoparticles with luciferase-encoding mRNA and Cre-recombinase showed selective expression in the ischemic brain. Anti-inflammatory drugs administered intravenously after ischemic stroke reduced cerebral infarct volume by 62% (interleukin-10 mRNA) or 35% (dexamethasone) only when they were encapsulated in VCAM-targeted NCs. Thus, VCAM-targeted lipid NCs represent a new platform for strongly concentrating drugs within the compromised BBB of penumbra, thereby ameliorating AIS.

Psychedelic substitution: altered substance use patterns following psychedelic use in a global survey.

Introduction: Recent research suggests that psychedelics may have potential for the treatment of various substance use disorders. However, most studies to date have been limited by small sample sizes and neglecting to include non-North American and European populations. Methods: We conducted a global, cross-sectional online survey of adults (n = 5,268, 47.2% women) self-reporting past or current psychedelic use and investigated whether psychedelic use was associated with changes in use of other substances. Results: Nearly three-quarters (70.9%; n = 3,737/5,268) reported ceasing or decreasing use of one or more non-psychedelic substances after naturalistic psychedelic use. Among those with previous use, 60.6% (n = 2,634/4,344) decreased alcohol use, 55.7% (n = 1,223/2,197) decreased antidepressant use, and 54.2% (n = 767/1,415) decreased use of cocaine/crack. Over a quarter of the sample indicated that their decrease in substance use persisted for 26 weeks or more following use of a psychedelic. Factors associated with decreased use included a motivation to either decrease one's substance use or self-treat a medical condition. Importantly, 19.8% of respondents also reported increased or initiated use of one or more other substances after psychedelic use, with illicit opioids (14.7%; n = 86/584) and cannabis (13.3%; n = 540/4,064) having the highest proportions. Factors associated with increased substance use included having a higher income and residing in Canada or the US. Discussion: Although limited by cross-sectional study design, this large observational study will help inform future studies aiming to investigate the relationship between substance use patterns and psychedelic use.

Ten promotion and tenure tips for microbiologists and immunologists.

In this editorial, I share advice and general principles based on recent experiences as a mentor and evaluator for early-career microbiology and immunology faculty seeking promotion and tenure. I outline 10 recommendations covering research, service, teaching, and mentoring. In addition, I encourage nuanced conversations with colleagues to strategically navigate the unique promotion and tenure processes at different institutions. I hope that these practical tips will assist early-career faculty in attaining promotion and tenure, contributing to long-term scientific and career advances.