A Randomized, Double-Blind, Placebo-Controlled Pilot Trial of the Acute Antisuicidal and Antidepressant Effects of Intranasal (R,S)-Ketamine in Severe Unipolar and Bipolar Depression With and Without Comorbid Alcohol Use Disorder.

Objective: Although individuals with a family history of alcohol use disorder (AUD) have a superior antidepressant response to ketamine, outcomes in patients with current AUD remain unclear. This study sought to investigate whether intranasal (IN) racemic (R,S)-ketamine had antisuicidal and antidepressant effects in unipolar and bipolar depression and whether comorbid AUD conferred superior antisuicidal outcomes for patients.Methods: This was a double-blind, randomized, placebo-controlled trial (May 2018 to January 2022) of single administration, fixed-dose (50 mg) IN (R,S)-ketamine (or saline comparator) in unmedicated inpatients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, criteria for a current major depressive episode (bipolar or unipolar), with current suicidal ideation (SI) and past attempt. Patients with and without comorbid AUD were enrolled. Change in Scale for Suicide Ideation score was the primary outcome measure, and change in Montgomery-Åsberg Depression Rating Scale score was the secondary outcome measure.Results: No significant group × time effect was noted for SI (F = 1.1, P = .36). A statistical trend toward superior improvement in suicidality was observed in participants with comorbid AUD. The group × time interaction was significant for improvements in depression (F = 3.06, P = .03) and largely unaffected by comorbid AUD or primary mood disorder type. Within the ketamine group, a significant correlation was observed between improvement in depressive symptoms and SI for patients without comorbid AUD (r =0.927, P = .023) that was absent in patients with AUD (r = 0.39, P = .44).Conclusion: IN ketamine induced rapid antidepressant effects compared to placebo but did not significantly alter SI scores. The treatment was well tolerated. Continued investigation with IN ketamine as a practical alternative to current formulations is warranted.Trial Registration: ClinicalTrials.gov identifier: NCT03539887.

Association between lipoprotein(a), LPA genetic risk score, aortic valve disease, and subsequent major adverse cardiovascular events.

AIMS: Cohort studies have demonstrated associations between calcific aortic valve disease (CAVD) and Lp(a). As Lp(a) is almost entirely genetically determined, in this study, we aim to determine whether Lp(a), when predicted from genetic data, is associated with CAVD and major adverse cardiovascular events (MACEs). METHODS AND RESULTS: Patients undergoing coronary angiography between January 2012 and May 2013 were invited to participate in the study. Of 752 analysable participants, 446 had their Lp(a) measured and 703 had a calculable LPA genetic risk score (GRS). The primary outcomes were the presence of CAVD at baseline and MACE over a 7-year follow-up. The GRS explained 45% of variation in Lp(a). After adjustment for cardiac risk factors and coronary artery disease (CAD), the odds of CAVD increased with increasing Lp(a) [odds ratio (OR) 1.039 per 10-unit increase, 95% confidence interval (CI) 1.022-1.057, P < 0.001] and GRS (OR 1.054 per 10-unit increase, 95% CI 1.024-1.086; P < 0.001). Lipoprotein(a) and the GRS as continuous variables were not associated with subsequent MACEs. A dichotomized GRS (>54) was associated with MACE, but this relationship became non-significant when CAD classification was added into the model (OR 1.333, 95% CI 0.927-1.912; P = 0.12). CONCLUSION: An LPA GRS can explain 45% of variation in Lp(a) levels, and both Lp(a) and the GRS are associated with CAVD. An elevated GRS is associated with future cardiac events in a secondary risk setting, but, if the CAD status is known, it does not provide additional prognostic information.

Lipoprotein (a) [Lp(a)] is a type of cholesterol that is determined almost entirely by genetics. It is associated with heart disease and also stiffening of the heart valves. Recent advancements have made it possible to predict Lp(a) levels by analysing a person's DNA. This study examines the association between genetically predicted Lp(a) and adverse outcomes. Genetically predicted Lp(a) accounts for 45% of the variability in the actual Lp(a) level.Both actual and genetically predicted Lp(a) are associated with heart valve disease and adverse heart outcomes. If the degree of narrowing of the arteries in the heart is already known, genetically predicted Lp(a) does not help further predict risk.

A validated restriction enzyme ddPCR cg05575921 (AHRR) assay to accurately assess smoking exposure.

BACKGROUND & METHODS: In this study, a novel restriction enzyme (RE) digestion-based droplet digital polymerase chain reaction (ddPCR) assay was designed for cg005575921 within the AHRR gene body and compared with matching results obtained by bisulfite conversion (BIS) ddPCR and Illumina DNA methylation array. RESULTS: The RE ddPCR cg05575921 assay appeared concordant with BIS ddPCR (r2 = 0.94, P < 0.0001) and, when compared with the Illumina array, had significantly better smoking status classification performance for current versus never smoked (AUC 0.96 versus 0.93, P < 0.04) and current versus ex-smoker (AUC 0.88 versus 0.83, P < 0.04) comparisons. CONCLUSIONS: The RE ddPCR cg05575921 assay accurately predicts smoking status and could be a useful component of 'precision-medicine' chronic disease risk screening tools.

Use of an ultrasound picture archiving and communication system to answer research questions: Description of data cleaning methods.

Introduction/Purpose: Ultrasound picture archiving and communication system (PACS) databases are useful for quality improvement and clinical research but frequently contain free text that is not easily readable. Here, we present a method to extract and clean a semi-structured echocardiography (cardiac ultrasound) PACS database. Methods: Echocardiography studies between 1 January 2010 and 31 December 2018 were extracted using a data mining tool. Numeric variables were recoded with extreme values excluded. Analysis of free text, including descriptions of the heart valves and right and left ventricular size and function, was performed using a rule-based system. Different levels of free text variables were initially identified using commonly used phrases and then iteratively developed. Randomly selected sets of 100 studies were compared to the electronic health record to validate the data cleaning process. Results: The data validation step was performed three times in total, with Cohen's kappa ranging between 0.88 and 1.00 for the final set of data validation across all measures. Conclusion: Free text cleaning of semi-structured PACS databases is possible using freely available open-source software. The accuracy of this method is high, and the resulting dataset can be linked to administrative data to answer research questions. We present a method that could be used to answer clinical questions or to develop quality improvement initiatives.

Outcomes of patients with early calcific aortic valve disease detected by clinically indicated echocardiography.

AIMS: Previous studies have demonstrated relatively slow rates of progression of early calcific aortic valve disease (CAVD), which encompasses aortic sclerosis (ASc) and mild aortic stenosis (AS). The potential evolution to clinically significant AS is unclear, and we therefore examined the long-term outcomes of patients with ASc and mild AS detected at the time of clinically indicated echocardiography. METHODS AND RESULTS: Data from initial clinically indicated echocardiograms performed between 2010 and 2018 in patients aged ≥18 years were extracted and linked to nationally collected outcome data. Those with impaired right or left systolic ventricular function or other significant left-sided valve disease were excluded. A time to first event analysis was performed with a composite primary outcome of cardiovascular death and aortic valve intervention (AVI). Of the 13 313 patients, 8973 had no CAVD, 3436 had ASc, and 455 had mild AS. The remainder had moderate or worse stenosis. Over a median follow-up period of 4.2 (interquartile range 1.8-6.7) years (and after adjustment for age and sex), those with ASc were at greater risk of the primary outcome [hazard ratio (HR) 2.9, 95% confidence interval (CI) 2.1-4.0] and need for AVI (HR 26.8, 95% CI 9.1-79.1) compared with those with no CAVD. Clinical event rates accelerated after ∼5 years in those with mild AS. CONCLUSION: Patients with ASc are >25 times more likely to require AVI than those with no CAVD, and follow-up echocardiography should be considered within 3-4 years in those with mild AS.

Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression.

Treatment-resistant depression (TRD) is a term used to describe a particular type of major depressive disorder (MDD). There is no consensus about what defines TRD, with various studies describing between 1 and 4 failures of antidepressant therapies, with or without electroconvulsive therapy (ECT). That is why TRD is such a growing concern among clinicians and researchers, and it explains the necessity for investigating novel therapeutic targets beyond conventional monoamine pathways. An imbalance between two primary central nervous system (CNS) neurotransmitters, L-glutamate and γ-aminobutyric acid (GABA), has emerged as having a key role in the pathophysiology of TRD. In this review, we provide an evaluation and comprehensive review of investigational antidepressants targeting these two systems, accessing their levels of available evidence, mechanisms of action, and safety profiles. N-methyl-D-aspartate (NMDA) receptor antagonism has shown the most promise amongst the glutamatergic targets, with ketamine and esketamine (Spravato) robustly generating responses across trials. Two specific NMDA-glycine site modulators, D-cycloserine (DCS) and apimostinel, have also generated promising initial safety and efficacy profiles, warranting further investigation. Combination dextromethorphan-bupropion (AXS-05/Auvelity) displays a unique mechanism of action and demonstrated positive results in particular applicability in subpopulations with cognitive dysfunction. Currently, the most promising GABA modulators appear to be synthetic neurosteroid analogs with positive GABAA receptor modulation (such as brexanolone). Overall, advances in the last decade provide exciting perspectives for those who do not improve with conventional therapies. Of the compounds reviewed here, three are approved by the Food and Drug Administration (FDA): esketamine (Spravato) for TRD, Auvelity (dextromethorphan-bupropion) for major depressive disorder (MDD), and brexanolone (Zulresso) for post-partum depression (PPD). Notably, some concerns have arisen with esketamine and brexanolone, which will be detailed in this study.

Gaps in current methods to detect polymorphic CpGs from Illumina Infinium human methylation microarrays and exploring their potential impact in multi-EWAS analyses.

DNA methylation (DNAm) epigenome-wide association studies (EWAS) have been performed on diverse ethnicities to discover novel biomarkers associated with various diseases, such as cancers, autoimmune diseases, and neurological disorders. However, genetic polymorphisms can influence DNAm levels resulting in methylation quantitative trait loci (meQTL). These can be either direct effects, by altering the sequence of the methylation (CpG) site itself, or, in the case of array-based measures, indirectly altering the detection probe-binding site interaction. Given that genetic variant frequencies associated with meQTL can differ between population groups, these have the potential to confound EWAS observations, particularly in multi-ethnic populations. In this study, we analysed publicly available DNA methylation profiles (450K array), consisting of 1342 individuals from 6 distinct ancestral groups. We investigate two distinct tools (GapHunter and MethylToSNP) specifically designed to identify CpG sites that may be influenced by genetic variation. Results from this aggregated trans-ancestral epigenome-wide dataset suggest that both tools fail to consistently identify not only rarer (MAF < 0.05) genetic variant effects but also more than half of sites predicted to be associated with variants with much higher allele frequencies (MAF >0.2). In addition, there is a relatively low concordance in the detection of polymorphic CpGs between GapHunter and MethylToSNP. Screening of CpG site associations from EWAS using either of these tools is unlikely to be a robust or comprehensive means of identifying all genetic variant confounding effects.

Diagnostic pitfalls in a young adult with new diabetes.

Summary: A 20-year-old South Asian male presented with polyuria, polydipsia, HbA1c 81 mmol/mol, BMI 28.8 and family history of both type 1 and type 2 diabetes mellitus. As autoantibody testing was negative and c-peptide level demonstrated significant endogenous insulin secretion, type 1 diabetes was excluded. Given his age and family history, the differential diagnosis included maturity-onset diabetes of the young (MODY), a rare form of diabetes caused by a single-gene variant. A high probability of MODY was calculated and he was subsequently referred for genetic testing. Although a useful tool, the pre-test probability calculator for MODY is only validated in White Europeans. A heterogenous variant of unknown clinical significance of the NEUROD1 gene was detected, leading to gliclazide use with poor response. The patient responded well to metformin. Type 2 diabetes was considered the most likely diagnosis. This case highlights the diagnostic challenges in young patients of Asian ethnicity and the importance of interpreting genetic results of unknown significance within the clinical context. Ethnicity-specific BMI thresholds should be used when classifying patients as overweight or obese. Learning points: Variants of unknown significance detected by genetic sequencing should be interpreted within the context of the patient's other clinical parameters. It is important to use ethnicity-specific BMI thresholds for obesity. Diagnosis of type 2 diabetes mellitus at younger ages is becoming increasingly common. The pre-test probability calculator for MODY is only validated in White Europeans; although a useful guide, results should be interpreted with caution in patients of other ethnicities.

A-Band Absorption Spectrum of the ClSO Radical: Electronic Structure of the Sulfinyl Group.

Sulfur oxide species (RSOx) play a critical role in many fields, ranging from biology to atmospheric chemistry. Chlorine-containing sulfur oxides may play a key role in sulfate aerosol formation in Venus' cloud layer by catalyzing the oxidation of SO to SO2 via sulfinyl radicals (RSO). We present results from the gas-phase UV-vis transient absorption spectroscopy study of the simplest sulfinyl radical, ClSO, generated from the pulsed-laser photolysis of thionyl chloride at 248 nm (at 40 Torr of N2 and 292 K). A weak absorption spectrum from 350 to 480 nm with a peak at 385 nm was observed, with partially resolved vibronic bands (spacing = 226 cm-1), and a peak cross section σ(385 nm) = (7.6 ± 1.9) × 10-20 cm2. From ab initio calculations at the EOMEE-CCSD/ano-pVQZ level, we assigned this band to 12A' ← X2A″ and 22A' ← X2A″ transitions. The spectrum was modeled as a sum of a bound-to-free transition to the 12A' state and a bound-to-bound transition to the 22A' state with similar oscillator strengths; the prediction agreed well with the observed spectrum. We attributed the vibronic structure to a progression in the bending vibration of the 22A' state. Further calculations at the XDW-CASPT2 level predicted a conical intersection between the excited 12A' and 22A' potential energy surfaces near the Franck-Condon region. The geometry of the minimum-energy conical intersection was similar to that of the ground-state geometry. The lack of structure at shorter wavelengths could be evidence of a short excited-state lifetime arising from strong vibronic coupling. From simplified molecular orbital analysis, we attributed the ClSO spectrum to transitions involving the out-of-plane π/π* orbitals along the S-O bond and the in-plane orbital possessing a σ/σ* character along the S-Cl bond. We hypothesize that these orbitals are common to other sulfinyl radicals, RSO, which would share a combination of a strong and a weak transition in the UV (near 300 nm) and visible (400-600 nm) regions.

Application of Allometric Scaling to Nanochelator Pharmacokinetics.

Deferoxamine (DFO) is an effective FDA-approved iron chelator; however, its use is considerably limited by off-target toxicities and an extremely cumbersome dose regimen involving daily infusions. The recent development of a deferoxamine-based nanochelator (DFO-NP) with selective renal excretion has shown promise in ameliorating iron overload and associated physiological complications in rodent models with a substantially improved safety profile. While the dose- and administration route-dependent pharmacokinetics (PK) of DFO-NPs have been recently characterized, the optimized PK model was not validated, and the prior studies did not directly address the clinical translatability of DFO-NPs into humans. In the present work, these gaps were addressed by applying allometric scaling of DFO-NP PK in rats to predict those in mice and humans. First, this approach predicted serum concentration-time profiles of DFO-NPs, which were similar to those experimentally measured in mice, validating the nonlinear disposition and absorption models for DFO-NPs across the species. Subsequently, we explored the utility of allometric scaling by predicting the PK profile of DFO-NPs in humans under clinically relevant dosing schemes. These in silico efforts demonstrated that the novel nanochelator is expected to improve the PK of DFO when compared to standard infusion regimens of native DFO. Moreover, reasonable formulation strategies were identified and discussed for both early clinical development and more sophisticated formulation development.

The Role of the Gut Microbiome in Bipolar Disorder and its Common Medical Comorbidities.

Bipolar disorder is a decidedly heterogeneous and multifactorial disease, with significant psychosocial and medical disease burden. Much difficulty has been encountered in developing novel therapeutics and objective biomarkers for clinical use in this population. In that regard, gut-microbial homeostasis appears to modulate several key pathways relevant to a variety of psychiatric, metabolic, and inflammatory disorders. Microbial impact on immune, endocrine, endocannabinoid, kynurenine, and other pathways are discussed throughout this review. Emphasis is placed on this system's relevance to current pharmacology, diet, and comorbid illness in bipolar disorder. Despite the high level of optimism promoted in many reviews on this topic, substantial obstacles exist before any microbiome-related findings can provide meaningful clinical utility. Beyond a comprehensive overview of pathophysiology, this review hopes to highlight several key areas where progress is needed. As well, novel microbiome-associated suggestions are presented for future research.

Conformer-Dependent Chemistry: Experimental Product Branching of the Vinyl Alcohol + OH + O2 Reaction.

The concentration of formic acid in Earth's troposphere is underestimated by detailed chemical models compared to field observations. Phototautomerization of acetaldehyde to its less stable tautomer vinyl alcohol, followed by the OH-initiated oxidation of vinyl alcohol, has been proposed as a missing source of formic acid that improves the agreement between models and field measurements. Theoretical investigations of the OH + vinyl alcohol reaction in excess O2 conclude that OH addition to the α carbon of vinyl alcohol produces formaldehyde + formic acid + OH, whereas OH addition to the ß site leads to glycoaldehyde + HO2. Furthermore, these studies predict that the conformeric structure of vinyl alcohol controls the reaction pathway, with the anti-conformer of vinyl alcohol promoting α OH addition, whereas the syn-conformer promotes ß addition. However, the two theoretical studies reach different conclusions regarding which set of products dominate. We studied this reaction using time-resolved multiplexed photoionization mass spectrometry to quantify the product branching fractions. Our results, supported by a detailed kinetic model, conclude that the glycoaldehyde product channel (arising mostly from syn-vinyl alcohol) dominates over formic acid production with a 3.6:1.0 branching ratio. This result supports the conclusion of Lei et al. that conformer-dependent hydrogen bonding at the transition state for OH-addition controls the reaction outcome. As a result, tropospheric oxidation of vinyl alcohol creates less formic acid than recently thought, increasing again the discrepancy between models and field observations of Earth's formic acid budget.

Practical Guide to Glucocorticoid Induced Hyperglycaemia and Diabetes.

Glucocorticoids, also known as steroids, are a class of anti-inflammatory drugs utilised widely in clinical practice for a variety of conditions. They are associated with a range of side effects including abnormalities of glucose metabolism. Multiple guidelines have been published to illustrate best management of glucocorticoid-induced hyperglycaemia and diabetes in a variety of settings. This article discusses current best clinical practice including diagnosis, investigations and ongoing management of glucocorticoid-induced dysglycaemia in both in- and outpatient settings.

DNA methylation patterns at birth predict health outcomes in young adults born very low birthweight.

BACKGROUND: Individuals born very low birthweight (VLBW) are at increased risk of impaired cardiovascular and respiratory function in adulthood. To identify markers to predict future risk for VLBW individuals, we analyzed DNA methylation at birth and at 28 years in the New Zealand (NZ) VLBW cohort (all infants born < 1500 g in NZ in 1986) compared with age-matched, normal birthweight controls. Associations between neonatal methylation and cardiac structure and function (echocardiography), vascular function and respiratory outcomes at age 28 years were documented. RESULTS: Genomic DNA from archived newborn heel-prick blood (n = 109 VLBW, 51 controls) and from peripheral blood at ~ 28 years (n = 215 VLBW, 96 controls) was analyzed on Illumina Infinium MethylationEPIC 850 K arrays. Following quality assurance and normalization, methylation levels were compared between VLBW cases and controls at both ages by linear regression, with genome-wide significance set to p < 0.05 adjusted for false discovery rate (FDR, Benjamini-Hochberg). In neonates, methylation at over 16,400 CpG methylation sites differed between VLBW cases and controls and the canonical pathway most enriched for these CpGs was Cardiac Hypertrophy Signaling (p = 3.44E-11). The top 20 CpGs that differed most between VLBW cases and controls featured clusters in ARID3A, SPATA33, and PLCH1 and these 3 genes, along with MCF2L, TRBJ2-1 and SRC, led the list of 15,000 differentially methylated regions (DMRs) reaching FDR-adj significance. Fifteen of the 20 top CpGs in the neonate EWAS showed associations between methylation at birth and adult cardiovascular traits (particularly LnRHI). In 28-year-old adults, twelve CpGs differed between VLBW cases and controls at FDR-adjusted significance, including hypermethylation in EBF4 (four CpGs), CFI and UNC119B and hypomethylation at three CpGs in HIF3A and one in KCNQ1. DNA methylation GrimAge scores at 28 years were significantly greater in VLBW cases versus controls and weakly associated with cardiovascular traits. Four CpGs were identified where methylation differed between VLBW cases and controls in both neonates and adults, three reversing directions with age (two CpGs in EBF4, one in SNAI1 were hypomethylated in neonates, hypermethylated in adults). Of these, cg16426670 in EBF4 at birth showed associations with several cardiovascular traits in adults. CONCLUSIONS: These findings suggest that methylation patterns in VLBW neonates may be informative about future adult cardiovascular and respiratory outcomes and have value in guiding early preventative care to improve adult health.

Genetic Risk Score for Intracranial Aneurysms: Prediction of Subarachnoid Hemorrhage and Role in Clinical Heterogeneity.

BACKGROUND: Recently, common genetic risk factors for intracranial aneurysm (IA) and aneurysmal subarachnoid hemorrhage (ASAH) were found to explain a large amount of disease heritability and therefore have potential to be used for genetic risk prediction. We constructed a genetic risk score to (1) predict ASAH incidence and IA presence (combined set of unruptured IA and ASAH) and (2) assess its association with patient characteristics. METHODS: A genetic risk score incorporating genetic association data for IA and 17 traits related to IA (so-called metaGRS) was created using 1161 IA cases and 407 392 controls from the UK Biobank population study. The metaGRS was validated in combination with risk factors blood pressure, sex, and smoking in 828 IA cases and 68 568 controls from the Nordic HUNT population study. Furthermore, we assessed association between the metaGRS and patient characteristics in a cohort of 5560 IA patients. RESULTS: Per SD increase of metaGRS, the hazard ratio for ASAH incidence was 1.34 (95% CI, 1.20-1.51) and the odds ratio for IA presence 1.09 (95% CI, 1.01-1.18). Upon including the metaGRS on top of clinical risk factors, the concordance index to predict ASAH hazard increased from 0.63 (95% CI, 0.59-0.67) to 0.65 (95% CI, 0.62-0.69), while prediction of IA presence did not improve. The metaGRS was statistically significantly associated with age at ASAH (ß=-4.82×10-3 per year [95% CI, -6.49×10-3 to -3.14×10-3]; P=1.82×10-8), and location of IA at the internal carotid artery (odds ratio=0.92 [95% CI, 0.86-0.98]; P=0.0041). CONCLUSIONS: The metaGRS was predictive of ASAH incidence, although with limited added value over clinical risk factors. The metaGRS was not predictive of IA presence. Therefore, we do not recommend using this metaGRS in daily clinical care. Genetic risk does partly explain the clinical heterogeneity of IA warranting prioritization of clinical heterogeneity in future genetic prediction studies of IA and ASAH.

Mechanism-Based Pharmacokinetic Modeling of Absorption and Disposition of a Deferoxamine-Based Nanochelator in Rats.

Deferoxamine (DFO) is an effective FDA-approved iron chelator. However, its use is considerably limited by off-target toxicities and an extremely cumbersome dose regimen with daily infusions. The recent development of a deferoxamine-based nanochelator (DFO-NP) with selective renal excretion has shown promise in ameliorating animal models of iron overload with a substantially improved safety profile. To further the preclinical development of this promising nanochelator and to inform on the feasibility of clinical development, it is necessary to fully characterize the dose and administration-route-dependent pharmacokinetics and to develop predictive pharmacokinetic (PK) models describing absorption and disposition. Herein, we have evaluated the absorption, distribution, and elimination of DFO-NPs after intravenous and subcutaneous (SC) injection at therapeutically relevant doses in Sprague Dawley rats. We also characterized compartment-based model structures and identified model-based parameters to quantitatively describe the PK of DFO-NPs. Our modeling efforts confirmed that disposition could be described using a three-compartment mamillary model with elimination and saturable reabsorption both occurring from the third compartment. We also determined that absorption was nonlinear and best described by parallel saturable and first-order processes. Finally, we characterized a novel pathway for saturable SC absorption of an ultrasmall organic nanoparticle directly into the systemic circulation, which offers a novel strategy for improving drug exposure for nanotherapeutics.

Pharmacokinetics and tissue distribution of deferoxamine-based nanochelator in rats.

Aim: To characterize the pharmacokinetics of deferoxamine-conjugated nanoparticles (DFO-NPs), a novel nanochelator for removing excess iron. Materials & methods: The pharmacokinetics of DFO-NPs were evaluated in Sprague-Dawley rats at three doses (3.3, 10 and 30 µmol/kg) after intravenous and subcutaneous administration. Results: DFO-NPs exhibited a biphasic concentration-time profile after intravenous administration with a short terminal half-life (2.0-3.2 h), dose-dependent clearance (0.111-0.179 l/h/kg), minimal tissue distribution and exclusive renal excretion with a possible saturable reabsorption mechanism. DFO-NPs after subcutaneous administration exhibited absorption-rate-limited kinetics with a prolonged half-life (5.7-10.1 h) and favorable bioavailability (47-107%). Conclusion: DFO-NPs exhibit nonlinear pharmacokinetics with increasing dose, and subcutaneous administration substantially improves drug exposure, thereby making it a clinically viable administration route for iron chelation.

Iron is an essential metal nutrient, but excess iron produces toxic effects that damage multiple organs including the heart, liver and pancreas. Deferoxamine (DFO) is a US FDA-approved drug for treating iron overload, but its use is limited by serious adverse effects and an inconvenient daily dose scheme. The recent development of a DFO-based nanomedicine (DFO-NP) has shown promise in treating iron overload in animals and was safer in animals. Before this new drug can be given to humans, how it is absorbed into the body, processed in the body and removed from the body when given in different amounts and dose routes must be determined. In this study, we tested the absorption, distribution and removal of DFO-NPs after intravenous and subcutaneous injection in rats. This study showed that DFO-NPs behave differently when changing the dose and that subcutaneous injection makes the drug stay in the body longer without ill effect, which means it could be given to patients this way.

Therapeutic setting as an essential component of psychedelic research methodology: Reporting recommendations emerging from clinical trials of 3,4-methylenedioxymethamphetamine for post-traumatic stress disorder.

Research of psychedelic assisted therapies is at an all-time high, though few studies highlight extra-pharmacological factors that may affect treatment efficacy. One critical set of attributes includes the therapeutic setting itself, which describe the physical and socio-cultural environments in which the drug-assisted session occurs. Despite enduring consensus of the influence of setting, recommendations for establishing and reporting key setting variables remain sparse across clinical trial protocols and published research methodologies. The purpose of this paper is to: (1) present what is known of the influence and implications of setting to psychedelic-assisted therapies, with a particular focus on 3,4-methylenedioxymethamphetamine (MDMA); and (2) propose a set of reporting guidelines for operationalizing and reporting key setting variables in clinical trials of psychedelic-assisted therapies, based on recommendations emerging from clinical trials of MDMA for PTSD. In fact, recommendations should be expanded to "set" - the subject's mood, expectations, and broader psychological condition - once this is more fully developed in the field. The proposed reporting guidelines offer a means of increasing the volume and variability of data necessary for future empirical examination of key setting attributes influencing treatment efficacy, while preserving practitioner and patient autonomy to co-construct adaptive therapy settings according to their respective needs and expertise.

History of Suicide Attempt and Clozapine Treatment in Veterans With Schizophrenia or Schizoaffective Disorder.

Objective: To evaluate whether a history of suicide attempt increases the odds of receiving clozapine treatment in veterans with schizophrenia or schizoaffective disorder.Methods: Electronic health record data were obtained for veterans with schizophrenia or schizoaffective disorder treated at any US Veterans Affairs Medical Center between January 1, 2000, and January 31, 2021 (N = 134,692). Logistic regression (adjusted and unadjusted) was applied to estimate odds ratios (ORs) for clozapine treatment in suicide attempters relative to nonattempters.Results: 3,407 patients had a documented history of suicide attempt, while 6,867 patients had received clozapine treatment. Also, 9.4% (n = 321) of suicide attempters versus 5.0% (n = 6546) of nonattempters had received clozapine treatment. The odds of being treated with clozapine was approximately 2-fold in patients with a history of suicide attempt in unadjusted (OR = 1.98, 95% CI, 1.76-2.22) and adjusted (OR = 1.91, 95% CI, 1.67-2.15) analyses.Conclusions: Despite the higher odds of clozapine treatment in suicide attempters with schizophrenia or schizoaffective disorder, clozapine was underutilized in the current sample of veterans. Concerted efforts should be made to expand the use of clozapine in patients with schizophrenia or schizoaffective disorder, especially those with a history of suicide attempt.