Racial Disparities in Diagnosis and Treatment of Depression Associated with Androgen Deprivation Therapy for Prostate Cancer.

OBJECTIVE: To analyze potential racial disparities in the diagnosis and management of depression associated with androgen deprivation therapy. METHODS: TriNetX health record network was queried for prostate cancer patients treated with androgen deprivation therapy from 2003-2023. Differences in rates of depression diagnosis and treatment were compared between White and Black patients. Means, odds ratios, and t tests were calculated in univariate analysis with 95% confidence intervals (CI). RESULTS: Data were queried from 93 health care organizations to yield 78,313 prostate cancer patients treated with androgen deprivation therapy. Patients on androgen deprivation therapy had 60% greater odds of developing depression vs other patients [9% vs 6%; odds ratio (OR) 1.6; 95% CI (1.5-1.7); P <.0001]. Of those with depression secondary to androgen deprivation therapy, only 35% were treated with antidepressants. After starting androgen deprivation therapy, White patients had 30% greater odds of being diagnosed with depression, compared to Black patients [10% vs 8%; OR 1.3; 95% CI (1.2-1.4); P <.001]. White patients also had higher odds of being treated with a first line antidepressant than Black patients [56% vs 48%; OR 1.4, 95% CI (1.2-1.6), P <.001]. CONCLUSION: This analysis confirms a significant association between androgen deprivation therapy and the development of clinical depression, and highlights its medical undertreatment. Importantly, our findings also indicate significant racial disparities in the identification and treatment of depression. Routine screening initiatives that account for social determinants of health may alleviate this disparity. Limitations of this study include retrospective design and lack of data describing severity of depression, which might correlate with need for medication.

Commonly Used Therapeutics Associated with Changes in Arousal Inhibit GABAAR Activation.

GABAA receptor-positive modulators are well-known to induce sedation, sleep, and general anesthesia. Conversely, GABAA receptor negative allosteric modulators (GABAARNAMs) can increase arousal and induce seizures. Motivated by our studies with patients with hypersomnia, and our discovery that two GABAARNAMs can restore the Excitation/Inhibition (E/I) balance in vitro and arousal in vivo, we chose to screen 11 compounds that have been reported to modulate arousal, to see if they shared a GABA-related mechanism. We determined modulation with both conventional and microfluidic patch clamp methods. We found that receptor activation was variably modulated by all 11 compounds: Rifampicin (RIF), Metronidazole (MET), Minocycline (MIN), Erythromycin (ERY), Ofloxacin (OFX), Chloroquine (CQ), Hydroxychloroquine sulfate (HCQ), Flumazenil (FLZ), Pentylenetetrazol (PTZ), (-)-Epigallocatechin Gallate (EGCG), and clarithromycin (CLR). The computational modeling of modulator-receptor interactions predicted drug action at canonical binding sites and novel orphan sites on the receptor. Our findings suggest that multiple avenues of investigation are now open to investigate large and brain-penetrant molecules for the treatment of patients with diminished CNS E/I balance.

Pharmacological evaluation of enantiomerically separated positive allosteric modulators of cannabinoid 1 receptor, GAT591 and GAT593.

Positive allosteric modulation of the type 1 cannabinoid receptor (CB1R) has substantial potential to treat both neurological and immune disorders. To date, a few studies have evaluated the structure-activity relationship (SAR) for CB1R positive allosteric modulators (PAMs). In this study, we separated the enantiomers of the previously characterized two potent CB1R ago-PAMs GAT591 and GAT593 to determine their biochemical activity at CB1R. Separating the enantiomers showed that the R-enantiomers (GAT1665 and GAT1667) displayed mixed allosteric agonist-PAM activity at CB1R while the S-enantiomers (GAT1664 and GAT1666) showed moderate activity. Furthermore, we observed that the R and S-enantiomers had distinct binding sites on CB1R, which led to their distinct behavior both in vitro and in vivo. The R-enantiomers (GAT1665 and GAT1667) produced ago-PAM effects in vitro, and PAM effects in the in vivo behavioral triad, indicating that the in vivo activity of these ligands may occur via PAM rather than agonist-based mechanisms. Overall, this study provides mechanistic insight into enantiospecific interaction of 2-phenylindole class of CB1R allosteric modulators, which have shown therapeutic potential in the treatment of pain, epilepsy, glaucoma, and Huntington's disease.

Plasmon-controlled shaping of gold nanostar photothermal therapy agents.

Tunable gold nanostars were synthesized through the reduction of gold salt by an aminosugar, N-methyl-D-glucamine, in a seed-less route. The nanoparticle morphology and size were facilely tuned through adjustments in reaction pH and LED light-mediated synthesis. The materials demonstrated low inherent cytotoxicity and high potential for photothermal therapy.

The type 1 cannabinoid receptor positive allosteric modulators GAT591 and GAT593 reduce spike-and-wave discharges in Genetic Absence Epilepsy Rats from Strasbourg.

Childhood absence epilepsy (CAE) is a non-convulsive seizure disorder primarily in children characterized by absence seizures. Absence seizures consist of 2.5-5 Hz spike-and-wave discharges (SWDs) detectable using electroencephalography (EEG). Current drug treatments are only partially effective and adverse side effects have spurred research into alternative treatment approaches. Recent research shows that positive allosteric modulation of the type-1 cannabinoid receptor (CB1R) reduces the frequency and duration of SWDs in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model that recapitulates the SWDs in CAE. Here, we tested additional CB1R ago-PAMs, GAT591 and GAT593, for their potential in alleviating SWD activity in GAERS. In vitro experiments confirm that GAT591 and GAT593 exhibit increased potency and selectivity in cell cultures and behave as CB1R allosteric agonists and PAMs. To assess drug effects on SWDs, bilateral electrodes were surgically implanted in the somatosensory cortices of male GAERS and EEGs recorded for 4 h following systemic administration of GAT591 or GAT593 (1.0, 3.0 and 10.0 mg/kg). Both GAT591 and GAT593 dose-dependently reduced total SWD duration during the recording period. The greatest effect on SWD activity was observed at 10.0 mg/kg doses, with GAT591 and GAT593 reducing seizure duration by 36% and 34% respectively. Taken together, these results support the continued investigation of CB1R PAMs as a potential therapeutic to alleviate SWDs in absence epilepsy.

Deep eutectic solvents comprising creatine and citric acid and their hydrated mixtures.

We report the phase diagram for the binary creatine-citric acid mixture which features a stable and broad eutectic region. Combinations containing 10-60 mol% creatine yield a deep eutectic solvent with a glass transition temperature at 270 K. Addition of up to 70 mol% water to the binary mixture affords retention of the eutectic nature and a handle to vary solvent viscosity and polarity.

Assessment of select synthetic cannabinoid receptor agonist bias and selectivity between the type 1 and type 2 cannabinoid receptor.

The first synthetic cannabinoid receptor agonists (SCRAs) were designed as tool compounds to study the endocannabinoid system's two predominant cannabinoid receptors, CB1R and CB2R. Unfortunately, novel SCRAs now represent the most rapidly proliferating novel psychoactive substances (NPS) of abuse globally. Unlike ∆9-tetrahydrocannabinol, the CB1R and CB2R partial agonist and the intoxicating constituent of Cannabis, many SCRAs characterized to date are full agonists of CB1R. Gaining additional insight into the pharmacological activity of these SCRAs is critical to assess and regulate NPSs as they enter the marketplace. The purpose of this study was to assess select SCRAs recently identified by Canadian police, border service agency, private companies and the illicit market as potential CB1R and CB2R agonists. To this end, fifteen SCRAs were screened for in vitro activity and in silico interactions at CB1R and CB2R. Several SCRAs were identified as being highly biased for cAMP inhibition or ßarrestin2 recruitment and receptor subtype selectivity between CB1R and CB2R. The indazole ring and halogen-substituted butyl or pentyl moieties were identified as two structural features that may direct ßarrestin2 bias. Two highly-biased SCRAs-JWH-018 2'-napthyl-N-(3-methylbutyl) isomer (biased toward cAMP inhibition) and 4-fluoro MDMB-BINACA (biased toward ßarrestin2 recruitment) displayed unique and differential in vivo activity in mice. These data provide initial insight into the correlations between structure, signalling bias, and in vivo activity of the SCRAs.

Serotonin 2A Receptor (5-HT2AR) Activation by 25H-NBOMe Positional Isomers: In Vitro Functional Evaluation and Molecular Docking.

Serotonergic psychedelics are defined as compounds having serotonin 2A receptor (5-HT2AR) activation as an important pharmacological mechanism. These compounds include the phenylalkylamine class, containing substances with e.g. 2C-X structures (phenethylamines) or their N-methoxybenzyl analogues (NBOMes). Besides their abuse potential, psychedelics are increasingly recognized for having therapeutic benefits. However, many psychedelics remain incompletely characterized, even concerning their structure-activity relationships. Here, five positional isomers of 25H-NBOMe, with two methoxy groups on the different positions of the phenyl ring of the phenethylamine moiety, were subjected to split-nanoluciferase assays assessing the in vitro recruitment of cytosolic proteins to the 5-HT2AR. Furthermore, molecular docking at the 5-HT2AR allowed estimation of which residues interact with the specific isomers' methoxy groups. Although the optimal substitution pattern of N-unsubstituted phenylalkylamines has been extensively studied, this is the first comparative evaluation of the functional effects of the positioning of the methoxy groups in the phenethylamine moiety of NBOMes.

Bespoke nanostars: synthetic strategies, tactics, and uses of tailored branched gold nanoparticles.

Interest in branched colloidal gold nanosystems has gained increased traction due to the structures' outstanding optical and plasmonic properties, resulting in utilization in techniques such as surface-enhanced spectroscopy and bioimaging, as well as plasmon photocatalysis and photothermal therapy. The unique morphologies of nanostars, multipods, urchins, and other highly branched nanomaterials exhibit selective optical and crystallographic features accessible by alterations in the respective wet-chemical syntheses, opening a vast array of useful applications. Examination of discriminatory reaction conditions, such as seeded growth (e.g., single-crystalline vs. multiply twinned seeds), underpotential deposition of Ag(i), galvanic replacement, and the dual use of competing reducing and capping agents, is shown to reveal conditions necessary for the genesis of assorted branched nanoscale gold frameworks. By observing diverse approaches, including template-directed, microwave-mediated, and aggregation-based methods, among others, a schema of synthetic pathways can be constructed to provide a guiding roadmap for obtaining the full range of desired branched gold nanocrystals. This review presents a comprehensive summary of such advances and these nuances of the underlying procedures, as well as offering mechanistic insights into the directed nanoscale growth. We conclude the review by discussing various applications for these fascinating nanomaterials, particularly surface-enhanced Raman spectroscopy, photothermal and photodynamic therapy, catalysis, drug delivery, and biosensing.

The Impact of a Concierge Medicine Model on Door to Doctor Time and Patient Flow in an Urban Emergency Department.

INTRODUCTION: Emergency Department (ED) crowding negatively impacts patient outcomes, patient satisfaction, and patient safety. One solution involves introducing a Concierge Physician (CP) whose sole purpose is to provide a brief initial assessment (BIA) and aid patient navigation through the ED. The goal of this study was to quantify the impact of a CP on patient flow dynamics in an urban ED setting. METHODS: We performed a retrospective observational cohort study in an urban academic ED over a 6-month period. Initially, the CP was present in the treatment area during weekdays; during the last half of the observation period, an additional CP was added to the waiting room on weekends. We identified four major milestones in the ED visit with regards to patient throughput. Adult patients presenting to the ED with a triage level of Urgent (ESI 3) were analyzed for this study. Data were stratified based on the patient's ultimate disposition (admitted or discharged) and presented as means with predictive analysis. RESULTS: Between August 2016 and January 2017, the ED evaluated 42,397 adult patients. Of those, 26,976 (64%) were triage level Urgent (3). Of the level 3 patients, 10,279 (38%) received a BIA from a CP. Patients evaluated by a CP were seen approximately 30 mins faster (40% reduction in Door to Doctor time), but stayed 30 mins longer in the ED on average, because the medical decision-making process took >1 hr longer when the patient was initially evaluated by a CP. CONCLUSION: Adapting a concierge medicine model to rapidly evaluate patients resulted in a dramatically reduced Door to Doctor time, but an increase in overall time spent in the ED. This discrepancy was a direct result of the delay in physician disposition.

The Endocannabinoid System and Synthetic Cannabinoids in Preclinical Models of Seizure and Epilepsy.

Cannabinoids are compounds that are structurally and/or functionally related to the primary psychoactive constituent of Cannabis sativa, [INCREMENT]-tetrahydrocannabinol (THC). Cannabinoids can be divided into three broad categories: endogenous cannabinoids, plant-derived cannabinoids, and synthetic cannabinoids (SCs). Recently, there has been an unprecedented surge of interest into the pharmacological and medicinal properties of cannabinoids for the treatment of epilepsies. This surge has been stimulated by an ongoing shift in societal opinions about cannabinoid-based medicines and evidence that cannabidiol, a nonintoxicating plant cannabinoid, has demonstrable anticonvulsant activity in children with treatment-refractory epilepsy. The major receptors of the endogenous cannabinoid system (ECS)-the type 1 and 2 cannabinoid receptors (CB1R, CB2R)-have critical roles in the modulation of neurotransmitter release and inflammation, respectively; so, it is not surprising therefore that the ECS is being considered as a target for the treatment of epilepsy. SCs were developed as potential new drug candidates and tool compounds for studying the ECS. Beyond the plant cannabinoids, an extensive research effort is underway to determine whether SCs that directly target CB1R, CB2R, or the enzymes that breakdown endogenous cannabinoids have anticonvulsant effects in preclinical rodent models of epilepsy and seizure. This research demonstrates that many SCs do reduce seizure severity in rodent models and may have both positive and negative pharmacodynamic and pharmacokinetic interactions with clinically used antiepilepsy drugs. Here, we provide a comprehensive review of the preclinical evidence for and against SC modulation of seizure and discuss the important questions that need to be addressed in future studies.

Application of Fluorine- and Nitrogen-Walk Approaches: Defining the Structural and Functional Diversity of 2-Phenylindole Class of Cannabinoid 1 Receptor Positive Allosteric Modulators.

Cannabinoid 1 receptor (CB1R) allosteric ligands hold a far-reaching therapeutic promise. We report the application of fluoro- and nitrogen-walk approaches to enhance the drug-like properties of GAT211, a prototype CB1R allosteric agonist-positive allosteric modulator (ago-PAM). Several analogs exhibited improved functional potency (cAMP, ß-arrestin 2), metabolic stability, and aqueous solubility. Two key analogs, GAT591 (6r) and GAT593 (6s), exhibited augmented allosteric-agonist and PAM activities in neuronal cultures, improved metabolic stability, and enhanced orthosteric agonist binding (CP55,940). Both analogs also exhibited good analgesic potency in the CFA inflammatory-pain model with longer duration of action over GAT211 while being devoid of adverse cannabimimetic effects. Another analog, GAT592 (9j), exhibited moderate ago-PAM potency and improved aqueous solubility with therapeutic reduction of intraocular pressure in murine glaucoma models. The SAR findings and the enhanced allosteric activity in this class of allosteric modulators were accounted for in our recently developed computational model for CB1R allosteric activation and positive allosteric modulation.

Tissue classification in intercostal and paravertebral ultrasound using spectral analysis of radiofrequency backscatter.

Paravertebral and intercostal nerve blocks have experienced a resurgence in popularity. Ultrasound has become the gold standard for visualization of the needle during injection of the analgesic, but the intercostal artery and vein can be difficult to visualize. We investigated the use of spectral analysis of raw radiofrequency (RF) ultrasound signals for identification of the intercostal vessels and six other tissue types in the intercostal and paravertebral spaces. Features derived from the one-dimensional spectrum, two-dimensional spectrum, and cepstrum were used to train four different machine learning algorithms. In addition, the use of the average normalized spectrum as the feature set was compared with the derived feature set. Compared to a support vector machine (SVM) (74.2%), an artificial neural network (ANN) (68.2%), and multinomial analysis (64.1%), a random forest (84.9%) resulted in the most accurate classification. The accuracy using a random forest trained with the first 15 principal components of the average normalized spectrum was 87.0%. These results demonstrate that using a machine learning algorithm with spectral analysis of raw RF ultrasound signals has the potential to provide tissue characterization in intercostal and paravertebral ultrasound.

Impact of integrated district level mental health care on clinical and social outcomes of people with severe mental illness in rural Ethiopia: an intervention cohort study.

AIM: There is limited evidence of the safety and impact of task-shared care for people with severe mental illnesses (SMI; psychotic disorders and bipolar disorder) in low-income countries. The aim of this study was to evaluate the safety and impact of a district-level plan for task-shared mental health care on 6 and 12-month clinical and social outcomes of people with SMI in rural southern Ethiopia. METHODS: In the Programme for Improving Mental health carE, we conducted an intervention cohort study. Trained primary healthcare (PHC) workers assessed community referrals, diagnosed SMI and initiated treatment, with independent research diagnostic assessments by psychiatric nurses. Primary outcomes were symptom severity and disability. Secondary outcomes included discrimination and restraint. RESULTS: Almost all (94.5%) PHC worker diagnoses of SMI were verified by psychiatric nurses. All prescribing was within recommended dose limits. A total of 245 (81.7%) people with SMI were re-assessed at 12 months. Minimally adequate treatment was received by 29.8%. All clinical and social outcomes improved significantly. The impact on disability (standardised mean difference 0.50; 95% confidence interval (CI) 0.35-0.65) was greater than impact on symptom severity (standardised mean difference 0.28; 95% CI 0.13-0.44). Being restrained in the previous 12 months reduced from 25.3 to 10.6%, and discrimination scores reduced significantly. CONCLUSIONS: An integrated district level mental health care plan employing task-sharing safely addressed the large treatment gap for people with SMI in a rural, low-income country setting. Randomised controlled trials of differing models of task-shared care for people with SMI are warranted.

Finding hens in a haystack: Consistency of movement patterns within and across individual laying hens maintained in large groups.

We sought to objectively quantify and compare the recorded movement and location patterns of laying hens within a commercial system. Using a custom tracking system, we monitored the location within five zones of a commercial aviary for 13 hens within a flock of 225 animals for a contiguous period of 11 days. Most hens manifested a hen-specific pattern that was (visually) highly consistent across days, though, within that consistency, manifested stark differences between hens. Three different methods were used to classify individual daily datasets into groups based on their similarity: (i) Linear Discriminant Analysis based on six summary variables (transitions into each zone) and total transitions; (ii) Hierarchical Clustering, a naïve clustering analysis technique, applied to summary variables and iii) Hierarchical Clustering applied to dissimilarity matrices produced by Dynamic Time Warping. The three methods correctly classified more than 85% of the hen days and provided a unique means to assess behaviour of a system indicating a considerable degree of complexity and structure. We believe the current effort is the first to document these location and movement patterns within a large, complex commercial system with a large potential to influence the assessment of animal welfare, health, and productivity.

A step in the right direction: an open-design pedometer algorithm for dogs.

BACKGROUND: Accelerometer-based technologies could be useful in providing objective measures of canine ambulation, but most are either not tailored to the idiosyncrasies of canine gait, or, use un-validated or closed source approaches. The aim of this paper was to validate algorithms which could be applied to accelerometer data for i) counting the number of steps and ii) distance travelled by a dog. To count steps, an approach based on partitioning acceleration was used. This was applied to accelerometer data from 13 dogs which were walked a set distance and filmed. Each footfall captured on video was annotated. In a second experiment, an approach based on signal features was used to estimate distance travelled. This was applied to accelerometer data from 10 dogs with osteoarthritis during normal walks with their owners where GPS (Global Positioning System) was also captured. Pearson's correlations and Bland Altman statistics were used to compare i) the number of steps measured on video footage and predicted by the algorithm and ii) the distance travelled estimated by GPS and predicted by the algorithm. RESULTS: Both step count and distance travelled could be estimated accurately by the algorithms presented in this paper: 4695 steps were annotated from the video and the pedometer was able to detect 91%. GPS logged a total of 20,184 m meters across all dogs; the mean difference between the predicted and GPS estimated walk length was 211 m and the mean similarity was 79%. CONCLUSIONS: The algorithms described show promise in detecting number of steps and distance travelled from an accelerometer. The approach for detecting steps might be advantageous to methods which estimate gross activity because these include energy output from stationary activities. The approach for estimating distance might be suited to replacing GPS in indoor environments or others with limited satellite signal. The algorithms also allow for temporal and spatial components of ambulation to be calculated. Temporal and spatial aspects of dog ambulation are clinical indicators which could be used for diagnosis or monitoring of certain diseases, or used to provide information in support of canine weight-loss programmes.

The Sin of Prediction: When Mentally Simulated Alternatives Compete With Reality.

Experiential and associative learning are essential to optimal decision making. However, research shows that, even when exposed to repeated trials, people often fail to learn probabilities and cause/effect covariations. Consistent with the counterfactual inflation hypothesis, it is proposed that counterfactuals can interfere with memory of repeated exposures and therefore inhibit learning. Five experimental studies tested counterfactual thinking as a potential mechanism underlying this learning deficit using a simple, biased coin flipping paradigm. Participants were instructed to either simply observe or to predict and observe outcomes of a biased coin being flipped in multiple trials (Experiments 1-4). In all four experiments, counterfactual thought frequency mediated the relationship between task instructions and the extent of bias detection (i.e., learning). Experiment 5 showed that mental simulations of alternative outcomes were especially deleterious to learning and decision making. Findings are discussed in light of experiential learning theory and applied implications.

Using the incidence and impact of health conditions in guide dogs to investigate healthy ageing in working dogs.

This study aimed to use retirement data from working guide dogs to investigate healthy ageing in dogs and the demographic factors that influence ageing. Using a dataset of 7686 dogs spanning 20 years, dogs withdrawn for health reasons before they reached retirement were identified. Cases of retirement for old age, rather than for health reasons, were also recorded, as was the length of working life for all dogs. Specific health reasons were grouped into 14 different health categories. The influence of purebred or crossbreed, breed, and sex on the incidence of these health categories and the length of working life within each health category was considered. The majority (n = 6465/7686; 84%) of working guide dogs were able to function as guide dogs until they had worked for 8.5 years, when they retired. This working life might constitute a reference for the different breeds considered, with the exception of the German shepherd dog, which had a shorter working life. The most common reason for health withdrawals was musculoskeletal conditions (n = 387/1362; 28%), mostly arthritis. Skin conditions (mostly comprised of cases of atopic dermatitis) reduced working life most commonly (mean, approximately 5 years). Nervous sensory conditions (35% of which were cases of epilepsy) reduced working life by 3 years.

Quality of life assessment in domestic dogs: An evidence-based rapid review.

Assessment of quality of life (QoL) is an important, increasingly popular outcome measure in veterinary research and practice, particularly in dogs. In humans, QoL is commonly assessed by self-reporting and since this is not possible for animals, it is crucial that instruments designed to measure QoL are tested for reliability and validity. Using a systematic, replicable literature search strategy, the aim of this study was to find published, peer-reviewed instruments for QoL assessment in dogs and to assess the quality of these. CAB Abstracts and PubMed were searched in July 2013 using terms relevant to dogs, wellbeing and QoL. Inclusion and exclusion criteria were applied. When instruments were not published in full, authors were contacted to obtain them. Criteria were applied to assess the quality, validity and reliability of the 52 instruments obtained. Twenty-seven additional instruments used in peer-reviewed publications were not included because they had not been fully described in the publication or were not provided by authors upon request. Most of the instruments reviewed (48/52) were disease-specific rather than generic. Only four publications provided a definition of QoL or wellbeing. Only 11/52 instruments demonstrated evidence of assessing reliability or validity, and the quality of these instruments was variable. Many novel, unvalidated instruments have been generated and applied as clinical outcomes before it was known whether they measured QoL. This rapid review can be used to identify currently available and validated canine QoL instruments, and to assess the validity and quality of new or existing instruments.