A scoping review of hormonal clinical trials in menstrual cycle-related brain disorders: Studies in premenstrual mood disorder, menstrual migraine, and catamenial epilepsy.

Cyclic variations in hormones during the normal menstrual cycle underlie multiple central nervous system (CNS)-linked disorders, including premenstrual mood disorder (PMD), menstrual migraine (MM), and catamenial epilepsy (CE). Despite this foundational mechanistic link, these three fields operate independently of each other. In this scoping review (N = 85 studies), we survey existing human research studies in PMD, MM, and CE to outline the exogenous experimental hormone manipulation trials conducted in these fields. We examine a broad range of literature across these disorders in order to summarize existing diagnostic practices and research methods, highlight gaps in the experimental human literature, and elucidate future research opportunities within each field. While no individual treatment or study design can fit every disease, there is immense overlap in study design and established neuroendocrine-based hormone sensitivity among the menstrual cycle-related disorders PMD, MM, and CE. SCOPING REVIEW STRUCTURED SUMMARY: Background. The menstrual cycle can be a biological trigger of symptoms in certain brain disorders, leading to specific, menstrual cycle-linked phenomena such as premenstrual mood disorders (PMD), menstrual migraine (MM), and catamenial epilepsy (CE). Despite the overlap in chronicity and hormonal provocation, these fields have historically operated independently, without any systematic communication about methods or mechanisms. OBJECTIVE: Online databases were used to identify articles published between 1950 and 2021 that studied hormonal manipulations in reproductive-aged females with either PMD, MM, or CE. We selected N = 85 studies that met the following criteria: 1) included a study population of females with natural menstrual cycles (e.g., not perimenopausal, pregnant, or using hormonal medications that were not the primary study variable); 2) involved an exogenous hormone manipulation; 3) involved a repeated measurement across at least two cycle phases as the primary outcome variable. CHARTING METHODS: After exporting online database query results, authors extracted sample size, clinical diagnosis of sample population, study design, experimental hormone manipulation, cyclical outcome measure, and results from each trial. Charting was completed manually, with two authors reviewing each trial. RESULTS: Exogenous hormone manipulations have been tested as treatment options for PMD (N = 56 trials) more frequently than MM (N = 21) or CE (N = 8). Combined oral contraceptive (COC) trials, specifically those containing drospirenone as the progestin, are a well-studied area with promising results for treating both PMDD and MM. We found no trials of COCs in CE. Many trials test ovulation suppression using gonadotropin-releasing hormone agonists (GnRHa), and a meta-analysis supports their efficacy in PMD; GnRHa have been tested in two MM-related trials, and one CE open-label case series. Finally, we found that non-contraceptive hormone manipulations, including but not limited to short-term transdermal estradiol, progesterone supplementation, and progesterone antagonism, have been used across all three disorders. CONCLUSIONS: Research in PMD, MM, and CE commonly have overlapping study design and research methods, and similar effects of some interventions suggest the possibility of overlapping mechanisms contributing to their cyclical symptom presentation. Our scoping review is the first to summarize existing clinical trials in these three brain disorders, specifically focusing on hormonal treatment trials. We find that PMD has a stronger body of literature for ovulation-suppressing COC and GnRHa trials; the field of MM consists of extensive estrogen-based studies; and current consensus in CE focuses on progesterone supplementation during the luteal phase, with limited estrogen manipulations due to concerns about seizure provocation. We argue that researchers in any of these respective disciplines would benefit from greater communication regarding methods for assessment, diagnosis, subtyping, and experimental manipulation. With this scoping review, we hope to increase collaboration and communication among researchers to ultimately improve diagnosis and treatment for menstrual-cycle-linked brain disorders.

Implementation of PSMA PET/CT and alignment of ordering to SNMMI appropriate use criteria in a large network system.

INTRODUCTION: The Society of Nuclear Medicine and Molecular Imaging (SNMMI) provides appropriate use criteria (AUC) for prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) which include guidance on imaging in newly diagnosed prostate cancer and in patients with biochemically recurrent (BCR) disease. This study aims to examine trends in PSMA implementation and the prevalence and outcomes of scans ordered in scenarios deemed rarely appropriate or not meeting SNMMI AUC. METHODS: We retrospectively identified patients who were diagnosed with presumptive National Comprehensive Cancer Network unfavorable intermediate, high, or very high risk prostate cancer, patients who underwent staging for BCR, and all patients staged with PSMA between July 2021 and March 2023. Positivity was validated by adherence to a predetermined reference standard. RESULTS: The frequency of PSMA use increased in initial staging from 24% to 80% and work-up of BCR from 91% to 99% over our study period. In addition, 5% (17/340) of PSMA scans ordered for initial staging did not meet AUC and 3% (15/557) of posttreatment scans were deemed rarely appropriate. Initial staging orders not meeting SNMMI AUC resulted in no positivity (0/17), while rarely appropriate posttreatment scans were falsely positive in 75% (3/4) of cases. Urologists (53%, 17/32) comprised the largest ordering specialty in rarely appropriate use. CONCLUSION: The frequency of PSMA use rose across the study period. A significant minority of patients received PSMA PET/CT in rarely appropriate scenarios yielding no positivity in initial staging and significant false positivity post-therapy. Further education of providers and electronic medical record-based interventions could help limit the rarely appropriate use of PET imaging.

Subsecond Codetection of Dopamine and Estradiol at a Modified Sharkfin Waveform.

17ß-Estradiol (E2) is a ubiquitously expressed hormone that is active in a wide range of neuroprotective and regenerative roles throughout the brain. In particular, it is a well-known dopamine (DA) regulator and is responsible for modulating the expression of dopaminergic receptors and transporters. Recent studies point to E2 release occurring on a rapid time scale and having impacts on DA activity within seconds to minutes. As such, tools capable of monitoring the release of both E2 and DA in real time are essential for developing an accurate understanding of their interactive roles in neurotransmission and regulation. Currently, no analytical techniques capable of codetection of both analytes with high sensitivity, spatiotemporal resolution, extended monitoring, and minimal tissue damage exist. We describe a modified waveform using fast-scan cyclic voltammetry that is capable of low nanomolar detection of both DA and E2 on a subsecond time scale. Both analytes have limits of detection at or below 30 nM and high sensitivity: 11.31 ± 0.55 nA/µM for DA and 9.47 ± 0.36 nA/µM for E2. The waveform is validated in a tissue matrix, confirming its viability for measurement in a biologically relevant setting. This is the first method capable of codetection of fluctuations in DA and E2 with the temporal, spatial, and sensitivity requirements necessary for studying real-time neurochemical signaling.

Tissue Contamination Challenges the Credibility of Machine Learning Models in Real World Digital Pathology.

Machine learning (ML) models are poised to transform surgical pathology practice. The most successful use attention mechanisms to examine whole slides, identify which areas of tissue are diagnostic, and use them to guide diagnosis. Tissue contaminants, such as floaters, represent unexpected tissue. Although human pathologists are extensively trained to consider and detect tissue contaminants, we examined their impact on ML models. We trained 4 whole-slide models. Three operate in placenta for the following functions: (1) detection of decidual arteriopathy, (2) estimation of gestational age, and (3) classification of macroscopic placental lesions. We also developed a model to detect prostate cancer in needle biopsies. We designed experiments wherein patches of contaminant tissue are randomly sampled from known slides and digitally added to patient slides and measured model performance. We measured the proportion of attention given to contaminants and examined the impact of contaminants in the t-distributed stochastic neighbor embedding feature space. Every model showed performance degradation in response to one or more tissue contaminants. Decidual arteriopathy detection--balanced accuracy decreased from 0.74 to 0.69 ± 0.01 with addition of 1 patch of prostate tissue for every 100 patches of placenta (1% contaminant). Bladder, added at 10% contaminant, raised the mean absolute error in estimating gestational age from 1.626 weeks to 2.371 ± 0.003 weeks. Blood, incorporated into placental sections, induced false-negative diagnoses of intervillous thrombi. Addition of bladder to prostate cancer needle biopsies induced false positives, a selection of high-attention patches, representing 0.033 mm2, and resulted in a 97% false-positive rate when added to needle biopsies. Contaminant patches received attention at or above the rate of the average patch of patient tissue. Tissue contaminants induce errors in modern ML models. The high level of attention given to contaminants indicates a failure to encode biological phenomena. Practitioners should move to quantify and ameliorate this problem.

Surface-Roughened Graphene Oxide Microfibers Enhance Electrochemical Reversibility.

Here, we provide an optimized method for fabricating surface-roughened graphene oxide disk microelectrodes (GFMEs) with enhanced defect density to generate a more suitable electrode surface for dopamine detection with fast-scan cyclic voltammetry (FSCV). FSCV detection, which is often influenced by adsorption-based surface interactions, is commonly impacted by the chemical and geometric structure of the electrode's surface, and graphene oxide is a tunable carbon-based nanomaterial capable of enhancing these two key characteristics. Synthesized GFMEs possess exquisite electronic and mechanical properties. We have optimized an applied inert argon (Ar) plasma treatment to increase defect density, with minimal changes in chemical functionality, for enhanced surface crevices to momentarily trap dopamine during detection. Optimal Ar plasma treatment (100 sccm, 60 s, 100 W) generates crevice depths of 33.4 ± 2.3 nm with high edge plane character enhancing dopamine interfacial interactions. Increases in GFME surface roughness improve electron transfer rates and limit diffusional rates out of the crevices to create nearly reversible dopamine electrochemical redox interactions. The utility of surface-roughened disk GFMEs provides comparable detection sensitivities to traditional cylindrical carbon fiber microelectrodes while improving temporal resolution ten-fold with amplified oxidation current due to dopamine cyclization. Overall, surface-roughened GFMEs enable improved adsorption interactions, momentary trapping, and current amplification, expanding the utility of GO microelectrodes for FSCV detection.

Evaluating relugolix for the treatment of prostate cancer in real-world settings of care: the OPTYX study protocol.

OPTYX is a multi-center, prospective, observational study designed to further understand the actual experience of patients with advanced prostate cancer treated with relugolix (ORGOVYX®), an oral androgen deprivation therapy (ADT), by collecting clinical and patient-reported outcomes from routine care settings. The study aims to enroll 1000 consented patients with advanced prostate cancer from community, academic and government operated clinical practices across the USA. At planned timepoints, real-world data analysis on treatment patterns, adherence and safety as well as health outcomes and health-related quality-of-life (HRQOL) after treatment discontinuation will be published in scientific peer-reviewed journals and presented at relevant conferences. This study will provide real-world data for practitioners and researchers in their understanding of the safety and effectiveness of relugolix. Clinical Trial Registration: NCT05467176 (ClinicalTrials.gov).

What is this summary about? This is a protocol summary for a research study named OPTYX. Who can participate in this research? Men 18 or older with advanced prostate cancer initiating treatment with relugolix, an oral androgen deprivation therapy (ADT), at the time of enrollment or within the 1 month before enrollment (remaining on treatment at enrollment) and are willing and able to complete patient assessments during the study. What institutions are performing this research? Community practices, academic institutions and Veterans Health Administration facilities across the USA. What are the research assessments to obtain the results? Data will be collected from the routine medical visits twice yearly including patient demographics, medical history (co-morbidities and cardiac risk factors), prostate cancer history and treatments and test results (routine lab testosterone, PSA levels and imaging). Relugolix response and all serious adverse events (SAEs) and any nonserious adverse events (AE) leading to relugolix treatment discontinuation will be assessed. Patients will be asked to respond to evaluations about their health-related quality of life and adherence to relugolix treatment. How long would the study last? Up to 5 years from enrollment date and/or up to 2 years after relugolix discontinuation. Follow-up will end with consent withdrawal, loss to follow-up, death, or study termination, whichever comes first. What do the results of the study mean? Real-world understanding of the experience and clinical outcomes in patients with advanced prostate cancer in routine clinical care and their clinical trajectory following cessation of relugolix therapy.

Measuring neuron-regulated immune cell physiology via the alpha-2 adrenergic receptor in an ex vivo murine spleen model.

The communication between the nervous and immune systems plays a crucial role in regulating immune cell function and inflammatory responses. Sympathetic neurons, which innervate the spleen, have been implicated in modulating immune cell activity. The neurotransmitter norepinephrine (NE), released by sympathetic neurons, influences immune cell responses by binding to adrenergic receptors on their surface. The alpha-2 adrenergic receptor (α2AR), expressed predominantly on sympathetic neurons, has received attention due to its autoreceptor function and ability to modulate NE release. In this study, we used fast-scan cyclic voltammetry (FSCV) to provide the first subsecond measurements of NE released in the white pulp region of the spleen and validated it with yohimbine, a known antagonist of α2AR. For further application of FSCV in neuroimmunology, we investigated the extent to which subsecond NE from sympathetic neurons is important for immune cell physiology and cytokine production, focusing on tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), and interleukin-6 (IL-6). Our findings provide insights into the regulatory mechanisms underlying sympathetic-immune interactions and show the significance of using FSCV, a traditional neurochemistry technique, to study these neuroimmune mechanisms.

Utilization of genetic testing in men with advanced prostate cancer.

BACKGROUND: Genetic evaluation of men with advanced prostate cancer is recognized as imperative both to guide treatment decisions and to trigger cascade genetic testing of family members. Here we investigate utilization patterns of genetic testing among a contemporary cohort of men with advanced prostate cancer at our institution. METHODS: We queried the Northwestern Electronic Data Warehouse from January 2021 to present for all men diagnosed with National Comprehensive Cancer Network high-risk/very high-risk, regional, or metastatic prostate cancer. Patients were excluded from analyses if treated at an outside institution and/or presented for a second opinion evaluation. Statistics were performed using t-test, Chi-squared test, and univariable and multivariable logistic regression with significance defined as p < 0.05. RESULTS: Atotal of 320 men (52.5%) had local/regional disease and 290 (47.5%) had metastatic disease, 53 (18.3%) of whom had castrate resistant prostate cancer. Rates of germline genetic testing rate were low in patients with localized disease (9.4%) and metastatic disease (34.1%). Only 19 (35.8%) men diagnosed with metastatic castrate resistant prostate cancer underwent germline genetic evaluation. Germline testing was most frequently discussed or ordered by medical oncologists (52%) followed by urologists (20%). Men who underwent germline testing were younger (p < 0.001), more likely to have Medicaid or private insurance (p = 0.002), and more likely to have metastatic disease (p < 0.001). There were no statistically significant differences in baseline PSA, ethnicity, race, or castration sensitivity status. Age (odds ratio [OR]: 0.94, 95% confidence interval [CI]: 0.91-0.97, p < 0.001) and metastatic disease (OR: 5.71, 95% CI: 3.63-9.22, p < 0.001) were significant independent predictors of genetic testing on multivariable logistic regression. CONCLUSIONS: Here we report that utilization of genetic testing is associated with metastatic disease and inversely associated with age. Overall, utilization rates of genetic testing remain low in all patient groups, including in the metastatic castrate resistant setting, where genetic testing can identify patients with homologous recombination repair deficiency who may benefit from use of targeted therapeutics such as PARP inhibitors. Genetic testing in men with aggressive prostate cancer is critical and barriers to routine implementation of testing require further study to develop strategies to improve utilization rates.

Risk Stratification of Low-risk Prostate Cancer: Individualizing Care in the Era of Active Surveillance.

PURPOSE: While active surveillance is the preferred management for most men with low-risk prostate cancer, a subset may harbor more aggressive disease. In this review we examine the evidence underlying an accurate and nuanced assessment of oncologic risk in these men. MATERIALS AND METHODS: We performed a nonsystematic literature review current to January 2023 on PubMed for articles relating to clinical, pathological, molecular, and imaging-based modalities available for risk assessment in men with low-risk prostate cancer. Relevant articles were reviewed by the authors and evidence was summarized. RESULTS: Many tools are available to personalize clinical decision-making for men with low-risk prostate cancer. Total volume of cancer, PSA density, and presence of ductal components have been consistently and strongly associated with current or future evidence of higher-grade disease. PSA kinetics, Prostate Imaging Reporting & Data System 4/5 lesions on MRI, perineural invasion, germline mutations, and genomic classifiers all appear to be associated with an increased risk, although are not as extensively validated. Race, percent free PSA, and other serum biomarkers such as Prostate Health Index and 4Kscore do not appear to be associated with long-term elevated risk. CONCLUSIONS: Long-term prognosis for men diagnosed with low-risk prostate cancer is excellent. There are many factors which should be routinely integrated into the initial management decision as well as determining intensity and frequency of active surveillance. Development of comprehensive multivariable instruments to guide clinical decisions is encouraged.

Association of B7-H3 expression with racial ancestry, immune cell density, and androgen receptor activation in prostate cancer.

BACKGROUND: B7 homolog 3 (B7-H3) is an immunomodulatory molecule that is highly expressed in prostate cancer (PCa) and belongs to the B7 superfamily, which includes PD-L1. Immunotherapies (antibodies, antibody-drug conjugates, and chimeric antigen receptor T cells) targeting B7-H3 are currently in clinical trials; therefore, elucidating the molecular and immune microenvironment correlates of B7-H3 expression may help to guide trial design and interpretation. The authors tested the interconnected hypotheses that B7-H3 expression is associated with genetic racial ancestry, immune cell composition, and androgen receptor signaling in PCa. METHODS: An automated, clinical-grade immunohistochemistry assay was developed by to digitally quantify B7-H3 protein expression across 2 racially diverse cohorts of primary PCa (1 with previously reported transcriptomic data) and pretreatment and posttreatment PCa tissues from a trial of intensive neoadjuvant hormonal therapy. RESULTS: B7-H3 protein expression was significantly lower in self-identified Black patients and was inversely correlated with the percentage African ancestry. This association with race was independent of the significant association of B7-H3 protein expression with ERG/ETS and PTEN status. B7-H3 messenger RNA expression, but not B7-H3 protein expression, was significantly correlated with regulatory (FOXP3-positive) T-cell density. Finally, androgen receptor activity scores were significantly correlated with B7-H3 messenger RNA expression, and neoadjuvant intensive hormonal therapy was associated with a significant decrease in B7-H3 protein expression. CONCLUSIONS: The current data underscore the importance of studying racially and molecularly diverse PCa cohorts in the immunotherapy era. This study is among the first to use genetic ancestry markers to add to the emerging evidence that PCa in men of African ancestry may have a distinct biology associated with B7-H3 expression. LAY SUMMARY: B7-H3 is an immunomodulatory molecule that is highly expressed in prostate cancer and is under investigation in clinical trials. The authors determined that B7-H3 protein expression is inversely correlated with an individual's proportion of African ancestry. The results demonstrate that B7-H3 messenger RNA expression is correlated with the density of tumor T-regulatory cells. Finally, in the first paired analysis of B7-H3 protein expression before and after neoadjuvant intensive hormone therapy, the authors determined that hormone therapy is associated with a decrease in B7-H3 protein levels, suggesting that androgen signaling may positively regulate B7-H3 expression. These results may help to guide the design of future clinical trials and to develop biomarkers of response in such trials.

Graphene-Fiber Microelectrodes for Ultrasensitive Neurochemical Detection.

Here, we have synthesized and characterized graphene-fiber microelectrodes (GFME's) for subsecond detection of neurochemicals with fast-scan cyclic voltammetry (FSCV) for the first time. GFME's exhibited extraordinary properties including faster electron transfer kinetics, significantly improved sensitivity, and ease of tunability that we anticipate will have major impacts on neurochemical detection for years to come. GF's have been used in the literature for various applications; however, scaling their size down to microelectrodes and implementing them as neurochemical microsensors is significantly less developed. The GF's developed in this paper were on average 20-30 µm in diameter and both graphene oxide (GO) and reduced graphene oxide (rGO) fibers were characterized with FSCV. Neat GF's were synthesized using a one-step dimension-confined hydrothermal strategy. FSCV detection has traditionally used carbon-fiber microelectrodes (CFME's) and more recently carbon nanotube fiber electrodes; however, uniform functionalization and direct control of the 3D surface structure of these materials remain limited. The expansion to GFME's will certainly open new avenues for fine-tuning the electrode surface for specific electrochemical detection. When comparing to traditional CFME's, our GFME's exhibited significant increases in electron transfer, redox cycling, fouling resistance, higher sensitivity, and frequency independent behavior which demonstrates their incredible utility as biological sensors.

Nanostructured carbon-fiber surfaces for improved neurochemical detection.

Fundamental insight into the extent to which the nanostructured surface and geometry impacts neurochemical interactions at electrode surfaces could provide significant advances in our ability to design and fabricate ultrasensitive neurochemical detection probes. Here, we investigate the extent to which the nanostructure of the carbon-fiber surface impacts detection of catecholamines and purines with fast-scan cyclic voltammetry (FSCV). Carbon-fibers were treated with argon (Ar) plasma to induce variations in the nano- and micro-structure without changing the functionalization of the surface. We tested variations in topology by measuring the extent to which the flow rate, RF power, and treatment time affect the surface roughness. Flow rates from 50-100 sccm, plasma power from 20-100 W, and treatment times from 30 s to 5 min were compared. Two Ar-treatments were chosen from the optimization studies for comparison, and the surface roughness was evaluated using atomic force microscopy (AFM). To ensure no changes in chemical composition, fibers were analyzed with X-ray photoelectron spectroscopy (XPS). On average, at the optimized Ar-plasma treatment procedure, oxidative current for adenosine and ATP increased by 3.5 ± 1.4-fold and 3.2 ± 0.6-fold, and guanosine and GTP by 1.7 ± 0.3-fold and 1.8 ± 0.3-fold, respectively (n = 9). Dopamine increased by 1.7 ± 0.3-fold. The extent to which changes in the electrode structure impact adsorption, sensitivity, and electron transfer rates were measured. A COMSOL Multiphysics simulation was developed to enable the modeling of mass transport of electroactive species at varying electrode geometries. Overall, this study provides critical insight into the extent to which the nanostructure of the surface impacts the electrochemical detection of neurochemicals.

Changes in retail sales of tobacco products in Ontario after a menthol sales restriction.

BACKGROUND: Ontario, Canada prohibited menthol tobacco product sales beginning 1 January 2017. We measured retail sales of menthol cigarettes and possible substitute products before and after policy implementation in Ontario. METHODS: We licensed retail scanner data for tobacco product sales in Ontario and British Columbia (BC), a comparison province without a menthol tobacco policy at that time. We assessed changes in per capita unit sales (per 1000 people) from pre-policy (January-June 2016) to post-policy (January-June 2017) periods. Classification of cigarettes as menthol or non-menthol, or having menthol-suggestive descriptors ('green', 'blue', 'silver' and 'fresh'), was based on scanner data. RESULTS: Ontario menthol cigarette sales decreased 93%, from 596 to 40 packs per capita compared with a 2% decrease (696 to 679 packs per capita) in BC. Menthol capsule cigarette sales remained low in Ontario (<1% of total cigarette sales) but rose sixfold in BC. Although cigar sales data were unavailable, substitution appeared minimal; sales of non-menthol cigarettes increased 0.4% in Ontario (11 470 to 11 519 packs per capita) while vaping product sales decreased. Ontario had a larger increase in sales of cigarettes with menthol-suggestive descriptors (11% increase) than BC (3% increase). In Ontario, nearly all (>99%) pre-policy sales of cigarettes with 'green' menthol-suggestive descriptors were menthol cigarettes, but post-policy, 94% of 'green' cigarettes sold were non-menthol. CONCLUSIONS: Ontario's menthol policy was associated with a decrease in retail sales of cigarettes classified as menthol, with little evidence of product substitution. Understanding changes in sales of cigarettes with menthol-suggestive descriptors would be informative.

Expanding local sales restrictions on flavoured tobacco products to include menthol: retail sales changes in two Minnesota cities.

BACKGROUND: In 2018, Minneapolis and St. Paul, Minnesota, expanded existing local sales restrictions on flavoured (non-menthol/mint/wintergreen) tobacco products ('flavour policies') to include menthol/mint/wintergreen-flavoured tobacco products ('menthol policies'). All policies included exemptions for certain store types. METHODS: We obtained weekly retail tobacco product sales for 2015 through 2019 from NielsenIQ for convenience stores and other outlets in the policy jurisdictions and two comparison areas (rest of the state of Minnesota and total USA). We standardised unit sales across product categories and used NielsenIQ-provided descriptors to classify products as menthol (including mint/wintergreen) or flavoured (non-menthol/non-tobacco). Using single group interrupted time series models, we analysed unit sales by product category and by flavour separately for each geography to assess associations between menthol policy implementation and trends in tobacco product unit sales. RESULTS: Following menthol policy implementation, unit sales of menthol cigarettes and menthol smokeless tobacco decreased in both cities, with smaller decreases in comparison areas. Flavoured cigar sales-which decreased following the flavour policies-further decreased after the menthol policies, while sales of menthol electronic nicotine delivery systems (ENDS) increased in both cities and sales of flavoured ENDS increased in St. Paul. CONCLUSION: Expanding flavour policies to include menthol/mint/wintergreen was associated with significant decreases in unit sales of most menthol products and in total unit sales by tobacco product category. Increases in menthol and flavoured ENDS sales in these cities may be associated with legal sales by exempted retailers and/or illicit sales by non-compliant retailers, highlighting opportunities for retailer education and enforcement.

Platinum Nanoparticle Size and Density Impacts Purine Electrochemistry with Fast-Scan Cyclic Voltammetry.

We demonstrate the density and shape of platinum nanoparticles (PtNP) on carbon-fiber microelectrodes with fast-scan cyclic voltammetry (FSCV) directly impacts detection of adenosine. Previously, we showed that metal nanoparticle-modified carbon significantly improves adenine-based purine detection; however, how the size and shape of the particles impact electrochemical detection was not investigated. Electrochemical investigations of how the surface topology and morphology impacts detection is necessary for designing ultrasensitive electrodes and for expanding fundamental knowledge of electrode-analyte interactions. To change the density and shape of the PtNP's on the surface, we varied the concentration of K2PtCl6 and electrodeposition time. We show that increasing the concentration of K2PtCl6 increases the density of PtNP's while increasing the electrodeposition time impacts both the density and size. These changes manipulate the adsorption behavior which impacts sensitivity. Based on these results, an optimal electrodeposition procedure was determined to be 1.0 mg/mL of K2PtCl6 deposited for 45 s and this results in an average increase in adenosine detection by 3.5 ±0.3-fold. Interestingly, increasing the size and density of PtNPs negatively impacts dopamine detection. Overall, this work provides fundamental insights into the differences between adenosine and dopamine interaction at electrode surfaces.

Multi-scalar and multi-dimensional conceptions of social capital and mental health impacts after disaster: the case of Hurricane Harvey.

While much research investigates how social capital relates to mental health after disasters, less work employs a multi-scalar, multi-dimensional social capital framework. This study applies such a construct to an analysis of novel survey data of approximately 1,000 rural and urban Texans after Hurricane Harvey struck the United States in August 2017. On the individual level, it finds that greater social support is linked to fewer mental health impacts, but that greater civic and organisational engagement is connected to greater mental health impacts. At the community level, it finds that neither a density of bridging social capital organisations nor of bonding social capital organisations is associated with poorer mental health, although a greater number of bonding organisations is related to negative mental health impacts on rural residents. The paper concludes by focusing on how individual and community social capital relationships with mental health are contingent on measurement, scale, and rural or urban location.

Daily acute intermittent hypoxia enhances phrenic motor output and stimulus-evoked phrenic responses in rats.

Plasticity is a hallmark of the respiratory neural control system. Phrenic long-term facilitation (pLTF) is one form of respiratory plasticity characterized by persistent increases in phrenic nerve activity following acute intermittent hypoxia (AIH). Although there is evidence that key steps in the cellular pathway giving rise to pLTF are localized within phrenic motor neurons (PMNs), the impact of AIH on the strength of breathing-related synaptic inputs to PMNs remains unclear. Furthermore, the functional impact of AIH is enhanced by repeated/daily exposure to AIH (dAIH). Here, we explored the effects of AIH versus 2 wk of dAIH preconditioning on spontaneous and evoked phrenic responses in anesthetized, paralyzed, and mechanically ventilated rats. Evoked phrenic potentials were elicited by respiratory cycle-triggered lateral funiculus stimulation at the C2 spinal level delivered before and 60 min post-AIH (or the equivalent in time controls). Charge-balanced biphasic pulses (100 µs/phase) of progressively increasing intensity (100-700 µA) were delivered during the inspiratory and expiratory phases of the respiratory cycle. Although robust pLTF (∼60% from baseline) was observed after a single exposure to moderate AIH (3 × 5 min; 5-min intervals), there was no effect on evoked phrenic responses, contrary to our initial hypothesis. However, in rats preconditioned with dAIH, baseline phrenic nerve activity and evoked responses were increased, suggesting that repeated exposure to AIH enhances functional synaptic strength when assessed using this technique. The impact of daily AIH preconditioning on synaptic inputs to PMNs raises interesting questions that require further exploration.NEW & NOTEWORTHY Two weeks of daily acute intermittent hypoxia (dAIH) preconditioning enhanced stimulus-evoked phrenic responses to lateral funiculus stimulation (targeting respiratory bulbospinal projection to phrenic motor neurons). Furthermore, dAIH preconditioning enhanced baseline phrenic motor output responses to maximal chemoreflex activation in intact rats.

Oncologic outcomes among Black and White men with grade group 4 or 5 (Gleason score 8-10) prostate cancer treated primarily by radical prostatectomy.

BACKGROUND: The aim of this study was to describe pathologic and short-term oncologic outcomes among Black and White men with grade group 4 or 5 prostate cancer managed primarily by radical prostatectomy. METHODS: This was a multi-institutional, observational study (2005-2015) evaluating radical prostatectomy outcomes by self-identified race. Descriptive analysis was performed via nonparametric statistical testing to compare baseline clinicopathologic data. Univariable and multivariable time-to-event analyses were performed to assess biochemical recurrence (BCR), metastasis, cancer-specific mortality (CSM), and overall survival between Black and White men. RESULTS: In total, 1662 men were identified with grade group 4 or 5 prostate cancer initially managed by radical prostatectomy. Black men represented 11.3% of the cohort (n = 188). Black men were younger, demonstrated a longer time from diagnosis to surgery, and were at a lower clinical stage (all P < .05). Black men had lower rates of pT3/4 disease (49.5% vs 63.5%; P < .05) but higher rates of positive surgical margins (31.6% vs 26.5%; P = .14) on pathologic evaluation. There was no difference in BCR, CSM, or overall survival over a median follow-up of 40.7 months. Black men had a lower 5-year cumulative incidence of metastasis-free survival (93.6%; 95% confidence interval [CI], 86.5%-97.0%) in comparison with White men (85.8%; 95% CI, 83.1%-88.0%), which did not persist in an age-adjusted analysis. CONCLUSIONS: Black and White men with high-grade prostate cancer at diagnosis demonstrated similar oncologic outcomes when they were managed by primary radical prostatectomy. Our findings suggest that racial disparities in prostate cancer mortality are not related to differences in the efficacy of extirpative therapy.

Extended sawhorse waveform for stable zinc detection with fast-scan cyclic voltammetry.

Zinc (Zn(II)) is a divalent cation involved in regulating intracellular signal transduction and gene expression through transcription factor activity, and can act as a metal neurotransmitter by modulating synaptic activity and neuronal plasticity. Previous research has demonstrated spatial heterogeneity of Zn(II) in the brain, has estimated extracellular concentrations of Zn(II) across various brain regions, and has measured rapid intracellular changes in Zn(II) concentration during glutamate flux. Despite this work, quantification of rapid extracellular Zn(II) release from neurons, on a millisecond time scale, in real time has remained difficult with existing technologies. Here, we have developed an electrochemical waveform, called the "extended sawhorse waveform (ESW)," for fast-scan cyclic voltammetry detection at carbon-fiber microelectrodes which enabled rapid and stable Zn(II) monitoring over time. This waveform was developed to overcome existing challenges in monitoring metallotransmitters stably over time electrochemically by introducing a brief cleaning step to facilitate rapid cleaning of the electrode surface in between scans. The ESW scans from 0.5 V down to -1.0 V, up to 1.45 V for 3 ms (cleaning step), and back to 0.5 V at a scan rate of 400 V/s. Repeated introductions of Zn(II) at the electrode using a traditional waveform cause plating which ultimately deteriorates the sensitivity over time; however, using the ESW, significant improvements in stability were observed. Overall, we provide a unique approach to monitor and quantitate rapid Zn(II) signaling in the brain at carbon electrodes which will impact our ability to advance fundamental knowledge of Zn(II) involvement in extracellular signaling pathways in the brain.

Comprehensive skin microbiome analysis reveals the uniqueness of human skin and evidence for phylosymbiosis within the class Mammalia.

Skin is the largest organ of the body and represents the primary physical barrier between mammals and their external environment, yet the factors that govern skin microbial community composition among mammals are poorly understood. The objective of this research was to generate a skin microbiota baseline for members of the class Mammalia, testing the effects of host species, geographic location, body region, and biological sex. Skin from the back, torso, and inner thighs of 177 nonhuman mammals was sampled, representing individuals from 38 species and 10 mammalian orders. Animals were sampled from farms, zoos, households, and the wild. The DNA extracts from all skin swabs were amplified by PCR and sequenced, targeting the V3-V4 regions of bacterial and archaeal 16S rRNA genes. Previously published skin microbiome data from 20 human participants, sampled and sequenced using an identical protocol to the nonhuman mammals, were included to make this a comprehensive analysis. Human skin microbial communities were distinct and significantly less diverse than all other sampled mammalian orders. The factor most strongly associated with microbial community data for all samples was whether the host was a human. Within nonhuman samples, host taxonomic order was the most significant factor influencing skin microbiota, followed by the geographic location of the habitat. By comparing the congruence between host phylogeny and microbial community dendrograms, we observed that Artiodactyla (even-toed ungulates) and Perissodactyla (odd-toed ungulates) had significant congruence, providing evidence of phylosymbiosis between skin microbial communities and their hosts.