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Introduction: This qualitative research study was conducted to develop a novel, comprehensive, patient-reported outcome measure (PRO), the "Symptoms and Impacts of Androgen Deprivation Therapy (ADT) for Prostate Cancer" (SIADT-PC), assessing hormonal therapy-related symptoms and their impacts on men with advanced prostate cancer., Methods: Concept elicitation (CE) interviews were conducted among adult men with prostate cancer to evaluate their experiences with ADT. Based on key symptom and impact concepts mentioned, an initial PRO measure was developed. The draft measure was further assessed in cognitive debriefing (CD) interviews with men with prostate cancer, in which participants reviewed items, response options, and recall periods. Initial item-based psychometric analyses were conducted using interview data. The draft questionnaire was revised on the basis of participant feedback, quantitative psychometric results, and consultation with clinical experts., Results: A total of 21 participants were interviewed (CE concept elicitation, n = 12; CD cognitive debriefing, n = 17; n = 8 completed both). Mean participant age (SD) was 59.7 (8.7) years and 76.2% were white. The de novo SIADT-PC measure consists of 27 items: 11 symptoms (e.g., fatigue, hot flashes, and erectile dysfunction), 2 long-term symptoms (e.g., weight gain), 10 impacts (e.g., impacts on physical activities and relationships), and 4 related to mode of administration (i.e., injection-site reactions). Items were assessed with a 5-point verbal rating scale, with answer choices that capture frequency or severity., Conclusions: Once fully validated, this de novo measure may be used in clinical studies and clinical practice to assess hormone therapy-related symptoms and impacts, enabling physicians to identify timely and appropriate interventions., (© 2024. The Author(s).)

Background: In the HERO study, relugolix demonstrated sustained testosterone suppression superior to that of leuprolide acetate (97% vs 89%; difference 7.9% [95% confidence interval, 4.1-12%; p < 0.001])., Objective: To analyze testosterone recovery in a prespecified subset of men from the HERO study not indicated to continue androgen deprivation therapy., Design, Setting, and Participants: Men (N = 934) were randomized (2:1) to receive relugolix 120 mg orally daily or leuprolide acetate injections every 12 wk for 48 wk., Outcome Measurements and Statistical Analysis: Testosterone recovery was assessed in 184 men who completed 48 wk of treatment. During the 90-d recovery period, assessments included time to testosterone recovery (>280 ng/dl; ≥80% of baseline testosterone), serum levels of prostate-specific antigen and pituitary hormones, and adverse events., Results and Limitations: The cumulative incidence rate of testosterone recovery to >280 ng/dl at 90 d following drug discontinuation was significantly higher in the relugolix cohort (n = 137) than in the leuprolide acetate cohort (n = 47; 54% vs 3.2%; nominal p = 0.002). The median time to testosterone recovery was faster following relugolix treatment than with leuprolide acetate treatment (86.0 d vs 112.0 d). Compared with leuprolide acetate, more men treated with relugolix achieved ≥80% of baseline testosterone levels (39% vs 2.1%). Men ≤65 yr and those with baseline testosterone greater than the median had a higher incident rate of testosterone recovery. Adverse events were generally similar between treatment groups. One limitation is the short testosterone recovery follow-up period., Conclusions: Oral relugolix had faster and more complete recovery of testosterone to normal levels after treatment discontinuation than leuprolide acetate in a subset of men from the HERO study. The clinical implications of a faster testosterone recovery with relugolix may be significant for men being treated with androgen deprivation therapy and influence treatment decisions., Patient Summary: The male hormone testosterone is reduced during androgen deprivation therapy for prostate cancer. Reduced testosterone levels cause side effects, impacting patient quality of life. When treatment is stopped, the side effects lessen over time as the levels of testosterone come back to pretreatment range (testosterone recovery). In this study, we found that the time to testosterone recovery was faster with relugolix than with leuprolide acetate., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objectives: Scrupulosity, despite its considerable prevalence and morbidity, remains under-investigated. The present study develops and examines the psychometric properties of a comprehensive assessment tool, the Scrupulosity Inventory (SI)., Methods: The SI, along with other measures of obsessive-compulsive disorder (OCD) and perfectionism, were administered to a sample (N = 150) of college undergraduates similar in size to other scale development studies of related measures. We conducted exploratory and confirmatory factor analyses of the SI, examined its convergent and divergent validity, and assessed its ability to predict categorical diagnoses of scrupulosity using a receiver operator characteristic analysis., Results: We found a well-fitting confirmatory bifactor model (RMSEA = 0.049) with a strong general Scrupulosity factor ( [Formula: see text] ) and specific factors for Personal Violations ( [Formula: see text] ), Ritualized Behavior ( [Formula: see text] ), Interference with Life ( [Formula: see text] ), and Problem Pervasiveness ( [Formula: see text] ). As predicted, we also found the strongest convergence (r = 0.63) between the SI and the Penn Inventory of Scrupulosity (PIOS), intermediate convergence (r = 0.54) between the SI and Perfectionism Inventory (PI), and weaker convergence (r = 0.47) between the SI and YBOCS. Finally, we found that a categorical diagnosis of scrupulosity was highly predicted by the SI (AUC = 0.84), less well-predicted by the PIOS (AUC = 0.75) and less well predicted by the YBOCS (AUC = 0.69)., Limitations: This study was conducted among a sample of undergraduates at a religiously affiliated university., Conclusions: These results suggest utility in using the SI to measure the severity of scrupulosity symptoms and that scrupulosity and OCD may present significantly different clinical features., Competing Interests: Declaration of competing interest All authors report no competing interests and no funding for this project., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Intermittent oil-water wetting can have a significant effect on the internal corrosion of steel pipelines. This paper presents a combined experimental and molecular modeling study of several influential factors on the surface properties and corrosion behavior of mild steel in CO 2 environments. The influence of different model oils (LVT-200 and Aromatic-200) and select surface-active compounds (myristic acid, cyclohexane butyric acid, and oleic acid) on the corrosion behavior of carbon steel during intermittent oil-water wetting was determined by measuring the corrosion rate after intermittent wetting cycles. The interfacial tension measurements were performed to study the incorporation of the oil phase along with surface-active molecules in the protective layer formed on the specimen surface. Results showed that the interfacial tension for an aromatic oil-water interface is lower than that for an aliphatic oil-water interface. To understand this result, molecular dynamics simulations of oil-water interfaces were performed in the presence of surface-active molecules and different oils to analyze the structure of the layer formed at the interface. The simulations supported the hypothesis that aromatic molecules are less structured at the interface, which results in the incorporation of more water molecules into the protective layer formed at the steel surface, causing a higher corrosion rate. On the other hand, the simulations revealed that myristic acid in an aliphatic oil forms a well-aligned structure at the interface, devoid of any water molecules. This is in agreement with the hypothesis that the linear molecular structure of myristic acid favors the alignment of molecules at an aliphatic oil-water interface, resulting in a lower interfacial tension and more effective corrosion mitigation as compared to the other two nonlinear compounds tested. It is concluded that an important factor controlling the corrosion behavior is the molecular structure of the oil-water interface, which is adopted by the steel surface layer through the Langmuir-Blodgett process.

Importance: Combination androgen deprivation therapy (ADT) with radiotherapy is commonly used for patients with localized and advanced prostate cancer., Objective: To assess the efficacy and safety of the oral gonadotropin-releasing hormone antagonist relugolix with radiotherapy for treating prostate cancer., Design, Setting, and Participants: This multicenter post hoc analysis of patients with localized and advanced prostate cancer receiving radiotherapy in 2 randomized clinical trials (a phase 2 trial of relugolix vs degarelix, and a subset of the phase 3 HERO trial of relugolix vs leuprolide acetate) included men who were receiving radiotherapy and short-term (24 weeks) ADT (n = 103) from 2014 to 2015 and men receiving radiotherapy and longer-term (48 weeks) ADT (n = 157) from 2017 to 2019. The data were analyzed in November 2022., Interventions: Patients receiving short-term ADT received relugolix, 120 mg, orally once daily (320-mg loading dose) or degarelix, 80 mg, 4-week depot (240-mg loading dose) for 24 weeks with 12 weeks of follow-up. Patients receiving longer-term ADT received relugolix, 120 mg, orally once daily (360-mg loading dose) or leuprolide acetate injections every 12 weeks for 48 weeks, with up to 90 days of follow-up., Main Outcomes and Measures: Castration rate (testosterone level <50 ng/dL [to convert to nmol/L, multiply by 0.0347) at all scheduled visits between weeks 5 and 25 for patients receiving short-term ADT and weeks 5 and 49 for patients receiving longer-term ADT., Results: Of 260 patients (38 Asian [14.6%], 23 Black or African American [8.8%], 21 Hispanic [8.1%], and 188 White [72.3%] individuals), 164 (63.1%) received relugolix. Relugolix achieved castration rates of 95% (95% CI, 87.1%-99.0%) and 97% (95% CI, 90.6%-99.0%) among patients receiving short-term and longer-term ADT, respectively. Twelve weeks post-short-term relugolix, 34 (52%) achieved testosterone levels to baseline or more than 280 ng/dL. Ninety days post longer-term ADT, mean (SD) testosterone levels were 310.5 (122.4) (106.7) ng/dL (relugolix; n = 15) vs 53.0 ng/dL (leuprolide acetate; n = 8) among the subset assessed for testosterone recovery. Castration resistance-free survival was not statistically different between the relugolix and leuprolide acetate cohorts (hazard ratio, 0.97; 95% CI, 0.35-2.72; P = .62). Adverse events grade 3 or greater for short-term or longer-term relugolix (headache, hypertension, and atrial fibrillation) were uncommon (less than 5%)., Conclusions and Relevance: The results of these 2 randomized clinical trials suggest that relugolix rapidly achieves sustained castration in patients with localized and advanced prostate cancer receiving radiotherapy. No new safety concerns were identified when relugolix was used with radiotherapy.

Introduction: Hospital-acquired infections (HAIs) after stroke are associated with additional morbidity and mortality, but whether HAIs increase long-term cognitive decline in stroke patients is unknown. We hypothesized that older adults with incident stroke with HAI experience faster cognitive decline than those having stroke without HAI and those without stroke., Methods: We performed a longitudinal analysis in the population-based prospective Cardiovascular Health Study. Medicare-eligible participants aged ≥65 years with and without incident stroke had cognition assessed annually. HAIs were assessed by hospital discharge codes. Global cognitive function was assessed annually by the Modified Mini-Mental State Examination (3MSE) and executive function by the Digit Symbol Substitution Test (DSST). We used linear mixed models to estimate the mean decline and 95% confidence intervals (95% CI) for 3MSE and DSST scores by incident stroke and HAI status, adjusted for demographics and vascular risk factors., Results: Among 5,443 participants ≥65 years without previous history of stroke, 393 participants had stroke with HAI (SI), 766 had a stroke only (SO), and 4,284 had no stroke (NS) throughout a maximum 9-year follow-up. For 3MSE, compared with NS participants, SO participants had a similar adjusted mean decline (additional 0.08 points/year, 95% CI: -0.15, 0.31), while SI participants had a more rapid decline (additional 0.28 points/year, 95% CI: 0.16, 0.40). Adjusted mean decline was 0.20 points/year faster (95% CI: -0.05, 0.45) among SI than SO participants. For DSST, compared with NS participants, SO participants had a faster adjusted mean decline (additional 0.17 points/year [95% CI: 0.003, 0.33]), as did SI participants (additional 0.27 points/year [95% CI: 0.19, 0.35])., Conclusion: Stroke, when accompanied by HAI, leads to a faster long-term decline in cognitive ability than in those without stroke. The clinical and public health implications of the effect of infection on post-stroke cognitive decline warrant further attention., (© 2023 S. Karger AG, Basel.)

Introduction: Cardiovascular disease (CVD) is the leading cause of death among prostate cancer (PC) patients. Androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone receptor (GnRH) agonist or antagonist is the standard treatment for advanced PC. Since 2010, the Food and Drug Administration has required labeling for GnRH agonists to include warnings about increased risk for diabetes and some CVDs., Methods: In this observational, retrospective, real-world study, we evaluated time to a first cardiovascular (CV) event within 3 years postinitiation of ADT in PC patients while controlling for CVD history and risk factors. Data from a large administrative US claims dataset (2010-2019) were analyzed using Kaplan-Meier survival analysis to calculate the HR for time to first CV event and Cox regressions to identify factors associated with time to first CV event., Results: Of 10,530 patients, 92% had no history of CVD, 8% had history of CVD, and 95% were exposed to a GnRH agonist during follow-up. Kaplan-Meier analysis indicated that patients with a baseline history of CVD had increased risk of CV events within 3 years of ADT initiation vs those without such history (HR, 3.20; 95% CI, 2.58-3.96; P < .0001). Among covariates associated with higher likelihood of CV event, baseline history of CVD yielded the highest HR (2.83; 95% CI, 2.40-3.32, P < .0001)., Conclusions: PC patients with a history of CVD are at increased risk of a CV event within 3 years of ADT initiation compared with those with no history of CVD.

Background: Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, demonstrated testosterone suppression to castrate levels in men with advanced prostate cancer (PCa) in the HERO study. Since advanced PCa and its treatments can impact patients' daily life, it is imperative to understand the impact of systemic therapy on patient health-related quality of life (HRQOL)., Objective: To report the HRQOL for patients on relugolix compared with those on leuprolide in on-treatment and testosterone recovery periods of the HERO study., Design, Setting, and Participants: A phase 3 randomized controlled study was conducted in 934 patients with advanced PCa., Intervention: Patients underwent 2:1 randomization and received relugolix 120 mg orally once daily or leuprolide 3-mo injections for 48 wk. Testosterone recovery was evaluated in a patient subset., Outcome Measurements and Statistical Analysis: HRQOL evaluations were based on the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC QLQ-C30) and the Prostate Cancer Module (EORTC QLQ-PR25) during treatment and testosterone recovery phases. In a post hoc analysis, predictors of HRQOL deterioration were evaluated., Results and Limitations: No statistically significant differences between the two groups were found in changes from baseline to the end of treatment in either the EORTC QLQ-C30 or the EORTC QLQ-PR25 instrument. During the testosterone recovery phase, hormonal treatment-related symptoms scores were lower for relugolix than for leuprolide, suggesting a lower burden of hormone-related symptoms associated with a treatment that has more rapid testosterone recovery after treatment cessation. Limitations include low patient numbers in the testosterone recovery group., Conclusions: Oral relugolix is a therapeutic option with similar patient-reported HRQOL to leuprolide, providing an oral option for androgen deprivation therapy associated with a more rapid testosterone reduction., Patient Summary: In men with advanced prostate cancer, relugolix had similar health-related quality of life to leuprolide., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Cardiovascular (CV) events are the leading cause of death in prostate cancer. Men with prostate cancer are likely to have CV risk factors and use CV-related concomitant medications. In the phase 3 HERO study, a 54% lower incidence of major adverse cardiac events was reported in men treated with the oral gonadotropin-releasing hormone (GnRH) receptor antagonist, relugolix, vs leuprolide. Herein, we characterize the impact of concomitant CV therapies on efficacy and safety in the HERO study., Methods: In HERO, 930 men with advanced prostate cancer (APC) were randomized 2:1 and treated with relugolix (120 mg orally once daily; after single 360 mg loading dose) or leuprolide (injections every 3 months) for 48 weeks. Subgroups analyzed included men who received antihypertensives, antithrombotics, or lipid-modifying therapies (LMAs), as well as the most common drug classes (> 10%) and single most common agent within each class. Assessments included sustained testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks and safety., Results: Antihypertensives, antithrombotics, and LMAs were utilized by 52.7%, 39.1%, and 39.6% of men in HERO, respectively. In the main subgroups, point estimates for sustained castration rates were generally consistent with overall estimates of relugolix and leuprolide observed in the overall population. Sustained castration rates were also mostly consistent for men taking the most common drug classes and individual agents in each class (losartan [n = 103]: relugolix, 95.4% vs leuprolide, 80.6%; amlodipine [n = 229]: 97.2% vs 85.5%; metoprolol [n = 88]: 95.7% vs 86.9%; acetylsalicylic acid [n = 259]: 97.0% vs 92.1%; clopidogrel [n = 43]: 96.4% vs 86.7%; simvastatin [n = 78]: 98.0% vs 87.3%). Incidence and types of adverse events (AEs) among men who received these medications were mostly consistent with overall population results, with some increases in grade ≥ 3 and fatal AEs., Conclusion: Relugolix suppressed testosterone and was generally well tolerated when given with concomitant CV agents., Trial Registration: Clinical Trial ID NCT03085095., Prior Presentation: Data presented at 15th Annual Genitourinary Cancers Symposium; February 17-19, 2022, San Francisco, CA, USA [Abstract 101, Poster board E11]. The published abstract from this presentation can be found at https://ascopubs.org/doi/10.1200/JCO.2022.40.6&#95;suppl.101 ., (© 2023. The Author(s).)

Background: Relugolix is an oral GnRH receptor antagonist approved for men with advanced prostate cancer. Relugolix treatment has demonstrated an ability to lower testosterone to sustained castration levels in the phase 4 HERO study. Herein, we describe the results of a secondary endpoint of castration resistance-free survival (CRFS) during 48 weeks of treatment and profile patients with castration-resistant prostate cancer (CRPC). Methods: Subjects were 2:1 randomized to either relugolix 120 mg orally once daily (after a single 360 mg loading dose) or 3-monthly injections of leuprolide for 48 weeks. CRFS, defined as the time from the date of first dose to the date of confirmed prostate-specific antigen progression while castrated or death due to any reason was conducted in the metastatic disease population and the overall modified intention-to-treat (mITT) populations. Results: The CRFS analysis (mITT population) included 1074 men (relugolix: n = 717; leuprolide: n = 357) with advanced prostate cancer as well as 434 men (relugolix: n = 290; leuprolide: n = 144) with metastatic prostate cancer. In the metastatic disease populations, CRFS rates were 74.3% (95% CI: 68.6%, 79.2%) and 75.3% (95% CI: 66.7%, 81.9%) in the relugolix and leuprolide groups, respectively (hazard ratio: 1.03 [0.68, 1.57]; p = 0.84) at week 48. Results in the overall mITT population were similar to the metastatic population. No new safety findings were identified. Conclusions: In men with metastatic disease or in the overall population of the HERO study, CRFS assessed during the 48-week treatment with relugolix was not significantly different than standard-of-care leuprolide. Relugolix had similar efficacy for men with/without CRFS progression events.

Opioid use disorder (OUD)-associated overdose deaths have reached epidemic proportions worldwide over the past two decades, with death rates for men reported at twice the rate for women. Using a controlled, cross-sectional, age-matched (18-56 y) design to better understand the cognitive neuroscience of OUD, we evaluated the electroencephalographic (EEG) responses of male and female participants with OUD vs. age- and gender-matched non-OUD controls during a simple visual object recognition Go/No-Go task. Overall, women had significantly slower reaction times (RTs) than men. In addition, EEG N200 and P300 event-related potential (ERP) amplitudes for non-OUD controls were significantly larger for men, while their latencies were significantly shorter than for women. However, while N200 and P300 amplitudes were not significantly affected by OUD for either men or women in this task, latencies were also affected differentially in men vs. women with OUD. Accordingly, for both N200 and P300, male OUD participants exhibited longer latencies while female OUD participants exhibited shorter ones than in non-OUD controls. Additionally, robust oscillations were found in all participants during a feedback message associated with performance in the task. Although alpha and beta power during the feedback message were significantly greater for men than women overall, both alpha and beta oscillations exhibited significantly lower power in all participants with OUD. Taken together, these findings suggest important gender by OUD differences in cognitive processing and reflection of performance in this simple visual task.

Associated with gastritis, peptic-ulcer disease, and gastric carcinoma, Helicobacter pylori (H. pylori) also has been associated with decreased cognitive function and dementia. In this study, we used data from the UK Biobank to further examine associations between H. pylori seropositivity and serointensity and performance on several cognitive tasks in adults 40 to 70 years of age (M = 55.3, SD = 8.1). In these analyses, H. pylori seropositivity (i.e., either positive or negative for H. pylori) and serointensity (concentration of antibodies against H. pylori antigens) in adjusted models were associated with worse function on tasks of Numeric memory, Reasoning, and errors on the Pairs matching test but better function on the Tower rearrangement task. Together, these findings suggest that H. pylori seropositivity and serointensity might be associated with worse cognitive function in this age group., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Erickson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: To characterize the impact of concomitant prostate cancer treatments with the use of relugolix, the oral GnRH receptor antagonist, in advanced prostate cancer, a subgroup and pharmacokinetic/pharmacodynamic analyses of the HERO study was undertaken., Patients and Methods: Overall, 934 patients were randomized 2:1 to receive relugolix 120 mg orally once daily or leuprolide injections every 12 weeks for 48 weeks. In the setting of rising PSA, patients could receive enzalutamide or docetaxel 2 months after study initiation. Assessments included sustained testosterone suppression to castrate levels (<50 ng/dL) through 48 weeks and safety parameters. Subgroups analyzed included patients with or without concomitant enzalutamide or docetaxel. A sensitivity analysis of the primary endpoint was performed excluding patients who received concomitant therapies that may affect testosterone. Pharmacokinetic/pharmacodynamic analyses of 20 participants in the relugolix treatment group assessed the net effect of enzalutamide on exposure to relugolix., Results: Overall, 125 patients (13.4%) took concomitant therapies that could impact testosterone levels. Enzalutamide (n = 23) was the most frequently used therapy in the relugolix (2.7%) and leuprolide groups (1.9%). Docetaxel (n = 13) was used by 1.3% and 1.6% of patients in the relugolix and leuprolide groups, respectively. All other relevant concomitant therapy were used in <1% of population. Sensitivity analysis showed concomitant therapy did not impact the testosterone levels. Castration rates were similar with and without concomitant use of enzalutamide or docetaxel. No clinically relevant differences in adverse events were observed between subgroups in either treatment group. No differences in relugolix C trough or testosterone concentrations were observed, suggesting that any induction or inhibition properties of enzalutamide on relugolix metabolism result in a neutral net effect on relugolix exposure and testosterone suppression., Conclusion: Treatment with relugolix was associated with similar efficacy and safety profiles with and without concomitant enzalutamide or docetaxel. Standard-of-care use of relugolix in combination with these agents is supported by these data., Competing Interests: Disclosure DJG: grants from Acerta Pharmaceuticals, other from American Association for Cancer Research, grants and personal fees from Astellas, personal fees from Astrazeneca, personal fees from Axess Oncology, grants, personal fees and nonfinancial support from Bayer H/C Pharmaceuticals, grants and personal fees from BMS, grants from Calithera, grants and personal fees from Capio Biosciences, personal fees from EMD Serona, grants, personal fees and nonfinancial support from Exelixis, Inc, personal fees from Flatiron, personal fees from Ipsen, grants and personal fees from Janssen Pharmaceuticals, personal fees from Merck, Sharp & Dohme, personal fees from Michael J Hennessey Assoc, personal fees from Millennium Medical Publishing, personal fees from Modra Pharmaceuticals B.V., personal fees from Myovant Sciences, Inc, personal fees from NCI Genitourinary, personal fees from Nektar Therapeutics, grants and personal fees from Novartis, personal fees from Physician Education Resource, grants and personal fees from Pfizer, grants, personal fees and nonfinancial support from Sanofi, personal fees from UroGPO, personal fees and nonfinancial support from UroToday, personal fees from Vizuri Health Sciences, personal fees from Platform Q. FS: Advisory roles for Astellas Pharma, AstraZeneca/ MedImmune, Bayer, Janssen Oncology, and Sanofi; has received honoraria from AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bayer, Janssen Oncology, and Sanofi; and has received research funding grants provided to the institution from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Janssen Oncology, Pfizer, and Sanofi. MSC: Honoraria: Merck, Janssen Biotech, Bayer, Astellas Pharma, Myovant Sciences Consulting or Advisory Role: Merck, Janssen Biotech, MDxHealth, Bayer, Astellas Pharma, Myovant Sciences, TesoRx Pharma, Genomic Health, Ferring Pharmaceuticals, Precision Biopsy. DRS: No relevant conflicts. RT: No relevant conflicts. AB: No relevant conflicts. BT: grants from Myovant, during the conduct of the study; grants and personal fees from Astellas, grants and personal fees from Bayer, grants and personal fees from Janssen, grants and personal fees from Ferring, grants and personal fees from Sanofi. NDS: Consulting or Advisory Role: Bayer, Janssen Scientific Affairs, Dendreon, Tolmar, Ferring, Medivation/Astellas, Amgen, Pfizer, AstraZeneca, Genentech, Myovant Sciences Speakers' Bureau: Janssen, Bayer, Dendreon. BB, BS, SL, AND DB: employees of Myovant Sciences, Inc., (Copyright © 2023. Published by Elsevier Inc.)

Background: Androgen deprivation therapy (ADT), a cornerstone of prostate cancer treatment, is commonly co-prescribed as combination therapy., Objective: To better understand the safety and tolerability profile of relugolix, an oral non-peptide gonadotropin-releasing hormone (GnRH) receptor antagonist, in combination with abiraterone acetate (abiraterone) and apalutamide, a phase I study was undertaken., Patients and Methods: This is an ongoing, 52-week, open-label, parallel cohort study of relugolix in combination with abiraterone in men with metastatic castration-sensitive prostate cancer (mCSPC) or metastatic castration-resistant prostate cancer (mCRPC) [Part 1] and apalutamide in men with mCSPC or non-metastatic castration-resistant prostate cancer (nmCRPC) [Part 2]. Eligible patients treated with leuprolide acetate or degarelix with abiraterone or apalutamide prior to baseline, at which time they were transitioned to relugolix. Assessments included reporting of adverse events, clinical laboratory tests, vital sign measurements, electrocardiogram (ECG) parameters, and testosterone serum concentrations. In this interim report, patients completing ≥12 weeks were included., Results: Overall, 15 men were enrolled in Part 1 and 10 in Part 2. Adverse events were mostly mild-to-moderate in intensity and were consistent with the known safety profiles of the individual medications. No transition (from prior ADT treatment)- or time-related trends in clinical laboratory tests, vital sign measurements, or ECG parameters were observed. Mean testosterone concentrations remained below castration levels., Conclusions: Combination therapy of relugolix and abiraterone or apalutamide was associated with a favorable safety and tolerability profile consistent with the known profiles of the individual medications. Castration levels of testosterone were maintained after transitioning to relugolix from other ADTs., Clinical Trial Registration: ClinicalTrials.gov identifier: NCT04666129., (© 2023. The Author(s).)

We analyzed, through a Pavlovian conditioning procedure in rats, the temporal pattern of behavior in appetitive and aversive conditions within subjects, and the difference in inferred temporal working memory functioning with the Gap paradigm. For both conditions, we paired a 60-s conditioned stimulus (CS: tone1 or tone2) with an unconditioned stimulus (US: shock or chocolate pellet) delivered 20s after CS onset. The analyses of mean response rate and individual-trial data were performed during Probe trials, consisting of CS alone, and trials in which gaps of different position or duration were inserted, to assess the effect of the temporal manipulation on behavior. The results showed: (1) An anticipatory peak time in the aversive condition but better accuracy in the appetitive condition, (2) constancy in the Weber fraction suggesting that the difference in peak time was under clock control, (3) a graded effect of gap parameters only in the aversive condition and (4) different gap effects between conditions when a gap was inserted early in the CS. These results highlight behavioral differences between aversive and appetitive conditions and suggest that the temporal working memory mechanism was not engaged in the same manner in each condition., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The nematodes Toxocara canis (Werner, 1782) and Toxocara cati (Schrank, 1788) have been associated with worse human cognitive function in children and middle-aged adults. In this study, we sought to determine the association between Toxocara seropositivity and serointensity determined by detection of IgG antibodies against the Toxocara antigen recombinant Tc-CTL-1 and cognitive function in older adults, including approximately 1,350 observations from the 2013-2014 National Health and Nutrition Examination Survey. Mean fluorescence intensity was used to quantify IgG antibodies against the Toxocara recombinant Tc-CTL-1 antigen, and respondents were considered positive at values greater than 23.1. In adjusted models from sample sizes ranging from 1,274 to 1,288 depending on the individual cognitive task, we found that Toxocara seropositivity was associated with worse performance on the animal-fluency task (b = -1.245, 95% CI: -2.392 to -0.099, P< 0.05) and the digit-symbol coding task (b = -5.159, 95% CI: -8.337 to -1.980, P< 0.001). Toxocara serointensity assessed using log-transformed mean fluorescence intensity as a continuous variable was associated with worse performance on the digit-symbol coding task (b = -1.880, 95% CI: -2.976 to -0.783, P < 0.001). There were no significant associations with tasks assessing memory. Further, age modified the association between Toxocara and cognitive function, although sex, educational attainment, and income did not. These findings suggest that Toxocara might be associated with deficits in executive function and processing speed in older U.S. adults, although additional research is required to better describe cognitive function in older adults who are seropositive for Toxocara spp.

Infecting much of the world's population, the herpesviridae virus cytomegalovirus has been associated with lower cognitive function in some but not all studies. In this study, we further investigate associations between cytomegalovirus and cognitive function in a community-based sample of adults aged 40 to 70 years (M = 55.3; SD = 8.1) from the United Kingdom. Adjusted multiple-regression modeling showed no significant associations between cytomegalovirus and performance on nine cognitive tasks. Further, in adjusted interaction models, age, sex, educational attainment, and income did not moderate associations between cytomegalovirus and cognitive function. In this community-based adult sample, cytomegalovirus was not associated with cognitive function., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objectives: Describe clinical characteristics of adolescents hospitalized with e-cigarette or vaping product use-associated lung injury (EVALI) and to investigate association between EVALI and coagulopathy., Methods: We conducted a retrospective cohort study of adolescents admitted to the general inpatient or ICUs at 2 major tertiary children's hospitals from January 2019 to June 2021. We included analysis of demographics, clinical findings, laboratory and imaging results, and outcomes., Results: Forty-four hospitalizations met diagnostic criteria for inclusion per Centers for Disease Control and Prevention guidelines, with 55% of patients admitted after April 2020. Compared with adults, pediatric patients were less likely to present with pulmonary symptoms. Significant laboratory work included elevated white blood cell count of 14.3 k/uL (confidence interval [CI], 13.7-15.0) with neutrophilic predominance, C-reactive protein of 25.2 mg/dL (CI, 22.1-28.2), and erythrocyte sedimentation rate of 66.7 mm/hour (CI, 26.9-76.4). Chest radiographs were poor predictors of disease in 53% of our patients but computed tomography was 100% sensitive. Significant coagulation abnormalities included prothrombin time of 17.7 seconds (CI, 16.4-19.1) and international normalized ratio of 1.54 (CI, 1.43-1.66). Coagulation studies improved with vitamin K and steroid administration. Nine of 16 patients (56%) had abnormal diffusing capacity of the lung for carbon monoxide divided by alveolar volume <80% predicted, suggesting evidence of pulmonary vascular disease, or >100%, suggesting pulmonary hemorrhage., Conclusions: EVALI continues to be an important differential diagnosis in the adolescent population. EVALI is likely a result of systemic inflammation with consequences beyond the pulmonary system. The novel report of coagulopathy among adolescents with EVALI in this cohort reveals an opportunity to detect coagulopathy and initiate early therapy., Competing Interests: CONFLICT OF INTEREST DISCLOSURE: The authors have indicated they have no potential conflicts of interest to disclose. Authors have not published, posted, or submitted any related papers from the same study., (Copyright © 2022 by the American Academy of Pediatrics.)

Several viral, bacterial, and parasitic diseases have been associated with cognitive function and neuropsychiatric outcomes in humans, including human T-cell lymphotropic virus 1 (HTLV-1). In this study, we sought to further generalize previously reported associations of cognitive function and depression with HTLV-1 seropositivity and serointensity using a community-based sample of adults aged approximately 40 to 70 years (mean = 55.3 years) from the United Kingdom. In this sample, the results of adjusted linear regression models showed no associations of HTLV-1 seropositivity or serointensity with reasoning, pairs-matching, or reaction-time cognitive tasks or with depression. In addition, neither age, sex, educational attainment, nor income moderated associations of HTLV-1 seropositivity or serointensity with cognitive function or depression. In this middle-aged to older middle-aged adult community sample, HTLV-1 seropositivity and serointensity do not appear to be associated with reasoning, pairs-matching, and reaction-time tasks or with depression.

Background: Novel coronavirus disease 2019 (COVID-19) vaccine administration has faced distribution barriers across the United States. We sought to delineate our vaccine delivery experience in the first week of vaccine availability, and our effort to prioritize employees based on risk with a goal of providing an efficient infrastructure to optimize speed and efficiency of vaccine delivery while minimizing risk of infection during the immunization process., Objective: This article aims to evaluate an employee prioritization/invitation/scheduling system, leveraging an integrated electronic health record patient portal framework for employee COVID-19 immunizations at an academic medical center., Methods: We conducted an observational cross-sectional study during January 2021 at a single urban academic center. All employees who met COVID-19 allocation vaccine criteria for phase 1a.1 to 1a.4 were included. We implemented a prioritization/invitation/scheduling framework and evaluated time from invitation to scheduling as a proxy for vaccine interest and arrival to vaccine administration to measure operational throughput., Results: We allotted vaccines for 13,753 employees but only 10,662 employees with an active patient portal account received an invitation. Of those with an active account, 6,483 (61%) scheduled an appointment and 6,251 (59%) were immunized in the first 7 days. About 66% of invited providers were vaccinated in the first 7 days. In contrast, only 41% of invited facility/food service employees received the first dose of the vaccine in the first 7 days ( p  < 0.001). At the vaccination site, employees waited 5.6 minutes (interquartile range [IQR]: 3.9-8.3) from arrival to vaccination., Conclusion: We developed a system of early COVID-19 vaccine prioritization and administration in our health care system. We saw strong early acceptance in those with proximal exposure to COVID-19 but noticed significant difference in the willingness of different employee groups to receive the vaccine., Competing Interests: S.M. and R.J.M. report research grants from the Centers for Disease Control and Prevention (Grant U01CK000590). S.M., M.A.B., and R.J.M. report research funding from the Sergey Brin Family Foundation and Verily Life Sciences. M.A.B. reports other from Sergey Brin Family Foundation, other from Verily Life Sciences, outside the submitted work. S.M. reports grants from Centers for Disease Control and Prevention, from Verily Life Sciences, from Sergey Brin Family Foundation, outside the submitted work. R.J.M. reports grants from Centers for Disease Control and Prevention, other from Verily Life Sciences, other from Sergey Brin Family Foundation, outside the submitted work., (Thieme. All rights reserved.)

Introduction: Recent clinical trials are considering inclusion of more than just apolipoprotein E ( APOE ) ε4 genotype as a way of reducing variability in analysis of outcomes., Methods: Case-control data were used to compare the capacity of age, sex, and 58 Alzheimer's disease (AD)-associated single nucleotide polymorphisms (SNPs) to predict AD status using several statistical models. Model performance was assessed with Brier scores and tenfold cross-validation. Genotype and sex × age estimates from the best performing model were combined with age and intercept estimates from the general population to develop a personalized genetic risk score, termed age, and sex-adjusted GenoRisk., Results: The elastic net model that included age, age x sex interaction, allelic APOE terms, and 29 additional SNPs performed the best. This model explained an additional 19% of the heritable risk compared to APOE genotype alone and achieved an area under the curve of 0.747., Discussion: GenoRisk could improve the risk assessment of individuals identified for prevention studies., Competing Interests: Suzanne Hendrix, as the owner of Pentara, received support from Affirmative Diagnostics for the manuscript and received contract work from AC Immmune, Acumen, ADCS, ADDF, Affirmativ Dignpostics, Alector, Alkahest, Allergan, Alzheon, Amylyx, Apodemus, Athira, Avanir, Banner, Biogen, Biohaven, Cadent, Capricor, Cerecin, Cognito, Cognoptix, Cortexyme, Elusis, Green Valley, Grifols, Ionis, Janssen, Kyowa‐Kirin, Lexeo, LuMind, Lundbeck, NCRI, Nilvad, NovoNordisk, Nutricia, Photopharmics, PTCBio, Regenera, Retrotope, Richard Isaacson, Samus, Soleno, Spaulding, Suven, Takeda, Telocyte, Tetra Discovery, Toyama, United Neuroscience, Vaccinex, Vacinity, vTv Therapeutics, and WGU. Suzanne Hendrix has also received royalties from Wiley in the last 36 months; received honoraria for lectures, presentations, etc. from Biogen; received support in the last 36 months from Grifols and Nutricia for presentations and conference attendance; claims one patent pending Brown BL, Hedges DW, Hendrix SB (2014) Extracting A periodic Components from a Time Series Wave Data Set—Patent Pending with a filing date of October 16, 2013, Application Number PCT/US2013/065327; and participated in Alzheon, Cortexyme, and Janssen DSMB or Advisory Board in the last 36 months. Samuel P. Dickson received support from Pentara, which in turn received support from Affirmativ Diagnostics for the manuscript. S. B. Booth received support from Affirmative Diagnostics for the manuscript; received travel support from her employer for work events; ADX provides profit sharing incentives with additional salary which were broadly applied to any work performed for the company (including manuscript generation). J. S. K. Kauwe received support for the manuscript from Brigham Young university and has received honoraria from UH Hilo. B. L. Brown received support through the following grants: Measuring the Interactive Effects of COVID‐19 and Latent Infections on Patterns of cognitive Timing: A Middle‐Aged to Elderly Sample from the Utah Valley Community. Translational Medicine Award from the BYU Simmons Research Endowment ($31,300). This is an intramural grant from a research endowment within our university to my departmental research fund. Brown also claims one patent pending Brown BL, Hedges DW, Hendrix SB (2014) Extracting A periodic Components from a Time Series Wave Data Set—Patent Pending with a filing date of October 16, 2013, Application Number PCT/US2013/065327. Data used in this manuscript is publically available. Participant consent is not needed, and was obtained from investigators who ran each study. M. L. Hardy has received paid consulting fees to the LLC solely owned by ML Hardy from ixLayer, NW Pathology & Labs, Mt. Baker Imaging, PlumCare, ADx Healthcare, Architectural Elements; received travel support from her employer for work events; and was the past Volunteer Secretary for the Lets Pool Together and Hope Philantropies non‐profit boards. P. G. Ridge had received honoraria from University of Kansas Alzheimer's Disease Center for a seminar presentation. R. R. Fortna is a board member of Northwest Pathology and ADx Healthcare and is co‐owner and holds stock for ADx healthcare. J. Nicodemus Johnson has nothing to disclose., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Infecting approximately one-third of the world's population, the neurotropic protozoan Toxoplasma gondii has been associated with cognition and several neuropsychiatric diseases including schizophrenia and bipolar disorder. Findings have been mixed, however, about the relationship between Toxoplasma gondii and depression, with some studies reporting positive associations and others finding no associations. To further investigate the association between Toxoplasma gondii and depression, we used data from the UK Biobank and the National Health and Examination Survey (NHANES). Results from adjusted multiple-regression modeling showed no significant associations between Toxoplasma gondii and depression in either the UK Biobank or NHANES datasets. Further, we found no significant interactions between Toxoplasma gondii and age, sex, educational attainment, and income in either dataset that affected the association between Toxoplasma gondii and depression. These results from two community-based datasets suggest that in these samples, Toxoplasma gondii is not associated with depression. Differences between our findings and other findings showing an association between Toxoplasma gondii and depression could be due to several factors including differences in socioeconomic variables, differences in Toxoplasma gondii strain, and use of different covariates in statistical modeling.

The intracellular protozoal parasite Toxoplasma gondii has been associated with worsened cognitive function in animal models and in humans. Despite these associations, the mechanisms by which Toxoplasma gondii might affect cognitive function remain unknown, although Toxoplasma gondii does produce physiologically active intraneuronal cysts and appears to affect dopamine synthesis. Using data from the UK Biobank, we sought to determine whether Toxoplasma gondii is associated with decreased prefrontal, hippocampal, and thalamic gray-matter volumes and with decreased total gray-matter and total white-matter volumes in an adult community-based sample. The results from adjusted multivariable regression modelling showed no associations between Toxoplasma gondii and prefrontal, hippocampal, and thalamic brain gray-matter volumes. In contrast, natural-log transformed antibody levels against the Toxoplasma gondii p22 (b = -3960, 95-percent confidence interval, -6536 to -1383, p < .01) and sag1 (b = -4863, 95-percent confidence interval, -8301 to -1425, p < .01) antigens were associated with smaller total gray-matter volume, as was the mean of natural-log transformed p22 and sag1 titers (b = -6141, 95-percent confidence interval, -9886 to -2397, p < .01). There were no associations between any of the measures of Toxoplasma gondii and total white-matter volume. These findings suggest that Toxoplasma gondii might be associated with decreased total gray-matter in middle-aged and older middle-aged adults in a community-based sample from the United Kingdom., Competing Interests: The authors have declared that no competing interests exist.

The present study investigated the effects of selective food devaluation on performance in the temporal bisection procedure with rats. Differential outcomes (sucrose vs. grain pellets) were associated with correct responding for a short and a long duration in order to analyze the effects of a selective duration-specific food devaluation on the temporal bisection function. Selective prefeeding produced differential changes in proportion of responding, the p(long) function, and PSE. A more consistent impact was observed when the food associated with the long anchor duration was devalued than when the short anchor duration food was devalued. The results are discussed in relation to the bias as well as a choose-short effect., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Infecting approximately one-third of the world's human population, Toxoplasma gondii has been associated with cognitive function. Here, we sought to further characterize the association between Toxoplasma gondii and cognitive function in a community sample of adults aged approximately 40 to70 years. Using adjusted linear regression models, we found associations of Toxoplasma gondii seropositivity with worse reasoning (b = -.192, p < .05) and matrix pattern completion (b = -.681, p < .01), of higher anti-Toxoplasma gondii p22 antibody levels with worse reasoning (b = -.078, p < .01) and slower Trails (numeric) performance (b = 5.962, p < .05), of higher anti-Toxoplasma gondii sag1 levels with worse reasoning (b = -.081, p < .05) and worse matrix pattern completion (b = -.217, p < .05), and of higher mean of the anti-Toxoplasma gondii p22 and sag1 levels with worse reasoning (b = -.112, p < .05), slower Trails (numeric) performance (b = 9.195, p < .05), and worse matrix pattern completion (b = -.245, p < .05). Neither age nor educational attainment moderated associations between the measures of Toxoplasma gondii seropositivity or serointensity. Sex, however, moderated the association between the sag1 titer and digit-symbol substitution and the association between the mean of the p22 and sag1 levels and digit-symbol substitution, and income moderated the association between Toxoplasma gondii seropositivity and numeric memory and the association between the p22 level and symbol-digit substitution. Based on the available neuropsychological tasks in this study, Toxoplasma gondii seropositivity and serointensity were associated with some aspects of poorer executive function in adults., Competing Interests: The authors have declared that no competing interests exist.

Purpose: African Americans experience greater prostate cancer risk and mortality than do Caucasians. An analysis of pooled phase III data suggested differences in overall survival (OS) between African American and Caucasian men receiving sipuleucel-T. We explored this in PROCEED (NCT01306890), an FDA-requested registry in over 1900 patients with metastatic castration-resistant prostate cancer (mCRPC) treated with sipuleucel-T., Patients and Methods: OS for patients who received ≥1 sipuleucel-T infusion was compared between African American and Caucasian men using an all patient set and a baseline prostate-specific antigen (PSA)-matched set (two Caucasians to every one African American with baseline PSAs within 10% of each other). Univariable and multivariable analyses were conducted. Survival data were examined using Kaplan-Meier and Cox proportional hazard methodologies., Results: Median follow-up was 46.6 months. Overall survival differed between African American and Caucasian men with hazard ratios (HR) of 0.81 (95% confidence interval [CI]: 0.68-0.97, P = 0.03) in the all patient set and 0.70 (95% CI: 0.57-0.86, P < 0.001) in the PSA-matched set. Median OS was longer in African Americans than in Caucasian men for both analysis sets, e.g., 35.3 and 25.8 months, respectively, in the PSA-matched set. Similar results were observed in the all patient set. Differences were larger when treatment began at lower baseline PSA; curves were more similar among patients with higher baseline PSA. In patients with baseline PSA below the median, the HR was 0.52 (95% CI: 0.37-0.72, P < 0.001), with median OS of 54.3 versus 33.4 months. Known prognostic factors and African American race (multivariable analyses; HR: 0.60, 95% CI: 0.48-0.74, P < 0.001) were independently associated with OS. Use of post-sipuleucel-T anticancer interventions was balanced between races., Conclusion: In this exploratory analysis of a registry including nearly 12% African American men with mCRPC, OS was significantly different between African Americans and Caucasians, indicating further research is warranted.

Associated with numerous cognitive and behavioral functions and with several diseases, the prefrontal cortex is vulnerable to environmental insult. Among other factors, toxins in air pollution have been associated with damage to the prefrontal cortex in children and older adults. We used data from the UK Biobank to assess further associations between an array of toxins in air pollution and gray matter in the prefrontal cortex including the left and right frontal poles, left and right superior frontal gyri, left and right frontal medial cortex, left and right orbitofrontal cortex, and left and right frontal opercula, using multivariate models adjusted for covariates that possibly could confound the association between air pollution and volume of prefrontal gray matter. The results showed inverse associations between PM 2.5, PM 10, and nitrogen oxides and prefrontal volume in models adjusted for age, sex, education, socioeconomic status, race-ethnicity, self-rated overall health, body mass index, total brain volume, smoking status, and alcohol use frequency. Education appeared to moderate the association between air pollution and prefrontal volume. The data in these analyses came from regions whose mean PM 2.5 was near the upper limit and whose mean PM 10 was under those recommended by the World Health Organization. These findings suggest that comparatively low levels of air pollution might be associated with reduced volume of the prefrontal cortex., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Air pollution has been associated with cognitive function and brain volume. While most previous research has examined the association between air pollution and brain volume in cortical structures or total brain volume, less research has investigated associations between exposure to air pollution and subcortical structures, including the thalamus. Further, the few available previous studies investigating associations between air pollution and thalamic volume have shown mixed results., Methods: In this study, we evaluated the association between PM2.5, PM2.5-10, PM10, nitrogen dioxide, and nitrogen oxides and volume of the thalamus in adults using the UK Biobank resource, a large community-based sample, while adjusting for multiple covariates that could confound an association between air pollution and thalamic volume., Results: In adjusted models, the left but not right thalamus volume was significantly inversely associated with PM2.5-10, although there were no significant associations between PM2.5, PM10, nitrogen dioxide, and nitrogen oxides with either left or right thalamic volumes. In addition, interactions between age and PM2.5-10 and PM10 were inversely associated with thalamic volume, such that thalamic volume in older people appeared more vulnerable to the adverse effects of PM2.5-10 and PM10, and interactions between educational attainment and PM2.5, nitrogen dioxide, and nitrogen oxides and between self-rated health and PM2.5-10 were positively associated with thalamic volume, such that higher educational attainment and better self-rated health appeared protective against the adverse effects of air pollution on the thalamus., Conclusion: These findings suggest a possible association between thalamic volume and air pollution particularly in older people and in people with comparatively low educational attainment at levels of air pollution found in the United Kingdom., Competing Interests: The authors have declared that no competing interests exist.

Total brain gray-matter and white-matter volumes can be indicators of overall brain health. Among the factors associated with gray-matter and white-matter volumes is exposure to air pollution. Using data from the UK Biobank, we sought to determine associations between several components of air pollution-PM 2.5 , PM 2.5-10 , PM 10 , nitrogen dioxide, and nitrogen oxides-and total gray-matter and total white-matter volumes in multivariable regression models in a large sample of adults. We found significant inverse associations between PM 2.5 concentration and total white-matter volume and between PM 2.5 , PM 2.5-10 , PM 10 , nitrogen dioxide, and nitrogen oxide concentrations and total gray-matter volume in models adjusted for age, sex, body-mass index, self-assessment of overall health, frequency of alcohol use, smoking status, educational attainment, and income. These findings of pollutant-associated decreases in total gray-matter and total white-matter volumes are in the context of mean PM 2.5 concentrations near the upper limit of the World Health Organization's recommendations. Similarly, mean PM 10 concentrations were below the recommended upper limit, and nitrogen dioxide concentration was slightly above. Still, there are many areas in the world with much higher concentrations of these pollutants, which could be associated with larger effects. If replicated, these findings suggest that air pollution could be a risk factor for neurodegeneration.

Research on emotion often involves the use of emotion-evoking stimuli that are used to manipulate emotional state across groups or conditions. One standardized set of stimuli that has been used for this purpose is the International Affective Picture System (IAPS) [1]. The data described in this article were obtained over the course of two experiments in which the primary task was for participants to judge the presentation duration of six IAPS pictures in the temporal bisection task [2-4]. Each of these experiments contained three types of phases (rating, training, and testing). In rating phases, participants rated the IAPS pictures for evoked valence, arousal, and fear. In training phases, participants were trained to classify the presentation duration of green squares (Experiment 1) or IAPS pictures (Experiment 2) as either "short" or "long." In testing phases, participants were instructed to use what they had learned in the preceding training phases to classify the IAPS pictures as either "short" or "long." The findings related to these data were published in Grommet, Hemmes, and Brown [5], and the data are available in Mendeley Data, DOI: 10.17632/xx6zh6mmjw.1 [6]., (© 2019 The Authors.)

Background: The hippocampus is important for memory processing. Several neuropsychiatric diseases including Alzheimer's disease are associated with reduced hippocampal volume, and further the hippocampus appears vulnerable to environmental insult. Air pollution has been associated with cardiovascular disease, abnormal brain structure, and cognitive deficits., Objective: Because of hippocampal vulnerability to environmental insults and based on the association between exposure to air pollution and cognitive function and brain structure, we evaluated the association between exposure to toxins in air pollution and left and right hippocampal volume using brain-imaging and air-pollution data from the UK Biobank, a large community-based dataset., Methods: We used regression modelling to evaluate the association between exposure to nitrogen dioxide, nitrogen oxides, PM 2.5 , PM 2.5-10 , and PM 10. and left and right hippocampal volume controlling for age, sex, body-mass index, overall health, alcohol use, smoking, educational attainment, socioeconomic status, inverse distance from the nearest major road, and a measure of total brain volume., Results: In these models, PM 2.5 concentration was associated with smaller left hippocampal volume. None of the other measures of air pollution was associated with either left or right hippocampal volume, although interaction models provided some evidence that sex might moderate the relationship between air pollution and hippocampal volume. In adjusted models, age, sex, educational attainment, income, overall health, current smoking, alcohol intake, and body-mass index were associated with hippocampal volume., Conclusions: PM 2.5 at levels found in the United Kingdom was associated with smaller left hippocampal volume. Additional associations between several covariates and hippocampal volumes indicate that hippocampal volume might be associated with several potentially modifiable variables., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Recent research on the effects of fear on timing has focused on two accounts proposed by Scalar Expectancy Theory for why the durations of fear stimuli are overestimated in comparison to the durations of neutral stimuli. One possibility is that fear serves as an arouser that increases the speed of a hypothetical internal clock. The other possibility is that fear increases attention to time, which results in organisms' beginning to time fear-evoking stimuli sooner than they do neutral stimuli. In Experiment 1, we asked which of these two possibilities was the underlying mechanism of temporal overestimation of fear cues by presenting emotion-evoking pictures (fear-evoking vs. neutral) across multiple duration ranges in the temporal bisection task. Larger effects of fear were observed at the longest duration range in comparison to the shortest duration range, supporting the arousal hypothesis. Penney et al. 1998 and Penney et al., 2000 memory-mixing hypothesis proposes that overestimation is only possible in preparations that allow for recalled reference memories for stimulus durations to be mixed across conditions. Therefore, in Experiment 2, we manipulated whether or not fear and neutral cues were presented within the same session, a condition that may be necessary for memory mixing to occur. Fear cues were overestimated relative to neutral cues within the session in which fear and neutral cues were both presented, but no effect of emotion was observed between the two sessions in which fear and neutral cues were presented separately., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Infectious diseases might affect cognitive aging and dementia risk, possibly via neuroinflammation. Similarly, risk factors for cardiovascular and cerebrovascular diseases are associated with cognitive function and dementia. We hypothesized that cardiovascular risk factors moderate the association of exposure to infectious diseases with cognitive function., Methods: We studied 5662 participants aged 20 to 59 years from the third National Health and Nutrition Examination Survey (1988-1994) in the United States. We used linear regression to investigate whether the Framingham general cardiovascular risk index moderated the association of infection burden based on exposure to eight different infectious diseases with cognitive functioning as measured by the Symbol Digit Substitution, Serial Digit Learning, and Reaction Time tests., Results: The multiplicative interaction between the infection-burden index and the cardiovascular-risk index was associated with performance on the Symbol Digit Substitution (B = .019 [95% CI: .008, .031], p < .001) but not on the Serial Digit Learning (B = .034 [95% CI: -.025, .094]) or for Reaction Time (B = -.030 [95% CI: -.848, .787]). Participants with a lower cardiovascular risk appeared to be more resilient against the potential adverse effects of higher infection burden on the Symbol Digit Substitution task., Conclusions: Participants at zero risk for a cardiovascular event in the next 10 years had no differences in processing speed with increasing exposure to infectious disease, whereas participants with higher risk for a cardiovascular event had worse processing speed with increased exposure to infectious disease., Competing Interests: The authors have declared that no competing interests exist.

The voltage gated sodium channel Na V 1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole Na V 1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile., (Copyright © 2018. Published by Elsevier Ltd.)

This study demonstrates that overtraining in temporal discrimination modifies temporal stimulus control in a bisection task and produces habitual responding, as evidenced through insensitivity to food devaluation. Rats were trained or overtrained in a 2- versus 8-sec temporal discrimination task, with each duration associated with a lever (left or right) and food (grain or sucrose). Overtraining produced a leftward shift in the bisection point. Devaluation treatment induced a differential loss of responding depending on stimulus duration (short versus long) and the level of training (training versus overtraining). The relationships between timing behavior and habitual behavior are discussed., (© 2018 Araiba et al.; Published by Cold Spring Harbor Laboratory Press.)

Introduction: Enzalutamide and abiraterone acetate (plus prednisone) are new hormonal treatments for metastatic castration-resistant prostate cancer (mCRPC). This study compared treatment duration, healthcare resource utilization (HRU), and treatment costs for chemotherapy-naïve mCRPC patients treated with enzalutamide or abiraterone acetate in the USA., Methods: Chemotherapy-naïve mCRPC patients initiating treatment with enzalutamide or abiraterone acetate were identified from administrative claims. Continuous enrollment ≥ 6 months before and ≥ 3 months after the index date (initiation date of enzalutamide or abiraterone acetate) was required. Treatment duration, all-cause and prostate cancer-related HRU, and costs were estimated during the post-index period. Multivariable analyses compared HRU and costs between cohorts, adjusting for baseline characteristics., Results: Overall, 920 chemotherapy-naïve patients initiated enzalutamide and 2310 initiated abiraterone acetate (median follow-up, 10.7 and 13.5 months, respectively). More enzalutamide-treated patients had corticosteroid-sensitive comorbidities at baseline. Treatment duration was longer with enzalutamide versus abiraterone acetate (median, 10.7 vs. 8.8 months; P = 0.008). Enzalutamide was associated with fewer all-cause inpatient admissions [adjusted incidence rate ratio (95% confidence interval) 0.87 (0.76, 0.99)], days of hospitalization [0.84 (0.70, 1.02)], and outpatient visits [0.94 (0.90, 0.98)], and fewer prostate cancer-related outpatient visits [0.92 (0.87, 0.96)] compared with abiraterone acetate. Enzalutamide was also associated with lower prostate cancer-related inpatient and emergency department costs [adjusted differences, $122 (P = 0.024) and $28 (P = 0.009), respectively]., Conclusion: Chemotherapy-naïve mCRPC patients treated with enzalutamide versus abiraterone acetate had longer treatment duration and incurred lower HRU and prostate cancer-related inpatient and emergency department costs., Funding: Astellas Pharma Inc.

It has been highlighted that in the original article [1] there was a typesetting mistake in the Results - NNT in Strive section. This Correction article states the incorrect and correct sentence.

The intracellular parasite Toxoplasma gondii (Nicolle et Manceaux, 1908) infects humans resulting in acute toxoplasmosis, an infection that in immunocompetent people is typically mild but results in persistent latent toxoplasmosis. In that T. gondii appears to affect dopamine synthesis and because addicting drugs affect midbrain dopamine transmission, latent toxoplasmosis could influence substance use. Using both the third and continuous National Health and Nutrition Examination Surveys from the US Centers for Disease Control and Prevention, we used logistic regression to test for associations between T. gondii seropositivity and subject self-report of having ever used tobacco, alcohol, marijuana, cocaine, heroin, or methamphetamine. In the third NHANES dataset, which included data for tobacco, alcohol, marijuana and cocaine, T. gondii seropositivity was associated with a reduced likelihood of self-reported marijuana (OR = 0.71 [95% CI: 0.58; 0.87]; p = 0.001) and cocaine use (OR = 0.72 [95% CI: 0.56; 0.91]; p = 0.006). In the continuous National Health and Nutrition Examination Surveys dataset, which included data for all six substances, T. gondii seropositivity was associated with a reduced likelihood of self-reported tobacco (OR = 0.87 [95% CI: 0.76; 1.00]; p = 0.044), marijuana (OR = 0.60 [95% CI: 0.50; 0.72]; p < 0.001), heroin (OR = 0.60 [95% CI: 0.42; 0.85]; p = 0.005) and methamphetamine use (OR = 0.54 [95% CI: 0.38; 0.77]; p = 0.001). We observed interactions between sex and T. gondii seropositivity in the prediction of self-reported use of tobacco and alcohol. Further, T. gondii seropositivity appeared to remove the protective effect of education and economic status against self-reported cigarette smoking. These findings suggest that T. gondii seropositivity may be inversely associated with some but not all types of substance use in US adults.

Background: This analysis estimated the number needed to treat with enzalutamide versus bicalutamide to achieve one additional patient with chemotherapy-naïve metastatic castration-resistant prostate cancer who would obtain clinical benefit regarding progression-free survival, radiographic progression-free survival, or no prostate-specific antigen progression at 1 and 2 years following treatment initiation., Methods: Clinical event rates were obtained from the STRIVE (NCT01664923) and TERRAIN (NCT01288911) trials, and the number needed to treat was the inverse of the absolute rate difference between the event rates of enzalutamide and bicalutamide. The 95% Confidence Interval of the number needed to treat was derived from the 95% Confidence Interval of the event rate difference., Results: Using STRIVE data (patients with metastatic disease: n = 128 enzalutamide; n = 129 bicalutamide) comparing enzalutamide with bicalutamide at 1 and 2 years, the numbers needed to treat to achieve one additional patient with chemotherapy-naïve metastatic castration-resistant prostate cancer with progression-free survival were 2.0 and 2.8, respectively; with radiographic progression-free survival, 2.6 and 3.0, respectively; and without prostate-specific antigen progression, 1.8 and 2.4, respectively. Using TERRAIN data (n = 184 enzalutamide; n = 191 bicalutamide) comparing enzalutamide with bicalutamide at 1 and 2 years, the numbers needed to treat to achieve one additional patient with progression-free survival were 4.3 and 3.7, respectively; with radiographic progression-free survival, 10.0 and 2.8, respectively; and without prostate-specific antigen progression, 2.1 and 3.2, respectively., Conclusions: The combined data from TERRAIN and STRIVE demonstrated that treating chemotherapy-naïve metastatic castration-resistant prostate cancer with enzalutamide leads to more patients without clinical progression at 1 and 2 years than with bicalutamide., Trial Registration: STRIVE (NCT01664923; registration date: August 10, 2012) and TERRAIN (NCT01288911; registration date: February 1, 2011).

Huntington disease (HD) is an autosomal dominantly inherited, progressive neurodegenerative disorder which is accompanied by executive dysfunctions and emotional alteration. The aim of the present study was to assess the impact of emotion/stress on on-going highly demanding cognitive tasks, i.e., temporal processing, as a function of age in BACHD rats (a "full length" model of HD). Middle-aged (4-6 months) and old (10-12 months) rats were first trained on a 2 vs. 8-s temporal discrimination task, and then exposed to a series of bisection tests under normal and stressful (10 mild unpredictable foot-shocks) conditions. The animals were then trained on a peak interval task, in which reinforced fixed-interval (FI) 30-s trials were randomly intermixed with non-reinforced probe trials. After training, the effect of stress upon time perception was again assessed. Sensitivity to foot-shocks was also assessed independently. The results show effects of both age and genotype, with largely greater effects in old BACHD animals. The older BACHD animals had impaired learning in both tasks, but reached equivalent levels of performance as WT animals at the end of training in the temporal discrimination task, while remaining impaired in the peak interval task. Whereas sensitivity to foot-shock did not differ between BACHD and WT rats, delivery of foot-shocks during the test sessions had a disruptive impact on temporal behavior in WT animals, an effect which increased with age. In contrast, BACHD rats, independent of age, did not show any significant disruption under stress. In conclusion, BACHD rats showed a disruption in temporal learning in late symptomatic animals. Age-related modification in stress-induced impairment of temporal control of behavior was also observed, an effect which was greatly reduced in BACHD animals, thus confirming previous results suggesting reduced emotional reactivity in HD animals. The results suggest a staggered onset in cognitive and emotional alterations in HD, with emotional alteration being the earliest, possibly related to different time courses of degeneration in cortico-striatal and amygdala circuits.

Mood disorders are common mental illnesses. Among the factors associated with major depression are exposures to infectious diseases including hepatitis C, influenza, varicella-zoster, and herpes viruses. In this study, we sought to evaluate further associations between viral exposure and depression. From the US Center for Disease Control's National Health and Nutrition Examination Survey, we obtained data about depression status, antidepressant use, exposure to hepatitis A, hepatitis B, herpes simplex virus type 1, herpes simplex virus type 2, human immunodeficiency virus, and cytomegalovirus, and sociodemographic variables and evaluated associations between depression and viral exposure in adjusted multivariable models. Herpes simplex virus type 2 was associated with an increased risk of depression, whereas hepatitis A, hepatitis B, and herpes simplex virus type 1 were not. Higher cytomegalovirus antibody levels were associated with depression in subjects seropositive for cytomegalovirus. In conclusion, exposure to herpes simplex virus type 2 and possibly cytomegalovirus are associated with depression in an adult US sample., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To explore potential interactions between folate-cycle factors and Helicobacter pylori seropositivity in the prediction of cognitive function., Methods: We used data obtained from the 1999-2000 continuous National Health and Nutrition Examination Survey produced by the United States' Centers for Disease Control and Prevention. Using Ordinary Least Squares regression, we tested for associations between multiple folate-cycle factors, Helicobacter pylori seropositivity, and cognitive function assessed by the digit symbol coding subtest of the Wechsler Adult Intelligence Scale-III. We then tested for interactions between each of the folate-cycle factors and Helicobacter pylori in the prediction of cognitive function., Results: Although Helicobacter pylori seropositivity, 5-methyltetrahydrofolate, vitamin B-12, and homocysteine were not associated with performance on the digit symbol coding task, Helicobacter pylori seropositivity interacted with 5-methyltetrahydrofolate concentration to predict performance on the digit symbol coding task. The Helicobacter pylori seropositive group performed worse on the digit symbol coding task as 5-methyltetrahydrofolate concentration decreased., Conclusion: The interaction between Helicobacter pylori seropositivity and reduced folate-cycle factor 5-methyltetrahydrofolate might impair aspects of cognitive function.

Caused by the parasitic nematodes Toxocara canis and cati , toxocariasis in humans can result in covert toxocariasis, ocular toxocariasis, visceral larval migrans, and neurotoxocariasis. A common infection, toxocariasis exposure varies widely within and between countries, with a previous estimate of Toxocara seroprevalence using data from 1988 to 1994 in the United States of approximately 13%. Age, poverty, sex, educational attainment, ethnicity, and region have been associated with Toxocara seroprevalence. In this study, we sought to determine the seroprevalence of and factors associated with Toxocara seropositivity in the United States using data from the National Health and Nutrition Examination Survey from 2011 to 2014 to provide a more recent estimate of Toxocara seroprevalence in the United States. We found an overall Toxocara seroprevalence of 5.1%. Increasing age, male sex, low educational attainment, low income, and immigration status each was associated with Toxocara seropositivity. Mexican Americans had reduced odds of exposure. These findings show that exposure to Toxocara continues in the United States and that several demographic factors influence the risk of exposure.

Although highly heritable, adult height is also associated with numerous environmental factors, including exposure to infection. Particularly in developing regions of the world, infection burden appears to slow growth during childhood. Using a large database representative of the US population, we examined associations between adult height and leg length and an infection-burden index based on past exposure to Toxocara species, Toxoplasmosis gondii, cytomegalovirus, hepatitis A, hepatitis B, hepatitis C, herpes simplex virus 1, and herpes simplex virus 2. In models controlled for age, sex, educational attainment, socioeconomic status, and race-ethnicity, we found that the infection-burden index predicted height (β=-0.10 [95% CI: -0.15, -0.05], p .001<0.001) but not leg length (β=-0.04 [95% CI: -0.12, 0.04], p=0.357). Both sex and race-ethnicity moderated this association. In addition, exposures to Toxocara species, cytomegalovirus, and hepatitis A were each individually associated with reduced height and reduced leg length. While associations between growth and infection have been found principally in children in developing regions of the world, our findings suggest that the effects of infection on height may persist into adulthood even in developed nations., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective Na V 1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective Na V 1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.

Toxoplasma gondii ( T. gondii ) is a microscopic, apicomplexan parasite that can infect muscle or neural tissue, including the brain, in humans. While T. gondii infection has been associated with changes in mood, behavior, and cognition, the mechanism remains unclear. Recent evidence suggests that T. gondii may harvest folate from host neural cells. Reduced folate availability is associated with an increased risk of neurodevelopmental disorders, neurodegenerative diseases, and cognitive decline. We hypothesized that impairment in cognitive functioning in subjects seropositive for T. gondii might be associated with a reduction of folate availability in neural cells. We analyzed data from the third National Health and Nutrition Examination Survey to determine the associations between T. gondii infection, multiple folate-cycle factors, and three tests of cognitive functioning in U.S. adults aged 20 to 59 years. In these analyses, T. gondii moderated the associations of folate, vitamin B-12, and homocysteine with performance on the Serial Digit Learning task, a measure of learning and memory, as well as the association of folate with reaction time. The results of this study suggest that T. gondii might affect brain levels of folate and/or vitamin B-12 enough to affect cognitive functioning., Competing Interests: The authors declare no conflict of interest.

The present study investigated how the value of the long anchor duration influences the bisection point (BP) in the temporal bisection procedure. The ratio similarity rule (Gibbon, 1981, On the form and location of the psychometric bisection function for time. Journal of Mathematical Psychology, 24(1), 58-87) hypothesizes that the location of the BP is determined by a ratio comparison between the short and long anchor durations. The Short/no short hypothesis (Machado and Keen, 2003, Temporal discrimination in a long operant chamber. Behavioural Processes, 62(1), 157-182) indicates that the location of the BP is influenced mainly by the short duration. Two experiments with pigeons manipulated the long anchor duration while fixing the short anchor duration in a series of anchor pairs. The results showed that the location of the BP depended on the initial training condition, a primacy effect. When the initial training condition used anchors of 3- vs. 9-s, a relatively strong influence of the long anchor duration was observed as predicted by the ratio similarity rule. On the other hand, when anchors were 3- vs. 27-s in the initial training condition, the effect of the long duration was relatively small, conforming more closely to the Short/no short hypothesis. Keypecking to the sample key during a trial, sample-cue responding, was also observed. The functions relating sample-cue responding to elapsed trial time also indicated the primacy effect., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: Enzalutamide (ENZA) and abiraterone acetate plus prednisone (AA) are approved second-generation hormone therapies for chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). This study compared ENZA with AA in chemotherapy-naïve mCRPC by calculating the number needed to treat (NNT) and associated incremental costs to achieve one additional chemotherapy-naïve patient with mCRPC free of radiographic progression, chemotherapy, or death over a 1-year time horizon., Methods: Clinical outcomes were obtained from the PREVAIL and COU-AA-302 trials. Three outcomes were evaluated: radiographic progression-free survival, time to cytotoxic chemotherapy initiation, and overall survival at 1 year. NNT was calculated as the reciprocal of the outcome event rate difference for ENZA compared with AA. The incremental costs to achieve one additional outcome at 1 year were calculated as the difference in cost per treated patient multiplied by the NNT. Per-treated-patient costs were considered from a US payer perspective and included medications, monitoring, adverse events, post-progression treatments, and end-of-life care., Results: Within a 1-year time horizon, the total cost per treated patient for ENZA was $2,666 less than AA. Compared with AA, treating 14 patients with ENZA resulted in one additional patient free of progression or death over 1 year; treating 26 patients with ENZA resulted in one additional patient with chemotherapy delayed over 1 year; and treating 91 patients with ENZA resulted in one additional patient free of death over 1 year. Therefore, ENZA is cost-effective compared with AA for all three outcomes evaluated, and the modeled results suggest ENZA is associated with potentially improved clinical outcomes in delaying chemotherapy initiation and disease progression for chemotherapy-naïve patients. The results are robust in sensitivity analyses, where the effect of changes in key model inputs and assumptions were tested., Conclusion: The results modeled in the present study suggest ENZA is cost-effective compared with AA for treating chemotherapy-naïve patients with mCRPC.

Background: Helicobacter pylori (H. pylori) infection is associated with cognitive deficits in humans, an association potentially mediated or moderated by folate concentration or inflammation., Materials and Methods: We used the National Health and Nutrition Examination Survey (NHANES) datasets to examine whether folate concentration or inflammation mediates or moderates the relationship between H. pylori and cognitive function. Models were performed using linear, Poisson, and zero-inflated Poisson regression, and we performed separate analyses for groups aged 20-59 and 60-90 years with sample sizes ranging from 700 to 1700., Results: We did not find evidence of mediation in either age group. In the 20- to 59-year group, interactions between H. pylori and ferritin (p values ranging from .004 to .039) were associated with worse processing speed, better working memory, and worse reaction time. Interactions between H. pylori and fibrinogen (p values ranging from .023 to .045), C-reactive protein (CRP) (p = .023), and the inflammatory index (p = .045) were associated with worse processing speed. In 60- to 90-year-olds, H. pylori interacted with ferritin and the inflammatory index to predict fewer mathematical errors (p values of .036 and .023). Interactions with folate (p values of .016 and .006) and C-reactive protein (p values ranging from <.001 to .048) were inconsistent in directionality., Conclusions: In this dataset, representative of the US population, inflammation and folate concentrations moderated but did not mediate the association between H. pylori seropositivity and cognition., (© 2016 John Wiley & Sons Ltd.)