The impact of co-occurring mental health problems on referral to and initiation of treatment among youth under probation supervision: Findings from a cluster randomized trial.

INTRODUCTION: Many youth under community supervision have substance use and co-occurring mental health issues. Yet, access to treatment is limited, and many programs cannot address co-occurring disorders. This study examines how co-occurring symptoms among youth on probation affect referral to and initiation of treatment. We hypothesize that both referral and initiation rates will be lower for youth with any co-occurring indicators. METHODS: This study collected administrative data from 14 sites in three states between March 2014 and November 2017 using JJ-TRIALS, a cluster randomized trial. Among 8552 youth in need of treatment (screened as having a substance use problem, drug possession arrest, positive drug test, etc.), 2069 received a referral to treatment and 1630 initiated treatment among those referred. A co-occurring indicator (n = 2828) was based on symptoms of an internalizing and/or externalizing issue. Descriptive analyses compared referral and initiation by behavioral health status. Two-level mixed effects logistic regression models estimated effects of site-level variables. RESULTS: Among youth in need with co-occurring internal, external, or both indicators, only 16 %, 18 %, and 20 % were referred to treatment and of those referred, 63 %, 69 %, and 57 % initiated treatment, respectively. Comparatively, 27 % and 83 % of youth with a substance use only indicator were referred and initiated treatment respectively. Multi-level multivariate models found that, contrary to our hypothesis, co-occurring-both (p = 0.00, OR 1.44) and co-occurring-internal indicators (p = 0.06, OR 1.25) predicted higher referral but there were no differences in initiation rates. However, there was substantial site-level variation. CONCLUSIONS: Youth on probation in need of substance use treatment with co-occurring issues have low referral rates. Behavioral health status may influence youth referral to treatment depending on where a youth is located. Depending on the site, there may be a lack of community programs that can adequately treat youth with co-occurring issues and reduce unmet service needs.

Reducing psychiatric illness in the perinatal period: A review and commentary.

This brief overview highlights the global crisis of perinatal psychiatric illness (PPI). PPI is a major contributor to many adverse pregnancy, childbirth, and childhood development outcomes. It contributes to billions of dollars in spending worldwide each year and has a significant impact on the individual, their family, and their community. It is also highly preventable. Current recommendations for intervention and management of PPI are limited and vary considerably from country to country. Furthermore, there are several significant challenges asso-ciated with implementation of these recommendations. These challenges are magnified in number and consequence among women of color and/or minority populations, who experience persistent and negative health disparities during pregnancy and the postpartum period. This paper aims to provide a broad overview of the current state of recommendations and implementation challenges for PPI and layout a framework for overcoming these challenges. An equity-informed model of care that provides universal intervention for pregnant women may be one solution to address the preventable consequences of PPI on child and maternal health. Uniquely, this model emphasizes the importance of managing and eliminating known barriers to traditional health care models. Culturally and contextually specific challenges must be overcome to fully realize the impact of improved management of PPI.

Monounsaturated and Diunsaturated Fatty Acids Sensitize Cervical Cancer to Radiation Therapy.

Obesity induces numerous physiological changes that can impact cancer risk and patient response to therapy. Obese patients with cervical cancer have been reported to have superior outcomes following chemoradiotherapy, suggesting that free fatty acids (FFA) might enhance response to radiotherapy. Here, using preclinical models, we show that monounsaturated and diunsaturated FFAs (uFFA) radiosensitize cervical cancer through a novel p53-dependent mechanism. UFFAs signaled through PPARγ and p53 to promote lipid uptake, storage, and metabolism after radiotherapy. Stable isotope labeling confirmed that cervical cancer cells increase both catabolic and anabolic oleate metabolism in response to radiotherapy, with associated increases in dependence on mitochondrial fatty acid oxidation for survival. In vivo, supplementation with exogenous oleate suppressed tumor growth in xenografts after radiotherapy, an effect that could be partially mimicked in tumors from high fat diet-induced obese mice. These results suggest that supplementation with uFFAs may improve tumor responses to radiotherapy, particularly in p53 wild-type tumors. SIGNIFICANCE: Metabolism of monounsaturated and diunsaturated fatty acids improves the efficacy of radiotherapy in cancer through modulation of p53 activity. See related commentary by Jungles and Green, p. 4513.

Phase I Trial of Stereotactic MRI-Guided Online Adaptive Radiation Therapy (SMART) for the Treatment of Oligometastatic Ovarian Cancer.

PURPOSE: Stereotactic body radiation therapy is increasingly used to treat a variety of oligometastatic histologies, but few data exist for ovarian cancer. Ablative stereotactic body radiation therapy dosing is challenging in sites like the abdomen, pelvis, and central thorax due to proximity and motion of organs at risk. A novel radiation delivery method, stereotactic magnetic-resonance-guided online-adaptive radiation therapy (SMART), may improve the therapeutic index of stereotactic body radiation therapy through enhanced soft-tissue visualization, real-time nonionizing imaging, and ability to adapt to the anatomy-of-the-day, with the goal of producing systemic-therapy-free intervals. This phase I trial assessed feasibility, safety, and dosimetric advantage of SMART to treat ovarian oligometastases. METHODS AND MATERIALS: Ten patients with recurrent oligometastatic ovarian cancer underwent SMART for oligometastasis ablation. Initial plans prescribed 35 Gy/5 fractions with goal 95% planning target volume coverage by 95% of prescription, with dose escalation permitted, subject to strict organ-at-risk dose constraints. Daily adaptive planning was used to protect organs-at-risk and/or increase target dose. Feasibility (successful delivery of >80% of fractions in the first on-table attempt) and safety of this approach was evaluated, in addition to efficacy, survival metrics, quality-of-life, prospective timing and dosimetric outcomes. RESULTS: Ten women with seventeen ovarian oligometastases were treated with SMART, and 100% of treatment fractions were successfully delivered. Online adaptive plans were selected at time of treatment for 58% of fractions, due to initial plan violation of organs-at-risk constraints (84% of adapted fractions) or observed opportunity for planning target volume dose escalation (16% of adapted fractions), with a median on-table time of 64 minutes. A single Grade ≥3 acute (within 6 months of SMART) treatment-related toxicity (duodenal ulcer) was observed. Local control at 3 months was 94%; median progression-free survival was 10.9 months. Median Kaplan-Meier estimated systemic-therapy-free survival after radiation completion was 11.5 months, with concomitant quality-of-life improvements. CONCLUSIONS: SMART is feasible and safe for high-dose radiation therapy ablation of ovarian oligometastases of the abdomen, pelvis, and central thorax with minimal toxicity, high rates of local control, and prolonged systemic-therapy-free survival translating into improved quality-of-life.

An Emergency Preparedness Response to Opioid-Prescribing Enforcement Actions in Maryland, 2018-2019.

Federal and state enforcement authorities have increasingly intervened on the criminal overprescribing of opioids. However, little is known about the health effects these enforcement actions have on patients experiencing disrupted access to prescription opioids or medication-assisted treatment/medication for opioid use disorder. Simultaneously, opioid death rates have increased. In response, the Maryland Department of Health (MDH) has worked to coordinate mitigation strategies with enforcement partners (defined as any federal, state, or local enforcement authority or other governmental investigative authority). One strategy is a standardized protocol to implement emergency response functions, including rapidly identifying health hazards with real-time data access, deploying resources locally, and providing credible messages to partners and the public. From January 2018 through October 2019, MDH used the protocol in response to 12 enforcement actions targeting 34 medical professionals. A total of 9624 patients received Schedule II-V controlled substance prescriptions from affected prescribers under investigation in the 6 months before the respective enforcement action; 9270 (96%) patients were residents of Maryland. Preliminary data indicate fatal overdose events and potential loss of follow-up care among the patient population experiencing disrupted health care as a result of an enforcement action. The success of the strategy hinged on endorsement by leadership; the establishment of federal, state, and local roles and responsibilities; and data sharing. MDH's approach, data sources, and lessons learned may support health departments across the country that are interested in conducting similar activities on the front lines of the opioid crisis.

Genomic Characterization and Therapeutic Targeting of HPV Undetected Cervical Carcinomas.

Cervical cancer tumors with undetectable HPV (HPVU) have been underappreciated in clinical decision making. In this study, two independent CC datasets were used to characterize the largest cohort of HPVU tumors to date (HPVU = 35, HPV+ = 430). Genomic and transcriptome tumor profiles and patient survival outcomes were compared between HPV+ and HPVU tumors. In vitro analyses were done to determine efficacy of the selective CDK4/6 inhibitor palbociclib on HPVU cancer cell lines. Patients with HPVU CC tumors had worse progression-free and overall survival outcomes compared to HPV+ patients. TP53, ARID1A, PTEN, ARID5B, CTNNB1, CTCF, and CCND1 were identified as significantly mutated genes (SMGs) enriched in HPVU tumors, with converging functional roles in cell cycle progression. In vitro HPVU, but not HPV+, cancer cell lines with wild type RB1 were sensitive to palbociclib monotherapy. These results indicate that HPVU status can be translated into the clinic as a predictive biomarker of poor patient response to standard of care treatments. We suggest primary cervix tumors be routinely tested for HPV prior to treatment to identify patients who will benefit from more aggressive precision-driven therapy. Our results identify palbociclib as a lead candidate as an alternative treatment strategy for HPVU CC patients.

Holding on to pieces of the past: Daily reports of nostalgia in a life-span sample.

Nostalgia, the fond remembrance of one's past, is a common experience hypothesized to increase across the life span. Yet data on the specific features of nostalgia, such as daily frequency and associated affect, are scarce. This study sought to address this limitation by assessing the daily experience of nostalgia using experience-sampling methods. A life-span sample of 108 participants (47 young, 31 middle-aged, and 30 older adults) completed a 2-week, twice-daily experience-sampling study that yielded data describing the frequency and emotions of everyday nostalgia. Multilevel logistic regression analyses supported increased nostalgia frequency at every life stage: Young adults were 60% less likely to report nostalgia compared with middle-aged adults (odds ratio [OR] = .40), whereas older adults were 3 times more likely than middle-aged adults to report nostalgia (OR = 3.05). Additionally, the experience of nostalgia was associated with significant heterogeneity in positive and negative affect. Approximately 72% of participants experienced an increase in positive affect, and 51% experienced an increase in negative affect. For young and middle-aged adults, a change in positive affect was associated with a 2-times-larger increase in nostalgia likelihood, whereas a change in negative affect was more strongly associated with a nostalgia experience in older adults. The current study provides increased evidence for the affectively mixed nature of nostalgia and how the affective pattern differs for adults of different ages. Greater nostalgia frequency may be instrumental during life review when individuals make meaning of their lives, fulfilling developmental goals of late adulthood. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Age similarities in matching pro- and contra-hedonic emotional strategies to everyday scenarios.

Older adults are motivated to maximize positive affect in the present. Young adults will purposely feel negative and high arousal emotions in order to achieve a goal. However, this type of contra-hedonic emotional alignment has not been extensively studied with older adults. We expected older adults are less likely than young adults to select high arousal and negative emotions within specific scenarios where those states could be useful. In two studies, participants selected the emotion they preferred in hypothetical problems that varied on the arousal and valence best suited for goal achievement. Young and older adults were equally likely to endorse affective strategies that matched both pro and contra-hedonic scenarios. While older adults may be generally motivated to avoid negative and high-arousing emotions, they are just as likely as young adults to indicate that these states could be helpful in certain situations.

Introducing a Face Sort Paradigm to Evaluate Age Differences in Emotion Perception.

OBJECTIVES: Previous research has uncovered age-related differences in emotion perception. To date, studies have relied heavily on forced-choice methods that stipulate possible responses. These constrained methods limit discovery of variation in emotion perception, which may be due to subtle differences in underlying concepts for emotion. METHOD: We employed a face sort paradigm in which young (N = 42) and older adult (N = 43) participants were given 120 photographs portraying six target emotions (anger, disgust, fear, happiness, sadness, and neutral) and were instructed to create and label piles, such that individuals in each pile were feeling the same way. RESULTS: There were no age differences in number of piles created, nor in how well labels mapped onto the target emotion categories. However, older adults demonstrated lower consistency in sorting, such that fewer photographs in a given pile belonged to the same target emotion category. At the same time, older adults labeled piles using emotion words that were acquired later in development, and thus are considered more semantically complex. DISCUSSION: These findings partially support the hypothesis that older adults' concepts for emotions and emotional expressions are more complex than those of young adults, demonstrate the utility of incorporating less constrained experimental methods into the investigation of age-related differences in emotion perception, and are consistent with existing evidence of increased cognitive and emotional complexity in adulthood.

Ageism and Behavior Change During a Health Pandemic: A Preregistered Study.

The COVID-19 pandemic has led to a suspected surge of ageism in America and has imposed critical health and safety behavior modifications for people of all ages (Ayalon et al., 2020; Lichtenstein, 2020). Given that older adults are a high-risk group, maintaining their safety has been paramount in implementing preventive measures (i.e., more handwashing, social distancing); however, making such behavior modifications might be contingent on how one views older adults (i.e., ageist stereotypes). Therefore, the goal of the current pre-registered study was to explore if hostile and benevolent ageism relate to pandemic-related fear and behavior change. An online survey assessing responses to the pandemic was taken by 164 younger and 171 older adults. Higher hostile ageism predicted lower pandemic-related behavior modification. Those high in benevolent ageism reported lower behavior change, but also reported higher pandemic-related fear; however, when pandemic-related fear was considered a mediator between the two, the directionality between benevolent ageism and behavior change switched, indicating a suppression effect. These findings highlight that ageist attitudes do predict responses to the pandemic and that hostile and benevolent ageism are distinct facets that have unique implications during a health pandemic.

Tumor Microenvironment as a Regulator of Radiation Therapy: New Insights into Stromal-Mediated Radioresistance.

: A tumor is a complex "organ" composed of malignant cancer cells harboring genetic aberrations surrounded by a stroma comprised of non-malignant cells and an extracellular matrix. Considerable evidence has demonstrated that components of the genetically "normal" tumor stroma contribute to tumor progression and resistance to a wide array of treatment modalities, including radiotherapy. Cancer-associated fibroblasts can promote radioresistance through their secreted factors, contact-mediated signaling, downstream pro-survival signaling pathways, immunomodulatory effects, and cancer stem cell-generating role. The extracellular matrix can govern radiation responsiveness by influencing oxygen availability and controlling the stability and bioavailability of growth factors and cytokines. Immune status regarding the presence of pro- and anti-tumor immune cells can regulate how tumors respond to radiation therapy. Furthermore, stromal cells including endothelial cells and adipocytes can modulate radiosensitivity through their roles in angiogenesis and vasculogenesis, and their secreted adipokines, respectively. Thus, to successfully eradicate cancers, it is important to consider how tumor stroma components interact with and regulate the response to radiation. Detailed knowledge of these interactions will help build a preclinical rationale to support the use of stromal-targeting agents in combination with radiotherapy to increase radiosensitivity.

Single-Institution Phase 1/2 Prospective Clinical Trial of Single-Fraction, High-Gradient Adjuvant Partial-Breast Irradiation for Hormone Sensitive Stage 0-I Breast Cancer.

PURPOSE: We sought to evaluate the feasibility and tolerability of a novel accelerated partial breast irradiation regimen delivered in a single fraction postoperatively. METHODS AND MATERIALS: We enrolled 50 patients with low-risk, hormone-sensitive breast cancer from 2015 to 2018 on a prospective phase 1/2 trial to receive single-fraction, high-gradient partial-breast irradiation (SFHGPBI) 2 to 8 weeks after lumpectomy for node-negative, invasive, or in situ breast cancer. The high gradient was achieved by prescribing 20 Gy to the surgical bed and 5 Gy to the breast tissue within 1 cm of the surgical bed simultaneously in 1 fraction using external beam. RESULTS: The median age was 65 (range, 52-84). Ten patients (20%) had small-volume ductal carcinoma in situ while the remainder had stage I disease. At a median follow-up of 25 months, we evaluated toxicity, patient- and physician-reported cosmesis, patient-reported quality of life (QOL), and initial tumor control. There was no Common Terminology Criteria for Adverse Events v4.0 grade 3+ toxicity. Only 34% of patients experienced grade 1 erythema. Good-to-excellent pretreatment cosmesis was present in 100% and 98% per physicians and patients, respectively, and did not change post-SFHGPBI. Quantitative cosmesis by percentage of breast retraction assessment significantly improved over time during the post-SFHGPBI period per mixed repeated measures modeling (P = .0026). QOL per European Organization for Research and Treatment of Cancer QOL Questionnaires C30 and BR-23 did not decline other than temporarily in the systemic therapy effects and hair loss domains, both of which returned to pretreatment values. There was 1 noninvasive in-breast recurrence in a separate untreated quadrant 18 months post-SFHGPBI and 1 isolated axillary recurrence 30 months post-SFHGPBI, both salvaged successfully. There were no distant recurrences or cancer-related deaths observed. CONCLUSIONS: Accelerated partial-breast irradiation delivered in a single fraction postoperatively using external beam techniques is a novel, feasible, well-tolerated regimen. SFHGPBI does not adversely affect cosmesis or QOL as reported by both physicians and patients. Initial tumor control rates are excellent, with longer follow-up required to confirm efficacy.

Age Differences in Preferences for Fear-Enhancing Vs. Fear-Reducing News in a Disease Outbreak.

Older adults (OA) prefer positive over negative information in a lab setting, compared to young adults (YA; i.e., positivity effects). The extent to which OA avoid negative events or information relevant for their health and safety is not clear. We first investigated age differences in preferences for fear-enhancing vs. fear-reducing news articles during the Ebola Outbreak of 2014. We were able to collect data from 15 YA and 13 OA during this acute health event. Compared to YA, OA were more likely to read the fear-enhancing article, select hand-sanitizer over lip balm, and reported greater fear of Ebola. We further investigated our research question during the COVID-19 pandemic with 164 YA (18-30 years) and 171 OA (60-80 years). Participants responded to an online survey about the COVID-19 pandemic across 13 days during the initial peak of the pandemic in the United States (U.S.). Both YA and OA preferred to read positive over negative news about the coronavirus, but OA were even more likely than YA to prefer the positive news article. No age differences in the fear of contraction were found, but OA engaged in more health-protective behaviors compared to YA. Although OA may not always report greater fear than YA or seek out negative information related to a health concern, they still engage in protective health behaviors. Thus, although positivity effects were observed in attention and emotional reports (in the COVID-19 study), OA still modified their behaviors more than YA (giveaway in both studies, and health-protective behavior change in the COVID-19 study), suggesting that positivity effects did not hamper OA ability to respond to a health crisis.

"We" Before "Me": Differences in Usage of Collectivistic and Individualistic Language Influence Judgments of Electability and Performance.

OBJECTIVES: Older adults are often judged to be warm, but not competent, which contradicts their representation in positions of authority. This study sought to extend evidence of age differences in more individualistic (e.g., "I") and collectivistic (e.g., "we") language and explore their impact on judgments of performance and electability. METHOD: Speeches from young and older adults who campaigned for a fictitious position were analyzed using Linguistic and Inquiry Word Count Software. Words fitting specified categories (e.g., pronouns, affect) were compared to outcome judgments obtained from trained coders on the dimensions of performance and electability. RESULTS: Older adults used significantly more "we"-language. Young adults used more "I"-language, and more positive affect, achievement, and power language. Language choices and coder judgments were associated such that the more "I"-language that was used during the speech, the less electable the candidate was judged. This relationship was not found for "we"-language. DISCUSSION: This study found no evidence for collectivistic language enhancing ratings of electability or performance; however, an age-invariable, negative relationship was obtained between increased individualistic language and reduced coder judgments of electability. This suggests that speakers should minimize "I"-statements to promote electability, a characteristic that is reflected more in older adults' speeches than young.

A comparison of the effectiveness of two types of deceit detection training methods in older adults.

BACKGROUND: In general, people are poor at detecting deception. Older adults are even worse than young adults at detecting deceit, which might make them uniquely vulnerable to certain types of financial fraud. One reason for poor deceit detection abilities is that lay theories of cues to deception are not valid. This study compared the effectiveness of two training methods to improve deceit detection among older adults: valid facial cues versus valid verbal cues to deception. Approximately 150 older adults were randomly assigned to facial training, verbal training, or a control condition. Participants completed a pre-test deceit detection task, their assigned training, and a post-test deceit detection task. RESULTS: Both training groups significantly improved at recognizing their respectively trained cues after training. However, the facial cue training group were less accurate at detecting deception post-test compared to pre-test and the control group exhibited improved accuracy of deceit detection from pre-test to post-test. CONCLUSIONS: These results are consistent with the body of literature on deception suggesting people hover around chance accuracy, even after training. Older adults' facial and verbal cue recognition can be improved with training, but these improvements did not translate into more accurate deceit detection, and actually hampered performance in the facial condition. Older adults showed the most benefit from sheer practice at detecting deception (in the control condition), perhaps because this condition encouraged implicit rather than explicit judgments of deception.

Occult Cervical Avulsion: A Rare Cause of Intrapartum Vaginal Bleeding.

BACKGROUND: Cervical avulsion, complete or partial, is a rare intrapartum complication that can go unrecognized without proper physician vigilance. CASES: Case 1 is a 32-year-old multiparous woman admitted for induction of labor at 37 2/7 weeks for abnormal antenatal testing. Case 2 is a 22-year-old multiparous woman at 29 0/7 with spontaneous preterm labor 10 days after cerclage removal for preterm contractions. Vaginal bleeding and fetal heart rate decelerations complicated each patient's intrapartum course. Annular cervical detachment noted at time of delivery resulted in partial or complete amputation of the cervix. Both women recovered well postpartum. CONCLUSION: This rare phenomenon should be considered in the differential of intrapartum vaginal bleeding to avoid a missed or delayed diagnosis.

Intrauterine Foley Balloon Catheter to Manage Acute Heavy Menstrual Bleeding in a Perimenarchal 10-Year-Old Girl.

BACKGROUND: Intrauterine balloon tamponade is commonly used to treat postpartum hemorrhage refractory to pharmacologic interventions. It has not been well-studied in girls or adolescents for treatment of acute heavy menstrual bleeding. CASE: A 10-year old girl presented with heavy menstrual bleeding that did not respond to medical management. Placement of a Foley catheter for intrauterine tamponade was used to control bleeding. She was subsequently diagnosed with a platelet function disorder. CONCLUSION: Foley catheter placement is a low-risk, low-cost, and readily accessible option for intrauterine tamponade to consider for young girls and adolescents with acute heavy menstrual bleeding resistant to medical management.

An Age-Friendly University (AFU) assists with technology learning and social engagement among older adults and individuals with developmental disabilities.

As an Age-Friendly University (AFU), University of Akron is striving to support lifelong learning. A collaborative research effort developed between aging researchers at the university and a government-sponsored pilot program aimed to provide learning opportunities for older adults (OA) and engagement for individuals with developmental disabilities (IDD). The present study assessed the success of a pilot program to increase comfort with technology and community engagement. OA and IDD participants met twice a month for 9 months to discuss how to use technology (e.g., an IPad). We assessed satisfaction, perceived changes in comfort with technology, perceived changes in connection with others, and motivations for participating with questionnaires and a structured interview. On average, participants reported very high satisfaction with the group, and moderate increases in comfort with technology and how connected they feel to others as a result of participating in the group. The most common motivations for participation were related to values, strengthening social ties, seeking to learn, and bringing joy to others. These findings suggest that the pilot was successful at improving community engagement. The involvement of the university in the assessment of this pilot program situates the university as an age-friendly partner for community efforts to support lifelong learning.

Identification of 5-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)thiophene-2-Carboxamides as Novel and Selective Monoamine Oxidase B Inhibitors Used to Improve Memory and Cognition.

Initial work in Drosophila and mice demonstrated that the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) is a master control gene for memory formation. The relationship between CREB and memory has also been found to be true in other species, including aplysia and rats. It is thus well-established that CREB activation plays a central role in memory enhancement and that CREB is activated during memory formation. On the basis of these findings, a phenotypic high-throughput screening campaign utilizing a CRE-luciferase (CRE-Luci) SK-N-MC cell line was performed to identify compounds that enhance transcriptional activation of the CRE promoter with a suboptimal dose of forskolin. A number of small-molecule hits of unknown mechanisms of action were identified in the screening campaign, including HT-0411. Follow-up studies suggested that the CREB activation by HT-0411 is attributed to its specific and selective inhibition of monoamine oxidase B (MAO-B). Further, HT-0411 was shown to improve 24 h memory in rodents in a contextual fear conditioning model. This report describes the lead optimization of a series of 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl) thiophene-2-carboxamides that were identified as novel, potent, and selective inhibitors of MAO-B. Extensive SAR studies and in vivo behavioral evaluations of this and other related analogue series identified a number of potential clinical development candidates; ultimately, compound 8f was identified as a candidate molecule with high selectivity toward MAO-B (29-56 nM) over MAO-A (19% inhibition at a screening concentration of 50 µM), an excellent profile against a panel of other enzymes and receptors, good pharmacokinetic properties in rodents and dogs, and efficacy in multiple rodent memory models.