bluuebunny/crossref_metadata_2025 huggingface dataset:
Bi-cross validation of spectral clustering hyperparameters
Authors: Zohar Sioan , Yoon Chun Hong
Published: April 2020

One challenge impeding the analysis of terabyte scale X-ray scattering data from the Linac Coherent Light Source (LCLS) is determining the number of clusters required for the execution of traditional clustering algorithms. Here, we demonstrate that the previous work using bi-cross validation to determine the number of singular vectors directly maps to the spectral clustering problem of estimating both the number of clusters and hyperparameter values. Applying this method to LCLS X-ray scattering data enables the identification of dropped shots without manually setting boundaries on detector fluence and provides a path toward identifying rare and anomalous events.
Impacts of invasive rats and tourism on a threatened island bird: the Palau Micronesian Scrubfowl
Authors: RADLEY PAUL M. , DAVIS ROBERT A. , DOHERTY TIM S.
Published: April 2020

Invasive predators have decimated island biodiversity worldwide. Rats (Rattus spp.) are perhaps the greatest conservation threat to island fauna. The ground nesting Palau Micronesian Scrubfowl Megapodius laperouse senex (Megapodiidae) inhabits many of the islands of Palau’s Rock Island Southern Lagoon Conservation Area (RISL) in the western Pacific. These islands are also heavily visited by tourists and support populations of introduced rats, both of which may act as added stressors for the scrubfowl. Using passive chew-tag and call playback surveys on five tourist-visited and five tourist-free islands, we investigated if rats and tourists negatively affect scrubfowl, and if higher rat activity is associated with tourist presence. Rat detection probability and site occupancy were significantly higher on tourist visited (89% and 99%, respectively) compared to tourist-free islands (52% and 73%). Scrubfowl were detected at significantly more stations on tourist-free (93%) than tourist visited (47%) islands and their relative abundance was higher (2.66 and 1.58 birds per station, respectively), although not statistically significantly. While rat occupancy probability likewise had a non-significant negative effect on scrubfowl numbers across islands, our results show a negative relationship between tourist presence and scrubfowl in the RISL. Our findings also suggest that rat populations may be augmented by tourist visitation in the RISL. Although this situation may not seriously affect the scrubfowl, it may be highly detrimental to populations of other threatened island landbirds.
Hieroglyphic Texting: Ideologies and Practices of Classic Maya Written Evidence
Authors: Jackson Sarah E.
Published: April 2020

Given current interests in indigenous ontologies and multiple worldviews, archaeologists drawing on textual evidence must more fully contextualize ancient texts according to how they were perceived and experienced, and understood as capable, in the cultures that created them. This endeavour has methodological impacts for modern interpretations, shifting how we interpret textual evidence as a result of how written realities and histories might have been conceptualized in the past. I examine these topics through the case study of the Classic Maya (250–900ad, Mexico and Central America), using imagery on painted ceramic vessels. I examine how the Classic Maya understood text and writing, asking: how were texts perceived? How did people relate to them? What capabilities were texts understood to have? Based on observations gleaned from the ways in which glyphs are shown, the ways people are shown interacting with them and the work that glyphs apparently accomplish, I argue that the Classic Maya understood texts to be real, relational and persistent. This article suggests a new direction for archaeological thinking about ancient written sources, complementary to other interpretive approaches to texts, by exploring productive possibilities that emerge when we take ancient experiential perspectives into account.
102 Extracurricular Activity Involvement and Depression Among High School Students
Authors: Waler Alex , Taliaferro Lindsay
Published: April 2020

Introduction:

While physical activity has been shown to promote positive mental health and aid in treatment, the association between involvement in other activities and depressive symptoms among adolescents remains unclear. We sought to fill a gap in the literature by examining relationships between involvement in sports, art, and leadership activities during high school and depressive symptoms among adolescents. Hypothesis: We hypothesized that all types of involvement would be associated with lower levels of depressive symptoms.

Methods:

We performed a secondary data analysis using the 2016 Minnesota Student Survey, a population-based survey of students in grades 9 and 11 (N=81,885). Descriptive sample statistics (e.g., frequencies) and chi-square tests, stratified by sex, were used to examine relationships between depressive symptoms and involvement in different extracurricular activities among males and females. Analyses were performed using SPSS.

Results:

For males and females, involvement in sports was associated with lower levels of depression, compared to non-involvement. Compared to males who did not participate in arts (16.6%), those who did were significantly more likely to report depressive symptoms (21.2%). In addition, females involved in leadership activities were significantly less likely to report depressive symptoms (21.9%) than those who were not involved in these activities (28.7%). Consistent with previous research, females were more likely to report depressive symptoms than males. Females also were more likely to participate in arts and leadership activities.

Conclusion:

For males and females, sports participation, and for females, involvement in leadership activities, may represent protective factors against depressive symptoms during adolescence. However, clinicians might consider inquiring about depressive symptoms among adolescent males involved in art-related activities.
112 A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study (P302): Efficacy and Safety of Extended-Release Viloxazine in Adolescents with ADHD
Authors: Nasser Azmi , Hull Joseph T. , Chowdhry Fatima A. , Adewole Toyin , Liranso Tesfaye , Schwabe Stefan
Published: April 2020

Study Objective:

SPN-812 (extended-release viloxazine) is a structurally distinct, bicyclic, Serotonin Norepinephrine Modulating Agent (SNMA) in development as a treatment for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. This Phase 3, randomized, double-blind study (P302) evaluated the efficacy and safety of once-daily SPN-812 at doses of 200 and 400 mg compared to placebo in adolescents ages 12-17yrs with ADHD.

Method:

Inclusion criteria required subjects have a confirmed Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) ADHD diagnosis, ADHD-Rating Scale-5 (ADHD-RS-5) score ≥28, Clinical Global Impression-Severity score ≥4, and be free of ADHD medication ≥1 week before randomization. This investigation was conducted at 34 study sites in the United States. Subjects (N=310) were randomized 1:1:1 to placebo:200 mg SPN-812:400 mg SPN-812. The treatment period included up to 1 week of titration and 5 weeks of maintenance (intent-to-treat population: N=301; placebo=104, 200 mg=94, 400 mg=103). The primary efficacy endpoint was change from baseline (CFB) at end of study (EOS) in ADHD-RS-5 total score. Key secondary endpoints included Clinical Global Impression-Improvement (CGI-I) score at EOS, and CFB at EOS in Conners 3-Parent Short Form (Conners 3-PS) Composite T-score and Weiss Functional Impairment Rating Scale-Parent Form (WFIRS-P) total average score. Safety assessments included adverse events (AEs), laboratory tests, vital signs, physical exams, electrocardiograms, and the Columbia-Suicide Severity Rating Scale.

Results:

Compared to placebo, a significantly greater improvement in ADHD-RS-5 total score was observed in the 200 mg and 400 mg SPN-812 treatment group at EOS (p=0.0232, p=0.0091; respectively). Significant improvement in CGI-I score at EOS for both 200 mg and 400 mg SPN-812 compared to placebo was also observed (p=0.0042, p=0.0003; respectively). No significant change was observed at either dose compared to placebo in the Conners 3-PS Composite T-score (p=0.6854, p=0.0518; respectively), or the WFIRS-P total average score (p=0.2062, p=0.0519; respectively). The most common (≥5%) treatment-related AEs were somnolence, decreased appetite, fatigue, headache, and nausea.

Conclusions:

In this study, SPN-812 met the primary objective for both the 200 and 400 mg doses, and a key secondary objective (CGI-I) for both the 200 and 400 mg doses. AE-related dropouts were ≤5%, indicating SPN-812 treatment was well tolerated.

This study is an encore of a poster presentation at the 2019 Annual Meeting of the American Academy of Child and Adolescent Psychiatry (AACAP).

Funding Acknowledgements:

This research was funded by Supernus Pharmaceuticals, Inc., Rockville, MD.
119 Assessment of Health-Related Quality of Life and Health Status in Patients with Treatment-resistant Depression
Authors: Jamieson Carol , Popova Vanina , Daly Ella , Cooper Kimberly , Trivedi Madhukar H. , Drevets Wayne , Singh Jaskaran
Published: April 2020

Objective:

To assess health-related quality of life (HRQoL) and health status of patients with treatment resistant depression (TRD), treated with esketamine nasal spray+oral antidepressant (ESK+AD) vs oral antidepressant+placebo nasal spray (AD+PBO) using European Quality of Life Group-5-Dimension-5-Level (EQ-5D-5L). The EQ-5D-5L descriptive system consists of five domains relevant for patients with depression (mobility, self-care, usual activities, pain, anxiety/depression) and the EQ-Visual Analogue Scale (EQ-VAS).

Methods:

Data from TRANSFORM-2 (NCT02418585), a randomized, double-blind short-term study were analyzed. Patients (18-64 years inclusive) with TRD were included. Patient reported health status change using EQ-5D-5L and EQ-VAS was measured from baseline to end of 4-week induction phase (endpoint). Each domain of EQ-5D-5L included 5 levels of perceived problems (L1: no problems; L5: extreme problems).

Results:

Full analysis set included 223 patients (ESK+AD: 114; AD+PBO: 109). At endpoint, mean (SD) change in health status index was 0.288 (0.2317) for ESK+AD group and 0.231 (0.2506) for AD+PBO group with higher score reflecting higher levels of functioning. At endpoint, percentage of patients reporting problems (grouped L2-L5 responses for each dimension) in ESK+AD vs AD+PBO group: mobility (13.5% vs 25.7%), self-care (16.2% vs 30.5%), usual activities (55.0% vs 71.4%), pain (38.7% vs 52.4%), and anxiety/depression (71.2% vs 78.1%). Mean (SD) change in EQ-VAS score at endpoint was 29.1 (26.32) for ESK+AD and 20.9 (26.60) for AD+PBO group.

Conclusion:

Greater improvement in HRQoL and health status using EQ-5D-5L and EQ-VAS was observed among patients with TRD treated with ESK+AD vs AD+PBO.

Funding Acknowledgements:

This study was sponsored by Janssen Research and Development, LLC.
122 Burning Mouth Syndrome as a Focus of Delusion
Authors: Winchester Chevelle , Hirsch Alan
Published: April 2020

Background:

Parasitosis is a fixed belief of being infested with pathogens against all medical evidence [Freudenmann RW, Lepping P, 2009] Method: Case Report: A 53 year old right handed female presented with progressively severe BMS for 1 years. She noticed that aromas would project from her nose into her mouth and would experience this taste for days. Looking at the source of the odor would precipitate her to sense the smell of the product, immediately followed by the taste and then burning of the tongue, mouth and vagina. Fumes would eminent from her mouth, nose and anus. Five days prior she stopped eating and drinking. She had not brushed her teeth, showered, nor bathed for 3 weeks. Odors smell like ammonia and blood, which upon inhalation, effuse into her mouth which tastes like chemicals. Thereupon, she immediately experiences burning of her tongue and palate.

Results:

Abnormalities: Disheveled: Cacosmious. Personal hygiene poor. Facial expression odd and inappropriate. Loud but low quantity of speech. Unable to interpret similarities or proverbs. Calculation: poor.

Conclusion:

In those who present with BMS, query as to the delusional nature of their symptoms is warranted and may suggest a treatment strategy.
155 Symptom Stability in de Novo and Rollover Patients with Bipolar I Disorder Receiving Aripiprazole Once-monthly in a 52-Week, Open-label Study
Authors: Madera Jessica J , Such Pedro , Chen Maxine , Baker Ross A
Published: April 2020

Introduction:

Long-term maintenance treatment is essential in management of bipolar I disorder (BP-I) to achieve mood stability, prevent recurrence of mood episodes and improve functioning. Aripiprazole once-monthly 400 mg (AOM 400) is a long-acting formulation of aripiprazole for maintenance treatment of BP-I. In a double-blind, placebo-controlled, randomized withdrawal study in adult patients with BP-I after a manic episode (NCT01567527), AOM 400 delayed time to and reduced rate of recurrence of mood episodes and was safe and well tolerated (1). In an open-label, long-term safety study (NCT01710709), AOM 400 was safe and effective as long-term maintenance treatment (2).

Objective:

To evaluate the effect of long-term AOM 400 maintenance treatment on manic and depressive symptoms in BP-I patients from the open-label, long term safety study.

Methods:

Manic and depressive symptoms were assessed post-hoc by analysis of change from study entry in the Young-Mania Rating Scale (YMRS) and Montgomery-Åsberg Depression Rating Scale (MADRS) total scores and line item scores. The mean changes from baseline at last visit in YMRS and MADRS total scores, and single items were calculated using descriptive statistics, using last observation carried forward for total scores and observed cases for single items.

Results:

A total of 464 patients entered the maintenance phase: 379 were de novo and 85 were rollover patients who completed the double-blind, placebo-controlled withdrawal study. Overall, 63% (291/464) completed 52 weeks of open-label treatment. Mean YMRS and MADRS total scores were minimally changed from baseline (YMRS: 2.31, endpoint change -0.30; MADRS: 3.23, endpoint change +1.24) across the study in the total population.

Conclusion:

Patients entering an open-label safety study with stable manic and depressive symptoms maintained stability in both types of symptoms, as shown by minimal mean changes from baseline in YMRS and MADRS scores, suggesting that treatment with AOM 400 is effective in preventing re-emergence of both manic and depressive symptoms.

Funding Acknowledgements:

The study was supported by Otsuka Pharmaceutical Development & Commercialization, Inc.
157 Systematic Review: An Educational Strategy to Improve Medication Compliance and Decrease Hospital Readmission Among Adolescents with Bipolar Disorder
Authors: Reyes Madeleine , Buscemi Charles P.
Published: April 2020

The existence of bipolar disorder (BD) among teenagers is controversial. The study aims to review a number of studies regarding the diagnosis of BD in children and teenagers. The prevalence of BD-I is similar throughout many countries, apart from subsyndromal BD, with an estimated 1-3% of teenagers suffering from this illness. Both the presence of subsyndrome BD and full BD have a strong link with psychological difficulties and high risk for use of substances, issues related to legal utilization of services, and suicidality. Diagnosing BD in teenagers is difficult. Therefore, it requires a critical understanding of development stages, evaluation, and accurate recognition and diagnosis. If treatments are delayed, poor outcomes can result. Eight studies were conducted to evaluate the results, based on practices of increasing medical compliance and minimizing hospital readmission among youths with BD. Randomized trial of family-focused therapy was used to determine early interventions for symptomatic teenagers at risk for BD.
161 The NeuroStar Outcomes Registry
Authors: Mina Miriam , Hutton Todd , Heart Karen
Published: April 2020

Objective:

NeuroStar® Advanced Therapy System is an effective acute treatment for patients with major depressive disorder (MDD). To further understand the efficacy of the NeuroStar in a clinical setting, Neuronetics has established the largest patient treatment and outcomes registry for Major Depressive Disorder (MDD) to collect and analyze the efficacy of transcranial magnetic stimulation (TMS) on patients receiving NeuroStar treatment.

Methods:

Individual NeuroStar providers are invited to participate in the registry and over 100 clinical practice sites have agreed to provide their de-identified patient treatment data. An integrated electronic data management system (TrakStar) allows for large-scale data collection to be automated. The data collected for the registry include Demographic Elements (age, gender), Treatment Parameters, and Clinical Ratings. Clinical assessments performed at baseline and the end of acute treatment are the Patient Health Questionnaire 9-item (PHQ-9) and the Clinician Global Impression - Severity of Illness (CGI-S). De-identified patient data is uploaded to a Registry server; an independent statistical service then creates final data reports.

Results:

Over 3300 evaluable patients have entered the NeuroStar Outcomes Registry since September 2016. The population is 64% female with a mean patient age of 47.8 (SD±16.9); Mean baseline PHQ-9 is 19.0 (SD±5.0). Response & remission rate on PHQ-9 is 63% & 33%, and on CGI-S was 76% & 54%, respectively.

Conclusions:

For the over 3300 patients in the Outcomes Registry, approximately 2/3 patients achieve response and 1/3 patients achieve remission with an acute course of NeuroStar TMS. These treatment outcomes are consistent with previous open-label study data (Carpenter et al., 2012) using the NeuroStar system. The NeuroStar Outcomes Registry is ongoing and has surpassed Star*D dataset (Rush et al., 2006) with over 3300 evaluable patients from more than 100 clinical sites in 3 years.

Funding Acknowledgements:

Funding: Neuronetics, Inc.
162 Post-lithium Delirious Mania in Patients with Bipolar Disorder
Authors: Zaidi Muhammad , Champ Michael , Brown Aquanette , Dimitrova Tzvetelina
Published: April 2020

Delirious mania is a life-threatening condition, presenting with symptoms of acute delirium and psychotic mania as a complication of medical or psychiatric condition. It is not recognized as a diagnosis in DSM-V and is under recognized in clinical practice. It was first described by Calmeil (Calmeil, 1832). In 1849 Luther Bell described 40 cases with an associated 75% mortality rate. More recently, Jacobowski et al (2013) compiled a comprehensive review of clinical characteristics, diagnostic work up, and treatment recommendations for delirious mania. In addition to acute onset, clinical course is frequently worsened by psychosis and catatonia. Delirium leads to disequilibrium of neurotransmitters, particularly depletion of acetylcholine and elevation of dopamine.

Lithium has been used for the treatment of mania for many decades. Suppes et al performed a meta-analysis of 14 studies including 257 patients with Bipolar I disorder and concluded that patients relapsed 28 times more when stopping lithium compared to those who continued this medication. Baldessarini et al (1999) completed analysis of 227 patients with Bipolar I and II disorders, dividing the sample into “abrupt” (1-14 days) and “gradual” (15-30 days) discontinuation groups and concluded that the frequency of relapse following “abrupt” cessation was four times higher compared to following “gradual” cessation. In a study of 450 bipolar patients, Baldessarini et al (2003) reviewed the long-term treatment of lithium as monotherapy (86 % of the study’s population) in the context of lithium maintenance population morbidity. Greater pretreatment morbidity lead to larger relative reduction in morbidity as a result of treatment with lithium. A subgroup of bipolar patients with “abrupt” discontinuation became refractory when re-challenged with lithium.

Describing three clinical cases of delirious mania following conclusions can be derived:

•

Patients with bipolar disorder and comorbid chronic kidney injury currently or formerly receiving long-term therapy with lithium are at increased risk for delirious mania.

•

Abrupt lithium discontinuation in patients with bipolar disorder and comorbid chronic medical conditions (especially chronic kidney disease) increases risk for mania refractory to conventional treatment with medications.

•

In such patients, definitive treatment is ECT.
171 Buprenorphine – A Treatment for Psychic Pain and Suicidal Ideation?
Authors: Benhamou Ori-Michael , Lynch Sean , Klepacz Lidia
Published: April 2020

Buprenorphine (BPN) is an opiate medication that is increasingly used in the management of Opioid Use Disorder and pain disorders. This case report highlights the acute efficacy of using buprenorphine-naloxone (BPN-NAL) to reverse anhedonia and suicidal ideation in an individual with OUD, chronic pain and severe suicide attempts.

We present a case of a 39-year-old male with a history of bipolar disorder, several lethal suicide attempts and polysubstance abuse, who presented to the hospital after self-immolation, burning 45% total body surface area. He was admitted to the burn unit for three months, reporting continual anhedonia, suicidal ideation, and flashbacks of seeing and feeling himself on fire. He also endorsed chronic pain and hopelessness.

Upon transfer to the behavioral health unit, his symptoms persisted, despite trials of quetiapine, mirtazapine, methadone, oxycodone and prazosin. In consultation with pain management, he was initiated on sublingual BPN-NAL 8mg-2mg treatment as a transition from methadone; he immediately reported improvement in depressive symptoms and a reduction in pain. He was titrated on BPN-NAL and continued to report diminished pain and resolution of depression. Furthermore, his irritability was lessened and he newly cooperated with staff, participating in unit activities. Upon discharge, he exhibited stable mood, adequate pain control and the elimination of suicidal thoughts as well as a proactive drive for substance abuse treatment.

This case describes the significance of BPN on relieving psychic pain and stabilizing mood in a chronically suicidal patient. We speculate that BPN’s pharmacokinetic properties terminate the cycle of short-term opioid-induced analgesia and euphoria with opioid withdrawal-induced hyperalgesia and dysphoria. This results in a steady treatment of pain, as well as maintaining the dopaminergic system, symptomatically translating to mood stabilization and annulling suicidal ideation.
177 Treating Chronic Pain and Preventing Opioid Use Disorders in the Underserved: An Integrated Primary Care Model
Authors: Sorrell Tanya R. , Medina Rosario
Published: April 2020

This poster builds on the CDC pain management guidelines and the current ASAM recommendations for substance use assessment to build an integrated primary care model for holistic chronic pain management in an urban, underserved primary care clinic. Using a case from our Federally Qualified Health Care Center, which operates in a southwest Denver clinic, a program of integrated care assessment, diagnosis, and holistic treatment planning is outlined for this client with chronic pain, physical, and behavioral health issues. Using a comprehensive care approach for complex clients, which are typical presentations for urban, underserved clients, we discuss the utilization of best practices in medication management for chronic pain (Alternatives to Opioids (ALTOS), prescribed and complementary and alternative practices (e.g., PT, acupuncture, etc), and behavioral health services (psychiatric assessment and treatment, psychotherapy, support groups, etc) to improve outcomes for our clients.
178 Single-Dose Pharmacokinetics of Amphetamine Extended-Release Tablet Compared with Amphetamine Extended-Release Oral Suspension
Authors: Herman Barry K. , Kando Judith C. , King Thomas , Pardo Antonio
Published: April 2020

Objectives:

Evaluate comparative bioavailability of single-dose amphetamine extended-release tablet (AMPH ER TAB, Tris Pharma, Inc., Monmouth Junction, NJ) 20 mg, swallowed whole or chewed and amphetamine extended-release oral suspension (AMPH EROS) 2.5 mg/mL; and evaluate whether a PK food effect exists on AMPH ER TAB (contains a 3.2:1 ratio of d- to l-amphetamine).

METHODS:

Healthy volunteers (18-55 yr) were randomized to 1 dose of AMPH ER TAB 20 mg swallowed (fasted), chewed (fed/fasted), or 20 mg AMPH EROS (fasted).

A crossover design was used. Samples were collected each period pre-dose and at time points to 60 h post-dose. D-and l-amphetamine were measured, and PK was calculated (90% CIs of the ratios of the geometric mean plasma levels) for Cmax, AUCt, and AUC0∞. Comparative bioavailability was determined when ratios were within 80 and 125%. Safety was also assessed.

RESULTS:

32 subjects completed the study. Based on the calculated bioavailability ratios, for AMPH ER TAB swallowed vs. AMPH EROS fasted: d-amphetamine total and peak exposures were found to be similar: AUC0-t: 100.68-108.08%, AUC0-∞:101.47-109.52%, Cmax: 98.10-103.17%. For l-amphetamine, the total and peak exposures were similar: AUC0-t: 100.31-108.57%, AUC0-∞:101.27-111.09%, Cmax: 98.2-103.37%.

AMPH ER TAB chewed vs. AMPH EROS fasted: For d-amphetamine, the total and peak exposures were similar: AUC0-t: 99.23-106.62%, AUC0-∞: 99.58-107.59%, Cmax: 99.91-105.14%. For l-amphetamine, the total and peak exposure was similar: AUC0-t: 98.16-106.35%, AUC0-∞: 98.44-108.11%, Cmax: 99.53-104.75%.

Food effect: AMPH ER TAB, chewed, fasted vs. fed: For d-amphetamine, the total and peak exposure was similar: AUC0-t: 92.57-99.49%, AUC0-∞: 91.12-98.48%, Cmax: 94.22-99.17%.

For l-amphetamine, the total and peak exposure was similar: AUC0-t: 91.27-98.91%, AUC0-∞: 88.44-97.17%, Cmax: 94.52-99.50%).

No serious AEs were reported during the conduct of this study, and the AE profiles were observed to be similar in frequency of events and severity to other amphetamine formulations used in ADHD.

CONCLUSIONS:

Bioavailability of single dose of AMPH ER TAB for both d- and l-amphetamine was comparable, swallowed whole or chewed, to an equivalent 20 mg dose of the reference product AMPH EROS, 2.5 mg/mL fasted, and showed equivalent peak and overall exposure.

No food effect was observed for AMPH ER TAB administered chewed. All AEs were mild in severity and AE profiles were similar to other amphetamine formulations used for treatment of ADHD.

Funding Acknowledgements:

Tris Pharma, Inc.
180 Improvement of Sexual Function Observed During Treatment of Major Depressive Disorder with Adjunctive Pimavanserin
Authors: Freeman Marlene P. , Fava Maurizio , Dirks Bryan , Jha Manish K. , Shelton Richard C. , Thase Michael E. , Trivedi Madhukar H. , Papakostas George I. , Liu Keith , Whitworth Troy , Stankovic Srdjan
Published: April 2020

Study Objectives:

Sexual dysfunction occurs in 40%-60% of patients with major depressive disorder (MDD), due to either the illness itself and/or the effects of antidepressant treatment. The phase-2 CLARITY trial recently demonstrated the efficacy of adjunctive pimavanserin (PIM) for MDD when added to ongoing selective serotonin or serotonin–norepinephrine reuptake inhibitor (SSRI/SNRI) treatment. No new safety observations were reported in this study. This post-hoc analysis examines the potential impact of PIM treatment on sexual function.

Method:

Study methodology has been presented previously (APA 2019). Adult male and female patients with moderate-to-severe MDD were randomized to PIM 34 mg/day (n=51) or placebo (PBO, n=152) added to ongoing SSRI/SNRI treatment. Massachusetts General Hospital–Sexual Functioning Inventory (MGH-SFI) and Hamilton Depression Rating Scale, 17-item version (HAMD-17) item 14 (sexual interest) scores were examined by analysis of covariance.

Results:

Adjunctive PIM resulted in significantly greater 5-week reduction (improvement) relative to SSRI/SNRI treatment plus placebo on mean MGH-SFI scores (difference –0.634, SE 0.167; P<0.001; effect size [ES], Cohen’s d 0.614). Similarly, PIM resulted in greater improvement compared with placebo on individual MGH-SFI items that applied to both males and females: Interest in Sex (P=0.006; ES=0.483), Ability to Get Sexually Aroused/Excited (P=0.001; ES=0.560), Ability to Achieve Orgasm (P<0.001; ES=0.609), Overall Sexual Satisfaction (P=0.003; ES=0.524). HAMD-17 item 14 scores were also significantly more reduced (improved) with PIM (P<0.001; ES=0.574).

Conclusions:

These results underscore the potential of adjunctive PIM for improving sexual function in patients with MDD and inadequate response to SSRIs/SNRIs. Potential benefits should be confirmed in further studies.

Funding Acknowledgements:

ACADIA Pharmaceuticals Inc.
190 Treating Fibromyalgia Syndrome through Neuromodulation With Transcranial Magnetic Stimulation
Authors: Keays Ashley C
Published: April 2020

Fibromyalgia Syndrome (FM) affects 2-4% of the US adult population. It is a disorder characterized by widespread musculoskeletal pain accompanied by fatigue, disrupted sleep, memory and mood issues. Researchers believe that FM amplifies painful sensations by affecting the way the brain processes pain signals. In recent years there is converging data favoring the theory of a dysregulation of pain processing in the central nervous system of FM patients, particularly associated with an increase in cerebral glutamate levels. Traditional medications have not proven to be enough. Since 2017, Keays Medical Group has used neuromodulation with Transcranial Magnetic Stimulation to treat FM patients with comorbid major depressive disorder. Preliminary results have shown improvement in all standardized scoring measures including FIQ-R, GAD-7 and PHQ-9 when treated with our FMS Protocol.
Pathways to retirement through self-employment
Authors: Ramnath Shanthi , Shoven John B. , Slavov Sita Nataraj
Published: April 2020

We examine the role of self-employment in retirement transitions using a panel of administrative tax data. We find that the hazard of self-employment increases at popular retirement ages associated with Social Security eligibility, particularly for those with greater retirement wealth. Late-career transitions to self-employment are associated with a larger drop in income than similar mid-career transitions. Data from the Health and Retirement Study suggest that hours worked also fall upon switching to self-employment. These results suggest that self-employment at older ages may serve as a ‘bridge job,’ allowing workers to gradually reduce hours and earnings along the pathway to retirement.
Loneliness, hopelessness and suicide in later life: a case–control psychological autopsy study in rural China
Authors: Niu Lu , Jia Cunxian , Ma Zhenyu , Wang Guojun , Sun Bin , Zhang Dexing , Zhou Liang
Published: April 2020

Aims

Loneliness is increasingly recognised as a serious public health issue worldwide. However, there is scarce research addressing the association between loneliness and suicide in older adults in rural China. We set out to examine loneliness and other psychosocial factors in elderly suicide cases and explore their interaction effects.

Methods

Using a 1 : 1 matched case–control design, data were collected from 242 elderly suicide cases and 242 living community controls by psychological autopsy method in rural China, including demographic characteristics, loneliness, depression, hopelessness and social support. The chi-square automatic interaction detection (CHAID) tree model and multivariable logistic regression analysis were used to explore the relationships of these factors and suicide.

Results

The CHAID tree model showed that loneliness, hopelessness and depressive symptoms were closely associated with completed suicide and that loneliness and hopelessness interacted with each other. The result of multivariable logistic regression showed that individuals who were unemployed [odds ratio (OR) = 2.344; 95% confidence interval (CI): 1.233–4.457], living alone (OR = 2.176; 95% CI: 1.113–4.254), had lower levels of subjective social support (OR = 2.185; 95% CI: 1.243–3.843), experienced depressive symptoms (OR = 6.700; 95% CI: 3.405–13.182), showed higher levels of hopelessness (OR = 7.253; 95% CI: 3.764–13.974) and felt higher levels of hopelessness × higher levels of loneliness (OR = 2.446; 95% CI: 1.089–5.492) were significantly associated with an elevated suicide risk in older people in rural China.

Conclusions

Regular evaluation of loneliness, hopelessness and depression can help detect older adults who are at risk of committing suicide. Interventions should target social support systems, particularly among people living alone, to alleviate feelings of loneliness and hopelessness. Treating depression is also key to preventing suicide among elderly people in rural China.
Particle‐Size Distributions and Solubility of Aerosol Iron Over the Antarctic Peninsula During Austral Summer
Authors: Gao Yuan , Yu Shun , Sherrell Robert M. , Fan Songyun , Bu Kaixuan , Anderson James R.
Published: April 2020

This study provides new data on the properties of aerosol iron (Fe) over the Antarctic Peninsula, one of the fastest warming regions on Earth in recent decades. Atmospheric deposition delivers Fe, a limiting micronutrient, to the Southern Ocean, and aerosol particle size influences the air‐to‐sea deposition rate and fractional solubility of aerosol Fe. Size‐segregated aerosols were collected at Palmer Station on the West Antarctic Peninsula during austral summer 2016–2017. Results show single‐mode size distribution of aerosol Fe, peaking at 4.4 μm diameter. The average concentration of total aerosol Fe was 1.3 (±0.40) ng m−3 (range 0.74–1.8 ng m−3). High concentrations of total aerosol Fe occurred in January, implying increased Fe source strength then. Total labile Fe varied between 0.019 and 0.095 ng m−3, and labile Fe (II) accounted for ~90% of the total labile Fe. The average fractional solubility for total Fe was 3.8% (±1.5%) (range 2.5–7.3%). Estimated dry deposition fluxes for the study period were 3.2 μg m−2 year−1 for total labile Fe and 83 μg m−2 year−1 for total Fe in aerosols. We speculate that local and regional dust sources in Antarctica contributed to the observed aerosol Fe in austral summer and that warming on the Antarctic Peninsula during the past half century may have increased the formation of dust sources in this region. The potential biogeochemical impact of atmospheric Fe input to the West Antarctic Peninsula shelf waters and adjacent pelagic surface waters of the Southern Ocean may need to be re‐evaluated.
Vegetation Trajectories and Shortwave Radiative Forcing Following Boreal Forest Disturbance in Eastern Siberia
Authors: Stuenzi S. M. , Schaepman-Strub G.
Published: April 2020

Major boreal forest disturbance and associated carbon emissions have been reported in the coldest region of the Northern Hemisphere. Related biophysical feedbacks to climate remain highly uncertain but might reduce warming effects expected from carbon emissions. This study quantifies albedo change after disturbance, primarily fires, in larch‐dominated forests around Yakutsk as compared to undisturbed areas with natural albedo variability, using satellite‐based time series. The related annual mean shortwave radiative forcing was −6.015 W/m2 for the 13 years following forest disturbance. It was highly negative during snow‐covered months (−3.738 to −13.638 W/m2), but positive (+5.441 W/m2) for the summer months in the first year after disturbance, decreasing afterward and also turning into a negative forcing after 5 years. Forcing by surface shortwave radiation must be considered to assess the impact of boreal forest disturbance on climate and additional feedbacks, such as increased permafrost thaw or transition to alternative ecosystem states.
Magnetic Fabric Constraints on the Cenozoic Compressional Strain Changes in the Northern Qaidam Marginal Thrust Belt and Their Tectonic Implications
Authors: Li Bingshuai , Yan Maodu , Zhang Weilin , Parés Josep M. , Fang Xiaomin , Yang Yongpeng , Zhang Dawen , Guan Chong , Bao Jing
Published: April 2020

Reconstructing the compressional strain history of the northern Qaidam marginal thrust belt has significant implications for understanding the mountain building processes of the northeastern Tibetan Plateau and the tectonic evolution of the Altyn Tagh Fault. However, the variation of compressional strain in this region has rarely been studied. Here, we present Cenozoic anisotropy of the low‐field magnetic susceptibility records from the fluvial‐lacustrine Hongliugou profile within the middle part of the northern Qaidam marginal thrust belt. The magnetic fabrics of the Shizigou Formation are dominated by a primary sedimentary magnetic fabric, whereas those of the lower Lulehe Formation are undetermined, most likely due to the conglomerate lithology; in contrast, the magnetic fabrics of the middle Lulehe to Shangyoushashan Formations, all of which are dominated by antiferromagnetic hematite and paramagnetic components with crystallographic preferred orientations, are mostly embryonic tectonic fabrics induced by prefolding layer‐parallel shortening. Compared with previously reported paleomagnetic rotation results within the Hongliugou locality, the rotation‐corrected compressional strain directions that are perpendicular to the rotation‐corrected magnetic lineations exhibit a regular trend from nearly N‐S before ~33 Ma to NE‐SW at ~10 Ma. Integrated with other lines of evidence from the northern Qaidam Basin, we attribute the ~45° successive clockwise rotations of the compressional strain directions to the propagation of significant strike‐slip faulting along the Altyn Tagh Fault into the northern Qaidam marginal thrust belt that resulted in significant vertical axis clockwise rotations in the region.
Observing Waves in Sea Ice With ICESat‐2
Authors: Horvat C. , Blanchard‐Wrigglesworth Ed , Petty A.
Published: April 2020

The coupled interaction of ocean surface waves and sea ice is important in determining the thermodynamic and dynamic properties of sea ice and its relationship to the ocean and atmosphere. Wave‐ice interactions create the marginal ice zone (MIZ), a region critically important for ecology, transportation, and the polar energy budget. Typically, the MIZ is defined using satellite products as those regions where sea ice concentration is between 15% and 80%. Here we present a new technique to observe ocean surface waves in sea ice, leveraging NASA's ICESat‐2 satellite laser altimeter, and produce maps of wave‐affected sea ice regions in both hemispheres. Defining a new wave‐based metric for MIZ extent, we find that compared to a concentration‐based metric, wave‐based MIZ estimates are smaller. Further, the wave‐affected MIZ makes up a larger fraction of sea ice extent in winter than in summer, opposite to the seasonal cycle of concentration‐based MIZ.
A novel targeted RNA-Seq panel identifies a subset of adult patients with acute lymphoblastic leukemia with BCR-ABL1-like characteristics
Authors: Sánchez Ricardo , Ribera Jordi , Morgades Mireia , Ayala Rosa , Onecha Esther , Ruiz-Heredia Yanira , Juárez-Rufián Alexandra , de Nicolás Rodrigo , Sánchez-Pina José , Vives Susana , Zamora Lurdes , Mercadal Santiago , Coll Rosa , Cervera Marta , García Olga , Ribera Josep-Maria , Martínez-López Joaquín
Published: April 2020

BCR-ABL1-like B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains poorly characterized in adults. We sought to establish the frequency and outcome of adolescent and adult BCR-ABL1-like ALL using a novel RNA-Seq signature in a series of patients with BCP-ALL. To this end, we developed and tested an RNA-Seq custom panel of 42 genes related to a BCR-ABL1-like signature in a cohort of 100 patients with BCP-ALL and treated with risk-adapted ALL trials. Mutations related to BCR-ABL1-like ALL were studied in a panel of 33 genes by next-generation sequencing (NGS). Also, CRLF2 overexpression and IKZF1/CDKN2A/B deletions were analyzed. Twenty out of 79 patients (12–84 years) were classified as BCR-ABL1-like (25%) based on heatmap clustering, with significant overexpression of ENAM, IGJ, and CRLF2 (P ≤ 0.001). The BCR-ABL1-like subgroup accounted for 29% of 15–60-year-old patients, with the following molecular characteristics: CRLF2 overexpression (75% of cases), IKZF1 deletions (64%), CDKN2A/B deletions (57%), and JAK2 mutations (57%). Among patients with postinduction negative minimal residual disease, those with the BCR-ABL1-like ALL signature had a higher rate of relapse and lower complete response duration than non-BCR-ABL1-like patients (P = 0.007). Thus, we have identified a new molecular signature of BCR-ABL1-like ALL that correlates with adverse prognosis in adult patients with ALL.
CtBP determines ovarian cancer cell fate through repression of death receptors
Authors: Ding Boxiao , Yuan Fang , Damle Priyadarshan K. , Litovchick Larisa , Drapkin Ronny , Grossman Steven R.
Published: April 2020

C-terminal binding protein 2 (CtBP2) is elevated in epithelial ovarian cancer, especially in the aggressive and highly lethal subtype, high-grade serous ovarian cancer (HGSOC). However, whether HGSOC tumor progression is dependent on CtBP2 or its paralog CtBP1, is not well understood. Here we report that CtBP1/2 repress HGSOC cell apoptosis through silencing of death receptors (DRs) 4/5. CtBP1 or 2 knockdown upregulated DR4/5 expression, and triggered autonomous apoptosis via caspase 8 activation, but dependent on cell-type context. Activation of DR4/5 by CtBP1/2 loss also sensitized HGSOC cell susceptibility to the proapoptotic DR4/5 ligand TRAIL. Consistent with its function as transcription corepressor, CtBP1/2 bound to the promoter regions of DR4/5 and repressed DR4/5 expression, presumably through recruitment to a repressive transcription regulatory complex. We also found that CtBP1 and 2 were both required for repression of DR4/5. Collectively, this study identifies CtBP1 and 2 as potent repressors of DR4/5 expression and activity, and supports the targeting of CtBP as a promising therapeutic strategy for HGSOC.
FADS1 promotes the progression of laryngeal squamous cell carcinoma through activating AKT/mTOR signaling
Authors: Zhao Rui , Tian Linli , Zhao Bo , Sun Yanan , Cao Jing , Chen Kexin , Li Fengqing , Li Minghua , Shang Desi , Liu Ming
Published: April 2020

Metabolic abnormality is the major feature of laryngeal squamous cell carcinoma (LSCC), however, the underlying mechanism remain largely elusive. Fatty acid desaturase 1 (FADS1), as the key rate-limiting enzyme of polyunsaturated fatty acids (PUFAs), catalyzes dihomo-gamma-linolenic acid (DGLA) to arachidonic acid (AA). In this study, we reported that the expression of FADS1 was upregulated in LSCC, high FADS1 expression was closely associated with the advanced clinical features and poor prognosis of the recurrent LSCC patients after chemotherapy. Liquid chromatograph-mass spectrometry (LC-MS) analysis revealed that FADS1 overexpression induced greater conversion of DGLA to AA, suggesting an increased activity of FADS1. Similarly, the level of prostaglandin E2 (PGE2), a downstream metabolite of AA, was also elevated in cancerous laryngeal tissues. Functional assays showed that FADS1 knockdown suppressed the proliferation, migration and invasion of LSCC cells, while FADS1 overexpression had the opposite effects. Bioinformatic analysis based on microarray data found that FADS1 could activate AKT/mTOR signaling. This hypothesis was further validated by both in vivo and in vitro assays. Hence, our data has supported the viewpoint that FADS1 is a potential promoter in LSCC progression, and has laid the foundation for further functional research on the PUFA dietary supplementation interventions targeting FADS1/AKT/mTOR pathway for LSCC prevention and treatment.
DNA:RNA hybrids form at DNA double-strand breaks in transcriptionally active loci
Authors: Bader Aldo S. , Bushell Martin
Published: April 2020

The recent discovery of DNA:RNA hybrids, or R-loops, actively forming at DNA double-strand breaks (DSBs) has unlocked fresh insight into how RNA participates in DNA repair. However, the manner of DSB-induced R-loop formation is vital in determining its mechanism of action and is currently under debate. Here, we analyse published DNA:RNA-hybrid sequencing to elucidate the features that determine DSB-induced R-loop formation. We found that pre-existing transcriptional activity was critical for R-loop generation at break sites, suggesting that these RNAs are transcribed prior to break induction. In addition, this appeared to be a specific DSB response at the break, distinct from traditional, co-transcriptionally formed R-loops. We hypothesise that R-loop formation is orchestrated by the damage response at transcriptionally active DSB loci to specifically maintain these genomic regions. Further investigation is required to fully understand how canonical repair processes regulate R-loops at breaks and how they participate in the repair process.
Neddylation of sterol regulatory element-binding protein 1c is a potential therapeutic target for nonalcoholic fatty liver treatment
Authors: Ju Uk-Il , Jeong Do-Won , Seo Jieun , Park Jun Bum , Park Jong-Wan , Suh Kyung-Suk , Kim Jae Bum , Chun Yang-Sook
Published: April 2020

Nonalcoholic fatty liver disease (NAFLD) is a risk factor for progression of steatohepatitis, liver cirrhosis, and liver cancer. Although pathological condition of NAFLD, which arises from an excessive accumulation of triglyceride in the liver, is accompanied by elevated sterol regulatory element-binding protein 1c (SREBP1c) level, it is largely unknown which factors are involved in the modification of SREBP1c. In this study, we discovered that neddylation of SREBP1c competes with its ubiquitination and stabilizes SREBP1c protein level, and eventually promotes hepatic steatosis. We also demonstrated that human homolog of mouse double minute 2 (HDM2) acts as an E3 neddylation ligase of SREBP1c. Further, treatment with the neddylation inhibitor, MLN4924, attenuates high-fat diet-induced hepatic steatosis by reducing the levels of SREBP1c protein and hepatic triglyceride. Our results indicate that the blockade of SREBP1c neddylation could be a novel approach in the defense against NAFLD.
Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate
Authors: Hu Lei , Chen Meng , Chen Xueran , Zhao Chenggang , Fang Zhiyou , Wang Hongzhi , Dai Haiming
Published: April 2020

Many chemotherapy treatments induce apoptosis or pyroptosis through BAK/BAX-dependent mitochondrial pathway. BAK/BAX activation causes the mitochondrial outer membrane permeabilization (MOMP), which induces the activation of pro-apoptotic caspase cascade. GSDME cleavage by the pro-apoptotic caspases determines whether chemotherapy drug treatments induce apoptosis or pyroptosis, however, its regulation mechanisms are not clear. In this study, we showed that TNFα+CHX and navitoclax-induced cancer cell pyroptosis through a BAK/BAX-caspase-3-GSDME signaling pathway. GSDME knockdown inhibited the pyroptosis, suggesting the essential role of GSDME in this process. Interestingly, GSDME was found to be palmitoylated on its C-terminal (GSDME-C) during chemotherapy-induced pyroptosis, while 2-bromopalmitate (2-BP) could inhibit the GSDME-C palmitoylation and chemotherapy-induced pyroptosis. Mutation of palmitoylation sites on GSDME also diminished the pyroptosis induced by chemotherapy drugs. Moreover, 2-BP treatment increased the interaction between GSDME-C and GSDME-N, providing a potential mechanism of this function. Further studies indicated several ZDHHC proteins including ZDHHC-2,7,11,15 could interact with and palmitoylate GSDME. Our findings offered new targets to achieve the transformation between chemotherapy-induced pyroptosis and apoptosis.