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BackgroundAsthma-associated single nucleotide polymorphisms from large genome-wide association studies only explain a fraction of genetic heritability. Likely causes of the missing heritability include broad phenotype definitions and gene-environment interactions (GxE). The mechanisms underlying GxE in asthma are poorly understood. Previous GxE studies on pet ownership showed discordant results.ObjectivesWe sought to study the GxE between the 17q12-21 locus and pet ownership in infancy in relation to wheeze.MethodsWheezing classes derived from 5 UK-based birth cohorts (latent class analysis) were used to study GxE between the 17q12-21 asthma-risk variant rs2305480 and dog and cat ownership in infancy, using multinomial logistic regression. A total of 9149 children had both pet ownership and genotype data available. Summary statistics from individual analyses were meta-analyzed.Resultsrs2305480 G allele was associated with increased risk of persistent wheeze (additive model odds ratio, 1.37; 95% CI, 1.25-1.51). There was no evidence of an association between dog or cat ownership and wheeze. We found significant evidence of a GxE interaction between rs2305480 and dog ownership (P = 8.3 × 10−4) on persistent wheeze; among dog owners, the G allele was no longer associated with an increased risk of persistent wheeze (additive model odds ratio, 0.95; 95% CI, 0.73-1.24). For those without pets, G allele was associated with increased risk of persistent wheeze (odds ratio, 1.61; 95% CI, 1.40-1.86). Among cat owners, no such dampening of the genetic effect was observed.ConclusionsAmong dog owners, rs2305480 G was no longer associated with an increased risk of persistent wheeze (or asthma). Early-life environmental exposures may therefore attenuate likelihood of asthma in those carrying 17q12-21 risk alleles.

Rationale: The relationship between eczema, wheeze or asthma, and rhinitis is complex, and epidemiology and mechanisms of their comorbidities is unclear. Objectives: To investigate within-individual patterns of morbidity of eczema, wheeze, and rhinitis from birth to adolescence/early adulthood. Methods: We investigated onset, progression, and resolution of eczema, wheeze, and rhinitis using descriptive statistics, sequence mining, and latent Markov modeling in four population-based birth cohorts. We used logistic regression to ascertain if early-life eczema or wheeze, or genetic factors (filaggrin [FLG] mutations and 17q21 variants), increase the risk of multimorbidity. Measurements and Main Results: Single conditions, although the most prevalent, were observed significantly less frequently than by chance. There was considerable variation in the timing of onset/remission/persistence/intermittence. Multimorbidity of eczema1wheeze1rhinitis was rare but significantly overrepresented (three to six times more often than by chance). Although infantile eczema was associated with subsequent multimorbidity, most children with eczema (75.4%) did not progress to any multimorbidity pattern. FLG mutations and rs7216389 were not associated with persistence of eczema/wheeze as single conditions, but both increased the risk of multimorbidity (FLG by 2- to 3-fold, rs7216389 risk variant by 1.4- to 1.7-fold). Latent Markov modeling revealed five latent states (no disease/low risk, mainly eczema, mainly wheeze, mainly rhinitis, multimorbidity). The most likely transition to multimorbidity was from eczema state (0.21). However, although this was one of the highest transition probabilities, only one-fifth of those with eczema transitioned to multimorbidity. Conclusions: Atopic diseases fit a multimorbidity framework, with no evidence for sequential atopic march progression. The highest transition to multimorbidity was from eczema, but most children with eczema (more than three-quarters) had no comorbidities.

There is considerable interest in the clinical development of inhibitors of mTOR complexes mTORC1 and 2. Because mTORC1 and its downstream mRNA translation effectors may protect against genotoxic DNA damage, we investigated the inhibition of mTORC1 and mTORC1/2 in the ability to reverse platinum resistance in tissue culture and in animal tumor models of serous ovarian cancer. Cell survival, tumor growth, PI3K–AKT–mTOR pathway signaling, DNA damage and repair response (DDR) gene expression, and translational control were all investigated. We show that platinum-resistant OVCAR-3 ovarian cancer cells are resensitized to low levels of carboplatin in culture by mTOR inhibition, demonstrating reduced survival after treatment with either mTORC1 inhibitor everolimus or mTORC1/2 inhibitor PP242. Platinum resistance is shown to be associated with activating phosphorylation of AKT and CHK1, inactivating phosphorylation of 4E-BP1, the negative regulator of eIF4E, which promotes increased cap-dependent mRNA translation and increased levels of CHK1 and BRCA1 proteins. Animals with platinum-resistant OVCAR-3 tumors treated with carboplatin plus mTORC1/2 inhibition had significantly longer median survival and strikingly reduced metastasis compared with animals treated with carboplatin plus everolimus, which inhibits only mTORC1. Reduced tumor growth, metastasis, and increased survival by mTORC1/2 inhibition with carboplatin treatment was associated with reduced AKT-activating phosphorylation and increased 4E-BP1 hypophosphorylation (activation). We conclude that mTORC1/2 inhibition is superior to mTORC1 inhibition in reversing platinum resistance in tumors and strongly impairs AKT activation, DNA repair responses, and translation, promoting improved survival in the background of platinum resistance. Mol Cancer Ther; 15(7); 1557–67. ©2016 AACR.

Supplementary Figure S1: Growth inhibitory 50% (GI50) determination of single agent everolimus, PP242 and carboplatin using OVCAR-3 cells; Supplementary Figure S2: mTORC1 and mTORC1/2 inhibition sensitizes platinum resistant SKOV3 cells to carboplatin-mediated growth inhibition; Supplementary Figure S3: qRT-PCR analysis of select mRNAs in mTORC1 and mTORC1/2 inhibited cells with and without carboplatin treatment.

Supplementary Data from Loss-of-Function Fibroblast Growth Factor Receptor-2 Mutations in Melanoma

Alcohol’s effects on reactivity to stressors depend on the nature of the stressor and the reactivity being assessed. Research that identifies characteristics of stressors that modulate reactivity and clarifies the neurobehavioral, cognitive, and affective components of this reactivity may help prevent, reduce, or treat the negative impacts of acute and chronic alcohol use and have implications for other psychopathology involving maladaptive reactivity to stressors. We used a novel, multimeasure, cued, electric-shock-stressor paradigm in a greater-university community sample of adult recreational drinkers to test the effects of alcohol ( n = 64), compared with no alcohol ( n = 64), on reactivity to stressors that vary in both their perceived certainty and controllability. Preregistered analyses suggested alcohol significantly dampened subjective anxiety (self-report) and defensive reactivity (startle potentiation) more during uncertain stressors than during certain stressors regardless of controllability, which suggests that stressor uncertainty—but not uncontrollability—may be sufficient to enhance alcohol’s dampening of stress reactivity and thus negative reinforcement potential.

Supplementary Figures 1-2 from In Melanoma, RAS Mutations Are Accompanied by Switching Signaling from BRAF to CRAF and Disrupted Cyclic AMP Signaling

Melanocytes require the RAS/RAF/MEK/ERK and the cyclic AMP (cAMP) signaling pathways to maintain the fine balance between proliferation and differentiation. We have investigated how cross-talk between these pathways affects melanoma progression. We show that cAMP suppresses CRAF activity in melanocytes and that this is essential to suppress the oncogenic potential of CRAF in these cells. As a consequence, BRAF alone is responsible for signaling to MEK. However, when RAS is mutated in melanoma, the cells switch their signaling from BRAF to CRAF. This switch is accompanied by dysregulated cAMP signaling, a step that is necessary to allow CRAF to signal to MEK. Thus, a fundamental switch in RAF isoform usage occurs when RAS is mutated in melanoma, and this occurs in the context of disrupted cAMP signaling. These data have important implications for the development of therapeutic strategies to treat this life-threatening disease. (Cancer Res 2006; 66(19): 9483-91)

Supplementary Figure Legends 1-2 from In Melanoma, RAS Mutations Are Accompanied by Switching Signaling from BRAF to CRAF and Disrupted Cyclic AMP Signaling

Background In 2012, pneumococcal conjugate vaccine (PCV13) and pneumococcal polysaccharide vaccine (PPSV23) were recommended for immunocompromised adults ≥19 years, but pneumococcal vaccination (PV) in these patients (pts) remains suboptimal. With a new PV (PCV20) allowing for simplified PV, we study rates of PV in pts on infliximab (INX) 1 year post-initiation of a pt and provider education-based quality improvement project aiming to increase PV in pts on Tumor Necrosis Factor-alpha inhibitors (TNF-αI). Methods Starting in 11/2020, pamphlets detailing PV indications were distributed to the Walter Reed National Military Medical Center infusion center and pharmacies to be given to pts prescribed/administered TNF-αI. Provider educational materials and pt pamphlets were given to services prescribing TNF-αI. Provider education was also offered to these services. Up to date (UTD) on PV was defined as receipt of PCV13 and PPSV23 (including additional PPSV23 dose ≥5 years post-initial PPSV23 if applicable). Ongoing INX (o-INX) was defined as INX initiation before 10/1/2020. Newly initiated INX (new-INX) was 10/1/2020-10/1/2021. One-year post implementation, we reviewed the PCV13 and PPSV23 immunization records of pts ≥19 years of age on INX from 1/1/21-12/31/21. This project was approved by the IRB under a non-research determination. Results 111 pts prescribed INX between 1/1/21-12/31/21 met inclusion criteria (87 o-INX and 24 new-INX). Prior to the intervention, of 87 o-INX pts, 45 (52%), 45 (52%), and 18 (21%) pts had received PCV13, ≥1 PPSV23 dose, and were UTD on PV respectfully. Between 1/1/21-12/31/21, 14 o-INX pts had PV (1 PCV13 and PPSV23, 7 PCV13, and 6 PPSV23), with 7 newly UTD (10% of the 69 previously not UTD), totaling 25 (29%) o-INX pts UTD on PV (figure 1). Of 24 new-INX pts, only 12 (48%), 9 (36%), and 6 (24%) had had PCV13, PPSV23, and were UTD on PV as of 12/31/21. No services prescribing TNF-αI requested the offered PV educational talks. Conclusion Despite frequent healthcare in a system where vaccination has no out of pocket expense, guideline-concordant PV was low in this cohort. With new, simplified PV, next steps include updated pt and targeted provider education. However, with prior small gains using multidisciplinary education, additional efforts to remove PV barriers may be needed. Disclosures Benjamin L. Custer, MD, Beam Therapeutics: Stocks/Bonds|CRISPR Therapeutics: Stocks/Bonds|glaxo-smith-kline: Stocks/Bonds|Hologic: Stocks/Bonds|Moderna: Stocks/Bonds|Pfizer: Stocks/Bonds|Regeneron: Stocks/Bonds|sanofi: Stocks/Bonds|Vertex Pharmaceuticals: Stocks/Bonds.

Tobacco smoking imposes a staggering burden on public health, underscoring the urgency of developing a deeper understanding of the processes that maintain addiction. Clinical and experience-sampling data highlight the importance of anxious withdrawal symptoms, but the underlying neurobiology has remained elusive. Work in animals implicates the central extended amygdala (EAc), but the translational relevance of these discoveries remains speculative. Here we leveraged a randomized trial design, well-established threat-anticipation paradigm, and multidimensional battery of assessments to understand the consequences of 24-hour nicotine abstinence. The threat-anticipation paradigm had the expected consequences, amplifying subjective distress and arousal, and recruiting the canonical threat-anticipation network. Abstinence increased smoking urges and withdrawal symptoms, and potentiated threat-evoked distress, but had negligible consequences for EAc threat reactivity, raising questions about the translational relevance of prominent animal and human models of addiction. These observations provide a framework for conceptualizing nicotine abstinence and withdrawal, with implications for basic, translational, and clinical science.

Prior survey-based research has documented associations between greater levels of stress and increased prescription drug misuse behavior. These studies uniformly rely on assessments of both the stress experiences and the substance behavior after they occurred (commonly spanning 6- to 12-month retrospective timeframes). Less is known about the extent to which variations in momentary stress predict the actual occurrence of prescription misuse in daily life among college students with elevated risk for engaging in the behavior. In this study, 297 participants (69% females; Mage = 19.5 years, SDage = 0.71) completed a 28-day ecological momentary assessment (EMA) procedure that collected self-reported stress and other contextual experiences in moments preceding prescription drug misuse. Analyses tested the within-person association between momentary stress and prescription drug misuse and examined the extent to which the relation between stress and misuse was moderated by participants’ assigned sex or global stress and coping levels. Results from hierarchical generalized linear modeling indicated a significant within-person association between momentary stress (i.e., higher than usual relative to one’s own mean) and greater likelihood of prescription misuse in daily life, accounting for the number of stressors and timing covariates. No significant moderation by participant sex was found, and moderation effects by global stress and coping levels were not in the expected directions. Direct results highlight the role of momentary stress experiences on health-relevant substance behaviors and provide future directions for research and applied efforts.

Background: Personal sensing may improve digital therapeutics for mental health care by facilitating early screening, symptom monitoring, risk prediction, and personalized/adaptive interventions. However, further development and use of personal sensing first requires better understanding of its acceptability to people targeted for these mental health applications. Objective: We assessed the acceptability of both active and passive personal sensing methods in a sample of people with moderate to severe alcohol use disorder using both behavioral and self-report measures. Method: Participants (N = 154; 50% female; mean age = 41; 87% White, 97% Non-Hispanic) in early recovery (1 – 8 weeks of abstinence) from alcohol use disorder were recruited from the Madison, WI area to participate in a 3-month longitudinal study. Participants engaged with active (ecological momentary assessment; EMA, audio check-in, and sleep quality) and passive (geolocation, cellular communication logs, and text message content) personal sensing methods. We assessed 3 behavioral indicators of acceptability: participants’ choices about their participation in the study at various stages in the study procedure, their choice to opt-in to provide data for each personal sensing method, and their compliance for a subset of the active methods (EMA, audio check-in). We also assessed 3 self-report measures of acceptability (interference, dislike, and willingness to use for 1 year) for each method. Results: All but 1 of the individuals who were eligible to participate consented to the personal sensing procedures. Most of these individuals (88%) also returned 1 week later to formally enroll in the study and begin to provide these data. All participants (100%) opted-in to provide data for EMA, sleep quality, and all passive methods (geolocation, cellular communication logs, text message content). Three participants (2%) did not provide any audio check-ins while on study. The average completion rate for all requested EMAs (4X daily) was 81% for 4x daily and 94% for 1x daily. The completion rate for the daily audio check-in was 55%. Aggregate participant ratings indicated all personal sensing methods to be significantly more acceptable (all P’s < .05) compared to neutral across subjective measures of interference, dislike, and willingness to use for 1 year. Participants did not significantly differ in their dislike of active compared to passive methods (P = .23). However, participants reported a higher willingness to use passive methods for 1 year compared to active methods (P = .04). Conclusions: The results of our study suggest that both active and passive personal sensing methods are generally acceptable to people with alcohol use disorder over a longer period than has previously been assessed. This was true even for data streams that contained potentially more sensitive information (e.g., geolocation, cellular communications). Important individual differences were observed both across people and methods which indicate opportunities for future improvements.

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Clinicians and researchers alike have long believed that stressors play a pivotal etiologic role in risk, maintenance, and/or relapse of alcohol and other substance use disorders (SUDs). Numerous seminal and contemporary theories on SUD etiology posit that stressors may motivate drug use and that individuals who use drugs chronically may display altered responses to stressors. We use foundational basic stress biology research as a lens through which to evaluate critically the available evidence to support these key stress–SUD theses in humans. Additionally, we examine the field's success to date in targeting stressors and stress allostasis in treatments for SUDs. We conclude with our recommendations for how best to advance our understanding of the relationship between stressors and drug use, and we discuss clinical implications for treatment development.

Background Timely genetic testing at ovarian cancer diagnosis is essential as results impact front line treatment decisions. Our objective was to determine rates of genetic counseling and testing with an expedited genetics referral pathway wherein women with newly-diagnosed ovarian cancer are contacted by a genetics navigator to facilitate genetic counseling. Methods Patients were referred for genetic counseling by their gynecologic oncologist, contacted by a genetics navigator and offered appointments for genetic counseling. Patients completed quality of life (QoL) surveys immediately pre- and post-genetic assessment and 6 months later. The primary outcome was feasibility of this pathway defined by presentation for genetic counseling. Results From 2015 to 2018, 100 patients were enrolled. Seventy-eight had genetic counseling and 73 testing. Median time from diagnosis to genetic counseling was 34 days (range 10–189). Among patients who underwent testing, 12 (16%) had pathogenic germline mutations (BRCA1-7, BRCA2-4, MSH2-1). Sixty-five patients completed QoL assessments demonstrating stress and anxiety at time of testing, however, scores improved at 6 months. Despite the pathway leveling financial and logistical barriers, patients receiving care at a public hospital were less likely to present for genetic counseling compared to private hospital patients (56% versus 84%, P = 0.021). Conclusions Facilitated referral to genetic counselors at time of ovarian cancer diagnosis is effective, resulting in high uptake of genetic counseling and testing, and does not demonstrate a long term psychologic toll. Concern about causing additional emotional distress should not deter clinicians from early genetics referral as genetic testing can yield important prognostic and therapeutic information.

We examined central nervous system [CNS] stress responses among deprived and continuing heavy marijuana users and nonusers.Participants (Deprivation did not affect startle potentiation overall (timing task:A history of marijuana use or acute deprivation did not alter central stress responses despite prominent theoretical expectations. This study adds to growing research on central stress responses in individuals with a history of drug use and begins to parse moderating roles of individual differences and stressor characteristics. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Genome-wide and epigenome-wide association studies have identified genetic variants and differentially methylated nucleotides associated with childhood asthma. Incorporation of such genomic data may improve performance of childhood asthma prediction models which use phenotypic and environmental data. Using genome-wide genotype and methylation data at birth from the Isle of Wight Birth Cohort (n = 1456), a polygenic risk score (PRS), and newborn (nMRS) and childhood (cMRS) methylation risk scores, were developed to predict childhood asthma diagnosis. Each risk score was integrated with two previously published childhood asthma prediction models (CAPE and CAPP) and were validated in the Manchester Asthma and Allergy Study. Individually, the genomic risk scores demonstrated modest-to-moderate discriminative performance (area under the receiver operating characteristic curve, AUC: PRS = 0.64, nMRS = 0.55, cMRS = 0.54), and their integration only marginally improved the performance of the CAPE (AUC: 0.75 vs. 0.71) and CAPP models (AUC: 0.84 vs. 0.82). The limited predictive performance of each genomic risk score individually and their inability to substantially improve upon the performance of the CAPE and CAPP models suggests that genetic and epigenetic predictors of the broad phenotype of asthma are unlikely to have clinical utility. Hence, further studies predicting specific asthma endotypes are warranted.

Alcohol’s effects on reactivity to stressors depend on the nature of the stressor and the reactivity being assessed. Research identifying characteristics of stressors that modulate reactivity and clarifies the neurobehavioral, cognitive, and affective components of this reactivity may help prevent, reduce or treat the negative impacts of acute and chronic alcohol use with implications for other psychopathology involving maladaptive reactivity to stressors. We used a novel, multi-measure, cued electric shock stressor paradigm in a greater university community sample of adult recreational drinkers to test how alcohol (N=64), compared to No-alcohol (N=64), affects reactivity to stressors that vary in both their perceived certainty and controllability. Preregistered analyses suggested alcohol significantly dampened subjective anxiety (self-report) and defensive reactivity (startle potentiation) more during uncertain than during certain stressors regardless of controllability, suggesting that stressor uncertainty —but not uncontrollability— may be sufficient to enhance alcohol’s stress reactivity dampening and thus negative reinforcement potential.

BACKGROUND Successful long-term recovery from opioid use disorder (OUD) requires continuous lapse risk monitoring and appropriate use and adaptation of recovery-supportive behaviors as lapse risk changes. Available treatments often fail to support long-term recovery by failing to account for the dynamic nature of long-term recovery. OBJECTIVE The aim of this protocol paper is to describe research that aims to develop a highly contextualized lapse risk prediction model that forecasts the ongoing probability of lapse. METHODS The participants will include 480 US adults in their first year of recovery from OUD. Participants will report lapses and provide data relevant to lapse risk for a year with a digital therapeutic smartphone app through both self-report and passive personal sensing methods (eg, cellular communications and geolocation). The lapse risk prediction model will be developed using contemporary rigorous machine learning methods that optimize prediction in new data. RESULTS The National Institute of Drug Abuse funded this project (R01DA047315) on July 18, 2019 with a funding period from August 1, 2019 to June 30, 2024. The University of Wisconsin-Madison Health Sciences Institutional Review Board approved this project on July 9, 2019. Pilot enrollment began on April 16, 2021. Full enrollment began in September 2021. CONCLUSIONS The model that will be developed in this project could support long-term recovery from OUD—for example, by enabling just-in-time interventions within digital therapeutics. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/29563

Objective: We examined central nervous system stress responses among deprived and continuing heavy marijuana users and non-users. Method: Participants (N=210; 46.7% female; mean age=21.99; 91.4% White, 94.3% Non-Hispanic) were heavy marijuana users (N=134) and non-users (N=76). Heavy users were randomly assigned to a 3-day marijuana deprivation condition (N=68) or to continue using regularly (N=66). Participants completed 2 threat-of-shock stressor tasks that manipulated stressor predictability by varying shock probability or timing. We measured central stress responses via startle potentiation (stressor conditions minus matched no-stressor condition). We examined two group contrasts (heavy use: all heavy users vs. non-users; deprivation: deprived vs. continuing heavy users) on startle potentiation overall and moderated by stressor predictability (unpredictable vs. predictable). Results: Deprivation did not affect startle potentiation overall (timing task: p=0.184; probability task: p=0.328) or differently by stressor predictability (timing task: p=0.147; probability task: p=0.678). Heavy use did not affect startle potentiation overall (timing task: p=0.213; probability task: p=0.843) or differently by stressor predictability (timing task: p=0.655; probability task: p=0.273). Post-hoc analyses showed mixed evidence of general startle reactivity X deprivation interaction on startle potentiation overall (timing task: p=0.019; probability task: p=0.056) and differently by stressor predictability (probability task: p=0.024; timing task: p=0.364). Conclusions: A history of marijuana use or acute deprivation did not alter central stress responses despite prominent theoretical expectations. This study adds to growing research on central stress responses in individuals with a history of drug use and begins to parse moderating roles of individual differences and stressor characteristics.

Rationale: Norepinephrine plays a critical role in the stress response. Clarifying the psychopharmacological effects of norepinephrine manipulation on stress reactivity in humans has important implications for basic neuroscience and treatment of stress-related psychiatric disorders, such as posttraumatic stress disorder and alcohol use disorders. Preclinical research implicates the norepinephrine alpha-1 receptor in responses to stressors. The No Shock, Predictable Shock, Unpredictable Shock (NPU) task is a human laboratory paradigm that is well positioned to test cross- species neurobiological stress mechanisms and advance experimental therapeutic approaches to clinical trials testing novel treatments for psychiatric disorders.Objectives: We hypothesized that acute administration of prazosin, a noradrenergic alpha-1 antagonist, would have a larger effect on reducing stress reactivity during unpredictable, compared to predictable, stressors in the NPU task.Methods: We conducted a double-blind, placebo-controlled, crossover randomized controlled trial in which sixty-four healthy adults (32 female) completed the NPU task at two visits (2mg prazosin vs. placebo).Results: A single acute dose of 2mg prazosin did not reduce stress reactivity in a healthy adult sample. Neither NPU startle potentiation nor self-reported anxiety was reduced by prazosin (vs. placebo) during unpredictable (vs. predictable) stressors.Conclusions: Further research is needed to determine whether this failure to translate preclinical neuroscience to human laboratory models is due to methodological factors (e.g., acute vs. chronic drug administration, brain penetration, study population) and/or suggests limited clinical utility of noradrenergic alpha-1 antagonists for treating stress-related psychiatric disorders.

Objective: With the increasing age of the population, more elderly women undergo gynecologic surgery. While multiple studies have demonstrated the advantages of minimally invasive surgery ...

Biomedical research faces a scarcity of scientists able to work effectively at the interface of diverse scientific disciplines; we reflect on our experience over ten years of interdisciplinary training through our Masters of Research in Translational Medicine, preparing a new generation of researchers for post-genomic interdisciplinary medical research.

The present study addressed calls for research to identify real-time predictors of prescription drug misuse (Schepis et al., 2020) by testing young adults' momentary reports of their negative mood and positive mood as predictors of event-level misuse in daily life. We implemented a 28-day ecological momentary assessment (EMA) procedure that collected individuals' mood and other contextual experiences in moments preceding prescription drug misuse. Consistent with models of problematic substance use as a means to reduce negativity (Khantzian, 1997), results from hierarchical generalized linear modeling (HGLM) indicated within-person links between higher than usual negative mood and greater likelihood of prescription misuse in daily life. Contrary to the hypothesis, misuse was also more likely when preceded by elevated positive mood. We found consistent support for the hypothesized between-person effects, with prescription misuse in daily life associated with higher average levels of negative mood, and lower average levels of positive mood, across the reporting period. We further predicted that individuals reporting greater levels of social anxiety, depression, and externalizing symptoms would evidence stronger links between their momentary negative mood and prescription misuse. Partial support for this moderation hypothesis was found, with the positive within-person link between negative mood and prescription misuse significantly stronger among individuals higher (vs. lower) on social anxiety and depression. Results provide support for intricate connections between young adults' momentary mood, mental health symptoms, and prescription drug misuse. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The present study addressed calls for research to identify real-time predictors of prescription drug misuse (Schepis et al., 2020) by testing young adults’ momentary reports of their negative mood and positive mood as predictors of event-level misuse in daily life. We implemented a 28-day ecological momentary assessment (EMA) procedure that collected individuals’ mood and other contextual experiences in moments preceding prescription drug misuse. Consistent with models of problematic substance use as a means to reduce negativity (Khantzian, 1997), results from hierarchical generalized linear modeling indicated within-person links between higher than usual negative mood and greater likelihood of prescription misuse in daily life. Contrary to the hypothesis, misuse was also more likely when preceded by elevated positive mood. We found consistent support for the hypothesized between-person effects, with prescription misuse in daily life associated with higher average levels of negative mood, and lower average levels of positive mood, across the reporting period. We further predicted that individuals reporting greater levels of social anxiety, depression, and externalizing symptoms would evidence stronger links between their momentary negative mood and prescription misuse. Partial support for this moderation hypothesis was found, with the positive within-person link between negative mood and prescription misuse significantly stronger among individuals higher (vs. lower) on social anxiety and depression. Results provide support for intricate connections between young adults’ momentary mood, mental health symptoms, and prescription drug misuse.

Background In response to the ongoing COVID-19 pandemic, an emergency use authorization (EUA) was issued for neutralizing antibody therapies including BAM. Licensing trials suggest that use of BAM reduces hospitalizations when compared with placebo (1.6% vs 6.3%). However, the real world impact of BAM is not well-described. In this study, risk factors, outcomes, and hospitalization rates among high-risk outpatients presenting with mild-to-moderate COVID-19 who received BAM were examined. Methods This is a single center retrospective analysis of all patients who received BAM monotherapy between 11/11/2020 and 3/16/2021. Electronic health records were reviewed for baseline demographics, EUA indications, comorbidities, and outcomes to include infusion reactions, hospitalizations, and deaths occurring within 29 days of BAM administration. Moderate COVID-19 was defined as having any infiltrate on chest imaging prior to BAM administration. Chi-squared or Fisher’s exact tests were used to compare categorical values as appropriate, and Mann-Whitney U for continuous variables. Results Of the 101 patients who received BAM (median age 64 years; 21% black; 4% Hispanic; 55% male), 13 were subsequently admitted. 22 patients (22%) had moderately severe disease as evidenced by abnormal imaging. Severity on presentation, number of indications for therapy, hypertension, stroke, diabetes, and number of co-morbidities were significantly associated with subsequent admission (table 1). No patients had adverse infusion reactions. Of those hospitalized, 8 (61.5%) were for COVID-19, the median duration of hospitalization was 2 days, and 4 received guideline-directed treatment for COVID-19 (table 2). Table 1. Factors Associated with Hospitalization Following Bamlanivimab (BAM) Administration Table 1. (Continued) Factors Associated with Hospitalization Following Bamlanivimab (BAM) Administration Table 2: Characteristics and Resource Utilization of Patients Hospitalized After Bamlanivimab Therapy (n=13) Conclusion In a high-risk population, hospitalization rates were higher than those observed in clinical trials, with 8% of subjects being admitted for COVID-19. Disease severity on presentation, multiple indications for therapy, and the presence of multiple co-morbidities were all associated with subsequent admission. Reassuringly, BAM was well tolerated, and in those requiring admission, hospitalizations were short, resource utilization was low, and there were no deaths. Disclosures Benjamin L. Custer, M.D., Alexion Pharmaceuticals (Shareholder)Armata Pharmaceuticals (Shareholder)Biomarin Pharmaceutical (Shareholder)Crispr Therapeutics (Shareholder)CVS Health Corp (Shareholder)Editas Medicine (Shareholder)Gilead (Shareholder)Glaxo Smith Kline (Shareholder)Hologic Inc (Shareholder)Merck (Shareholder)Mesoblast LTD (Shareholder)Pfizer (Shareholder)Sanofi (Shareholder)Unitedhealth Group (Shareholder)Vertex Pharmaceuticals (Shareholder) Dana M. Blyth, MD, Nothing to disclose

Leishmaniasis, a chronic and persistent intracellular protozoal infection caused by many different species within the genus Leishmania, is an unfamiliar disease to most North American providers. Clinical presentations may include asymptomatic and symptomatic visceral leishmaniasis (so-called Kala-azar), as well as cutaneous or mucosal disease. Although cutaneous leishmaniasis (caused by Leishmania mexicana in the United States) is endemic in some southwest states, other causes for concern include reactivation of imported visceral leishmaniasis remotely in time from the initial infection, and the possible long-term complications of chronic inflammation from asymptomatic infection. Climate change, the identification of competent vectors and reservoirs, a highly mobile populace, significant population groups with proven exposure history, HIV, and widespread use of immunosuppressive medications and organ transplant all create the potential for increased frequency of leishmaniasis in the U.S. Together, these factors could contribute to leishmaniasis emerging as a health threat in the U.S., including the possibility of sustained autochthonous spread of newly introduced visceral disease. We summarize recent data examining the epidemiology and major risk factors for acquisition of cutaneous and visceral leishmaniasis, with a special focus on implications for the United States, as well as discuss key emerging issues affecting the management of visceral leishmaniasis.

Background By 2030, the number of US adults age ≥65 will exceed 70 million. Their quality of life has been declared a national priority by the US government. Objective Assess effects of an eHealth intervention for older adults on quality of life, independence, and related outcomes. Design Multi-site, 2-arm (1:1), non-blinded randomized clinical trial. Recruitment November 2013 to May 2015; data collection through November 2016. Setting Three Wisconsin communities (urban, suburban, and rural). Participants Purposive community-based sample, 390 adults age ≥65 with health challenges. Exclusions: long-term care, inability to get out of bed/chair unassisted. Intervention Access (vs. no access) to interactive website (ElderTree) designed to improve quality of life, social connection, and independence. Measures Primary outcome: quality of life (PROMIS Global Health). Secondary: independence (Instrumental Activities of Daily Living); social support (MOS Social Support); depression (Patient Health Questionnaire-8); falls prevention (Falls Behavioral Scale). Moderation: healthcare use (Medical Services Utilization). Both groups completed all measures at baseline, 6, and 12 months. Results Three hundred ten participants (79%) completed the 12-month survey. There were no main effects of ElderTree over time. Moderation analyses indicated that among participants with high primary care use, ElderTree (vs. control) led to better trajectories for mental quality of life (OR=0.32, 95% CI 0.10–0.54, P=0.005), social support received (OR=0.17, 95% CI 0.05–0.29, P=0.007), social support provided (OR=0.29, 95% CI 0.13–0.45, PP=0.034). Supplemental analyses suggested ElderTree may be more effective among people with multiple (vs. 0 or 1) chronic conditions. Limitations Once randomized, participants were not blind to the condition; self-reports may be subject to memory bias. Conclusion Interventions like ET may help improve quality of life and socio-emotional outcomes among older adults with more illness burden. Our next study focuses on this population. Trial Registration ClinicalTrials.gov; registration ID number: NCT02128789

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values, CP received funding from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. MMcC is a Wellcome Senior Investigator and an NIHR Senior Investigator. MMcC received funding from Wellcome (090532, 106130, 098381, 203141, 212259), NIDDK (U01DK105535), and NIHR (NF-SI-0617-10090). TGMV was supported by ZonMW (TOP 40-00812-9811010). DLC was supported by the American Diabetes Association Grant 1-17-PDF-077. SFAG is supported by the Daniel B. Burke Chair for Diabetes Research and NIH Grant R01 HD058886. NVT is funded by a pre-doctoral grant from the Agencia de Gestio d'Ajuts Universitaris i de Recerca (2017 FI_B 00636), Generalitat de Catalunya -Fons Social Europeu. BK received personal funding from the European Research Council Advanced Grant META-GROWTH (ERC-2012-AdG -no. 322605). BF was supported by an Oak Foundation Fellowship. RMF and RNB are supported by Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150). ATH is supported by a Wellcome Trust Senior Investigator award (grant number 098395/Z/12/Z). DM is supported by a Canada Research Chair. DLC was supported by the American Diabetes Association Grant 1-17-PDF077. JTL was supported by the Finnish Cultural Foundation. DIB received a KNAW Academy Professor Award (PAH/6635). MH received PhD scholarship funding from TARGET (http://target.ku.dk), The Danish Diabetes Academy (http://danishdiabetesacademy.dk) and the Copenhagen Graduate School of Health and Medical Sciences. VWVJ received funding from the Netherlands Organization for Health Research and Development (VIDI 016.136.361) and the European Research Council (ERC-2014-CoG-648916). ISF was supported by the European Research Council, Wellcome Trust (098497/Z/12/Z), Medical Research Council (MRC_MC_UU_12012/5), the NIHR Cambridge Biomedical Research Centre, the Botnar Foundation, the Bernard Wolfe Health Neuroscience Endowment and the European Community's Seventh Framework Programme (FP7/2007-2013) project Beta-JUDO n degrees 279153. IB acknowledges funding from Wellcome (WT206194). ES works in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3). GDS works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1). KC received funds from the French National Agency of Research, F-CRIN/FORCE. All funding for the studies that provided the underlying data for this manuscript can be found in S1 Text. The funders had no role in study design, data collection and analysis, data interpretation, decision to publish, or preparation of the manuscript.

Stressors can undermine smokers’ attempts to quit smoking. Although contemporary theories and animal models support this idea, human research has struggled to demonstrate definitively the relationship between stressors and smoking. Researchers have begun to employ more ecologically valid methods like ecological momentary assessment to address this question, but studies focusing explicitly on stressors remain sparse and findings inconsistent. The purpose of this study was to examine the effect of stressful event intensity on smoking and craving among cigarette smokers during a quit attempt. We conducted preregistered, complementary concurrent and prospective (i.e., 8-hour lag window between stressful event and outcomes) analyses to maximize statistical power and provide temporal ordering, respectively. We also conducted follow-up moderation (lag X stressful event intensity) analyses. We hypothesized that smokers would be more likely to report both smoking and craving as the intensity of stressful events increased. Cigarette smokers (N=125; 77 male) were randomly assigned to take nicotine replacement therapy (NRT) or placebo and provided 4X daily self-reports during the first 2 weeks of a quit attempt. Stressful events increased craving and the probability of smoking in concurrent analyses, and lag moderated the effect of stressful event intensity in follow-up prospective lagged analyses. NRT reduced the probability of smoking but not craving and did not moderate the effect of stressful events on smoking or craving. This study supports a prospective relationship between stressful events and smoking/craving in situ and demonstrates that NRT does not reduce the impact of stressors on smoking or craving.

Males have excess morbidity and mortality from respiratory viral infections and especially so in COVID-19. The mechanisms explaining this excess in disease burden in males are unknown. Innate immune responses are likely critical in protection against a novel virus like SARS-CoV-2. We hypothesised that innate immune responses may be deficient in males relative to females. To test this we stimulated peripheral blood mononuclear cells (PBMCs) from participants in a population-based birth cohort with three respiratory viruses (rhinoviruses-RV-A16 and RV-A1, and respiratory syncytial virus-RSV) and two viral mimics (R848 and CpG-A, to mimic responses to SARS-CoV-2). We measured interferon (IFN) and IFN-induced chemokine responses and investigated sex differences in virus-induced responses. IFN-α, IFN-β and IFN-γ responses to RV-A16 were deficient in males compared to females, fold-inductions being 1.92-fold (P<0.001), 2.04-fold (PP=0.003) lower in males than females, respectively. Similar significant deficiencies in innate immune responses were observed in males for eleven other cytokine-stimulus pairs. Responses in males were greater than those in females in only one of 35 cytokine-stimulus pairs investigated. Review of healthcare records revealed that 12.1% of males but only 6.6% of females were admitted to hospital with respiratory infections in the first year of life (P=0.017). Impaired innate anti-viral immunity in males likely results in high morbidity and mortality from respiratory viruses including COVID-19. Males may preferentially benefit from therapies that boost innate anti-viral immune responses.Significance StatementClinical outcomes including, mortality, Intensive care unit admissions and hospital admissions, during COVID-19 disease are consistently and substantially worse in males than in females. The mechanisms underlying this increased susceptibility to severe disease in males are not understood. We hypothesised that the differential outcomes between sexes could be a consequence of deficient innate interferon responses in males, and more robust innate interferon responses in females. We have investigated such responses in a large population-based cohort and found that indeed males have deficient innate interferon responses to viral stimuli, including stimuli that mimic SARS-CoV-2 infection, relative to females. Our findings have very important treatment implications as interferons are available for clinical use with immediate effect.

Psychological scientists are increasingly using machine learning to advance applied or basic science goals. Cross-validation is commonly used for training, selecting, and evaluating machine learning algorithms. Although cross-validation is often described as a tool that necessarily prevents overly optimistic estimates of a final model’s performance in new data, not all approaches to cross-validation offer accurate evaluation in all data contexts. Prior work in other fields has established that k-fold cross-validation can provide upwardly biased model evaluation. The extent of this optimization bias in data contexts typical of psychological science is not known. This Monte Carlo simulation study characterizes optimization bias in model evaluation when using three different approaches to cross-validation — k-fold cross-validation, k-fold cross-validation with a test set, and nested k-fold cross-validation — in factorial combinations of sample size (100; 500; 1,000), number of predictors (10; 100; 1,000), and outcome distribution (balanced, with a positive case probability of .50; unbalanced, with a positive case probability of .10). For each unique data context, 1,000 simulations were conducted by randomly sampling from multivariate normal predictor distributions and binomial outcome distributions such that predictors were known to have no population-level association with the outcome. We characterized the average, standard deviation, and maximum performance estimates resulting from model evaluation using each approach to cross-validation in each context, identifying biased evaluations as those with an Area Under the Receiver Operating Characteristic Curve (AUC) value greater than .50.

Managing pain has been identified (mainly through retrospective reports) as a robust motivator for individuals engaging in prescription opioid misuse. However, surprisingly little work has directly examined whether momentary pain experiences are associated with prescription opioid misuse in daily life. Participants included 297 young-adult college students recruited on the basis of recent prescription drug misuse. Ecological momentary assessment over a 28-day period was utilized to collect participants' pain experiences and prescription opioid misuse intention and behavior. Hierarchical generalized linear modeling and binary logistic regression tested hypotheses. Findings revealed that higher in-the-moment pain was positively associated with intentions to engage in prescription opioid misuse, accounting for report timing and participant sex and background substance use. Also, the between-person result indicated that participants who reported higher levels of pain across the reporting period were more likely to intend to misuse prescription opioids in daily life. There was a similar reliable association between higher pain ratings across the reporting period and greater likelihood of engaging in misuse behavior, although actual misuse frequency was low. Reliable moderation was observed: As hypothesized, the within-person association between momentary pain and misuse intentions was stronger for females compared with males. Also, the within-person link between pain and misuse intentions was stronger for those who reported lower (vs. higher) levels of problematic alcohol use; this was not consistent with the hypothesized direction. Understanding the role of college students' pain in their intentions to engage in prescription opioid misuse is important for informing future research and prevention efforts. (PsycInfo Database Record (c) 2020 APA, all rights reserved).