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Although dispositional optimism and pessimism have been prospectively associated with health outcomes, little is known about how these associations manifest in everyday life. This study examined how short-term optimistic and pessimistic expectations were associated with psychological and physiological stress processes.A diverse sample of adults (Moments that were more optimistic than typical for a person were followed by moments with lower likelihood of reporting a stressor, higher positive affect (PA), lower negative affect (NA), and less subjective stress (SS). Moments that were more pessimistic than typical were not associated with any affective stress outcome at the following moment. Neither optimism nor pessimism were associated with ABP, and did not moderate associations between reporting a stressor and outcomes.These findings suggest that intraindividual fluctuations in optimistic and pessimistic expectations are associated with stressor appraisals.

Coronavirus disease 2019 (COVID-19) in humans has a wide range of presentations, ranging from asymptomatic or mild symptoms to severe illness. Suitable animal models mimicking varying degrees of clinical disease manifestations could expedite development of therapeutics and vaccines for COVID-19. Here we demonstrate that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection resulted in subclinical disease in rhesus macaques with mild pneumonia and clinical disease in Syrian hamsters with severe pneumonia. SARS-CoV-2 infection was confirmed by formalin-fixed, paraffin-embedded (FFPE) polymerase chain reaction (PCR), immunohistochemistry, or in situ hybridization. Replicating virus in the lungs was identified using in situ hybridization or virus plaque forming assays. Viral encephalitis, reported in some COVID-19 patients, was identified in one macaque and was confirmed with immunohistochemistry. There was no evidence of encephalitis in hamsters. Severity and distribution of lung inflammation were substantially more in hamsters compared with macaques and exhibited vascular changes and virus-induced cytopathic changes as seen in COVID-19 patients. Neither the hamster nor macaque models demonstrated evidence for multisystemic inflammatory syndrome (MIS). Data presented here demonstrate that macaques may be appropriate for mechanistic studies of mild asymptomatic COVID-19 pneumonia and COVID-19-associated encephalitis, whereas Syrian hamsters may be more suited to study severe COVID-19 pneumonia.

Background Research pairing ecological momentary assessment (EMA) methodology and ambulatory cortisol during daily life is still rare, as is careful testing of the within-person associations between stress, affect, and cortisol. Using a circumplex approach, we considered both valence and arousal components of affect. Purpose To examine the within-person covariation of momentary cortisol with momentary perceived stress, affective valence, and affective arousal in everyday life. Methods 115 working adults (Mage = 41.2; 76% women; 76% white) completed six EMA surveys per day over 3 days. Each assessment included reports of perceived stress and affect (used to construct indicators of affective valence and arousal), followed by a saliva sample (from which cortisol was assessed). Multi-level models were used to examine the momentary associations between perceived stress, affective valence, affective arousal, and cortisol. Results Moments characterized by higher perceived stress were associated with higher cortisol (p = .036). Affective valence covaried with cortisol (p = .003) such that more positive valence was associated with lower cortisol and more negative valence with higher cortisol. Momentary affective arousal was not related to cortisol (p = .131). When all predictors were tested in the same model, only valence remained a significant predictor of cortisol (p = .047). Conclusion Momentary perceived stress and affective valence, but not affective arousal, were associated with naturalistic cortisol. Cortisol was more robustly associated with affective valence than perceived stress or affective arousal. These findings extend our understanding of how moments of stress and particular characteristics of affective states (i.e., valence but not arousal) may “get under the skin” in daily life.

Background The most frequently reported treatment‐related adverse event in clinical trials with the cyclin‐dependent kinase 4/6 (CDK4/6) inhibitor palbociclib is neutropenia. Allelic variants in ABCB1 and ERCC1 might be associated with early occurrence (i.e., end of week 2 treatment) of grade 3/4 neutropenia. Pharmacogenetic analyses were performed to uncover associations between single nucleotide polymorphisms (SNPs) in these genes, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia. Materials and Methods ABCB1 (rs1045642, rs1128503) and ERCC1 (rs3212986, rs11615) were analyzed in germline DNA from palbociclib‐treated patients from PALOMA‐2 (n = 584) and PALOMA‐3 (n = 442). SNP, race, and cycle 1 day 15 (C1D15) absolute neutrophil count (ANC) data were available for 652 patients. Univariate and multivariable analyses evaluated associations between SNPs, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia. Analyses were stratified by Asian (n = 122) and non‐Asian (n = 530) ethnicity. Median progression‐free survival (mPFS) was estimated using the Kaplan‐Meier method. The effect of genetic variants on palbociclib pharmacokinetics was analyzed. Results ABCB1 and ERCC1_rs11615 SNP frequencies differed between Asian and non‐Asian patients. Multivariable analysis showed that low baseline ANC was a strong independent risk factor for C1D15 grade 3/4 neutropenia regardless of race (Asians: odds ratio [OR], 6.033, 95% confidence interval [CI], 2.615−13.922, p < .0001; Non‐Asians: OR, 6.884, 95% CI, 4.138−11.451, p < .0001). ABCB1_rs1128503 (C/C vs. T/T: OR, 0.57, 95% CI, 0.311−1.047, p = .070) and ERCC1_rs11615 (A/A vs. G/G: OR, 1.75, 95% CI, 0.901−3.397, p = .098) were potential independent risk factors for C1D15 grade 3/4 neutropenia in non‐Asian patients. Palbociclib mPFS was consistent across genetic variants; exposure was not associated with ABCB1 genotype. Conclusion This is the first comprehensive assessment of pharmacogenetic data in relationship to exposure to a CDK4/6 inhibitor. Pharmacogenetic testing may inform about potentially increased likelihood of patients developing severe neutropenia (NCT01740427, NCT01942135). Implications for Practice Palbociclib plus endocrine therapy improves hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer outcomes, but is commonly associated with neutropenia. Genetic variants in ABCB1 may influence palbociclib exposure, and in ERCC1 are associated with chemotherapy‐induced severe neutropenia. Here, the associations of single nucleotide polymorphisms in these genes and baseline characteristics with neutropenia were assessed. Low baseline absolute neutrophil count was a strong risk factor (p, The most frequently reported treatment‐related adverse event in clinical trials with the cyclin‐dependent kinase 4/6 (CDK4/6) inhibitor palbociclib is neutropenia. In this study, pharmacogenetic analyses were performed to uncover associations between single nucleotide polymorphisms in the ABCB1 and ERCC1 genes, patient baseline characteristics, and early occurrence of grade 3/4 neutropenia.

Endogenous biomarkers are emerging to advance clinical drug-drug interaction (DDI) risk assessment in drug development. Twelve healthy subjects received a multidrug and toxin exclusion protein (MATE) inhibitor (pyrimethamine, 10, 25, and 75 mg) in a crossover fashion to identify an appropriate endogenous biomarker to assess MATE1/2-K-mediated DDI in the kidneys. Metformin (500 mg) was also given as reference probe drug for MATE1/2-K. In addition to the previously reported endogenous biomarker candidates (creatinine and N1 -methylnicotinamide (1-NMN)), N1 -methyladenosine (m1 A) was included as novel biomarkers. 1-NMN and m1 A presented as superior MATE1/2-K biomarkers since changes in their renal clearance (CLr ) along with pyrimethamine dose were well-correlated with metformin CLr changes. The CLr of creatinine was reduced by pyrimethamine, however, its changes poorly correlated with metformin CLr changes. Nonlinear regression analysis (CLr vs. mean total concentration of pyrimethamine in plasma) yielded an estimate of the inhibition constant (Ki ) of pyrimethamine and the fraction of the clearance pathway sensitive to pyrimethamine. The in vivo Ki value thus obtained was further converted to unbound Ki using plasma unbound fraction of pyrimethamine, which was comparable to the in vitro Ki for MATE1 (1-NMN) and MATE2-K (1-NMN and m1 A). It is concluded that 1-NMN and m1 A CLr can be leveraged as quantitative MATE1/2-K biomarkers for DDI risk assessment in healthy volunteers.

Although dispositional optimism and pessimism are associated with cardiovascular disease (CVD), their relative independence and unique contributions to CVD risk are unclear. This study addressed these issues by using multiple indicators of optimism and pessimism and linking them to objective risk factors for CVD. A diverse sample of adults (N = 300) completed baseline assessments (including global reports of optimism and pessimism), a 2-day/1-night EMA protocol with ambulatory blood pressure (BP) at 45-minute intervals, and had inflammatory markers and carotid intima media imaging collected. EMA reports of momentary positive and negative expectations were averaged to form intraindividual (person) means of optimism and pessimism, respectively. Optimism and pessimism were only modestly correlated between- and within-assessment methods. Higher pessimism, regardless of assessment method, predicted both lower odds of whether BP dipping occurred and a smaller degree of dipping, but was unrelated to other biomarkers. Optimism was not uniquely predictive of CVD risk factors. Pessimism thus appears to exhibit stronger relative contribution to risk indicators of CVD than optimism.

To address the most appropriate endogenous biomarker for drug–drug interaction risk assessment, eight healthy subjects received an organic anion transporting polypeptide 1B (OATP1B) inhibitor (rifampicin, 150, 300, and 600 mg), and a probe drug cocktail (atorvastatin, pitavastatin, rosuvastatin, and valsartan). In addition to coproporphyrin I, a widely studied OATP1B biomarker, we identified at least 4 out of 28 compounds (direct bilirubin, glycochenodeoxycholate‐3‐glucuronide, glycochenodeoxycholate‐3‐sulfate, and hexadecanedioate) that presented good sensitivity and dynamic range in terms of the rifampicin dose‐dependent change in area under the plasma concentration‐time curve ratio (AUCR). Their suitability as OATP1B biomarkers was also supported by the good correlation of AUC0‐24h between the endogenous compounds and the probe drugs, and by nonlinear regression analysis (AUCR−1 vs. rifampicin plasma Cmax (maximum total concentration in plasma)) to yield an estimate of the inhibition constant of rifampicin. These endogenous substrates can complement existing OATP1B‐mediated drug–drug interaction risk assessment approaches based on agency guidelines in early clinical trials.

DNA-Encoded Chemical Library (DECL) synthesis must occur in aqueous media under conditions that preserve the integrity of the DNA encoding tag. While the identification of “DNA-compatible” reaction conditions is critical for the development of DECL designs that explore previously inaccessible chemical space, reports measuring such compatibility have been largely restricted to methods that do not faithfully capture the impact of reaction conditions on DNA fidelity in solution phase. Here we report a comprehensive methodology that uses soluble DNA substrates that exactly recapitulate DNA’s exposure to the chemically reactive species of DECL synthesis. This approach includes the assessment of chemical fidelity (reaction yield and purity), encoding fidelity (ligation efficiency), and readability (DNA compatibility), revealing the fate of the DNA tag during DECL chemistry from a single platform.

It is of great challenge to predict human brain penetration for substrates of multidrug resistance protein 1 (MDR1) and breast cancer resistance protein (BCRP), 2 major efflux transporters at blood-brain barrier. Thus, a physiologically based pharmacokinetic (PBPK) model with the incorporation of in vitro MDR1 and BCRP transporter function data and transporter protein expression levels has been developed. As such, it is crucial to generate MDR1 and BCRP substrate data with a high fidelity. In this study, 2 widely used human MDR1 cell lines from Borst and National Institutes of Health laboratories were evaluated using rodent brain penetration data, and the study suggested that the MDR1 expressed in Madin-Darby canine kidney (MDCK) cell line from National Institutes of Health laboratory predicted brain penetration better, particularly for compounds with a high passive permeability. In addition, human BCRP-MDCK cell line with 1 μM PSC833, a specific MDR1 inhibitor, demonstrated the ability to identify BCRP substrates without the confounding of endogenous canine Mdr1. Comparison of human BCRP and mouse Bcrp transporter functions revealed that the functional differences of BCRP between the 2 species is minimal. The incorporation of both the validated MDR1 and BCRP assays into our brain PBPK model has significantly improved the prediction for the brain penetration of MDR1 and BCRP substrates across species.

Teachers engage in sustained peer collaboration about formative assessment with a focus on students' mathematical thinking.

Clinical genomic tests increasingly use a next-generation sequencing (NGS) platform due in part to the high fidelity of variant calls, yet rare errors are still possible. In germline DNA screening, failure to correct such errors could have serious consequences for patients, who may follow an unwarranted screening or surgical management path. It has been suggested that routine orthogonal confirmation by Sanger sequencing is required to verify NGS results, especially low-confidence positives with depressed allele fraction ( 15,000 samples. Licensed reviewers manually inspected both raw and processed data at the batch, sample, and variant levels, including raw NGS read pileups. Of ambiguous variant calls with 99% (n = 1701) as true positives (enriched for long insertions or deletions and homopolymers) or true negatives (often conspicuous NGS artifacts), with the remaining

Background Artificial intelligence has provided new opportunities for human interactions with technology for the practice of medicine. Among the recent artificial intelligence innovations, personal voice assistants have been broadly adopted. This highlights their potential for health care–related applications such as behavioral counseling to promote healthy lifestyle habits and emotional well-being. However, the use of voice-based applications for behavioral therapy has not been previously evaluated. Objective This study aimed to conduct a formative user evaluation of Lumen, a virtual voice-based coach developed as an Alexa skill that delivers evidence-based, problem-solving treatment for patients with mild to moderate depression and/or anxiety. Methods A total of 26 participants completed 2 therapy sessions—an introductory (session 1) and a problem-solving (session 2)—with Lumen. Following each session with Lumen, participants completed user experience, task-related workload, and work alliance surveys. They also participated in semistructured interviews addressing the benefits, challenges and barriers to Lumen use, and design recommendations. We evaluated the differences in user experience, task load, and work alliance between sessions using 2-tailed paired t tests. Interview transcripts were coded using an inductive thematic analysis to characterize the participants’ perspectives regarding Lumen use. Results Participants found Lumen to provide high pragmatic usability and favorable user experience, with marginal task load during interactions for both Lumen sessions. However, participants experienced a higher temporal workload during the problem-solving session, suggesting a feeling of being rushed during their communicative interactions. On the basis of the qualitative analysis, the following themes were identified: Lumen’s on-demand accessibility and the delivery of a complex problem-solving treatment task with a simplistic structure for achieving therapy goals; themes related to Lumen improvements included streamlining and improved personalization of conversations, slower pacing of conversations, and providing additional context during therapy sessions. Conclusions On the basis of an in-depth formative evaluation, we found that Lumen supported the ability to conduct cognitively plausible interactions for the delivery of behavioral therapy. Several design suggestions identified from the study including reducing temporal and cognitive load during conversational interactions, developing more natural conversations, and expanding privacy and security features were incorporated in the revised version of Lumen. Although further research is needed, the promising findings from this study highlight the potential for using Lumen to deliver personalized and accessible mental health care, filling a gap in traditional mental health services.

Artificial intelligence (AI)-based voice technology offers considerable promise in healthcare; however, its application for behavioral therapy in a real-world or research setting has yet to be determined. We describe the design and evaluation of 1Lumen™, a fully functional voice-only virtual coach that delivers evidence-based, problem-solving treatment (PST) for patients with mild-to-moderate depression and/or anxiety. Participants (N=26) completed surveys and semi-structured interviews after two therapy sessions with Lumen. Participants found Lumen to provide high pragmatic usability and favorable user experience, with marginal task load during interactions. Participants emphasized its on-demand accessibility and the delivery of a complex PST task with a simplistic structure for achieving therapy goals. Suggestions for improvement included streamlining and improved personalization and pacing of conversations and providing additional context during therapy sessions. Lumen offers a realistic and cognitively plausible verbal interaction that can potentially lead to personalized and accessible mental health care, filling a gap in traditional mental health services.

Extracellular vesicles (EVs) are small, nonreplicating, lipid-encapsulated particles that contain a myriad of protein and nucleic acid cargo derived from their tissue of origin. The potential role of EV-derived biomarkers to the study of drug metabolism and disposition (DMD) has gained attention in recent years. The key trait that makes EVs an attractive biomarker source is their capacity to provide comparable insights to solid organ biopsy through an appreciably less invasive collection procedure. Blood-derived EVs exist as a heterogenous milieu of biologically distinct particles originating from different sources through different biogenesis pathways. Furthermore, blood (plasma and serum) contains an array of vesicular and nonvesicular contaminants, such as apoptotic bodies, plasma proteins, and lipoproteins that are routinely coisolated with EVs, albeit to a different extent depending on the isolation technique. The following minireview summarizes current studies reporting DMD biomarkers and addresses elements of EV isolation and quantification relevant to the application of EV-derived DMD biomarkers. Evidence based-best practice guidance aligned to Minimum Information for the Study of Extracellular Vesicles and EV-TRACK reporting standards are summarized in the context of DMD studies. SIGNIFICANCE STATEMENT: Extracellular vesicle (EV)-derived protein and nucleic acid cargo represent a potentially game-changing source of novel DMD biomarkers with the capacity to define within- and between-individual variability in drug exposure irrespective of etiology. However, robust translation of EV-derived biomarkers requires the generation of transparent reproducible evidence. This review outlines the critical elements of data generation and reporting relevant to achieving this evidence in a drug metabolism and disposition context.

Liver-derived small extracellular vesicles (sEVs), prepared from small sets of banked serum samples using a novel two-step protocol, were deployed as liquid biopsy to study the induction of cytochromes P450 (CYP3A4, CYP3A5, and CYP2D6) and organic anion transporting polypeptides (OATP1B1 and OATP1B3) during pregnancy (nonpregnant (T0), first, second, and third (T3) trimester women; N = 3 each) and after administration of rifampicin (RIF) to healthy male subjects. Proteomic analysis revealed induction (mean fold-increase, 90% confidence interval) of sEV CYP3A4 after RIF 300 mg × 7 days (3.5, 95% CI = 2.5-4.5, N = 4, P = 0.029) and 600 mg × 14 days (3.7, 95% CI = 2.1-6.0, N = 5, P = 0.018) consistent with the mean oral midazolam area under the plasma concentration time curve (AUC) ratio in the same subjects (0.28, 95% CI = 0.22-0.34, P

Objective Altered diurnal cortisol rhythms are a potential mechanism through which symptoms of fatigue are maintained in post-treatment cancer survivors. Exposure to early morning bright light may target this underlying dysregulation, resulting in improved diurnal cortisol patterns, subsequently improving symptoms of fatigue. This research investigates the effects of a 4-week light therapy intervention on the diurnal cortisol slopes and output in fatigued cancer survivors. Methods Post-treatment adult cancer survivors who met diagnostic criteria for cancer-related fatigue were randomly assigned to receive either a bright white light (BWL) or dim red light (DRL) device, used daily for 30 min over four consecutive weeks. Assessments of fatigue and salivary cortisol were collected at baseline and post-intervention. Cortisol was sampled four times per day (waking, noon, 5 pm, bedtime) for three days at each timepoint. Diurnal cortisol slopes and total cortisol output were calculated at baseline and post-intervention. Linear mixed models were used to analyze the data. Results Seventy-seven participants were included in this analysis (BWL n = 40; DRL n = 37). Participants in both groups displayed increased steepness in cortisol slope (B = -0.02, p = .01, Cohen's d = 0.57) and increased total cortisol output (B = 9.58, p = .03, Cohen's d = 0.49) from baseline to post-intervention, indicating only a moderate effect of time. Neither diurnal cortisol slopes nor total cortisol output mediated the relationship between the light therapy intervention and fatigue levels. Conclusion Though the results of this trial are promising for light therapy as an effective intervention to reduce fatigue in cancer survivors, this does not appear to be achieved through alterations in neuroendocrine function. ClinicalTrials.gov registration #: NCT01780623

Although stress is a common experience in everyday life, a clear understanding of how often an individual experiences and reports stress is lacking. Notably, there is little information regarding factors that may influence how frequently stress is reported, including which stress dimension is measured (i.e., stressors-did an event happen, subjective stress-how stressed do you feel, conditional stress-how stressful a stressor was) and the temporal features of that assessment (i.e., time of day, day of study, weekday vs. weekend day). The purpose of the present study was to conduct a coordinated analysis of five independent ecological momentary assessment studies utilizing varied stress reporting dimensions and temporal features. Results indicated that, within days, stress was reported at different frequencies depending on the stress dimension. Stressors were reported on 15-32% of momentary reports made within a day; across days, the frequency ranged from 42 to 76% of days. Depending on the cutoff, subjective stress was reported more frequently ranging about 8-56% of all moments within days, and 40-90% of days. Likewise, conditional stress ranged from just 3% of moments to 22%, and 11-69% of days. For the temporal features, stress was reported more frequently on weekdays (compared to weekend days) and on days earlier in the study (relative to days later in the study); time of day was inconsistently related to stress reports. In sum, stress report frequency depends in part on how stress is assessed. As such, researchers may wish to measure stress in multiple ways and, in the case of subjective and conditional stress with multiple operational definitions, to thoroughly characterize the frequency of stress reporting.

Answer questions and earn CME/CNE Patients with breast cancer commonly use complementary and integrative therapies as supportive care during cancer treatment and to manage treatment-related side effects. However, evidence supporting the use of such therapies in the oncology setting is limited. This report provides updated clinical practice guidelines from the Society for Integrative Oncology on the use of integrative therapies for specific clinical indications during and after breast cancer treatment, including anxiety/stress, depression/mood disorders, fatigue, quality of life/physical functioning, chemotherapy-induced nausea and vomiting, lymphedema, chemotherapy-induced peripheral neuropathy, pain, and sleep disturbance. Clinical practice guidelines are based on a systematic literature review from 1990 through 2015. Music therapy, meditation, stress management, and yoga are recommended for anxiety/stress reduction. Meditation, relaxation, yoga, massage, and music therapy are recommended for depression/mood disorders. Meditation and yoga are recommended to improve quality of life. Acupressure and acupuncture are recommended for reducing chemotherapy-induced nausea and vomiting. Acetyl-L-carnitine is not recommended to prevent chemotherapy-induced peripheral neuropathy due to a possibility of harm. No strong evidence supports the use of ingested dietary supplements to manage breast cancer treatment-related side effects. In summary, there is a growing body of evidence supporting the use of integrative therapies, especially mind-body therapies, as effective supportive care strategies during breast cancer treatment. Many integrative practices, however, remain understudied, with insufficient evidence to be definitively recommended or avoided. CA Cancer J Clin 2017;67:194-232. © 2017 American Cancer Society.

Fatigue is a common and distressing symptom that can last for months or years in up to one-third of cancer survivors. Despite its prevalence, the nature and mechanisms of cancer-related fatigue are poorly understood and the available treatments may not provide sufficient relief. Fatigue has been identified as a significant contributor to decreased quality of life, making it an important target for intervention. One approach that may be a safe and inexpensive treatment is bright light therapy. Methods This study is a 4-week blinded randomized controlled trial. Subjects will be men and women who meet criteria for cancer-related fatigue and have completed cancer treatment. Subjects will be randomly assigned to receive a Litebook treatment device that produces either bright white light (treatment) or dim red light (active control). The devices will be used daily for 30 min upon waking for a period of four weeks. The primary outcome, fatigue, will be measured with the Multidimensional Fatigue Symptom Inventory-SF. Secondary outcomes include mood disturbance, sleep quality, quality of life, diurnal cortisol, and inflammatory biomarkers. Fatigue assessments will be completed weekly and secondary outcomes will be assessed at pre- and post-intervention. Conclusions The current research will examine the effect of light exposure on cancer-related fatigue and its potential psychological, behavioral, and biological mechanisms. If successful, this research would support the use of light therapy for the management of persistent fatigue in cancer survivors, expanding existing treatment options. It may also improve upon the current understanding of the mechanisms that underlie cancer-related fatigue.

Background Positive affect journaling (PAJ), an emotion-focused self-regulation intervention, has been associated with positive outcomes among medical populations. It may be adapted for Web-based dissemination to address a need for scalable, evidence-based psychosocial interventions among distressed patients with medical conditions. Objective This study aimed to examine the impact of a 12-week Web-based PAJ intervention on psychological distress and quality of life in general medical patients. Methods A total of 70 adults with various medical conditions and elevated anxiety symptoms were recruited from local clinics and randomly assigned to a Web-based PAJ intervention (n=35) or usual care (n=35). The intervention group completed 15-min Web-based PAJ sessions on 3 days each week for 12 weeks. At baseline and the end of months 1 through 3, surveys of psychological, interpersonal, and physical well-being were completed. Results Patients evidenced moderate sustained adherence to Web-based intervention. PAJ was associated with decreased mental distress and increased well-being relative to baseline. PAJ was also associated with less depressive symptoms and anxiety after 1 month and greater resilience after the first and second month, relative to usual care. Conclusions Web-based PAJ may serve as an effective intervention for mitigating mental distress, increasing well-being, and enhancing physical functioning among medical populations. PAJ may be integrated into routine medical care to improve quality of life. Trial Registration ClinicalTrials.gov NCT01873599; https://clinicaltrials.gov/ct2/show/NCT01873599 (Archived by WebCite at http://www.webcitation.org/73ZGFzD2Z)

BACKGROUND Positive affect journaling (PAJ), an emotion-focused self-regulation intervention, has been associated with positive outcomes among medical populations. It may be adapted for Web-based dissemination to address a need for scalable, evidence-based psychosocial interventions among distressed patients with medical conditions. OBJECTIVE This study aimed to examine the impact of a 12-week Web-based PAJ intervention on psychological distress and quality of life in general medical patients. METHODS A total of 70 adults with various medical conditions and elevated anxiety symptoms were recruited from local clinics and randomly assigned to a Web-based PAJ intervention (n=35) or usual care (n=35). The intervention group completed 15-min Web-based PAJ sessions on 3 days each week for 12 weeks. At baseline and the end of months 1 through 3, surveys of psychological, interpersonal, and physical well-being were completed. RESULTS Patients evidenced moderate sustained adherence to Web-based intervention. PAJ was associated with decreased mental distress and increased well-being relative to baseline. PAJ was also associated with less depressive symptoms and anxiety after 1 month and greater resilience after the first and second month, relative to usual care. CONCLUSIONS Web-based PAJ may serve as an effective intervention for mitigating mental distress, increasing well-being, and enhancing physical functioning among medical populations. PAJ may be integrated into routine medical care to improve quality of life. CLINICALTRIAL ClinicalTrials.gov NCT01873599; https://clinicaltrials.gov/ct2/show/NCT01873599 (Archived by WebCite at http://www.webcitation.org/73ZGFzD2Z)

Clinical genomic tests increasingly use a next-generation sequencing (NGS) platform due in part to the high fidelity of variant calls, yet rare errors are still possible. In germline DNA screening, failure to correct such errors could have serious consequences for patients, who may follow an unwarranted screening or surgical management path. It has been suggested that routine orthogonal confirmation by Sanger sequencing is required to verify NGS results, especially low-confidence positives with depressed allele fraction (30% of alternate allele). We evaluated whether an alternative method of confirmation-software-assisted manual call review-performed comparably with Sanger confirmation in15,000 samples. Licensed reviewers manually inspected both raw and processed data at the batch, sample, and variant levels, including raw NGS read pileups. Of ambiguous variant calls with30% allele fraction (1707 total calls at 38 unique sites), manual call review classified99% (n = 1701) as true positives (enriched for long insertions or deletions and homopolymers) or true negatives (often conspicuous NGS artifacts), with the remaining1% (n = 6) being mosaic. Critically, results from software-assisted manual review and retrospective Sanger sequencing were concordant for samples selected from all ambiguous sites. We conclude that the confirmation required for high confidence in NGS-based germline testing can manifest in different ways; a trained NGS expert operating platform-tailored review software achieves quality comparable with routine Sanger confirmation.

Clinical genomic tests increasingly utilize a next generation sequencing (NGS) platform due in part to the high fidelity of variant calls, yet rare errors are still possible. In hereditary cancer screening, failure to correct such errors could have serious consequences for patients, who may follow an unwarranted screening or surgical-management path. It has been suggested that routine orthogonal confirmation via Sanger sequencing is required to verify NGS results, especially low-confidence positives with depressed allele fraction (15,000 samples. Licensed reviewers manually inspected both raw and processed data at the batch-, sample-, and variant-level, including raw NGS read pileups. Of ambiguous variant calls with 99% (1,701) as true positives (enriched for long insertions or deletions (“indels”) and homopolymers) or true negatives (often conspicuous NGS artifacts), with the remaining

Background Perceived growth (PG) refers to perceptions of positive changes that unfold over time after experiencing trauma. Higher PG is often associated with positive long-term health, but the processes through which PG may influence health are unclear. The present study examines two potential pathways among individuals living with asthma or RA: (1) by promoting momentary indicators of health and well-being in everyday life, and (2) by buffering against stress. Method In a micro-longitudinal design, 128 participants with asthma (n = 97) or rheumatoid arthritis (n = 31) reported perceived growth using the Post-Traumatic Growth (PTG) Inventory and subsequently completed ecological momentary assessments (EMAs) for one week. Participants were signaled five times a day to report on health-related indicators, including affect, disease interference, social interactions, and stress. Results Multilevel modeling revealed that higher PTG was associated with significantly less negative affect and greater positive affect in everyday life. There were no significant associations between PTG and momentary disease interference, pleasantness of social interactions, or stress, nor evidence that PTG buffered against effects of stress on health-related outcomes. Conclusions This research highlights the utility of examining PG in everyday life. Results suggest that closer examination of momentary affect as a process by which PG may facilitate positive health outcomes is warranted.

IntroductionPsychosocial factors are increasingly recognised as important determinants of cardiovascular disease risk. The North Texas Heart Study aims to understand the mechanisms responsible for this association with a focus on social vigilance (ie, scanning the environment for social threats). There is also growing interest in supplementing traditional methods (eg, survey assessment of psychosocial risk paired with cross-sectional and longitudinal health outcomes) with daily or repeated momentary assessment of psychosocial factors. However, there are relatively few longitudinal studies directly comparing these approaches with hard endpoints.Methods and analysisThe North Texas Heart Study proposes a longitudinal measurement burst design to examine psychosocial determinants of subclinical atherosclerosis. A sample of 300 healthy community participants, stratified by age and gender, will complete survey measures, as well as 2 days of ecological momentary assessment at baseline and at a 2-year follow-up. A range of psychosocial and behavioural factors, objective biomarkers, as well as carotid intima-media thickness (cIMT) will be assessed at both time points. Unadjusted and adjusted models will evaluate cross-sectional associations and determinants of change in the cIMT.Ethics and disseminationThe Institutional Review Board at the study coordinating institute (University of North Texas) has approved this study. Positive, negative or inconclusive primary and ancillary findings will be disseminated in scientific journals and conferences.

Cancer-related fatigue (CRF) is a common and distressing symptom that can persist after cancer treatment has concluded. Bright light therapy has shown preliminary efficacy in reducing CRF, but its impact on other psychosocial factors is unclear. The purpose was to examine the impact of a 1-month light therapy intervention on fatigue, mood, and quality of life in cancer survivors with fatigue. This 4-week blinded randomized controlled trial recruited cancer survivors who met diagnostic criteria for CRF. Participants were randomly assigned to receive a light therapy device that produced either bright white light (BWL; intervention) or dim red light (DRL; active control). Participants were instructed to use the device daily for 30 min upon waking for 28 days. The primary outcome, fatigue, was assessed weekly. Secondary outcomes assessed pre- and post-intervention included mood, depressive symptoms, and quality of life. A total of 81 participants were randomly assigned to receive BWL (n = 42) or DRL (n = 39). Analyses revealed a group-by-time interaction for fatigue (p = .034), wherein the BWL condition reported a 17% greater reduction in fatigue than those in the DRL condition (between group d = .30). There were also significant improvements over time for both groups on measures of mood, depressive symptoms, and quality of life (p’s

Background: The Smoothened inhibitor glasdegib (GLAS) was recently approved in combination with low-dose cytarabine (LDAC) in adults with AML when intensive chemotherapy is not an option. GLAS in combination with intensive chemotherapy has also been well tolerated and shown clinical activity, and is undergoing further evaluation. This analysis aimed to identify molecular drivers that predict overall response (OR) and OS with GLAS. Materials and Methods: We included AML patients receiving LDAC alone or with GLAS 100 mg QD (nonintensive arm) or GLAS 100 mg QD & 7+3 (intensive arm) from Phases 1b and 2 of a multicenter study (NCT01546038). We assessed correlation of OS/OR with mRNA expression of 19 genes, expression levels of 38 cytokines, and mutations in 109 genes. For correlation analyses, a cut-off < or ≥ the median was used for gene expression and cytokine levels and mutated or not for gene mutations. Results: Within the nonintensive arm (LDAC + GLAS, n=68; LDAC, n=30), improved OS with GLAS + LDAC correlated with lower FOXM1 and MSI2, and higher BCL2 and CCND2 expression. For cytokines, lower levels of 6CKINE, BAFF, ICAM-1, MIP-1α, MIP-1β and MMP-3 correlated with improved OS. The low number of responders in the LDAC arm (n=2) prevented correlation analysis of mRNA or cytokines; however, within the LDAC + GLAS arm, OR correlated with high PTCH1 levels, and high EOTAXIN but low BAFF levels. In the intensive arm (GLAS & 7+3, n=59), higher PTCH1 expression correlated with improved OS (median OS 10.8 vs 39.5 months) but no significant correlations were found with OR; no cytokines correlated with OS or with OR. For gene mutation, in the nonintensive arm (LDAC + GLAS, n=65; LDAC alone, n=25), OS differed with PLEKHH1 and STAG2 mutation status, but no genes correlated with OR. In the intensive arm (n=55), mutations in FLT3, TP53, CEP170, PHF6, and ANKRD26 correlated with OS. Patients in this arm with FLT3 mutations (including ITD) responded better vs wild type FLT3 (median OS 13.4 months vs unreached for FLT3 mutant). We also examined mRNA expression and cytokine levels at various times after starting treatment: statistically significant changes included modulation of SMO, BDNF, ITAC, and IL-23 levels in the nonintensive arm, and SMO, MYCN, CDKN1A, and a number of cytokines including IL-8, TNF-α and IL-5 in the intensive arm. Conclusions: In this analysis, expression levels of a select number of genes and circulating cytokines implicated in AML appear to correlate with OS and OR. The improved response with FLT3 mutations and high PTCH1 expression levels in the intensive arm, along with the analysis appearing to indicate modulation of select genes (eg SMO) and cytokines in both arms while on treatment, deserves further investigation. These preliminary findings will need to be verified in larger randomized trials, which are on-going. Citation Format: Akil Merchant, Catriona Jamieson, Michael Heuser, Geoffrey Chan, Panpan Wang, Keith A. Ching, Jillian Johnson, Thomas O’Brien, Jorge E. Cortes. Biomarkers correlating with overall survival (OS) and response to glasdegib and intensive or nonintensive chemotherapy in patients with acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-009.

1060 Background: The most common PAL treatment related adverse event is neutropenia. ABCB1 and ERCC1 variants are associated with increased chemotherapy drug exposure and CYP3A7*1C may be associated with reduced exposure. Pharmacogenetic analyses of these variants in patients (pts) from P2/3 may reveal associations between single nucleotide polymorphisms (SNPs) and early occurrence of grade 3/4 (G3/4) neutropenia. Methods: ABCB1 (rs1045642, rs1128503), ERCC1 (rs3212986, rs11615), and CYP3A7*1C (rs45446698) variants were analyzed in germline DNA from pts with HR+/HER2– advanced breast cancer from P2 (n=584) and P3 (n=442) by TaqMan assay. Association between variants and incidence of G3/4 low absolute neutrophil count (ANC) at Cycle 1 Day 15 (C1D15) was assessed with the exact Cochran-Armitage trend test. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression. Results: In total, 652 PAL-treated pts had SNP, race, and C1D15 ANC data. Minor allele frequencies (MAF), incidence rates, and relative risk of G3/4 C1D15 ANC for ABCB1 and ERCC1 variants are given in the Table. CYP3A7*1C was only found in non-Asians (MAF 6%). Conclusions: This is the first comprehensive assessment of pharmacogenetic data from P2/3. ABCB1 and ERCC1 SNP allele frequencies differ between Asians and non-Asians. Despite combining P2/3 data, we lacked power to detect moderate associations; further investigation of these SNPs with G3/4 C1D15 ANC is warranted. Pfizer Clinical trial information: NCT01740427, NCT01942135. [Table: see text]

The observation of caspase-like activity during cell death has provided a new framework for understanding the evolutionary and ecological contexts of programmed cell death in phytoplankton. However, additional roles for this caspase-like activity, the enzymes responsible, and the targets of this enzyme activity in phytoplankton remain largely undefined. In the present study, the role of caspase-like activity in aging and ROS-mediated cell death were investigated and death programs both dependent on and independent of caspase-like activity were observed in the toxic dinoflagellate, Karenia brevis. The dual use of in situ caspase 3/7 and TUNEL staining identified previously undescribed death-associated morphotypes in K. brevis. In silico motif analysis identified several enzymes with predicted caspase-like activity in the K. brevis transcriptome, although bona fide caspases are absent. Lastly, computational prediction of downstream caspase substrates, using sequence context and predicted secondary structure, identified proteins involved in a wide range of biological processes including regulation of protein turnover, cell cycle progression, lipid metabolism, coenzyme metabolism, apoptotic and autophagic death. To confirm the computational predictions, a short peptide was designed around the predicated caspase cleavage site in a predicted novel K. brevis caspase 3/7-like target, S-adenosylmethionine synthetase (KbAdoMetS). Cleavage of the peptide substrate with recombinant caspase 3 enzyme was determined by MALDI-TOF MS, confirming that KbAdoMetS is indeed a bona fide caspase substrate. These data identify the involvement of caspase-like activity in both aging and cell death in K. brevis and identify novel executioner enzymes and downstream targets that may be important for bloom termination.

Dinoflagellates are prolific producers of polyketide secondary metabolites. Dinoflagellate polyketide synthases (PKSs) have sequence similarity to Type I PKSs, megasynthases that encode all catalytic domains on a single polypeptide. However, in dinoflagellate PKSs identified to date, each catalytic domain resides on a separate transcript, suggesting multiprotein complexes similar to Type II PKSs. Here, we provide evidence through coimmunoprecipitation that single-domain ketosynthase and ketoreductase proteins interact, suggesting a predicted multiprotein complex. In Karenia brevis (C.C. Davis) Gert Hansen & O. Moestrup, previously observed chloroplast localization of PKSs suggested that brevetoxin biosynthesis may take place in the chloroplast. Here, we report that PKSs are present in both cytosol and chloroplast. Furthermore, brevetoxin is not present in isolated chloroplasts, raising the question of what chloroplast-localized PKS enzymes might be doing. Antibodies to K. brevis PKSs recognize cytosolic and chloroplast proteins in Ostreopsis cf. ovata Fukuyo, and Coolia monotis Meunier, which produce different suites of polyketide toxins, suggesting that these PKSs may share common pathways. Since PKSs are closely related to fatty acid synthases (FAS), we sought to determine if fatty acid biosynthesis colocalizes with either chloroplast or cytosolic PKSs. [(3) H]acetate labeling showed fatty acids are synthesized in the cytosol, with little incorporation in chloroplasts, consistent with a Type I FAS system. However, although 29 sequences in a K. brevis expressed sequence tag database have similarity (BLASTx e-value

1. Penciclovir, ganciclovir, creatinine, para-aminohippuric acid (PAH), ketoprofen, estrone 3-O-sulfate (E3S), dehydroepiandrosterone 3-O-sulfate (DHEAS) and cyclic guanosine monophosphate (cGMP) were screened as substrates of human liver organic anion transporters OAT2 and OAT7. 2. For OAT7, high uptake ratios (versus mock transfected HEK293 cells) of 29.6 and 15.3 were obtained with E3S and DHEAS. Less robust uptake ratios (≤3.6) were evident with the other substrates. OAT2 (transcript variant 1, OAT2-tv1) presented high uptake ratios of 30, 13, ∼35, ∼25, 8.5 and 9 with cGMP, PAH, penciclovir, ganciclovir, creatinine and E3S, respectively. No uptake was observed with DHEAS. 3. Although not a substrate of either transporter, ketoprofen did inhibit transfected OAT2-tv1 (IC50 of 17, 22, 23, 24, 35 and 586 μM; creatinine, ganciclovir, penciclovir, cGMP, E3S and prostaglandin F2α, respectively) and penciclovir uptake (IC50 = 27 µM; >90% inhibition) by plated human hepatocytes (PHH). 4. It is concluded that penciclovir and ketoprofen may serve as useful tools for the assessment of OAT2 activity in PHH. However, measurement of OAT7 activity therein will prove more challenging, as high uptake rates are evident with E3S and DHEAS only and both sulfoconjugates are known to be substrates of organic anion transporting polypeptides.

Aquatic crustaceans can experience low levels of O2 alone but more often in combination with high levels of CO2 both in natural estuaries and in aquaculture ponds. Hemocyanin, the respiratory pigment in many crustacean species, facilitates O2 transport and is documented to change in abundance, structure, and function in response to low O2 The impacts of high CO2 on the respiratory pigment are less clear. In this synthesis we bring together data from recently published and new RNA-Seq studies toward the aims of defining the full repertoire of hemocyanin subunits, as well as their differential expression and regulation in the Penaeoidea family in response to low O2 with or without high CO2 RNA-Seq data were collected from the hepatopancreas tissues of aquacultured Pacific whiteleg shrimp Litopenaeus vannamei, wild-caught L. vannamei, and wild-caught Atlantic brown shrimp Farfantepenaeus aztecus. De novo assembly yielded high-quality stranded transcriptomes. Manual curation of the hemocyanin subunits from all three groups of penaeid shrimp confirmed the existence of a small γ-type hemocyanin subunit (HcS), greater sequence diversity in the large γ-type hemocyanin subunit than previously identified (HcL1-3 isoforms) and expression of a β-type hemocyanin subunit (HcB) previously unidentified in Penaeid shrimp. Relative abundance of transcripts encoding these hemocyanin isoforms differed within and among the three species/strains. Exposure to low O2 induced expression of all of the subunits in aquacultured L. vannamei With concurrent exposure to high CO2, the number of γ-type hemocyanin transcripts decreased while the expression of β-type transcripts remained unchanged. Together with functional data for hemocyanins in the same shrimp species/strains, the RNA-Seq approach shows great promise to provide new insights into the connection between sequence, protein structure, and physiological function of respiratory pigments in this decapod crustacean family.

Background: In a previously reported Phase 2 randomized study of patients with acute myeloid leukemia (AML), addition of the investigational agent glasdegib (PF-04449913) to low-dose cytarabine (LDAC) improved overall survival (OS) when compared with LDAC alone. In a non-randomized study arm, glasdegib together with 7+3 chemotherapy was well tolerated and associated with clinical activity. We used a comprehensive biomarker analysis, evaluating gene expression, circulating cytokine levels, and gene mutations, to identify molecular drivers that predict overall response (OR) and OS. Methods: In this Phase 2 multicenter study (NCT01546038), patients with AML who were suitable for non-intensive therapy were randomized (2:1) to LDAC + glasdegib 100 mg QD or LDAC alone, and patients suitable for intensive therapy were assigned 7+3 plus glasdegib 100 mg QD. Whole blood, serum, and bone marrow aspirate samples were collected at baseline, and used to assess 19 genes for expression analysis, 38 analytes for circulating cytokine levels, and 109 genes for mutation analysis. Gene expression was analyzed using TaqMan Low Density Array Cards (TLDCs), cytokine levels were analyzed using quantitative, multiplexed immunoassays (Myriad RBM), and mutation analysis was performed using the Illumina® MiSeq instrument (San Diego, CA). All correlations were performed either for OS or for OR. For gene expression and cytokine analysis, a cut-off value above or below the median expression level for each treatment arm was used to separate samples into two subgroups (< or ≥ the median value) to explore the relationship of expression levels with OS data. Criteria for significance in the non-intensive cohort required one subgroup to have a p-value of Results: Within the non-intensive arm (LDAC + glasdegib, n=68; LDAC alone, n=30), expression levels of several genes correlated with improved OS with glasdegib plus LDAC. Lower levels of expression of FOXM1 and MSI2, and higher expression levels of BCL2 and CCND2 correlated with improved OS with the combination. Additionally, lower levels of the cytokines 6CKINE (CCL21), ICAM-1, MIP-1α, and MMP-3 correlated with improved OS. An analysis of correlations of gene expression and cytokine levels with OR could not be completed due to the low number of responders in the LDAC only group (n=2). In the intensive treatment arm (glasdegib and 7+3, n=59), higher PTCH1 expression correlated with improved OS (p=0.0219, median OS 10.8 versus 39.5 months). In this cohort, lower levels of IL-8 (p=0.0225) and MIP-3β (p=0.0403) correlated with lower OS. Expression levels of no genes or cytokines significantly correlated with OR in this arm. We also examined correlations between gene mutation status and OS in both study arms. In the non-intensive arm (LDAC + glasdegib, n=58; LDAC alone, n=25), no genes mutated in at least 5 patients correlated with OS. In the intensive treatment arm (n=47), mutations in FLT3, TP53, CEP170, NPM1, and ANKRD26 correlated with OS (all p Conclusions: In this biomarker analysis, we found that expression levels of a select number of genes and circulating cytokines implicated in AML correlated with OS in the non-intensive and the intensive arms. The improved response for patients with FLT3 mutations and high PTCH1 expression levels in the intensive arm deserves further investigation. These findings need to be verified in larger controlled studies, which are ongoing. Disclosures Cortes: Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. Pollyea:Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Curis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Heuser:Astellas: Research Funding; Daiichi Sankyo: Research Funding; Sunesis: Research Funding; Tetralogic: Research Funding; Bayer Pharma AG: Consultancy, Research Funding; StemLine Therapeutics: Consultancy; Janssen: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BergenBio: Research Funding; Karyopharm: Research Funding. Chan:Pfizer: Employment, Equity Ownership. Wang:Pfizer: Employment, Equity Ownership. Ching:Pfizer Inc: Employment, Equity Ownership. Johnson:Pfizer Inc: Employment, Equity Ownership. O'Brien:Pfizer Inc: Employment, Equity Ownership.

The dinoflagellate Karenia brevis (C. C. Davis) Gert Hansen et Moestrup produces a suite of brevetoxins, potent neurotoxins that have adverse effects on marine animal and human health. Brevetoxins are polyketides proposed to be synthesized by polyketide synthases (PKSs), and genes for type I PKSs have been predicted by PCR and transcript analysis. However, the full-length transcripts in K. brevis predict an unusual protein structure for type I PKS in that individual transcripts encode for single catalytic domains. In this study, we developed peptide antibodies to in silico translated transcripts for two PKS proteins to characterize their expression and localization. Immunoreactive proteins identified by Western blotting at 40 kDa (KR domain) and 100 kDa (KS domain) are consistent with the sizes predicted by the full-length transcripts. Immunolocalization and Western blot analysis indicate that these PKSs are associated with the chloroplasts. In order to establish evidence for a role in brevetoxin biosynthesis, PKS transcript and protein levels were examined in a “nontoxic”K. brevis substrain and its parental toxic isolate, K. brevis Wilson. DNA microarray analysis of the global transcript profiles in the “nontoxic” isolate showed that ∼7% of transcripts were differentially expressed, including photosystem genes; however, no difference was observed in PKS transcript abundance. By contrast, KS domain proteins were 55%–70% less abundant in “nontoxic”K. brevis cultures compared to toxic cultures. This finding suggests that K. brevis PKS expression is regulated posttranscriptionally, like many other processes in dinoflagellates. Further, the decrease in PKS protein abundance in the “nontoxic” cultures provides correlative evidence for their involvement in brevetoxin biosynthesis.