Adaptive therapy achieves long-term control of chemotherapy resistance in high grade ovarian cancer.

Drug resistance results in poor outcomes for most patients with metastatic cancer. Adaptive Therapy (AT) proposes to address this by exploiting presumed fitness costs incurred by drug-resistant cells when drug is absent, and prescribing dose reductions to allow fitter, sensitive cells to re-grow and re-sensitise the tumour. However, empirical evidence for treatment-induced fitness change is lacking. We show that fitness costs in chemotherapy-resistant ovarian cancer cause selective decline and apoptosis of resistant populations in low-resource conditions. Moreover, carboplatin AT caused fluctuations in sensitive/resistant tumour population size in vitro and significantly extended survival of tumour-bearing mice. In sequential blood-derived cell-free DNA and tumour samples obtained longitudinally from ovarian cancer patients during treatment, we inferred resistant cancer cell population size through therapy and observed it correlated strongly with disease burden. These data have enabled us to launch a multicentre, phase 2 randomised controlled trial (ACTOv) to evaluate AT in ovarian cancer.

No robust evidence for an interaction between early-life adversity and protective factors on global and regional brain volumes.

Childhood adversity is associated with brain morphology and poor psychological outcomes, and evidence of protective factors counteracting childhood adversity effects on neurobiology is scarce. We examined the interplay of childhood adversity with protective factors in relation to brain morphology in two independent longitudinal cohorts, the Generation R Study (N = 3008) and the Mannheim Study of Children at Risk (MARS) (N = 179). Cumulative exposure to 12 adverse events was assessed across childhood until age 9 years in Generation R and 11 years in MARS. Protective factors (temperament, cognition, self-esteem, maternal sensitivity, friendship quality) were assessed at various time-points during childhood. Global brain volumes and volumes of amygdala, hippocampus, and the anterior cingulate, medial orbitofrontal and rostral middle frontal cortices were assessed with anatomical scans at 10 years in Generation R and at 25 years in MARS. Childhood adversity was related to smaller cortical grey matter, cerebral white matter, and cerebellar volumes in children. Also, no buffering effects of protective factors on the association between adversity and the brain outcomes survived multiple testing correction. We found no robust evidence for an interaction between protective factors and childhood adversity on broad brain structural measures. Small interaction effects observed in one cohort only warrant further investigation.

Momentary Self-regulation: Scale Development and Preliminary Validation.

BACKGROUND: Self-regulation refers to a person's ability to manage their cognitive, emotional, and behavioral processes to achieve long-term goals. Most prior research has examined self-regulation at the individual level; however, individual-level assessments do not allow the examination of dynamic patterns of intraindividual variability in self-regulation and thus cannot aid in understanding potential malleable processes of self-regulation that may occur in response to the daily environment. OBJECTIVE: This study aims to develop a brief, psychometrically sound momentary self-regulation scale that can be practically administered through participants' mobile devices at a momentary level. METHODS: This study was conducted in 2 phases. In the first phase, in a sample of 522 adults collected as part of a larger self-regulation project, we examined 23 previously validated assessments of self-regulation containing 594 items in total to evaluate the underlying structure of self-regulation via exploratory and confirmatory factor analyses. We then selected 20 trait-level items to be carried forward to the second phase. In the second phase, we converted each item into a momentary question and piloted the momentary items in a sample of 53 adults over 14 days. Using the results from the momentary pilot study, we explored the psychometric properties of the items and assessed their underlying structure. We then proposed a set of subscale and total score calculations. RESULTS: In the first phase, the selected individual-level items appeared to measure 4 factors of self-regulation. The factors identified were perseverance, sensation seeking, emotion regulation, and mindfulness. In the second phase of the ecological momentary assessment pilot, the selected items demonstrated strong construct validity as well as predictive validity for health risk behaviors. CONCLUSIONS: Our findings provide preliminary evidence for a 12-item momentary self-regulation scale comprising 4 subscales designed to capture self-regulatory dynamics at the momentary level.

Momentary Influences on Self-Regulation in Two Populations With Health Risk Behaviors: Adults Who Smoke and Adults Who Are Overweight and Have Binge-Eating Disorder.

Introduction: Self-regulation has been implicated in health risk behaviors and is a target of many health behavior interventions. Despite most prior research focusing on self-regulation as an individual-level trait, we hypothesize that self-regulation is a time-varying mechanism of health and risk behavior that may be influenced by momentary contexts to a substantial degree. Because most health behaviors (e.g., eating, drinking, smoking) occur in the context of everyday activities, digital technologies may help us better understand and influence these behaviors in real time. Using a momentary self-regulation measure, the current study (which was part of a larger multi-year research project on the science of behavior change) used ecological momentary assessment (EMA) to assess if self-regulation can be engaged and manipulated on a momentary basis in naturalistic, non-laboratory settings. Methods: This one-arm, open-label exploratory study prospectively collected momentary data for 14 days from 104 participants who smoked regularly and 81 participants who were overweight and had binge-eating disorder. Four times per day, participants were queried about momentary self-regulation, emotional state, and social and environmental context; recent smoking and exposure to smoking cues (smoking sample only); and recent eating, binge eating, and exposure to binge-eating cues (binge-eating sample only). This study used a novel, momentary self-regulation measure comprised of four subscales: momentary perseverance, momentary sensation seeking, momentary self-judgment, and momentary mindfulness. Participants were also instructed to engage with Laddr, a mobile application that provides evidence-based health behavior change tools via an integrated platform. The association between momentary context and momentary self-regulation was explored via mixed-effects models. Exploratory assessments of whether recent Laddr use (defined as use within 12 h of momentary responses) modified the association between momentary context and momentary self-regulation were performed via mixed-effects models. Results: Participants (mean age 35.2; 78% female) in the smoking and binge-eating samples contributed a total of 3,233 and 3,481 momentary questionnaires, respectively. Momentary self-regulation subscales were associated with several momentary contexts, in the combined as well as smoking and binge-eating samples. For example, in the combined sample momentary perseverance was associated with location, positively associated with positive affect, and negatively associated with negative affect, stress, and tiredness. In the smoking sample, momentary perseverance was positively associated with momentary difficulty in accessing cigarettes, caffeine intake, and momentary restraint in smoking, and negatively associated with temptation and urge to smoke. In the binge-eating sample, momentary perseverance was positively associated with difficulty in accessing food and restraint in eating, and negatively associated with urge to binge eat. While recent Laddr use was not associated directly with momentary self-regulation subscales, it did modify several of the contextual associations, including challenging contexts. Conclusions: Overall, this study provides preliminary evidence that momentary self-regulation may vary in response to differing momentary contexts in samples from two exemplar populations with risk behaviors. In addition, the Laddr application may modify some of these relationships. These findings demonstrate the possibility of measuring momentary self-regulation in a trans-diagnostic way and assessing the effects of momentary, mobile interventions in context. Health behavior change interventions may consider measuring and targeting momentary self-regulation in addition to trait-level self-regulation to better understand and improve health risk behaviors. This work will be used to inform a later stage of research focused on assessing the transdiagnostic mediating effect of momentary self-regulation on medical regimen adherence and health outcomes. Clinical Trial Registration: ClinicalTrials.gov, Identifier: NCT03352713.

Carvedilol targets ß-arrestins to rewire innate immunity and improve oncolytic adenoviral therapy.

Oncolytic viruses are being tested in clinical trials, including in women with ovarian cancer. We use a drug-repurposing approach to identify existing drugs that enhance the activity of oncolytic adenoviruses. This reveals that carvedilol, a ß-arrestin-biased ß-blocker, synergises with both wild-type adenovirus and the E1A-CR2-deleted oncolytic adenovirus, dl922-947. Synergy is not due to ß-adrenergic blockade but is dependent on ß-arrestins and is reversed by ß-arrestin CRISPR gene editing. Co-treatment with dl922-947 and carvedilol causes increased viral DNA replication, greater viral protein expression and higher titres of infectious viral particles. Carvedilol also enhances viral efficacy in orthotopic, intraperitoneal murine models, achieving more rapid tumour clearance than virus alone. Increased anti-cancer activity is associated with an intratumoural inflammatory cell infiltrate and systemic cytokine release. In summary, carvedilol augments the activity of oncolytic adenoviruses via ß-arrestins to re-wire cytokine networks and innate immunity and could therefore improve oncolytic viruses for cancer patient treatment.

Compassion, stigma, and professionalism among emergency personnel responding to the opioid crisis: An exploratory study in New Hampshire, USA.

OBJECTIVE: Drug overdoses are the leading cause of death in the United States for those under 50 years of age, and New Hampshire has been disproportionately affected, resulting in increased encounters with the emergency response system. The ensuing impact on emergency personnel has received little attention. The present study aimed to explore the experiences and perspectives of emergency personnel responding to the opioid crisis in NH, with a focus on their views toward people who use opioids. METHODS: Thirty-six emergency personnel (emergency department clinicians, n = 18; emergency medical service providers, n = 6; firefighters, n = 6; and police officers, n = 6) in 6 New Hampshire counties were interviewed about their experiences responding to overdoses and their perspectives on individuals who use opioids. Directed content analysis was used to identify themes in the transcribed, semistructured interviews. The results were reviewed for consensus. RESULTS: Several categories of themes were identified among emergency personnel's accounts of their overdose response experiences and perspectives, including varied degrees of compassion and stigma toward people who use opioids; associations between compassion or stigma and policy- and practice-related themes, such as prehospital emergency care and the role of emergency departments (EDs); and primarily among personnel expressing compassion, a sense of professional responsibility that outweighed personal biases. CONCLUSIONS: Despite the magnitude of the ongoing opioid crisis, some emergency personnel in New Hampshire have sustained or increased their compassion for people who use opioids. Others' perspectives remain or have become increasingly stigmatizing. The associations of compassion and stigma with various policy- and practice-related themes warrant further investigation.

Early life stress and behavior problems in early childhood: Investigating the contributions of child temperament and executive functions to resilience.

This preregistered study examined whether child temperament and executive functions moderated the longitudinal association between early life stress (ELS) and behavior problems. In a Dutch population-based cohort (n = 2803), parents reported on multiple stressors (age 0-6 years), child temperament (age 5), and executive functions (age 4), and teachers rated child internalizing and externalizing problems (age 7). Results showed that greater ELS was related to higher levels of internalizing and externalizing problems, with betas reflecting small effects. Lower surgency buffered the positive association of ELS with externalizing problems, while better shifting capacities weakened the positive association between ELS and internalizing problems. Other child characteristics did not act as moderators. Findings underscore the importance of examining multiple protective factors simultaneously.

Longitudinal association between CRP levels and risk of psychosis: a meta-analysis of population-based cohort studies.

Meta-analyses of cross-sectional studies suggest that patients with psychosis have higher circulating levels of C-reactive protein (CRP) compared with healthy controls; however, cause and effect is unclear. We examined the prospective association between CRP levels and subsequent risk of developing a psychotic disorder by conducting a systematic review and meta-analysis of population-based cohort studies. Databases were searched for prospective studies of CRP and psychosis. We obtained unpublished results, including adjustment for age, sex, body mass index, smoking, alcohol use, and socioeconomic status and suspected infection (CRP > 10 mg/L). Based on random effect meta-analysis of 89,792 participants (494 incident cases of psychosis at follow-up), the pooled odds ratio (OR) for psychosis for participants with high (>3 mg/L), as compared to low (≤3 mg/L) CRP levels at baseline was 1.50 (95% confidence interval [CI], 1.09-2.07). Evidence for this association remained after adjusting for potential confounders (adjusted OR [aOR] = 1.31; 95% CI, 1.03-1.66). After excluding participants with suspected infection, the OR for psychosis was 1.36 (95% CI, 1.06-1.74), but the association attenuated after controlling for confounders (aOR = 1.23; 95% CI, 0.95-1.60). Using CRP as a continuous variable, the pooled OR for psychosis per standard deviation increase in log(CRP) was 1.11 (95% CI, 0.93-1.34), and this association further attenuated after controlling for confounders (aOR = 1.07; 95% CI, 0.90-1.27) and excluding participants with suspected infection (aOR = 1.07; 95% CI, 0.92-1.24). There was no association using CRP as a categorical variable (low, medium or high). While we provide some evidence of a longitudinal association between high CRP (>3 mg/L) and psychosis, larger studies are required to enable definitive conclusions.

Implementation of a New Hampshire community-initiated response to the opioid crisis: A mixed-methods process evaluation of Safe Station.

BACKGROUND: New Hampshire (NH) ranked first for fentanyl- and all opioid-related overdose deaths per capita from 2014 to 2016 and third in 2017 with no rate reduction from the previous year relative to all other states in the US. In response to the opioid crisis in NH, Manchester Fire Department (MFD), the state's largest city fire department, launched the Safe Station program in 2016 in partnership with other community organizations. This community-based response to the crisis-described as a connection to recovery-focuses on reducing barriers to accessing resources for people with substance use and related problems. The study aim is to characterize the multi-organizational partnerships and workflow of the Safe Station model and identify key components that are engaging, effective, replicable, and sustainable. METHODS: A mixed-methods design included: semi-structured qualitative interviews conducted with 110 stakeholders from six groups of community partners (Safe Station clients, MFD staff and leadership, and local emergency department, ambulance, and treatment partner staff); implementation and sustainability surveys (completed by MFD stakeholders); and ethnographic observations conducted at MFD. Qualitative data were content analyzed and coded using the Consolidated Framework for Implementation Research. Survey subscales were scored and evaluated to corroborate the qualitative findings. RESULTS: Community partners identified key program characteristics including firefighter compassion, low-threshold access, and immediacy of service linkage. Implementation and sustainability survey data corroborate the qualitative interview and observation data in these areas. All participants agreed that community partnerships are key to the program's success. There were mixed evaluations of the quality of communication among the organizations. CONCLUSION: Safe Station is a novel response to the opioid crisis in New Hampshire that offers immediate, non-judgmental access to services for persons with opioid use disorders requiring community-wide engagement and communication. Data convergence provides guidance to the sustainability and replicability of the program.

Chloroxine overrides DNA damage tolerance to restore platinum sensitivity in high-grade serous ovarian cancer.

High-grade serous cancer (HGSC) accounts for ~67% of all ovarian cancer deaths. Although initially sensitive to platinum chemotherapy, resistance is inevitable and there is an unmet clinical need for novel therapies that can circumvent this event. We performed a drug screen with 1177 FDA-approved drugs and identified the hydroxyquinoline drug, chloroxine. In extensive validation experiments, chloroxine restored sensitivity to both cisplatin and carboplatin, demonstrating broad synergy in our range of experimental models of platinum-resistant HGSC. Synergy was independent of chloroxine's predicted ionophore activity and did not relate to platinum uptake as measured by atomic absorption spectroscopy. Further mechanistic investigation revealed that chloroxine overrides DNA damage tolerance in platinum-resistant HGSC. Co-treatment with carboplatin and chloroxine (but not either drug alone) caused an increase in γH2AX expression, followed by a reduction in platinum-induced RAD51 foci. Moreover, this unrepaired DNA damage was associated with p53 stabilisation, cell cycle re-entry and triggering of caspase 3/7-mediated cell death. Finally, in our platinum-resistant, intraperitoneal in vivo model, treatment with carboplatin alone resulted in a transient tumour response followed by tumour regrowth. In contrast, treatment with chloroxine and carboplatin combined, was able to maintain tumour volume at baseline for over 4 months. In conclusion, our novel results show that chloroxine facilitates platinum-induced DNA damage to restore platinum sensitivity in HGSC. Since chloroxine is already licensed, this exciting combination therapy could now be rapidly translated for patient benefit.

"It's way more than just writing a prescription": A qualitative study of preferences for integrated versus non-integrated treatment models among individuals with opioid use disorder.

BACKGROUND: Increasingly, treatment for opioid use disorder (OUD) is offered in integrated treatment models addressing both substance use and other health conditions within the same system. This often includes offering medications for OUD in general medical settings. It remains uncertain whether integrated OUD treatment models are preferred to non-integrated models, where treatment is provided within a distinct treatment system. This study aimed to explore preferences for integrated versus non-integrated treatment models among people with OUD and examine what factors may influence preferences. METHODS: This qualitative study recruited participants (n = 40) through Craigslist advertisements and flyers posted in treatment programs across the United States. Participants were 18 years of age or older and scored a two or higher on the heroin or opioid pain reliever sections of the Tobacco, Alcohol, Prescription Medications, and Other Substances (TAPS) Tool. Each participant completed a demographic survey and a telephone interview. The interviews were coded and content analyzed. RESULTS: While some participants preferred receiving OUD treatment from an integrated model in a general medical setting, the majority preferred non-integrated models. Some participants preferred integrated models in theory but expressed concerns about stigma and a lack of psychosocial services. Tradeoffs between integrated and non-integrated models were centered around patient values (desire for anonymity and personalization, fear of consequences), the characteristics of the provider and setting (convenience, perceived treatment effectiveness, access to services), and the patient-provider relationship (disclosure, trust, comfort, stigma). CONCLUSIONS: Among this sample of primarily White adults, preferences for non-integrated versus integrated OUD treatment were mixed. Perceived benefits of integrated models included convenience, potential for treatment personalization, and opportunity to extend established relationships with medical providers. Recommendations to make integrated treatment more patient-centered include facilitating access to psychosocial services, educating patients on privacy, individualizing treatment, and prioritizing the patient-provider relationship. This sample included very few minorities and thus findings may not be fully generalizable to the larger population of persons with OUD. Nonetheless, results suggest a need for expansion of both OUD treatment in specialty and general medical settings to ensure access to preferred treatment for all.

Correlation Database of 60 Cross-Disciplinary Surveys and Cognitive Tasks Assessing Self-Regulation.

Self-regulation is studied across various disciplines, including personality, social, cognitive, health, developmental, and clinical psychology; psychiatry; neuroscience; medicine; pharmacology; and economics. Widespread interest in self-regulation has led to confusion regarding both the constructs within the nomological network of self-regulation and the measures used to assess these constructs. To facilitate the integration of cross-disciplinary measures of self-regulation, we estimated product-moment and distance correlations among 60 cross-disciplinary measures of self-regulation (23 self-report surveys, 37 cognitive tasks) and measures of health and substance use based on 522 participants. The correlations showed substantial variability, though the surveys demonstrated greater convergent validity than did the cognitive tasks. Variables derived from the surveys only weakly correlated with variables derived from the cognitive tasks (M = .049, range = .000 to .271 for the absolute value of the product-moment correlation; M = .085, range = .028 to .241 for the distance correlation), thus challenging the notion that these surveys and cognitive tasks measure the same construct. We conclude by outlining several potential uses for this publicly available database of correlations.

Perceptions and preferences for long-acting injectable and implantable medications in comparison to short-acting medications for opioid use disorders.

Aim: Treatment for opioid use disorders has recently evolved to include long-acting injectable and implantable formulations of medications for opioid use disorder (MOUD). Incorporating patient preferences into treatment for substance use disorders is associated with increased motivation and treatment satisfaction. This study sought to assess treatment preferences for long-acting injectable and implantable MOUD as compared to short-acting formulations among individuals with OUD. Methods: We conducted qualitative, semi-structured telephone interviews with forty adults recruited from across the United States through Craigslist advertisements and flyers posted in treatment programs. Eligible participants scored a two or greater on the heroin or opioid pain reliever sections of the Tobacco, Alcohol, Prescription Medications, and Other Substances (TAPS) Tool, indicative of a past-year OUD. Interviews were transcribed, coded, and thematically analyzed. Results: Twenty-four participants (60%) currently or previously had been prescribed MOUD. Sixteen participants (40%) expressed general opposition to MOUD, citing concerns that MOUD is purely financial gain for pharmaceutical companies and/or a "band aid" solution replacing one drug with another, rather than a path to abstinence. Some participants expressed personal preference for long-acting injectable (n = 16/40: 40%) and implantable formulations (n = 12/40: 30%) over short-acting formulations. About half of the participants were not willing to use injectables (n = 19/40: 48%) or implantables (n = 22/40: 55%), preferring short-acting formulations. Mixed evaluations of long- and short-acting MOUD focused on considerations of medication-related beliefs (privacy, concern over an embedded foreign body), the medication-related burden (convenience, provision of structure and support, medication administration, potential side effects), and medication-taking practices (potential for non-prescribed use, control over dosage, and duration of treatment). Conclusions: Though many participants personally prefer short-acting to long-acting MOUD, some were open to including long-acting formulations in the range of options for those with OUD. Participants felt long-acting formulations may reduce medication-related burden and the risk of diversion. Conversely, participants expressed concern about invasive administration and loss of control over their treatment. Results suggest support for expanded access to a variety of formulations of MOUD. The use of shared decision making may also help patients select the formulation best aligned with their experiences, values, and treatment goals.

Understanding the increase in opioid overdoses in New Hampshire: A rapid epidemiologic assessment.

BACKGROUND: New Hampshire (NH) has had among the highest rates of fentanyl-related overdose deaths per capita in the United States for several years in a row-more than three times the national average in 2016. This mixed-methods study investigated drug-using practices and perspectives of NH residents who use opioids to inform policy in tackling the overdose crisis. METHODS: Seventy-six participants from six NH counties completed demographic surveys and semi-structured interviews focused on drug-using practices and perspectives, including use precursors, fentanyl-seeking behaviors, and experiences with overdose. Rigorous qualitative methods were used to analyze interview data including transcription, coding and content analysis. Descriptive statistics were calculated on quantitative survey data. RESULTS: Eighty-four percent of interviewees had knowingly used fentanyl in their lifetime, 70 % reported overdosing at least once, and 42 % had sought a batch of drugs known to have caused an overdose. The majority stated most heroin available in NH was laced with fentanyl and acknowledged that variability across batches increased overdose risk. Participants reported high availability of fentanyl and limited access to prevention, treatment, and harm reduction programs. There was widespread support for expanding education campaigns for youth, increasing treatment availability, and implementing needle exchange programs. CONCLUSIONS: A confluence of factors contribute to the NH opioid overdose crisis. Despite consensus that fentanyl is the primary cause of overdoses, individuals continue to use it and affirm limited availability of resources to address the problem. Policies targeting innovative prevention, harm reduction, and treatment efforts are needed to more effectively address the crisis.

Item Response Theory Analysis of the Five Facet Mindfulness Questionnaire and its Short Forms.

OBJECTIVES: The Five Facet Mindfulness Questionnaire (FFMQ) is a self-report measure of mindfulness with forms of several different lengths, including the FFMQ-39, FFMQ-24, and FFMQ-15. We use item response theory analysis to directly compare the functioning of these three forms. METHODS: Data were drawn from a non-clinical Amazon Mechanical Turk study (N = 522) and studies of aftercare treatment of individuals with substance use disorders (combined N = 454). The item and test functioning of the three FFMQ forms were studied and compared. RESULTS: All 39 items were strongly related to the facet latent variables, and the items discriminated over a similar range of the latent mindfulness constructs. Items provided more information in the low to medium range of latent mindfulness than in the high range. Scores in three of the five FFMQ-39 facets were unreliable when measuring individuals in the high range of latent mindfulness, resulting from ceiling effects in item responses. Reliability in the high range of mindfulness was further reduced in the FFMQ-24 and FFMQ-15, such that short forms may be ill-suited for applications that require reliable measurement in the high range. CONCLUSIONS: Results suggest the existing FFMQ item pool cannot be reduced without negatively affecting either overall reliability or the span of mindfulness over which reliability is assessed. Conditional test reliability curves and item functioning parameters can aid investigators in tailoring their choice of FFMQ form to the reliability they hope to achieve and to the range of latent mindfulness over which they must reliably measure.

Relationships Among Dietary Cognitive Restraint, Food Preferences, and Reaction Times.

OBJECTIVE: To assess the associations between dietary cognitive restraint, disinhibited eating, and how taste and health perceptions relate to food preference; and further, whether cognitive restraint and disinhibited eating are associated with food preference decision reaction time. METHODS: Five hundred and seventeen adults participated in the study. Dietary cognitive restraint and disinhibited eating were assessed using the shortened Three-Factor Eating Questionnaire (TFEQ-R18). Participants also completed a dietary decision-making task to examine their food-related decisions. Participants were presented with 50 food items and asked to rate them for health and for taste. Participants were then presented with a reference food item and comparison items one at a time and asked to indicate which of the two foods they would prefer to eat. RESULTS: Participants with higher levels of cognitive restraint were more sensitive to health perceptions whereas those with higher levels of disinhibited eating were more sensitive to taste perceptions when indicating food preference. Reaction time analysis corroborated these results. Being classified as high for cognitive restraint was associated with faster reaction times if the preferred food was rated as healthier than the referent food. Conversely, being classified as high for disinhibited eating was associated with faster reaction times if the preferred food was rated as tastier than the referent food. CONCLUSION: The dietary decision-making task appears to capture distinct aspects of dietary restraint and disinhibition and may be useful in future studies to measure and/or alter levels of dietary restraint and disinhibition.

Barriers to naloxone use and acceptance among opioid users, first responders, and emergency department providers in New Hampshire, USA.

BACKGROUND: The United States is in the midst of a devastating opioid crisis, and the state of New Hampshire (NH) has been disproportionately impacted. Naloxone is an opioid overdose reversal medication that is critical for saving lives. This study was conducted to understand emergency responders' and opioid users' experiences with, and opinions about, naloxone use and distribution in NH. METHODS: Semi-structured interviews were conducted with 76 opioid users and 36 emergency responders in six NH counties in 2016-2017. Interviews focused on respondents' experiences with opioid use and overdose. Interviews were transcribed, coded, and reviewed for consensus among coders. Directed content analysis was used to review high-level domains and identify subthemes. RESULTS: Users and responders largely agreed that naloxone had become increasingly available in NH at the time of the study. Reported responder barriers to naloxone acceptance included perceptions that increased naloxone availability may enable riskier opioid use and fails to address the underlying causes of addiction. Reported opioid-user barriers included cost, legality, and lack of knowledge regarding distribution locations and indications for use. CONCLUSION: Opioid users' and emergency responders' perceptions about naloxone may limit the optimal use of naloxone within the community. This study identifies opportunities to address misconceptions about naloxone and challenges in accessing naloxone, which may improve opioid overdose prevention strategies.

"You can see those concentric rings going out": Emergency personnel's experiences treating overdose and perspectives on policy-level responses to the opioid crisis in New Hampshire.

BACKGROUND: In parallel to a substantial increase in opioid overdose deaths in New Hampshire (NH), emergency personnel experienced an increase in opioid-related encounters. To inform public health responses to this crisis, insights into the experiences and perspectives of those emergency personnel who treat opioid-related overdoses are warranted. AIMS: Systematically examine emergency personnel's experiences treating opioid overdoses and obtain their perspectives on policy-level responses to the opioid crisis in NH. METHODS: Semi-structured qualitative interviews were conducted with 18 first responders [firefighters (n = 6), police officers (n = 6), emergency medical service providers (n = 6)] and 18 emergency department personnel employed in six NH counties. Interviews focused on emergency personnel's perspectives on fentanyl/heroin formulations, experiences treating overdoses, harm reduction strategies, and experiences with treatment referral. Interviews were audio recorded, transcribed verbatim, and analyzed using content analysis. RESULTS: Emergency personnel cited the potency and inconsistency of fentanyl-laced heroin as primary drivers of opioid overdose. Increases in overdose-related encounters took a substantial emotional toll on emergency personnel, who described a range of responses including feelings of burnout, exhaustion, and helplessness. While some emergency personnel felt conflicted about the implementation of harm reduction strategies like syringe services programs, others emphasized the necessity of these services. Emergency personnel expressed frustration with barriers to treatment referral in the state and recommended immediate treatment access after overdose events. CONCLUSIONS: Findings suggest that interventions addressing trauma and burnout are necessary to support emergency personnel, while expanded harm reduction and treatment access are critical to support those who experience opioid overdose in NH.

Evaluating the Factor Structure of Each Facet of the Five Facet Mindfulness Questionnaire.

OBJECTIVE: Nearly all studies treat the Five Facet Mindfulness Questionnaire as five independent scales (one measuring each of the five facets), yet almost no methodological work has examined the psychometric structure of the facets independently. We address this gap using factor analytic methods. METHODS: Exploratory and confirmatory factor models were fit to item response data from a sample of 522 adults recruited online. Findings were replicated in a sample of 454 adults receiving aftercare for substance use disorder. RESULTS: Parallel analysis suggested multiple factors for all five facets, in both samples. Exploratory factor models suggested the presence of method factors on the acting with awareness (items using the term "distraction") and describing facets (items that were reverse-scored). Confirmatory factor models fit poorly for all facets, in both samples. In follow-up analyses, model fit improved substantially on the acting with awareness and describing facets when method factors were included in a bifactor model. Model fit was also better for the facets of FFMQ short forms than for the full-length facets. The short-form facets and original facets correlated similarly with external criteria in both samples. CONCLUSIONS: None of the FFMQ facets fit a unidimensional factor model; yet, follow-up analyses suggested each can be considered substantively unidimensional. Initial tests suggest the facets' multidimensionality did not materially impact their relation to other psychological constructs, suggesting multidimensionality can be ignored for some purposes. The use of short-form facets or latent variable models (e.g., bifactor specifications) are both viable solutions for addressing multidimensionality when desired.

Oxygen gradients can determine epigenetic asymmetry and cellular differentiation via differential regulation of Tet activity in embryonic stem cells.

Graded levels of molecular oxygen (O2) exist within developing mammalian embryos and can differentially regulate cellular specification pathways. During differentiation, cells acquire distinct epigenetic landscapes, which determine their function, however the mechanisms which regulate this are poorly understood. The demethylation of 5-methylcytosine (5mC) is achieved via successive oxidation reactions catalysed by the Ten-Eleven-Translocation (Tet) enzymes, yielding the 5-hydroxymethylcytosine (5hmC) intermediate. These require O2 as a co-factor, and hence may link epigenetic processes directly to O2 gradients during development. We demonstrate that the activities of Tet enzymes display distinct patterns of [O2]-dependency, and that Tet1 activity, specifically, is subject to differential regulation within a range of O2 which is physiologically relevant in embryogenesis. Further, differentiating embryonic stem cells displayed a transient burst of 5hmC, which was both dependent upon Tet1 and inhibited by low (1%) [O2]. A GC-rich promoter region within the Tet3 locus was identified as a significant target of this 5mC-hydroxylation. Further, this region was shown to associate with Tet1, and display the histone epigenetic marks, H3K4me3 and H3K27me3, which are characteristic of a bivalent, developmentally 'poised' promoter. We conclude that Tet1 activity, determined by [O2] may play a critical role in regulating cellular differentiation and fate in embryogenesis.