The roles of structural dynamics in the cellular functions of RNAs.

RNAs fold into 3D structures that range from simple helical elements to complex tertiary structures and quaternary ribonucleoprotein assemblies. The functions of many regulatory RNAs depend on how their 3D structure changes in response to a diverse array of cellular conditions. In this Review, we examine how the structural characterization of RNA as dynamic ensembles of conformations, which form with different probabilities and at different timescales, is improving our understanding of RNA function in cells. We discuss the mechanisms of gene regulation by microRNAs, riboswitches, ribozymes, post-transcriptional RNA modifications and RNA-binding proteins, and how the cellular environment and processes such as liquid-liquid phase separation may affect RNA folding and activity. The emerging RNA-ensemble-function paradigm is changing our perspective and understanding of RNA regulation, from in vitro to in vivo and from descriptive to predictive.

Prepubescent Electronic Cigarette Exposure Affects Sexual Motivation and Puberty in Female But Not Male Long-Evans Rats.

INTRODUCTION: A method for delivering vaporized nicotine to animals has been developed using e-cigarette devices. The present experiment was designed to measure the effects of e-cigarette nicotine on pubertal onset and development of reproductive behavior in female and male Long-Evans rats. AIM AND METHODS: Rats received daily 10-min sessions of electronic-cigarette vaporized nicotine (5% Virginia Tobacco JUUL Pods) or room air in a whole-body exposure chamber (postnatal day 28-31). Pubertal onset was monitored daily (ie, vaginal opening in females, preputial separation in males). Two weeks later, rats were tested for sexual motivation using the partner-preference paradigm, whereby subjects were given the opportunity to approach either a sexual partner or a same-sex social partner. Four weeks later, partner preference was assessed again, 10 min after rats were re-exposed to their same prepubertal treatment. RESULTS: We found that prepubescent electronic-cigarette vaporized nicotine disrupted puberty and sexual motivation in female but not male rats. In vaped females, vaginal opening was delayed and less time was spent with the male stimulus compared to room-air controls. In contrast, no effect of e-cigarette vapor was observed on pubertal onset or on any measures of sexual behavior in male rats. No effects were observed in either female or male rats on the second partner-preference test. CONCLUSIONS: Prepubescent vaporized nicotine affected the development of reproductive physiology and behavior in female rats but not in male rats, whereas an additional acute exposure to nicotine vapor had no effect in either female or male adult rats. IMPLICATIONS: Given the prevalence of increasingly younger users, more animal research is needed to explore the effects of e-cigarette smoking on multiple developmental systems including reproductive physiology and behavior. This model could be useful in exploring multiple behavioral and physiological endpoints in both sexes. Adjustments to the duration of exposure and control conditions will be necessary for future experiments to best model human use.

Cognitive processing therapy (CPT) versus individual drug counseling (IDC) for PTSD for veterans with opioid use disorder maintained on buprenorphine.

BACKGROUND AND OBJECTIVES: There are high rates of comorbidity between posttraumatic stress disorder (PTSD) and opioid use disorder (OUD). Evidence-based trauma-focused psychotherapies such as Cognitive Processing Therapy (CPT) are a first-line treatment for PTSD. Veterans with OUD are treated primarily in substance use disorder (SUD) clinics where the standard of care is drug counseling; they often do not have access to first-line PTSD treatments. This study tested whether CPT can be conducted safely and effectively in veterans with comorbid OUD treated with buprenorphine. METHODS: This 12-week, 2-site, randomized clinical trial (RCT) included open-label randomization to two groups: (a) CPT versus (b) Individual Drug Counselling (IDC) in veterans with PTSD and comorbid OUD who were maintained on buprenorphine (N = 38). RESULTS: Veterans randomized to either IDC (n = 18) or CPT (n = 20) showed a significant reduction in self-reported PTSD symptoms over time as measured by the PTSD checklist (PCL-5) but there were no treatment group differences; there was some indication that reduction in PTSD symptoms in the CPT group were sustained in contrast to the IDC group. Recruitment was significantly impacted by COVID-19 pandemic, so this study serves as a proof-of-concept pilot study. DISCUSSION AND CONCLUSIONS: Veterans with OUD and PTSD can safely and effectively participate in evidence-based therapy for PTSD; further work should confirm that trauma-focused treatment may be more effective in leading to sustained remission of PTSD symptoms than drug counseling. SCIENTIFIC SIGNIFICANCE: This is the first study to evaluate CPT for PTSD in the context of buprenorphine treatment for OUD.

Why step in? Shifting justifications for bystander behaviors through interventions with youth in the Middle East.

Research shows positive bystander intervention effectively mitigates bullying experiences. Yet, more evidence regarding bystander responses to bias-based social exclusion (BSE) is needed in intergroup contexts, especially in the majority world and in areas of intractable conflict. This study assessed the effectiveness of skills and skills + contact-based interventions for BSE among 148 Palestinian Citizens of Israel (Mage = 10.55) and 154 Jewish-Israeli (Mage = 10.54) early adolescents (Girls = 52.32%) in Tel Aviv-Yafo. Bystander responses were assessed by participants' reactions to hypothetical BSE scenarios over three time points. Repeated measures ANOVAs revealed both interventions significantly increased positive and decreased negative bystander responses, with changes maintained at the follow-up. The opposite result pattern emerged for the control group. Findings suggest that both interventions can effectively encourage youth to publicly challenge BSE, even amidst intractable conflict.

COVID-19 lockdowns affected birthing outcomes in a regional New South Wales Health District.

INTRODUCTION: The 400 000 residents of the Illawarra Shoalhaven Local Health District (ISLHD) experienced two distinct lockdowns aimed at mitigating the transmission of severe acute respiratory syndrome coronavirus 2 infection. Analysing effects of these lockdowns on maternal and neonatal outcomes presents a valuable opportunity to assess the impact of pandemic-level restrictions on maternal and neonatal outcomes. AIM: Evaluate the impacts of restrictions from two lockdown periods on maternal, birthing, and neonatal outcomes within a regional local health district. MATERIALS AND METHODS: The study included 22 166 women who gave birth within ISLHD between 2017 and 2022. Groups included for analysis: Control Group - mothers pregnant before the pandemic (conception before 3 April 2019); Exposure Group 1 - mothers pregnant during the first lockdown (conception date 22 January 2020 to 5 May 2020); and Exposure Group 2 - mothers pregnant during the second lockdown (conception date 30 April 2021 to 13 Sep 2021). RESULTS: Odds of adverse birthing outcomes including non-reassuring fetal status (odds ratio (OR) 1.34; 95% CI 1.14-1.56 and OR 1.20; 95% CI 1.03-1.40), and postpartum haemorrhage (OR 2.04; 95% CI 1.73-2.41 and OR 1.74; 95% CI 1.48-2.05) were substantially increased in Exposure Groups 1 and 2, respectively. Gestational diabetes, gestational hypertension, low birth weight and admission to neonatal intensive care rates improved. CONCLUSIONS: Pregnant women exposed to pandemic restrictions within ISLHD had decreased odds of adverse antenatal and neonatal outcomes, but increased odds of poor peripartum outcomes.

Domains of Excellence: A CDC Framework for Developing High-Quality, Impact-Driven Public Health Science Publications.

CONTEXT: The Centers for Disease Control and Prevention (CDC) has a long history of using high-quality science to drive public health action that has improved the health, safety, and well-being of people in the United States and globally. To ensure scientific quality, manuscripts authored by CDC staff are required to undergo an internal review and approval process known as clearance. During 2022, CDC launched a scientific clearance transformation initiative to improve the efficiency of the clearance process while ensuring scientific quality. PROGRAM: As part of the scientific clearance transformation initiative, a group of senior scientists across CDC developed a framework called the Domains of Excellence for High-Quality Publications (DOE framework). The framework includes 7 areas ("domains") that authors can consider for developing high-quality and impactful scientific manuscripts: Clarity, Scientific Rigor, Public Health Relevance, Policy Content, Ethical Standards, Collaboration, and Health Equity. Each domain includes multiple quality elements, highlighting specific key considerations within. IMPLEMENTATION: CDC scientists are expected to use the DOE framework when conceptualizing, developing, revising, and reviewing scientific products to support collaboration and to ensure the quality and impact of their scientific manuscripts. DISCUSSION: The DOE framework sets expectations for a consistent standard for scientific manuscripts across CDC and promotes collaboration among authors, partners, and other subject matter experts. Many aspects have broad applicability to the public health field at large and might be relevant for others developing high-quality manuscripts in public health science. The framework can serve as a useful reference document for CDC authors and others in the public health community as they prepare scientific manuscripts for publication and dissemination.

A Narrative Review of Literature Examining Studies Researching the Impact of Law on Health and Economic Outcomes.

CONTEXT: Public health policy can play an important role in improving public health outcomes. Accordingly, there has been an increasing emphasis by policy makers on identifying and implementing evidence-informed public health policy interventions. PROGRAM OR POLICY: Growth and refinement of the field of research assessing the impact of legal interventions on health outcomes, known as legal epidemiology, prompted this review of studies on the relationship between laws and health or economic outcomes. IMPLEMENTATION: Authors systematically searched 8 major literature databases for all English language journal articles that assessed the effect of a law on health and economic outcomes published between January 1, 2009, and September 18, 2019. This search generated 12 570 unique articles 177 of which met inclusion criteria. The team conducting the systematic review was a multidisciplinary team that included health economists and public health policy researchers, as well as public health lawyers with expertise in legal epidemiological research methods. The authors identified and assessed the types of methods used to measure the laws' health impact. EVALUATION: In this review, the authors examine how legal epidemiological research methods have been described in the literature as well as trends among the studies. Overall, 3 major themes emerged from this study: (1) limited variability in the sources of the health data across the studies, (2) limited differences in the methodological approaches used to connect law to health outcomes, and (3) lack of transparency surrounding the source and quality of the legal data relied upon. DISCUSSION: Through highlighting public health law research methodologies, this systematic review may inform researchers, practitioners, and lawmakers on how to better examine and understand the impacts of legal interventions on health and economic outcomes. Findings may serve as a source of suggested practices in conducting legal epidemiological outcomes research and identifying conceptual and method-related gaps in the literature.

Understanding the characteristics of nonspecific binding of drug-like compounds to canonical stem-loop RNAs and their implications for functional cellular assays.

Identifying small molecules that selectively bind an RNA target while discriminating against all other cellular RNAs is an important challenge in RNA-targeted drug discovery. Much effort has been directed toward identifying drug-like small molecules that minimize electrostatic and stacking interactions that lead to nonspecific binding of aminoglycosides and intercalators to many stem-loop RNAs. Many such compounds have been reported to bind RNAs and inhibit their cellular activities. However, target engagement and cellular selectivity assays are not routinely performed, and it is often unclear whether functional activity directly results from specific binding to the target RNA. Here, we examined the propensities of three drug-like compounds, previously shown to bind and inhibit the cellular activities of distinct stem-loop RNAs, to bind and inhibit the cellular activities of two unrelated HIV-1 stem-loop RNAs: the transactivation response element (TAR) and the rev response element stem IIB (RREIIB). All compounds bound TAR and RREIIB in vitro, and two inhibited TAR-dependent transactivation and RRE-dependent viral export in cell-based assays while also exhibiting off-target interactions consistent with nonspecific activity. A survey of X-ray and NMR structures of RNA-small molecule complexes revealed that aminoglycosides and drug-like molecules form hydrogen bonds with functional groups commonly accessible in canonical stem-loop RNA motifs, in contrast to ligands that specifically bind riboswitches. Our results demonstrate that drug-like molecules can nonspecifically bind stem-loop RNAs most likely through hydrogen bonding and electrostatic interactions and reinforce the importance of assaying for off-target interactions and RNA selectivity in vitro and in cells when assessing novel RNA-binders.

Intersectionality in Intervention Development: Insights From Formative Work on a Tailored Tobacco Cessation Program for LGBTQIA+ Young Adults.

Tailored tobacco cessation interventions focusing on minoritized communities are proliferating, but the extent to which these interventions address the needs of individuals with multiple minoritized social identities is unclear. We developed Empowered, Queer, Quitting, and Living (EQQUAL), an avatar-led digital smoking cessation intervention tailored for lesbian, gay, bisexual, transgender, queer or questioning, intersex, asexual, and more (LGBTQIA+) young adults based on acceptance and commitment therapy (ACT), via a multistage user-centered design process. The purpose was to evaluate feedback from EQQUAL development activities using an intersectional lens. Intersectionality is a paradigm created by Kimberlé Crenshaw illustrating the multiple social identities each person possesses along with the marginalization of these different social identities. We conducted a rapid deductive content analysis focused on intersectional design gaps using interviewer notes from user testing (n = 7), a diary study (n = 8), and treatment satisfaction responses from a single-arm trial of the EQQUAL intervention (n = 22). Feedback related to intersectional design fell under three broad themes: (a) inadequate representativeness of the avatar, (2) inadequate representativeness within the program broadly, and (3) non-inclusive ACT intervention content. Feedback on inclusiveness included reference to socioeconomic status, race/ethnicity, religious/cultural affiliation, and ability/disability. Although we previously found that EQQUAL was highly acceptable and showed promise in terms of efficacy in a single-arm pilot trial, we identified several gaps in intersectional design as the iterative intervention development proceeded. Because intersectional design is a critical part of developing interventions with a health equity focus, applying standardized procedures for intersectional design and analysis could improve intervention design and better address tobacco cessation treatment needs of individuals who may experience multiple forms of marginalization.

The Asian monsoon over the past 640,000 years and ice age terminations.

Oxygen isotope records from Chinese caves characterize changes in both the Asian monsoon and global climate. Here, using our new speleothem data, we extend the Chinese record to cover the full uranium/thorium dating range, that is, the past 640,000 years. The record's length and temporal precision allow us to test the idea that insolation changes caused by the Earth's precession drove the terminations of each of the last seven ice ages as well as the millennia-long intervals of reduced monsoon rainfall associated with each of the terminations. On the basis of our record's timing, the terminations are separated by four or five precession cycles, supporting the idea that the '100,000-year' ice age cycle is an average of discrete numbers of precession cycles. Furthermore, the suborbital component of monsoon rainfall variability exhibits power in both the precession and obliquity bands, and is nearly in anti-phase with summer boreal insolation. These observations indicate that insolation, in part, sets the pace of the occurrence of millennial-scale events, including those associated with terminations and 'unfinished terminations'.

Revisiting the influence of offloading memory on free recall.

Relying on external memory aids is a common memory strategy that has long allowed us to "remember" vast amounts of information more reliably than with our internal memory alone. However, recent work has provided evidence consistent with the idea that offloading memory demands encourages a reduced engagement in intentional or top-down memory strategies/efforts, leading to lower memory performance in general. Evidence for this view comes from results demonstrating a reduced primacy effect but intact recency and isolation effects when individuals could offload memory demands (but had to unexpectedly rely on their internal memory at test). In the present investigation, we attempt a replication of these critical results, given some inconsistencies in the findings between studies. In addition, we extend the examination of offloading's impact on memory via examining individual differences in reliance on the external store (when available) and different strategies for the use of that store. Results of the replication are generally consistent with previous research. An individual differences analysis yielded results consistent with the notion that increased reliance on an external store can compromise internal/biological memory in the absence of that store. Finally, a verbal model of offloading memory demands within a framework of effort and study time allocation is presented. Together, the results both reinforce extant research and extend it in new directions.

Phytochemical Combination Is More Effective than Individual Components in Reducing Stress Signaling in Rat Hippocampal Neurons and Microglia In Vitro.

Age-related decrements in the central nervous system (CNS) are thought to result from: (1) increased susceptibility to and accumulating effects of free radicals and inflammation; and (2) dysregulation in Ca2+ homeostasis, which affects numerous signaling pathways. Certain bioactive phytochemicals exhibit potent anti-inflammatory activities which may mitigate these age-related CNS decrements. This study investigated the individual and combination effects of green tea catechin (epigallocatechin gallate, EGCG), curcumin from turmeric, and broccoli sprouts which contain the isothiocyanate sulforaphane on inflammation and dysregulation in Ca2+ homeostasis to determine if the individual compounds were working synergistically and/or through independent mechanisms. Rat hippocampal neurons or highly aggressive proliferating immortalized (HAPI) microglial cells were pre-treated for a week with either the individual components or all in combination before inducing Ca2+ buffering deficits with dopamine (DA, 0.1 µM for 2 h) or inflammation using lipopolysaccharide (LPS, 100 ng/mL for 18 h), respectively. The EGCG (3 µM) and combination protected against DA-induced deficits in Ca2+ buffering (both % of cells that recovered and recovery time, p < 0.05). Additionally, the EGCG and combination reduced stress-mediated inflammation in HAPI rat microglial cells by attenuating LPS-induced nitrite release, inducible nitrous oxide synthase (iNOS) expression, and tumor necrosis factor-alpha (TNF-α) release (p < 0.05), but not cyclooxygenase-2 (COX-2) expression. Overall, broccoli sprouts (2 µM) and curcumin (1 µM) were not as effective as the EGCG or combination. Further research is needed to determine if dietary intervention with a variety of foods containing compounds such as those found in green tea, turmeric, or broccoli sprouts can play a role in reducing age-related CNS inflammation, microglial activation, and downstream signaling pathways that can lead to neuronal dysfunction.

Incidence and Predictors of Gram-Negative Bacilli in Hospitalized People Who Inject Drugs with Injection Drug Use-Attributable Infections.

The objective of this study was to quantify incidence and determine predictors of Gram-negative bacilli (GNB) in people who inject drugs (PWID) with injection-drug use (IDU)-related infections. The investigation was a retrospective cohort of hospitalized PWID from January 2017 to December 2019. Inclusion criteria were age of ≥18 years, active IDU, treated IDU-attributable infection, and organism growth from microbiology cultures. Infection types included infective endocarditis (IE), acute bacterial skin/skin structure infection (ABSSSI), osteoarticular infection (OAI), and other bloodstream infections (BSI). Primary outcome was GNB identification from microbiologic culture; descriptive statistics were used to describe the cohort. Multivariable regression was used to identify variables associated with GNB infection. A total of 230 PWID were included, 65 (28%) with GNB infections and 165 (72%) with Gram-positive infections. The median (interquartile range [IQR]) population age was 38 (31 to 45) years. Most patients were women (56%); 37% had no insurance. Infection types were as follows: IE, 41%; ABSSSI, 37%; OAI, 20%; and other BSI, 2%. A total of 278 organisms were isolated from 230 patients. The most common organisms were methicillin-resistant Staphylococcus aureus (43%), Streptococcus spp. (19%), methicillin-susceptible S. aureus (17%), and Serratia marcescens (8%); 10% of infections were mixed GNB and Gram-positive infections. A total of 80% of patients received empirical Pseudomonas aeruginosa coverage; only 7% had P. aeruginosa infections. In multivariable regression, age of >50 years (adjusted odds ratio [adjOR], 2.9; 95% confidence interval [CI], 1.2 to 7.2), prior hospitalization within 90 days (adjOR, 2.2; 95% CI, 1.2 to 4.3), and OAI (adjOR, 3.2; 95% CI, 1.5 to 6.6) were associated with GNB infection. GNB in PWID with IDU-attributable infections were more frequently observed in recently hospitalized, older patients with OAI. The majority of patients received empirical antipseudomonal antibiotic coverage, but P. aeruginosa was infrequent. PWID are a potential population to target improved empirical antibiotic use.

Increased pupil dilation during tip-of-the-tongue states.

Tip-of-the-tongue states (TOTs) are feelings of impending word retrieval success during a current failure to retrieve a target word. Though much is known and understood about TOT states from decades of research, research on potential psychophysiological correlates of the TOT state is still in its infancy, and existing studies point toward the involvement of neural processes that are associated with enhanced attention, motivation, and information-seeking. In the present study, we demonstrate that, during instances of target retrieval failure, TOT states are associated with greater pupillary dilation (i.e., autonomic arousal) in 91% of our sample. This is the first study to demonstrate a pupillometric correlate of the TOT experience, and this finding provides an important step toward understanding emotional attributes associated with TOT states. Mean pupil dilation also increased such that instances of target identification failure that were unaccompanied by TOT states < instances in which TOTs occurred < instances of target identification success. It is possible that TOTs reflect an intermediary state between complete target retrieval failure and full target retrieval.

The gist of it: offloading memory does not reduce the benefit of list categorisation.

When we can offload to-be-remembered information to an external store, our ability to recall that information from internal memory can be diminished. However, previous research has suggested that associative memory processes may remain intact in the face of offloading behaviour. In the present investigation, we examine how the opportunity to offload memory demands affects the learning of categorised word lists. Across six experiments, participants studied and wrote down word lists that were either strongly associated with a semantic theme (categorised) or word lists that consisted of the same set of words but shuffled across the categorised lists (shuffled). When participants expected to have access to their written lists during the recall test (i.e., a condition that would encourage offloading) but were not given access to it, we found the typical recall advantage for categorised lists. This effect was found to be the same size or larger compared to a condition where participants did not expect to have access to their written lists during the recall test (i.e., a condition that would not allow offloading). We propose that gist memory supported by semantic associations is not substantially reduced in offloading.

On our susceptibility to external memory store manipulation: examining the influence of perceived reliability and expected access to an external store.

Offloading memory to external stores (e.g., a saved file) allows us to evade the limitations of our internal memory. One cost of this strategy is that the external memory store used may be accessible to others and, thus, may be manipulated. Here we examine how reducing the perceived reliability of an external memory store and manipulating one's expectation for future access to such a store can influence participants' susceptibility to its manipulation (i.e., endorsing manipulated information as authentic). Across three pre-registered experiments, participants were able to store to-be-remembered information in an external store. On a critical trial, we surreptitiously manipulated the information in that store. Results demonstrated that an explicit notification of a previous manipulation of that store and the warning that the store will be inaccessible in the future can decrease susceptibility to manipulation of that store. Results are discussed in the context of the metacognitive monitoring and control of memory reports in situations that involve the distribution of memory demands across both internal and external spaces.

Buprenorphine Naloxone and Extended Release Injectable Naltrexone for the Treatment of Opioid Use Disorder Among a Veteran Patient Sample: A Retrospective Chart Review.

OBJECTIVE: Previous research has demonstrated the effectiveness of both extended-release injectable naltrexone (XR-NTX) and buprenorphine/naloxone (BUP-NX) in the treatment of opioid use disorder (OUD). However, studies using real-world samples with multiple medical and psychiatric comorbidities are lacking. The study's primary aims were to: (1) compare clinical presentations in an inclusive sample of OUD-diagnosed US military veterans receiving XR-NTX and BUP-NX, and (2) investigate differences in 90-day treatment outcomes between these two groups. Methods: The medical records of 79 patients receiving medications to treat OUD in a VA hospital's addiction outpatient treatment program were reviewed retrospectively. The analysis included all veterans who initiated medication treatment during the study period. Differences between medication groups on co-occurring diagnoses, treatment retention, and related outcomes were examined. Results: The two groups were similar in medical and psychiatric comorbidity, although the BUP-NX group were more likely to have a pain diagnosis. No statistically significant differences in retention or toxicology results were found between the two groups over the 90-day study period. The rate of positive urine screens for the BUP-NX group was 19.2% for opiates and 13.5% for other illicit substances, and 3.7% and 11.1% respectively for the XR- NTX group. Conclusion: There was no evidence that 90-days outcomes differed for veterans based on medication received, and there were more similarities than differences in clinical characteristics. Additional research is needed, including larger sample size and prospective randomized control trial to evaluate VA patients' treatment outcomes receiving BUP-NX or XR-NTX for OUD.

Correlates of Obtaining Employment among Veterans Receiving Treatment for Severe PTSD in Specialized Intensive Programs.

Severe Post-Traumatic Stress Disorder (PTSD) has been identified as a significant impediment to employment. However, little is known about correlates of employment recovery after a period of not working among veterans with severe PTSD treated in specialized intensive treatment programs. This study examines rates and correlates of transitioning from not being employed at admission to working four months after discharge using national Veterans Health Administration (VHA) program evaluation data on veterans engaged in specialized intensive PTSD treatment (N = 27,339). Results suggest that only 5.68% of the sample made the transition to employment while 10.6% lost employment, 8.9% worked both at admission and following discharge, and 74.9%, did not work either at admission or following discharge. Multinomial regression analysis found that compared to other groups, veterans who became employed were younger, less likely to receive service-connected disability payments, and experienced a significantly greater reduction in PTSD symptoms. Findings from this study highlight that this distinct population has very poor employment outcomes and deserves more attention, and that reducing PTSD symptoms can lead to improved employment outcomes. Efforts to integrate evidence-based vocational rehabilitation practice into residential PTSD treatment targeting PTSD symptoms is encouraged.

Minimal Hepatic Encephalopathy and Mild Cognitive Impairment Worsen Quality of Life in Elderly Patients With Cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis are growing older. The overlap between minimal hepatic encephalopathy (MHE) and predementia mild cognitive impairment (MCI) could affect quality of life (QOL). We investigated the performance of elderly patients with cirrhosis on tests for MHE and MCI and their effects on QOL. METHODS: We recruited outpatients with cirrhosis (n = 109) and without cirrhosis (controls, n = 100), 65 years or older, at 4 centers (derivation cohort). All study participants were assessed for psychometric hepatic encephalopathy score (PHES), EncephalApp score, and QOL. MCI was tested in patients with cirrhosis using the repeatable battery for assessment of neuropsychological status and assigned to the following groups: unimpaired, MCI only, MHE only, and MCI+MHE. We created adjusted norms to detect MHE using PHES and EncephalApp scores from the controls. Findings were validated using data from a separate cohort of 77 patients with cirrhosis (mean age, 69.49 ± 4.36 y; 72% men) at the same study sites. RESULTS: Controls were older but were more educated, performed better cognitively, and had better QOL. Among patients with cirrhosis, age, education, model for end-stage liver disease score, EncephalApp score, and QOL were similar, but PHES and repeatable battery for assessment of neuropsychological status differed among sites. In the derivation cohort, the presence of MHE, with or without MCI, was associated with poor QOL, which was lowest in the MCI+MHE group. When we adjusted for age, sex, and education, 49% of patients with cirrhosis had MHE based on the EncephalApp and 8% had MHE based on the PHES. A similar pattern (49% MHE based on EncephalApp and 6% MHE based on PHES) was found in a validation cohort. CONCLUSIONS: In a multicenter study of patients with cirrhosis (>65 y) and controls, the presence of MHE, regardless of MCI, was associated with poor cognition and QOL. We created adjusted norms that defined the high sensitivity of EncephalApp for the detection of MHE in older individuals and validated it in a separate cohort.

Pilot Randomized Controlled Trial of Web-Delivered Acceptance and Commitment Therapy Versus Smokefree.gov for Smokers With Bipolar Disorder.

INTRODUCTION: Smokers with bipolar disorder (BD) are less successful at quitting than the general population. In this study, we evaluated in a pilot randomized controlled trial a novel, targeted, web-based intervention for smokers with BD based on acceptance and commitment therapy (ACT) and designed for reach and disseminability. AIMS AND METHODS: Daily smokers (n = 51) with bipolar I or II disorder were recruited from four US sites and randomly assigned to one of two web-based smoking cessation interventions-ACT-based WebQuit Plus (n = 25) or Smokefree.gov (n = 26) over a 10-week treatment period. All participants received nicotine patch for 8 weeks. Key outcomes were trial design feasibility, intervention acceptability, and cessation at end of treatment and 1-month follow-up. RESULTS: We screened 119 to enroll 51 participants (target sample size = 60) over 24 months. The most common reason for ineligibility was the inability to attend study appointments. Retention was 73% at end of treatment and 80% at follow-up, with no differences by arm. The mean number of logins was twice as high for WebQuit Plus (10.3 vs. 5.3). The usefulness of program skills was rated higher for WebQuit Plus (75% vs. 29%). Biochemically confirmed, 7-day abstinence at end of treatment was 12% in WebQuit Plus versus 8% in Smokefree.gov (odds ratio = 1.46, 95% confidence interval = 0.21 to 9.97). At follow-up, abstinence rates were 8% in both arms. CONCLUSIONS: Trial design produced favorable retention rates, although alternative recruitment methods will be needed for a larger trial. At end of treatment, acceptability and estimated effect size of WebQuit Plus relative to Smokefree.gov were promising and support continued program refinement and evaluation. IMPLICATIONS: In this first randomized controlled trial of a targeted intervention for smokers with BD, we found that the ACT-based WebQuit Plus intervention, delivered in combination with the nicotine patch, had promising acceptability and cessation outcomes relative to Smokefree.gov. The observed signals for acceptability and cessation suggest that the WebQuit Plus program should be refined based on participant feedback and evaluated in a larger trial. Feasibility findings from this study also provide direction for refining trial procedures to enhance the recruitment of smokers with BD.