Publications

OBJECTIVES: The EQ-5D-5L may not adequately capture the health-related quality of life in patients with sleep disturbances. We examined the psychometric properties of a hybrid PROM comprising a module of four sleep-related bolt-ons and EQ-5D-5L.

METHODS: We employed a sequential exploratory mixed method by first qualitatively testing the face validity of "sleep", "cognition", "tiredness" and "relationship" and refining these bolt-ons through in-depth interviews with 23 patients and clinicians. We then quantitatively assessed their performance by administering the four bolt-ons, appended to EQ-5D-5L, and three condition-specific patient-reported outcome measures (cPROMs) during two clinical visits of patients with respiratory-related sleep disorders. We compared ceiling effects and construct validity of EQ-5D-5L with and without the bolt-ons by testing a priori hypotheses about the cPROMs and polysomnographic characteristics via correlation and areas under the curves (AUC) analyses, respectively. We examined their responsiveness among "treated/improved" participants using standardized response means (SRM) and AUC analysis, and reliability among "untreated/no change" participants using intra-class correlation coefficient (ICC) or Cohen's Kappa (k).

RESULTS: 110 participants (mean [SD] age: 47[13]) were recruited and 90 returned for their review assessments (mean [SD] interval: 2.2 [2.1] months). The bolt-ons led to a reduction of 42.7% in ceiling effects. The bolt-ons were better correlated with cPROMs and exhibited higher discriminatory power and responsiveness, with comparable reliability to EQ-5D-5L. A combined module of the four bolt-ons provided better results than individual bolt-ons.

CONCLUSIONS: A "hybrid" PROM of sleep bolt-ons module added to EQ-5D-5L improved its psychometric properties among patients with sleep disturbances.

OBJECTIVE: The menopause transition (MT) may substantially contribute to increased systemic inflammation in later life, regardless of aging. We characterized inflammation trajectories over the MT and determined their associations with premenopausal obesity and race/ethnicity.

METHODS: Data comprising 15 follow-up visits from Study of Women's Health Across the Nation participants who had a known date of their final menstrual period (FMP) and at least 3 measures of high-sensitivity C-reactive protein (hs-CRP) (n = 1470) or IL-6 (n = 779) were evaluated using group-based trajectory modeling and piecewise linear mixed-effects models.

RESULTS: Based on 21 years of follow-up spanning the MT, we identified 3 trajectory groups for each inflammatory biomarker: (1) Low-Rise (hs-CRP = 27.2%; IL-6 = 36.0%); (2) Medium-Stable (hs-CRP = 41.9%) or Medium-Rise (IL-6 = 45.2%); and (3) High-Decline (hs-CRP = 30.9%) or High-Stable (IL-6 = 18.8%). The Low-Rise for both hs-CRP and IL-6 and the Medium-Rise for IL-6 trajectories showed significant increases as early as 1 year before to as late as 3 years after the FMP. The other trajectories showed either no change, or a decline around the FMP. Chinese and/or Japanese women were more likely to follow the Low-Rise hs-CRP and IL-6 trajectories, whereas Black women were more likely to follow the High-Decline hs-CRP and High-Stable IL-6 trajectories. Being overweight or obese was associated with the High-Decline hs-CRP and High-Stable IL-6 trajectories.

CONCLUSIONS: Midlife women experience distinct patterns of change in hs-CRP and IL-6 over the MT. Subgroups entering the MT with low-to-medium inflammation levels, particularly for IL-6, showed rises close to the FMP, supporting a contribution of menopause in progression of systemic inflammation.

IMPORTANCE: There is an unmet need for long-term, safe, effective, and hormone-free treatments for menopausal symptoms, including vasomotor symptoms (VMS) and sleep disturbances.

OBJECTIVE: To evaluate the 52-week efficacy and safety of elinzanetant, a dual neurokinin-targeted therapy, for treating moderate to severe VMS associated with menopause.

DESIGN, SETTING, AND PARTICIPANTS: OASIS-3 was a double-blind, placebo-controlled, randomized phase 3 clinical trial that was conducted at 83 sites in North America and Europe from August 27, 2021, to February 12, 2024, and included postmenopausal women aged 40 to 65 years who were seeking treatment for moderate to severe VMS (no requirement for a minimum number of VMS events per week). The data were analyzed on March 11, 2024.

INTERVENTION: Once-daily oral elinzanetant, 120 mg, or matching placebo for 52 weeks.

MAIN OUTCOMES AND MEASURES: The primary outcome was mean change from baseline to week 12 in the frequency of daily moderate to severe VMS, which was analyzed using a mixed model with repeated measures. Secondary end points included changes over 52 weeks in measures evaluating sleep disturbance and the effect on menopause-related quality of life. Exploratory end points included mean changes over 50 weeks in frequency and severity of daily moderate to severe VMS. Exploratory and secondary end points were analyzed using descriptive statistics. Safety was also assessed.

RESULTS: Overall, 313 women (mean [SD] age, 54.6 [4.7] years; 51 [16.3%] were Black or African American, and 240 [76.7%] were White individuals; 34 [10.9%] were Hispanic or Latina) were randomized to receive elinzanetant and 315 (mean [SD] age, 54.9 [5.0] years; 44 [14.0%] Black or African American, 34 [10.8%] Hispanic or Latina, and 253 [80.3%] White individuals) to receive placebo. At week 12, the mean change from baseline in daily moderate to severe VMS frequency was -5.4 (95% CI, -6.3 to -4.5) for elinzanetant and -3.5 (95% CI, -4.1 to -2.9) for placebo; the least-squares mean difference for elinzanetant vs placebo was -1.6 (95% CI, -2.0 to -1.1; P < .001). Although no statistical hypotheses were defined, nor was the study powered to detect between-group differences for the secondary and exploratory end points, descriptive analyses showed numerical advantages for elinzanetant vs placebo for improving VMS frequency and severity over 50 weeks and sleep disturbances and menopause-related quality of life over 52 weeks. Regarding safety, elinzanetant was not associated with hepatotoxic effects, endometrial hyperplasia, or meaningful changes in bone density or bone turnover markers. Treatment-related adverse events were more common with elinzanetant than placebo (30.4% vs 14.6%); the most frequent were somnolence, fatigue, and headache.

CONCLUSIONS AND RELEVANCE: The OASIS-3 randomized clinical trial expanded on findings from the 26-week OASIS-1 and OASIS-2 trials, exploring the use of elinzanetant over a longer duration and in a broader population. Elinzanetant shows promise as a treatment for moderate to severe VMS.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05030584.

CONTEXT: Risk of cardiometabolic disease increases in women transitioning to postmenopause, during which estradiol declines universally. Most of these women experience fragmentation of sleep due to nocturnal hot flashes, without a reduction in total sleep time.

OBJECTIVE: We examined the independent impact of estradiol suppression, sleep, and their combination on cardiometabolic outcomes categorized as satiety and hunger, lipid profile, cardiac vital signs, and glucoregulation.

DESIGN: Participants completed 5-night inpatient studies under eucaloric conditions, once during mid-follicular phase/estrogenized and again under estrogen suppressed conditions, using the same experimental protocol both times. For all participants, sleep was unfragmented the first two nights and then experimentally fragmented without reducing total sleep time the next three nights.

SETTING: Inpatient Intensive Physiological Monitoring research facility.

PARTICIPANTS: 38 healthy premenopausal women.

INTERVENTION(S): Clinical experimental induced menopause model including gonadotropin-releasing hormone agonist-induced hypoestrogenism and sleep fragmentation.

MAIN OUTCOME MEASURE(S): Leptin and satiety.

RESULTS: Estradiol suppression significantly decreased leptin and increased lipid profiles (FDR-adjusted p≤0.05). Sleep fragmentation significantly increased heart rate (FDR-adjusted p=0.002) and trended to increase fasting glucose (FDR-adjusted p=0.08). Estradiol suppression and sleep fragmentation worsened individual cardiometabolic outcomes by (median, IQR) 4.0% (1.5%, 6.3%) from normalized baseline values. Sleep fragmentation worsened a composite cardiometabolic index derived from individual clinical cardiometabolic measures by an additional 103% over estradiol suppression alone.

CONCLUSIONS: Independent of aging, there are significant adverse changes in cardiometabolic health induced by core components of the transition to postmenopause, including novel effects of sleep fragmentation, a modifiable target.

BACKGROUND: Although pandemic-related experiences have been linked to the psychological well-being of mothers, the effects of the COVID-19 pandemic on infant neurodevelopmental outcomes have not been sufficiently studied.

AIMS: To assess whether maternal COVID-19-related experiences (i.e., COVID-19-related health, risk, resource worries, and feelings of grief), parenting stress, and maternal self-efficacy are associated with infant neurodevelopment as measured by the Ages and Stages Questionnaire, Third Edition (ASQ-3) maternal report when infants were between 8 to 10 months of age. Furthermore, this study examined the moderating effect of maternal self-efficacy between maternal COVID-19-related experiences and infant neurodevelopment.

METHODS: This cross-sectional study included 122 women who were drawn from the Perinatal Experiences and COVID-19 Effects (PEACE) Study, with online surveys administered between November 2020 and August 2022.

RESULTS: After controlling for maternal anxiety and depression symptoms and demographic factors, hierarchical regression analysis indicated that parenting stress showed no effect on ASQ-3 scores. However, more adverse COVID-19-related experiences and higher levels of maternal self-efficacy were associated with better infant neurodevelopment. Moreover, there was a significant interaction effect between maternal self-efficacy and COVID-19-related experiences on infant neurodevelopment. For mothers with moderate to high levels of self-efficacy, more adverse COVID-19-related experiences were associated with better infant neurodevelopment. For mothers with low levels of self-efficacy, more adverse COVID-19-related experiences were associated with poorer developmental outcomes in infants.

CONCLUSIONS: Under adverse conditions, confidence in caregiving may afford more optimal infant neurodevelopment. Interventions aimed at fostering maternal self-efficacy and addressing specific stressors can be valuable in promoting positive developmental trajectories for infants born during the pandemic.

BACKGROUND: Attentional biases towards reward stimuli have been implicated in substance use-related problems. The value-modulated attentional capture (VMAC) task assesses such reward-related biases. The VMAC task widely used in lab studies tends to be monotonous and susceptible to low effort. We therefore tested a gamified online version of the VMAC that aimed to increase participant engagement. Our goal was to examine how VMAC is associated with substance use-related problems and addictive behaviors, and whether this association is moderated by cognitive control.

METHODS: We recruited 285 participants from an online community, including heavy alcohol users. All participants completed a novel gamified version of the VMAC task, measures of substance use and addictive behaviors (addictive-like eating behavior, problematic smartphone use), the WebExec measure of problems with executive functions, and the Stroop Adaptive Deadline Task (SDL) as a measure of cognitive control.

RESULTS: The gamified VMAC task successfully identified value-modulated attentional capture effects towards high-reward stimuli. We found no significant associations between VMAC scores, problematic alcohol or cannabis use, addictive behaviors, or any moderation by a behavioral measure of cognitive control. Exploratory analyses revealed that self-reported cognitive problems were associated with more alcohol-, and cannabis-related problems, and addictive behaviors. Greater attentional capture (VMAC) was associated with more cannabis use-related problems among individuals with higher levels of self-reported cognitive problems.

CONCLUSIONS: Our study is one of the first to demonstrate the utility of the gamified version of the VMAC task in capturing attentional reward biases. Self-reported problems with cognitive functions represent a key dimension associated with substance use-related problems and addictive behaviors.

BACKGROUND: Both impulsivity and compulsivity have been identified as risk factors for problematic use of the internet (PUI). Yet little is known about the relationship between impulsivity, compulsivity and individual PUI symptoms, limiting a more precise understanding of mechanisms underlying PUI.

AIMS: The current study is the first to use network analysis to (a) examine the unique association among impulsivity, compulsivity and PUI symptoms, and (b) identify the most influential drivers in relation to the PUI symptom community.

METHOD: We estimated a Gaussian graphical model consisting of five facets of impulsivity, compulsivity and individual PUI symptoms among 370 Australian adults (51.1% female, mean age = 29.8, s.d. = 11.1). Network structure and bridge expected influence were examined to elucidate differential associations among impulsivity, compulsivity and PUI symptoms, as well as identify influential nodes bridging impulsivity, compulsivity and PUI symptoms.

RESULTS: Results revealed that four facets of impulsivity (i.e. negative urgency, positive urgency, lack of premeditation and lack of perseverance) and compulsivity were related to different PUI symptoms. Further, compulsivity and negative urgency were the most influential nodes in relation to the PUI symptom community due to their highest bridge expected influence.

CONCLUSIONS: The current findings delineate distinct relationships across impulsivity, compulsivity and PUI, which offer insights into potential mechanistic pathways and targets for future interventions in this space. To realise this potential, future studies are needed to replicate the identified network structure in different populations and determine the directionality of the relationships among impulsivity, compulsivity and PUI symptoms.

INTRODUCTION: Drinking motives and neurocognition play significant roles in predicting alcohol use. There is limited research examining how relief-driven drinking motives interact with neurocognition in alcohol use, which would help to elucidate the neurocognitive-motivational profiles most susceptible to harmful drinking. This study investigated the interactions between neurocognition (response inhibition and cognitive flexibility) and relief-driven drinking, in predicting problem drinking.

METHODS: Participants completed the Alcohol Use Disorders Identification Test - Consumption items (AUDIT-C) to measure drinking behaviour, and online cognitive tasks, including the Value-Modulated Attentional Capture and Reversal Task (VMAC-R) and the Stop Signal Task (SST). The sample (N = 368) were individuals who drink alcohol, which included a subsample (N = 52) with problematic drinking, as defined by self-identifying as having a primary drinking problem. Drinking motives were assessed using a binary coping question in the overall sample, and the Habit, Reward, and Fear Scale (HRFS) in the subsample. Moderation analyses were conducted to investigate whether cognitive flexibility and response inhibition moderated relationships between relief-driven motives and drinking.

RESULTS: Cognitive flexibility moderated the relationship between relief-driven motives and drinking (overall sample: β = 13.69, p = 0.017; subsample: β = 1.45, p = 0.013). Greater relief-driven motives were associated with heavier drinking for individuals with low cognitive flexibility. There was no significant interaction between response inhibition and relief-driven motives.

CONCLUSIONS: Relief-driven drinking motives interact with cognitive inflexibility to drive heavier drinking. Greater understanding of these neurocognitive-motivational mechanisms may help to develop more targeted and effective interventions for reducing harmful drinking.

BACKGROUND AND AIMS: Cognitive control and reward-related abnormalities are centrally implicated in addiction. However, findings from longitudinal studies addressing neurocognitive predictors of addictive behaviors are mixed. Further, little work has been conducted predicting non-substance-related addictive behaviors. Our study aimed to assess predictors of substance and non-substance addictive behaviors in a community sample, systematically evaluating each neurocognitive function's independent influence on addictive behavior.

METHODS: Australians (N = 294; 51.7% female; M[SD] age = 24.8[4.7] years) completed online neurocognitive tasks and surveys at baseline and 3-month follow-up. Self-report scales assessed problematic alcohol use, addictive eating (AE), problematic pornography use (PPU), and problematic internet use (PUI) at 3- and 6-month follow-ups. Linear regressions with bootstrapping assessed neurocognitive predictors for each addictive behavior across a 6-month period.

RESULTS: Neurocognition at baseline did not predict AE or PUI severity at 6-month follow-up. Less delay discounting at baseline predicted higher PPU at 6-month follow-up (β = -0.16, p = 0.005). Poorer performance monitoring at baseline predicted higher AE at 3-month follow-up (β = -0.16, p = 0.004), and more reward-related attentional capture at 3-months predicted higher AE at 6-month follow-up (β = 0.14, p = 0.033). Less reward-related attentional capture (β = -0.14, p = 0.003) and less risk-taking under ambiguity (β = -0.11, p = 0.029) at baseline predicted higher PUI at 3-month follow-up. All findings were of small effect size. None of the neurocognitive variables predicted problematic alcohol use.

DISCUSSION AND CONCLUSIONS: We were unable to identify a core set of specific neurocognitive functions that reliably predict multiple addictive behavior types. However, our findings indicate both cognitive control and reward-related functions predict non-substance addictive behaviors in different ways. Findings suggest that there may be partially distinct neurocognitive mechanisms contributing to addiction depending on the specific addictive behavior.

Neurocognitive deficits have been implicated as transdiagnostic risk markers of substance use disorders. However, these have yet to be comprehensively evaluated in other, non-substance addictions. In a large, general community sample (N = 475) the present study evaluated the neurocognitive correlates of problem alcohol use and three non-substance-related addictive behaviors: addictive eating (AE), problematic pornography use (PPU), and problematic use of the internet (PUI), to identify potential shared and distinct neurocognitive correlates. A sample of Australian residents (54.4 % female M[SD] age = 32.4[11.9] years) completed a comprehensive online assessment of neurocognitive tasks tapping into eight distinct expert-endorsed domains purportedly associated with addiction. Multiple linear regressions with bootstrapping were used to examine associations among each addictive behavior of interest and neurocognition, trait impulsivity, and compulsivity, as well as key covariates. Neurocognition was differentially associated with each addictive behavior. None of the neurocognitive domains were significantly associated with problematic alcohol use or AE (p >.05), poorer performance monitoring was significantly associated with higher levels of PPU and PUI (β = -0.10, p =.049; β = -0.09, p =.028), and a preference for delayed gratification was associated with more severe PUI (β = -0.10, p =.025). Our findings have theoretical implications for how we understand non-substance addiction and suggest the need for a more nuanced approach to studying addictive behaviors that take into account the underlying neurocognitive mechanisms associated with each type of addiction.