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BACKGROUND: Increasing evidences suggest that nonalcoholic fatty liver disease (NAFLD) is associated with neuropsychiatric disorders. Nevertheless, whether there were causal associations between them remained vague. A causal association between neuropsychiatric disorders and NAFLD was investigated in this study. METHODS: We assessed the published genome-wide association study summary statistics for NAFLD, seven mental disorder-related diseases and six central nervous system dysfunction-related diseases. The causal relationships were first assessed using two-sample and multivariable Mendelian randomization (MR). Then, sensitivity analyses were performed, followed by a reverse MR analysis to determine whether reverse causality is possible. Finally, we performed replication analyses and combined the findings from the above studies. RESULTS: Our meta-analysis results showed NAFLD significantly increased the risk of anxiety disorders (OR = 1.016, 95% CI = 1.010-1.021, P value < 0.0001). In addition, major depressive disorder was the potential risk factor for NAFLD (OR = 1.233, 95% CI = 1.063-1.430, P value = 0.006). Multivariable MR analysis showed that the causal effect of major depressive disorder on NAFLD remained significant after considering body mass index, but the association disappeared after adjusting for the effect of waist circumference. Furthermore, other neuropsychiatric disorders and NAFLD were not found to be causally related. CONCLUSIONS: These results implied causal relationships of NAFLD with anxiety disorders and Major Depressive Disorder. This study highlighted the need to recognize and understand the connection between neuropsychiatric disorders and NAFLD to prevent the development of related diseases.

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BACKGROUND: Ecological momentary assessment (EMA) is a measurement methodology that involves the repeated collection of real-time data on participants' behavior and experience in their natural environment. While EMA allows researchers to gain valuable insights into dynamic behavioral processes, the need for frequent self-reporting can be burdensome and disruptive. Compliance with EMA protocols is important for accurate, unbiased sampling; yet, there is no "gold standard" for EMA study design to promote compliance. OBJECTIVE: The purpose of this study was to use a factorial design to identify optimal study design factors, or combinations of factors, for achieving the highest completion rates for smartphone-based EMAs. METHODS: Participants recruited from across the United States were randomized to 1 of 2 levels on each of 5 design factors in a 2×2×2×2×2 design (32 conditions): factor 1-number of questions per EMA survey (15 vs 25); factor 2-number of EMAs per day (2 vs 4); factor 3-EMA prompting schedule (random vs fixed times); factor 4-payment type (US $1 paid per EMA vs payment based on the percentage of EMAs completed); and factor 5-EMA response scale type (ie, slider-type response scale vs Likert-type response scale; this is the only within-person factor; each participant was randomized to complete slider- or Likert-type questions for the first 14 days or second 14 days of the study period). All participants were asked to complete prompted EMAs for 28 days. The effect of each factor on EMA completion was examined, as well as the effects of factor interactions on EMA completion. Finally, relations between demographic and socioenvironmental factors and EMA completion were examined. RESULTS: Participants (N=411) were aged 48.4 (SD 12.1) years; 75.7% (311/411) were female, 72.5% (298/411) were White, 18.0% (74/411) were Black or African American, 2.7% (11/411) were Asian, 1.5% (6/411) were American Indian or Alaska Native, 5.4% (22/411) belonged to more than one race, and 9.6% (38/396) were Hispanic/Latino. On average, participants completed 83.8% (28,948/34,552) of scheduled EMAs, and 96.6% (397/411) of participants completed the follow-up survey. Results indicated that there were no significant main effects of the design factors on compliance and no significant interactions. Analyses also indicated that older adults, those without a history of substance use problems, and those without current depression tended to complete more EMAs than their counterparts. No other demographic or socioenvironmental factors were related to EMA completion rates. Finally, the app was well liked (ie, system usability scale score=82.7), and there was a statistically significant positive association between liking the app and EMA compliance. CONCLUSIONS: Study results have broad implications for developing best practices guidelines for future studies that use EMA methodologies. TRIAL REGISTRATION: ClinicalTrials.gov number NCT05194228; https://clinicaltrials.gov/study/NCT05194228.

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Micro-randomized trials are commonly conducted for optimizing mobile health interventions such as push notifications for behavior change. In analyzing such trials, causal excursion effects are often of primary interest, and their estimation typically involves inverse probability weighting (IPW). However, in a micro-randomized trial, additional treatments can often occur during the time window over which an outcome is defined, and this can greatly inflate the variance of the causal effect estimator because IPW would involve a product of numerous weights. To reduce variance and improve estimation efficiency, we propose two new estimators using a modified version of IPW, which we call "per-decision IPW." The second estimator further improves efficiency using the projection idea from the semiparametric efficiency theory. These estimators are applicable when the outcome is binary and can be expressed as the maximum of a series of sub-outcomes defined over sub-intervals of time. We establish the estimators' consistency and asymptotic normality. Through simulation studies and real data applications, we demonstrate substantial efficiency improvement of the proposed estimator over existing estimators. The new estimators can be used to improve the precision of primary and secondary analyses for micro-randomized trials with binary outcomes.

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In mobile health, tailoring interventions for real-time delivery is of paramount importance. Micro-randomized trials have emerged as the "gold-standard" methodology for developing such interventions. Analyzing data from these trials provides insights into the efficacy of interventions and the potential moderation by specific covariates. The "causal excursion effect," a novel class of causal estimand, addresses these inquiries. Yet, existing research mainly focuses on continuous or binary data, leaving count data largely unexplored. The current work is motivated by the Drink Less micro-randomized trial from the UK, which focuses on a zero-inflated proximal outcome, i.e., the number of screen views in the subsequent hour following the intervention decision point. To be specific, we revisit the concept of causal excursion effect, specifically for zero-inflated count outcomes, and introduce novel estimation approaches that incorporate nonparametric techniques. Bidirectional asymptotics are established for the proposed estimators. Simulation studies are conducted to evaluate the performance of the proposed methods. As an illustration, we also implement these methods to the Drink Less trial data.

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Importance: The impact of group-based prenatal care (GPNC) model in the US on the risk of gestational diabetes (GD) and related adverse obstetric outcomes is unknown. Objective: To determine the effects of the GPNC model on risk of GD, its progression, and related adverse obstetric outcomes. Design, Setting, and Participants: This is a single-site, parallel-group, randomized clinical trial conducted between February 2016 and March 2020 at a large health care system in Greenville, South Carolina. Participants were individuals aged 14 to 45 years with pregnancies earlier than 21 weeks' gestational age; follow-up continued to 8 weeks post partum. This study used an intention-to-treat analysis, and data were analyzed from March 2021 to July 2022. Interventions: Eligible participants were randomized to receive either CenteringPregnancy, a widely used GPNC model, with 10 group-based sessions or traditional individual prenatal care (IPNC). Main Outcomes and Measures: The primary outcome was the incidence of GD diagnosed between 24 and 30 weeks of gestation. The secondary outcomes included progression to A2 GD (ie, GD treated with medications) and GD-related adverse obstetric outcomes (ie, preeclampsia, cesarean delivery, and large for gestational age). Log binomial models were performed to estimate risk differences (RDs), 95% CIs, and P values between GPNC and IPNC groups, adjusting for all baseline covariates. Results: Of all 2348 participants (mean [SD] age, 25.1 [5.4] years; 952 Black participants [40.5%]; 502 Hispanic participants [21.4%]; 863 White participants [36.8%]), 1176 participants were randomized to the GPNC group and 1174 were randomized to the IPNC group. Among all participants, 2144 (91.3%) completed a GD screening (1072 participants [91.3%] in GPNC vs 1071 [91.2%] in IPNC). Overall, 157 participants (6.7%) developed GD, and there was no difference in GD incidence between the GPNC (83 participants [7.1%]) and IPNC (74 participants [6.3%]) groups, with an adjusted RD of 0.7% (95% CI, -1.2% to 2.7%). Among participants with GD, GPNC did not reduce the risk of progression to A2 GD (adjusted RD, -6.1%; 95% CI, -21.3% to 9.1%), preeclampsia (adjusted RD, -7.9%; 95% CI, -17.8% to 1.9%), cesarean delivery (adjusted RD, -8.2%; 95% CI, -12.2% to 13.9%), and large for gestational age (adjusted RD, -1.2%; 95% CI, -6.1% to 3.8%) compared with IPNC. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial among medically low-risk pregnant individuals, the risk of GD was similar between participants who received GPNC intervention and traditional IPNC, indicating that GPNC may be a feasible treatment option for some patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02640638.

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Hippocampal sclerosis of aging (HS-A) is a common degenerative neuropathology in older individuals and is associated with dementia. HS-A is characterized by disproportionate hippocampal atrophy at autopsy but cannot be diagnosed during life. Therefore, little is known about the onset and progression of hippocampal atrophy in individuals with HS-A. To better understand the onset and progression of hippocampal atrophy in HS-A, we examined longitudinal hippocampal atrophy using serial MRI in participants with HS-A at autopsy (HS-A+, n = 8) compared to participants with limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) without HS-A (n = 13), Alzheimer's disease neuropathologic change (ADNC) without HS-A or LATE-NC (n = 16), and those without these pathologies (n = 7). We found that participants with HS-A had lower hippocampal volumes compared to the other groups, and this atrophy preceded the onset of dementia. There was also some evidence that rates of hippocampal volume loss were slightly slower in those with HS-A. Together, these results suggest that the disproportionate hippocampal atrophy seen in HS-A may begin early prior to dementia.

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Hippocampal sclerosis of aging (HS-A) is a common age-related neuropathological lesion characterized by neuronal loss and astrogliosis in subiculum and CA1 subfield of hippocampus. HS-A is associated with cognitive decline that mimics Alzheimer's disease. Pathological diagnosis of HS-A is traditionally binary based on presence/absence of the lesion. We compared this traditional measure against our novel quantitative measure for studying the relationship between HS-A and other neuropathologies and cognitive impairment. We included 409 participants from The 90+ study with neuropathological examination and longitudinal neuropsychological assessments. In those with HS-A, we examined digitized H&E and LFB stained hippocampal slides. The length of HS-A in each subfield of hippocampus and subiculum, each further divided into three subregions, was measured using Aperio eSlide Manager. For each subregion, the proportion affected by HS-A was calculated. Using regression models, both traditional/binary and quantitative measures were used to study the relationship between HS-A and other neuropathological changes and cognitive outcomes. HS-A was present in 48 (12%) of participants and was always focal, primarily affecting CA1 (73%), followed by subiculum (9%); overlapping pathology (subiculum and CA1) affected 18% of individuals. HS-A was more common in the left (82%) than the right (25%) hemisphere and was bilateral in 7% of participants. HS-A traditional/binary assessment was associated with limbic-predominant age-related TDP-43 encephalopathy (LATE-NC; OR = 3.45, p < 0.001) and aging-related tau astrogliopathy (ARTAG; OR = 2.72, p = 0.008). In contrast, our quantitative approach showed associations between the proportion of HS-A (CA1/subiculum/combined) and LATE-NC (p = 0.001) and arteriolosclerosis (p = 0.005). While traditional binary assessment of HS-A was associated with impaired memory (OR = 2.60, p = 0.007), calculations (OR = 2.16, p = 0.027), and orientation (OR = 3.56, p < 0.001), our quantitative approach revealed additional associations with impairments in language (OR = 1.33, p = 0.018) and visuospatial domains (OR = 1.37, p = 0.006). Our novel quantitative method revealed associations between HS-A and vascular pathologies and impairment in cognitive domains that were not detected using traditional/binary measures.

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BACKGROUND: Drink Less is a behavior change app to help higher-risk drinkers in the United Kingdom reduce their alcohol consumption. The app includes a daily notification asking users to "Please complete your drinks and mood diary," yet we did not understand the causal effect of the notification on engagement nor how to improve this component of Drink Less. We developed a new bank of 30 new messages to increase users' reflective motivation to engage with Drink Less. This study aimed to determine how standard and new notifications affect engagement. OBJECTIVE: Our objective was to estimate the causal effect of the notification on near-term engagement, to explore whether this effect changed over time, and to create an evidence base to further inform the optimization of the notification policy. METHODS: We conducted a micro-randomized trial (MRT) with 2 additional parallel arms. Inclusion criteria were Drink Less users who consented to participate in the trial, self-reported a baseline Alcohol Use Disorders Identification Test score of ≥8, resided in the United Kingdom, were aged ≥18 years, and reported interest in drinking less alcohol. Our MRT randomized 350 new users to test whether receiving a notification, compared with receiving no notification, increased the probability of opening the app in the subsequent hour, over the first 30 days since downloading Drink Less. Each day at 8 PM, users were randomized with a 30% probability of receiving the standard message, a 30% probability of receiving a new message, or a 40% probability of receiving no message. We additionally explored time to disengagement, with the allocation of 60% of eligible users randomized to the MRT (n=350) and 40% of eligible users randomized in equal number to the 2 parallel arms, either receiving the no notification policy (n=98) or the standard notification policy (n=121). Ancillary analyses explored effect moderation by recent states of habituation and engagement. RESULTS: Receiving a notification, compared with not receiving a notification, increased the probability of opening the app in the next hour by 3.5-fold (95% CI 2.91-4.25). Both types of messages were similarly effective. The effect of the notification did not change significantly over time. A user being in a state of already engaged lowered the new notification effect by 0.80 (95% CI 0.55-1.16), although not significantly. Across the 3 arms, time to disengagement was not significantly different. CONCLUSIONS: We found a strong near-term effect of engagement on the notification, but no overall difference in time to disengagement between users receiving the standard fixed notification, no notification at all, or the random sequence of notifications within the MRT. The strong near-term effect of the notification presents an opportunity to target notifications to increase "in-the-moment" engagement. Further optimization is required to improve the long-term engagement. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/18690.

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Methamphetamine use causes spikes in blood pressure. Chronic hypertension is a major risk factor for cerebral small vessel disease (cSVD). The aim of this study is to investigate whether methamphetamine use increases the risk of cSVD. Consecutive patients with acute ischemic stroke at our medical center were screened for methamphetamine use and evidence of cSVD on MRI of the brain. Methamphetamine use was identified by self-reported history and/or positive urine drug screen. Propensity score matching was used to select non-methamphetamine controls. Sensitivity analysis was performed to assess the effect of methamphetamine use on cSVD. Among 1369 eligible patients, 61 (4.5%) were identified to have a history of methamphetamine use and/or positive urine drug screen. Compared with the non-methamphetamine group (n = 1306), the patients with methamphetamine abuse were significantly younger (54.5 ± 9.7 vs. 70.5 ± 12.4, p < 0.001), male (78.7% vs. 54.0%, p < 0.001) and White (78.7% vs. 50.4%, p < 0.001). Sensitivity analysis showed that methamphetamine use was associated with increased white matter hyperintensities, lacunes, and total burden of cSVD. The association was independent of age, sex, concomitant cocaine use, hyperlipidemia, acute hypertension, and stroke severity. Our findings suggest that methamphetamine use increases the risk of cSVD in young patients with acute ischemic stroke.

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Micro-randomized trials (MRTs) are a novel experimental design for developing mobile health interventions. Participants are repeatedly randomized in an MRT, resulting in longitudinal data with time-varying treatments. Causal excursion effects are the main quantities of interest in MRT primary and secondary analyses. We consider MRTs where the proximal outcome is binary and the randomization probability is constant or time-varying but not data-dependent. We develop a sample size formula for detecting a nonzero marginal excursion effect. We prove that the formula guarantees power under a set of working assumptions. We demonstrate via simulation that violations of certain working assumptions do not affect the power, and for those that do, we point out the direction in which the power changes. We then propose practical guidelines for using the sample size formula. As an illustration, the formula is used to size an MRT on interventions for excessive drinking. The sample size calculator is implemented in R package MRTSampleSizeBinary and an interactive R Shiny app. This work can be used in trial planning for a wide range of MRTs with binary proximal outcomes.

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BACKGROUND: Problem anger is common after experiencing a traumatic event. Current evidence-driven treatment options are limited, and problem anger negatively affects an individual's capacity to engage with traditional psychological treatments. Smartphone interventions hold significant potential in mental health because of their ability to deliver low-intensity, precision support for individuals at the time and place they need it most. While wearable technology has the capacity to augment smartphone-delivered interventions, there is a dearth of evidence relating to several key areas, including feasibility of compliance in mental health populations; validity of in vivo anger assessment; ability to predict future mood states; and delivery of timely and appropriate interventions. METHODS: This protocol describes a cohort study that leverages 10 days of ambulatory assessment in the form of ecological momentary assessment and a wearable. Approximately 100 adults with problem anger will complete four-hourly in vivo mobile application-delivered micro-surveys on anger intensity, frequency, and verbal and physical aggression, as well as other self-reported mental health and wellbeing measures. Concurrently, a commercial wearable device will continuously record indicators of physiological arousal. The aims are to test the feasibility and acceptability of ambulatory assessment in a trauma-affected population, and determine whether a continuously measured physiological indicator of stress predicts self-reported anger intensity. DISCUSSION: This study will contribute new data around the ability of physiological indicators to predict mood state in individuals with psychopathology. This will have important implications for the design of smartphone-delivered interventions for trauma-affected individuals, as well as for the digital mental health field more broadly.

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Having previously seen an item helps uncover the item another time, given a perceptual or cognitive cue. Oftentimes, however, it may be difficult to quantify or test the existence and size of a perceptual or cognitive effect, in general, and a priming effect, in particular. This is because to examine the existence of and quantify the effect, one needs to compare two outcomes: the outcome had one previously seen the item vs. the outcome had one not seen the item. But only one of the two outcomes is observable. Here, we argue that the potential outcomes framework is useful to define, quantify, and test the causal priming effect. To demonstrate its efficacy, we apply the framework to study the priming effect using data from a between-subjects study involving English word identification. In addition, we show that what has been used intuitively by experimentalists to assess the priming effect in the past has a sound mathematical foundation. Finally, we examine the links between the proposed method in studying priming and the multinomial processing tree (MPT) model, and how to extend the method to study experimental paradigms involving exclusion and inclusion instructional conditions.

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INTRODUCTION: Vaccine hesitancy is still rampant in the United States, including health care personnel. Vaccination of frontline essential workers (e.g. health care workers) is very important, especially during a pandemic. We tested the efficacy of a 4-week online, peer-led intervention (Harnessing Online Peer Education) to promote requests for COVID-19 vaccine information among essential workers. METHODS: Participants (N = 120) and peer leaders (N = 12) were recruited through online advertisements from July 23 to August 20, 2021. Eligibility criteria included: 18 years or older, U.S. resident, English speaker, part of phase 1a or 1 b of COVID-19 vaccine rollout (e.g. frontline essential workers), hadn't received a COVID-19 vaccine but able to receive one. This was a parallel assignment randomised trial. STATA was used to create a randomisation using a random number generator so that all possible assignments of participants and peer leaders to groups were equally likely. Participants were randomly assigned to intervention or control arms that consisted of two private, hidden Facebook groups, each with 30 participants. Peer leaders were randomly assigned to an intervention group, each with six peer leaders. Participants in the intervention arm were randomly assigned to three peer leaders. Participants were blinded after assignment. Peer leaders were tasked with reaching out to their assigned participants at least three times each week. Participants completed a baseline and a post intervention survey. The study is registered on ClinicalTrials.org under identifier NCT04376515 and is no longer recruiting. This work was supported by the NIAID under grant 5R01AI132030-05. RESULTS: A total of 101 participants analysed (50 intervention and 51 control). Six people in the intervention group and 0 people in the control group requested vaccine information. Ten people in the intervention group and six people in the control group provided proof of vaccination. The odds of requesting vaccine information in the intervention group was 13 times that in the control group (95% confidence interval: (1.5, 1772), p-value = 0.015). Thirty-seven participants in the intervention group and 31 in the control group were engaged at some point during the study. CONCLUSIONS: Results suggest peer-led online community groups may help to disseminate health information, aid public health efforts, and combat vaccine hesitancy. Key MessagesThe odds of requesting vaccine information was 13 times in the intervention group.Peer-led online communities may help to disseminate information and aid public health efforts to combat vaccine hesitancy.

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Just-in-time adaptive interventions (JITAIs) are time-varying adaptive interventions that use frequent opportunities for the intervention to be adapted-weekly, daily, or even many times a day. The microrandomized trial (MRT) has emerged for use in informing the construction of JITAIs. MRTs can be used to address research questions about whether and under what circumstances JITAI components are effective, with the ultimate objective of developing effective and efficient JITAI. The purpose of this article is to clarify why, when, and how to use MRTs; to highlight elements that must be considered when designing and implementing an MRT; and to review primary and secondary analyses methods for MRTs. We briefly review key elements of JITAIs and discuss a variety of considerations that go into planning and designing an MRT. We provide a definition of causal excursion effects suitable for use in primary and secondary analyses of MRT data to inform JITAI development. We review the weighted and centered least-squares (WCLS) estimator which provides consistent causal excursion effect estimators from MRT data. We describe how the WCLS estimator along with associated test statistics can be obtained using standard statistical software such as R (R Core Team, 2019). Throughout we illustrate the MRT design and analyses using the HeartSteps MRT, for developing a JITAI to increase physical activity among sedentary individuals. We supplement the HeartSteps MRT with two other MRTs, SARA and BariFit, each of which highlights different research questions that can be addressed using the MRT and experimental design considerations that might arise. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

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Advances in wearables and digital technology now make it possible to deliver behavioral mobile health interventions to individuals in their everyday life. The micro-randomized trial is increasingly used to provide data to inform the construction of these interventions. In a micro-randomized trial, each individual is repeatedly randomized among multiple intervention options, often hundreds or even thousands of times, over the course of the trial. This work is motivated by multiple micro-randomized trials that have been conducted or are currently in the field, in which the primary outcome is a longitudinal binary outcome. The primary aim of such micro-randomized trials is to examine whether a particular time-varying intervention has an effect on the longitudinal binary outcome, often marginally over all but a small subset of the individual's data. We propose the definition of causal excursion effect that can be used in such primary aim analysis for micro-randomized trials with binary outcomes. Under rather restrictive assumptions one can, based on existing literature, derive a semiparametric, locally efficient estimator of the causal effect. Starting from this estimator, we develop an estimator that can be used as the basis of a primary aim analysis under more plausible assumptions. Simulation studies are conducted to compare the estimators. We illustrate the developed methods using data from the micro-randomized trial, BariFit. In BariFit, the goal is to support weight maintenance for individuals who received bariatric surgery.

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Morin is a natural compound isolated from moraceae family members and has been reported to possess a range of pharmacological activities. However, the effects of morin on bone-associated disorders and the potential mechanism remain unknown. In this study, we investigated the anti-osteoclastogenic effect of morin in vitro and the potential therapeutic effects on ovariectomy (OVX)-induced osteoporosis in vivo. In vitro, by using a bone marrow macrophage-derived osteoclast culture system, we determined that morin attenuated receptor activator of nuclear factor (NF)-κB ligand (RANKL)-induced osteoclast formation via the inhibition of the mitogen-activated protein kinase (MAPK), NF-κB and calcium pathways. In addition, the subsequent expression of nuclear factor of activated T cells c1 (NFATc1) and c-fos was significantly suppressed by morin. In addition, NFATc1 downregulation led to the reduced expression of osteoclastogenesis-related marker genes, such as V-ATPase-d2 and Integrin ß3. In vivo, results provided that morin could effectively attenuate OVX-induced bone loss in C57BL/6 mice. In conclusion, our results demonstrated that morin suppressed RANKL-induced osteoclastogenesis via the NF-κB, MAPK and calcium pathways, in addition, its function of preventing OVX-induced bone loss in vivo, which suggested that morin may be a potential therapeutic agent for postmenopausal osteoporosis treatment.

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Spinal cord injury (SCI) is a devastating neurological occurrence that usually leads to a loss of motor and sensory function in patients. Axon regeneration has been reported to be crucial for recovery after trauma to the nervous system. Morin, a natural bioflavonoid obtained from the Moraceae family, has previously been reported to exert neuroprotective effects. In our study, we investigated the protective effects of morin on PC12 cells and primary neurons treated with oxygen-glucose deprivation (OGD) and its function in an SCI model. In vitro experiments showed that treating neuronal cells with morin enhanced axonal regeneration after OGD treatment by regulating microtubule stabilization and protecting mitochondrial function. Mechanistically, morin protected neuronal cells exposed to OGD by activating the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway. An in vivo study illustrated that oral morin administration improved microtubule stability and promoted axon regeneration in SCI rats. Taken together, this study showed that treatment with morin improves functional recovery after SCI and that morin may serve as a potential agent for treating SCI.

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BACKGROUND: Relapse to smoking is commonly triggered by stress, but behavioral interventions have shown only modest efficacy in preventing stress-related relapse. Continuous digital sensing to detect states of smoking risk and intervention receptivity may make it feasible to increase treatment efficacy by adapting intervention timing. OBJECTIVE: Aims are to investigate whether the delivery of a prompt to perform stress management behavior, as compared to no prompt, reduces the likelihood of (a) being stressed and (b) smoking in the subsequent two hours, and (c) whether current stress moderates these effects. STUDY DESIGN: A micro-randomized trial will be implemented with 75 adult smokers who wear Autosense chest and wrist sensors and use the mCerebrum suite of smartphone apps to report and respond to ecological momentary assessment (EMA) questions about smoking and mood for 4 days before and 10 days after a quit attempt and to access a set of stress-management apps. Sensor data will be processed on the smartphone in real time using the cStress algorithm to classify minutes as probably stressed or probably not stressed. Stressed and non-stressed minutes will be micro-randomized to deliver either a prompt to perform a stress management exercise via one of the apps or no prompt (2.5-3 stress management prompts will be delivered daily). Sensor and self-report assessments of stress and smoking will be analyzed to optimize decision rules for a just-in-time adaptive intervention (JITAI) to prevent smoking relapse. SIGNIFICANCE: Sense2Stop will be the first digital trial using wearable sensors and micro-randomization to optimize a just-in-time adaptive stress management intervention for smoking relapse prevention.

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One of the causes of intervertebral disc degeneration (IVDD) is nucleus pulposus cell (NPC) death, possibly apoptosis. In this study, we explored the role of the Nrf2/Sirt3 pathway and tert-butylhydroquinone (t-BHQ) in IVDD and elucidated the potential working mechanism. Reactive oxygen species (ROS) assay kits and malondialdehyde (MDA) assay kits were used to assess oxidative stress. Western blot and TUNEL staining were used to examine apoptosis. After siRNA against Nrf2 or lentivirus against Sirt3 was transfected into NPCs, the mechanism of the effect of the Nrf2/Sirt3 pathway on NPCs was assessed. The interaction between t-BHQ and its potential interacting protein NRF2 was further investigated through protein docking analysis. ChIP examined the binding affinity between Nrf2 and Sirt3 promoter. In vivo experiments, X-ray, hematoxylin-eosin (HE) staining, Safranin O staining, and immunohistochemistry were used to evaluate IVDD grades. The results demonstrated that activation of the Nrf2/Sirt3 pathway inhibited tert-butyl hydroperoxide- (TBHP-) induced apoptosis and mitochondrial dysfunction in vitro. In addition to apoptosis, upregulation of the Nrf2/Sirt3 pathway induced by t-BHQ restored TBHP-induced autophagic flux disturbances. However, its protective effect was reversed by chloroquine and Si-ATG5. Furthermore, t-BHQ ameliorated IVDD development in a rat model. In conclusion, our findings indicate that the Nrf2/Sirt3 pathway and its agonist represent a potential candidate for treating IVDD.

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