Ubiquitination of the GluA1 Subunit of AMPA Receptors Is Required for Synaptic Plasticity, Memory, and Cognitive Flexibility.

Activity-dependent changes in the number of AMPA-type glutamate receptors (AMPARs) at the synapse underpin the expression of LTP and LTD, cellular correlates of learning and memory. Post-translational ubiquitination has emerged as a key regulator of the trafficking and surface expression of AMPARs, with ubiquitination of the GluA1 subunit at Lys-868 controlling the post-endocytic sorting of the receptors into the late endosome for degradation, thereby regulating their stability at synapses. However, the physiological significance of GluA1 ubiquitination remains unknown. In this study, we generated mice with a knock-in mutation in the major GluA1 ubiquitination site (K868R) to investigate the role of GluA1 ubiquitination in synaptic plasticity, learning, and memory. Our results reveal that these male mice have normal basal synaptic transmission but exhibit enhanced LTP and deficits in LTD. They also display deficits in short-term spatial memory and cognitive flexibility. These findings underscore the critical roles of GluA1 ubiquitination in bidirectional synaptic plasticity and cognition in male mice.SIGNIFICANCE STATEMENT Subcellular targeting and membrane trafficking determine the precise number of AMPA-type glutamate receptors at synapses, processes that are essential for synaptic plasticity, learning, and memory. Post-translational ubiquitination of the GluA1 subunit marks AMPARs for degradation, but its functional role in vivo remains unknown. Here we demonstrate that the GluA1 ubiquitin-deficient mice exhibit an altered threshold for synaptic plasticity accompanied by deficits in short-term memory and cognitive flexibility. Our findings suggest that activity-dependent ubiquitination of GluA1 fine-tunes the optimal number of synaptic AMPARs required for bidirectional synaptic plasticity and cognition in male mice. Given that increases in amyloid-ß cause excessive ubiquitination of GluA1, inhibiting that GluA1 ubiquitination may have the potential to ameliorate amyloid-ß-induced synaptic depression in Alzheimer's disease.

The essence of the engram: Cellular or synaptic?

Memory is composed of various phases including cellular consolidation, systems consolidation, reconsolidation, and extinction. In the last few years it has been shown that simple association memories can be encoded by a subset of the neuronal population called engram cells. Activity of these cells is necessary and sufficient for the recall of association memory. However, it is unclear which molecular mechanisms allow cellular engrams to encode the diverse phases of memory. Further research is needed to examine the possibility that it is the synapses between engram cells (the synaptic engram) that constitute the memory. In this review we summarize recent findings on cellular engrams with a focus on different phases of memory, and discuss the distinct molecular mechanism required for cellular and synaptic engrams.

Vaping Transitions and Incident Depressive Symptoms among Young Adults: A Marginal Structural Model Analysis.

The extent to which vaping influences depression is unclear, but could be estimated through application of novel epidemiologic methods. Among a prospective cohort of young adults from California who screened negative for depression, we estimated repeated measures marginal structural models to examine the association of four vaping transitions from time T to T+1 (persistent use, discontinuation, initiation, persistent nonuse) with risk of clinically significant depressive symptoms at T+1, simultaneously across three ~1.5 year time-intervals between 2017-2021. Stabilized inverse probability of treatment and censoring weights adjusted for time-dependent confounders and selection bias. Among n=3,496 observations (1,806 participants, mean pooled baseline age=19.5), 8.1% reported persistent vaping from T to T+1, 6.2% reported discontinuation (i.e., use at T and no use at T+1), 6.5% initiated e-cigarettes (i.e., no use at T and use at T+1), and 79.2% reported persistent nonuse at both time-points. Compared to persistent vaping at two waves, persistent nonuse (RR=0.76, 95%CI:0.62-0.93) and discontinuation (RR=0.71, 95%CI:0.52-0.96) were associated with lower risk of depression. Associations were robust to sensitivity analyses, including restricting to tobacco naïve participants and varying temporal assumptions to reduce potential for reverse causation. Young adults who consistently avoid or discontinue vaping may be protected from depressive symptom occurrence.

Longitudinal Transitions Between Use of Combustible, Noncombustible, and Multiple Cannabis Products From Adolescence to Young Adulthood and Intersections With Nicotine Use.

Understanding transitions across use of different types of cannabis products and multiple cannabis products and how they intersect with nicotine use in young people can inform etiology and prevention. In this study, we examined transitions across use of combustible and noncombustible forms of cannabis and multiple types of cannabis from adolescence to young adulthood and the role of nicotine use in transitions. In a Southern California longitudinal cohort study (n = 3,298; baseline mean age = 16.1 (standard deviation, 0.4) years) with 9 semiannual survey waves (2015-2021), we used Markov multistate transition modeling to estimate short-term (2-wave) and long-term (9-wave) probabilities of transition across 5 cannabis use states: never use of any product, prior use with no past-6-month (P6M) use of any product, and P6M use of exclusively noncombustible products, exclusively combustible products, and multiple (noncombustible + combustible) products. Sizable transition probabilities from prior and exclusive P6M noncombustible or combustible cannabis use to P6M poly-cannabis-product use were observed in short-term (10.7%-38.9%) and long-term (43.4%-43.8%) analyses. P6M nicotine use increased risk of transitioning from never and prior use to exclusive P6M noncombustible and combustible cannabis use. Cannabis use in any form, even temporary use, during midadolescence may often be followed by poly-cannabis-product use. Nicotine use may amplify the probability of future cannabis use onset or recurrence.

Parenting practices, mental health, and electronic cigarette use among U.S. young adolescents: A longitudinal panel analysis, 2013-2018.

PURPOSE: This study examined prospective association of parenting practices related to tobacco use with adolescent e-cigarette use and the moderating role of mental health among U.S. young adolescents. METHODS: We study used multi-wave longitudinal data (2013-2018) drawn from the Population Assessment of Tobacco and Health Study. A total of 5114 young adolescents (12-14 years) who were not lost to follow-ups across four waves (Wave 1-4) comprised the study sample. Weighted logistic regression models along with generalized linear mixed modeling assessed the within-subject associations of parenting practices related to tobacco use (tobacco availability at parent/guardian's home, past-year parent talk about tobacco use, and rules about non-combustible tobacco use at home) with adolescent current e-cigarette use. RESULTS: Prevalence of having home rules about non-combustible tobacco use increased (74.5%-80.2%) and that of parent talk about tobacco use decreased (52.0%-33.9%) over time while tobacco availability at home did not show a specific trend. Tobacco availability at home was associated with increased odds of adolescent e-cigarette use (adjusted odd ratio[OR] = 2.25, 95% confidence interval[CI] = 1.72-2.95), and having home rules about non-combustible tobacco use was linked to decreased likelihood of e-cigarette use (adjusted OR = 0.72, 95% CI = 0.55-0.92). The magnitude of negative association between having rules about non-combustible tobacco and adolescent e-cigarette use was stronger among adolescents with internalizing problems but weaker among those with externalizing problems. CONCLUSIONS: Our findings highlight the important role of home-based interventions in discouraging young adolescents from e-cigarette use. Parents/guardians should consider adolescents' mental health to provide more efficient home- and/or clinical-based e-cigarette use prevention.

Effect of packaging with versus without candy-oriented marketing themes on the appeal and sensory attributes of flavoured e-cigarettes.

SIGNIFICANCE: E-cigarettes with candy-themed marketing are implicated in decisions to first try e-cigarettes but have unknown effects on the experience of vaping. We compared adults' perceived appeal and sensory attributes after self-administering flavoured e-cigarettes in experimentally manipulated packaging with candy-themed versus standard marketing. We also assessed effect modification by salt vs free-base nicotine formulation. METHODS: Adults who currently used e-cigarettes and/or cigarettes (N=72; age M(SD)=31.4 (12.8) years) completed single-puff self-administrations from eight individually-packaged pods containing fruit or dessert-flavoured e-liquid via staff-guided video sessions. For each e-liquid flavour, we custom-manufactured packaging with standard (eg, 'mango'; mango fruit image) and candy (eg, 'mango gummy bear'; gummy bear image) marketing versions, which we varied within-subject (four pods candy; four pods standard). After participants opened the package and vaped the pod inside, they rated its sensory attributes and appeal (0-100 scale). Participants were randomised between subjects to salt or free-base ~2.3% nicotine in all pods. RESULTS: Marketing theme had no significant main effects on outcomes. Marketing theme × nicotine formulation interactions were significant; candy-themed (vs standard) packaging elevated composite appeal (Bdifference [estimated mean difference between marketing themes]=7.7), liking (Bdifference=8.4), and sweetness (Bdifference=5.7) ratings in free-base but not salt nicotine formulations. Marketing theme did not affect smoothness, harshness and bitterness ratings regardless of nicotine formulation. CONCLUSION: Candy-themed marketing may heighten the appeal and sweet sensory experience of vaping flavoured free-base nicotine e-cigarettes. While marketing restrictions are predominantly intended to prevent e-cigarette initiation, candy-themed marketing restrictions could also prevent persistent use by lowering the appeal of flavoured free-base nicotine e-cigarettes.

Association of over the counter "hangover remedy" use with alcohol use problems and consumption patterns among young adults.

This cross-sectional study of young adults examined associations of hangover remedy use with alcohol use problems. Results suggest that ever-use of hangover remedy products was positively associated with alcohol use problem score, drinks per typical drinking day, and alcohol use disorder symptom count. Use of hangover remedies among young adults merits further scientific and regulatory attention.

Application of a cognitive program with a comprehensive strategy feedback for Korean older adults.

This study assesses the effect of a cognitive program with a comprehensive strategy feedback on the cognitive function and memory self-efficacy of community-dwelling older adults and explores its applicability in Korea. The study employed a group pre-posttest design on 10 cognitively normal older participants. The four-week cognitive program involved daily completion of cognitive tasks at home using CoTras-Pro 2 and remotely provided individual non-face-to-face feedback. Additionally, biweekly face-to-face group feedback sessions were conducted with five participants. The Korean version of the Montreal Cognitive Assessment, the Korean-Color Word Stroop Test, and the Memory Self-Efficacy Questionnaire were used. Post-interviews were conducted to collect feedback. The program exerted a notable positive impact on cognitive function and memory self-efficacy. A study designed as a large-scale program conducted in collaboration with community-based public and private organizations holds the potential to be modeled for similar intervention programs involving a large number of participants.

Prevalence of and disparities in adolescents' susceptibility to novel oral nicotine products marketed as "tobacco-free".

Non-therapeutic, novel oral nicotine products are convenient, discreet to use, and flavored, with increasing sales in the United States. It is unclear whether these products appeal predominantly to adolescents already susceptible to inhalable nicotine products, or whether they attract adolescents who would not otherwise use nicotine. This study examined prevalence and correlates of susceptibility to inhalable and oral nicotine product use among adolescents. Ninth- and tenth-grade students from Southern California who had never used any nicotine product (N = 3129) completed an online survey in Fall 2021 assessing susceptibility to inhalable (i.e., cigarettes, e-cigarettes) and oral (e.g., pouches, gum, gummies) nicotine products. Multinomial logistic regression analyses estimated associations of demographic characteristics with odds of susceptibility to oral, inhalable, or both products. Susceptibility was highest for e-cigarettes (19.7%), followed by cigarettes (15.0%) and nicotine gum, lozenges, tablets and/or gummies (15.0%), and nicotine pouches (8.7%). Dual susceptibility to oral and inhalable products (vs. neither product type) was higher in cisgender female and non-cisgender (vs. cisgender male) adolescents (odds ratios [ORs] = 1.36-2.02; ps < 0.05). Hispanic adolescents (vs. Asian) were more susceptible to both products (OR = 1.47; p < .05). Lower-socioeconomic status (SES) and sexual minority adolescents were more susceptible to oral (ORs = 1.76-1.87; ps < 0.05) and both products (ORs = 1.32-1.88; ps < 0.05), compared to higher-SES and heterosexual adolescents. Adolescents in Southern California may be more susceptible to e-cigarettes than other nicotine/tobacco products. However, appreciable numbers may be susceptible to oral nicotine products, including some youth who might not otherwise use nicotine and youth from populations historically impacted by tobacco-related health disparities.

Statewide vaping product excise tax policy and use of electronic nicotine delivery systems among US young adults, 2014-2019.

OBJECTIVES: An increasing number of US states have required a tax on electronic nicotine delivery systems (ENDS) in the past few years. This study evaluated the effect of statewide vaping product excise tax policy on ENDS use among young adults. METHODS: We used the two recent waves (2014-2019) of the Tobacco Use Supplement to the Current Population Survey. A total of 17 896 US young adults were analysed. Difference-in-differences approach along with weighted multilevel logistic regressions was used to evaluate the association of vaping product excise tax policy adoption with current ENDS use, accounting for the clustering of respondents within the same states. RESULTS: There was an increase in current ENDS use prevalence from 2014-2015 (3.4%) to 2018-2019 (5.4%). Respondents living in states with vaping product excise tax policy showed significantly lower increase in ENDS use prevalence during the study period (interaction between within-state changes and between-state differences: adjusted OR (AOR)=0.57, 95% CI=0.35 to 0.91), controlling for other state-level policies and sociodemographic characteristics. Additional stratified analysis with state-fixed effects by vaping product excise tax policy implementation status showed consistent findings. CONCLUSIONS: Our findings suggest that adopting a vaping product excise tax policy may help reduce ENDS use and suppress the increase of ENDS use prevalence among young adults. Considering that there are still a number of US states that have not implemented vaping product excise tax policy, wider adoption of such policy across the nation would likely help mitigate ENDS use prevalence.

Dose-response effects of two nicotine salt formulations on electronic cigarette appeal and sensory attributes.

OBJECTIVES: Various organic acids are used to create nicotine salt formulations, which may improve the appeal and sensory experience of vaping electronic cigarettes (e-cigarettes). This clinical experiment examined the effects of partially and highly protonated forms of two nicotine salt formulations (nicotine lactate and benzoate) versus free-base (no acid additive) on the appeal and sensory attributes of e-cigarettes. METHODS: Current adult tobacco product users (n=116) participated in an online remote double-blind within-subject randomised experiment involving standardised self-administration of e-cigarette solutions varying in nicotine formulation (free-base, 50% nicotine lactate -1:2 lactic acid to nicotine molar ratio, 100% nicotine lactate - 1:1 ratio, 50% nicotine benzoate and 100% nicotine benzoate). Each formulation had equivalent nicotine concentrations (27.0-33.0 mg/mL) and was administered in four flavours in a pod-style device. After each administration, participants rated appeal (liking, disliking and willingness to use again) and sensory attributes (0-100 scale). RESULTS: Compared with free-base nicotine, 50% and 100% nicotine lactate and benzoate yielded higher appeal, smoothness and sweetness and lower harshness and bitterness. Dose-response analyses found 100% vs 50% nicotine salt improved appeal, smoothness, bitterness and harshness for nicotine lactate and sweetness, smoothness and harshness for nicotine benzoate. Solutions with higher pH were associated with worse appeal and sensory attributes across nicotine formulations. Nicotine formulation effects did not differ by tobacco use status and flavours. CONCLUSION: Restricting benzoic acid or lactic acid additives or setting minimal pHs in e-cigarettes merits consideration in regulations designed to reduce vaping among populations deterred from using e-cigarettes with aversive sensory properties. TRIAL REGISTRATION NUMBER: This study was registered under ClinicalTrials.gov Identifier: NCT03742817 under the title 'Effects of e-Cigarettes on Perceptions and Behavior'.

Effects of 'Ice' flavoured e-cigarettes with synthetic cooling agent WS-23 or menthol on user-reported appeal and sensory attributes.

BACKGROUND: This clinical experiment tested the effects of exposure to e-cigarettes with WS-23 or menthol cooling additives on user appeal and sensory attributes, and, secondarily, whether WS-23 effects generalised across base characterising flavour, nicotine concentration, or nicotine/tobacco product use status. METHODS: In this within-participant double-blind experiment, adult tobacco/nicotine users administered standardised puffs of 18 different e-cigarette solutions in randomised sequences using a pod-style device. Each of three base characterising e-cigarette flavour solutions ('bold tobacco', 'mango,' 'wintergreen') in both 2% and 4% concentrations of nicotine benzoate salt were manipulated by adding either: (1) Menthol (0.5%), (2) WS-23 (0.75%) or (3) No cooling agent. After each administration, participants rated 3 appeal and 5 sensory attributes (0-100 scales). RESULTS: Participants (n=84; M(SD)=38.6 (13.6) years old) were either exclusive e-cigarette (25.0%), cigarette (36.9%) or dual (38.1%) users. WS-23 versus no coolant products produced higher liking, willingness to use again, smoothness, and coolness and lower disliking, bitterness, and harshness ratings (|B|difference range: 4.8 to 20.1; ps<0.005). Menthol (vs no coolant) increased willingness to use again and reduced harshness and coolness (ps<0.05). Flavours with WS-23 (vs menthol) were rated as smoother, cooler and less harsh (ps<0.05). Coolant effects did not differ by base flavour, nicotine concentration, or tobacco use status. CONCLUSIONS: Adding synthetic coolant WS-23 to e-cigarettes appears to make the vaping user experience more appealing, regardless of characterising base flavour. Regulatory agencies should be aware that the manufacturing process of adding synthetic coolants may increase the attractiveness of various e-cigarette products.Cite Now.

Frequency of errors in the transfer of treatment parameters from the treatment planning system to the oncology information system in a multi-vendor environment.

BACKGROUND: Technological advancements have made it possible to improve patient outcomes in radiotherapy, sparing both normal tissues and increasing tumour control. However, these advancements have resulted in an increase in the number of software systems used, which each require data inputs to function. For institutions with multiple vendors for their treatment planning systems and oncology information systems, the transfer of data between them is potentially error prone and can lead to treatment errors. PURPOSE: The goal of this work was to determine the frequency of errors in data transfers between the Varian Eclipse treatment planning system and the Elekta Mosaiq oncology information system. METHODS: An in-house program was used to quantify the number of errors for 2700 unique plans over an 8-month period. Using this information, the frequency of the errors were calculated. A risk priority number was calculated using the calculated frequencies to determine the impact on the clinic. RESULTS: The most common errors discovered were backup timer settings (10.7%), Field label (8.5%), DRR associations (3.3%), imaging field types (3.1%), dose rate (1%), Field Id (0.8%), imaging isocenter (0.7% and SSD (0.7%). Based on the risk priority numbers, the DRR association error was ranked as having the highest potential impact on the patient. CONCLUSIONS: The results of the work show that the most effort should be focused on checking the manual steps performed in the transfer process, while items that are imported directly from DICOM-RT without modification are highly likely to be transferred accurately. The data can be used to help guide the implementation of future automated tools and process improvement in the clinic.

Within-Person Longitudinal Associations Between Electronic Nicotine Delivery Systems Use and Smoking Cessation Efforts Among US Continuing Adult Cigarette Smokers.

OBJECTIVES: Prior studies that examined the role of electronic nicotine delivery systems (ENDS) use in smoking cessation have shown divergent conclusions. This study examined the time-course of ENDS-associated smoking abstinent behaviors among continuing cigarette smokers who were willing but unable to quit smoking. METHODS: Data were drawn from the four waves of the Population Assessment of Tobacco and Health Study. Of the 1684 smokers who tried to quit smoking completely at Wave 1, a total of 1094 who were continuing smokers until Wave 4 and were not lost to follow-ups comprised the sample. Using generalized linear mixed modeling, we fitted weighted negative binomial regression models to examine within-person associations of ENDS use with quit attempts and number of days abstinent from smoking. RESULTS: Quit attempt frequency and smoking abstinent days were highest at Wave 1, dropped at Wave 2, and then either increased a little or remained stagnant in later waves. ENDS use to quit smoking was associated with more frequent quit attempts (aIRR = 1.67, 95% CI = 1.42-1.95) and more abstinent days (aIRR = 3.28, 95% CI = 2.43-4.44), and the magnitude of such associations became stronger over time. ENDS use was associated with becoming a nondaily smoker among baseline daily smokers. CONCLUSIONS: ENDS use among continuing smokers may help increase the number of quit attempts and smoking abstinent days. Given that the study sample is continuing smokers who failed in complete smoking cessation, future research would be desirable that evaluates whether such abstinent behaviors sustain and manifest harm reduction with improved health outcomes. IMPLICATIONS: Smokers increasingly adopt electronic nicotine delivery systems (ENDS) to quit smoking. However, the association of ENDS use with smoking cessation efforts among continuing cigarette smokers who were willing but unable to quit smoking is largely unknown. This study found that quit attempts and smoking abstinent days increased with ENDS use to quit smoking by following up with population-representative continuing smokers. Additionally, this study assessed whether cigarette smokers' abstinent behaviors vary with their use of ENDS by estimating within-person associations with frequent assessments of both exposures and outcomes in a long-term perspective.

Optomechanical engineering of quasi-continuous-wave background in mode-locked fiber laser.

Noise-like quasi-continuous-wave background (qCWB) in a mode-locked fiber laser mediates various multi-pulse dynamics via long-range inter-pulse interactions. This raises a possibility to control multi-pulse phenomena through manipulation of the qCWB, while it has been rarely studied yet. Here, we investigate the qCWB engineering by imposing optomechanically induced impulsive intensity modulations on the qCWB. The mode-locked pulses excite electrostrictively several transverse acoustic resonance modes inside the fiber cavity, which eventually leads to the formation of sharp qCWB modulations regularly spaced in the time domain. In particular, we experimentally demonstrate that the characteristics of the optomechanical qCWB modulations can be adjusted by controlling the in-fiber optomechanical interactions via changing the structure of the fiber core, cladding, and coating. Our observations are supported by directly measured forward stimulated Brillouin scattering spectra of the intracavity fibers.

The effectiveness and safety of local pleural anesthesia for pain control in patients undergoing CT-guided transthoracic needle biopsy.

OBJECTIVES: To evaluate the effectiveness and safety of pleural anesthesia for CT-guided transthoracic needle biopsy (TNB). METHODS: This retrospective study was performed between March 2019 and August 2019 in a tertiary care hospital. Patients undergoing CT-guided TNB received either (a) pleural and skin anesthesia (pleural anesthesia group) or (b) skin anesthesia only (skin anesthesia group). Pain score was reported on a 0-5 numeric rating scale, and pain scores 3-5 were classified as significant pain. The relationship between pleural anesthesia and pain score, significant pain, and pneumothorax was assessed by using multivariable linear and logistic regression models. RESULTS: A total of 111 patients (67 men, 66.0 ± 11.4 years) were included (pleural anesthesia group, 38; skin anesthesia group, 73). Pleural anesthesia group reported lower pain score (1.4 ± 1.0 vs. 2.3 ± 1.1, p < 0.001) and less frequent significant pain (18.4% [7/38] vs. 42.5% [31/73], p = 0.020) than skin anesthesia group. Pain score was negatively associated with pleural anesthesia (ß = -0.93, p < 0.001) and positively associated with procedure time (ß = 0.06, p < 0.001). Significant pain was negatively associated with pleural anesthesia (p = 0.004, adjusted odds ratio [OR] = 0.21 [95% confidence interval: 0.07, 0.61]) and positively associated with procedure time (p < 0.001, adjusted OR = 1.15 [95% confidence interval: 1.07, 1.24]). Pleural anesthesia was not associated with pneumothorax or chest tube placement (p = 0.806 and 0.291, respectively). CONCLUSION: Pleural anesthesia reduces subjective pain without increasing the risk of pneumothorax. KEY POINTS: • Local pleural anesthesia is a simple method that can be added to the conventional skin anesthesia for CT-guided transthoracic needle biopsy. • The addition of local pleural anesthesia can effectively reduce pain compared to the conventional skin anesthesia method. • This procedure is not associated with an increased risk of pneumothorax or chest tube placement.

Identifying emerging predictors for adolescent electronic nicotine delivery systems use: A machine learning analysis of the Population Assessment of Tobacco and Health Study.

Intervention strategies to prevent adolescents from using electronic nicotine delivery systems (ENDS) should be based on robust predictors of ENDS use that may differ from predictors of conventional cigarette use. Literature points to the need for uncovering emerging predictors of ENDS use. This study identified emerging predictors of adolescent ENDS use using machine learning (ML) techniques. We analyzed nationally representative multi-wave longitudinal survey data (2013-2018) drawn from the Population Assessment of Tobacco and Health Study. A sample of adolescents (12-17 years) who never used any tobacco products at baseline and completed Wave 2 (n = 7958), Wave 3 (n = 6260) and Wave 4 (n = 4544) were analyzed. We developed a supervised ML prediction model using the penalized logistic regression to assess self-reported past-month ENDS use (i.e., current use) at Waves 2-4 based on the variables measured at the previous wave. We then extracted important predictors from each model. The penalized logistic regression models showed suitable capability to discriminate between ENDS uses and non-uses at each wave based on the area under the receiver operating characteristic curve and the area under the precision-recall curve. Interestingly, social media use emerged as an important variable in predicting adolescent ENDS use. ML models appear to be a promising method to identify unique population-level predictors for U.S. adolescent ENDS use behaviors. More research is warranted to investigate emerging predictors of ENDS use and experimentally examine the mechanism by which these emerging predictors affect ENDS use behavior across different spectrum of populations.

Neur1 and Neur2 are required for hippocampus-dependent spatial memory and synaptic plasticity.

Neur1 and Neur2, mouse homologs of the Drosophila neur gene, consist of two neuralized homology repeat domains and a RING domain. Both Neur1 and Neur2 are expressed in the whole adult brain and encode E3 ubiquitin ligases, which play a crucial role in the Notch signaling pathways. A previous study reported that overexpression of Neur1 enhances hippocampus-dependent memory, whereas the role of Neur2 remains largely unknown. Here, we aimed to elucidate the respective roles of Neur1 and Neur2 in hippocampus-dependent memory using three lines of genetically modified mice: Neur1 knock-out, Neur2 knock-out, and Neur1 and Neur2 double knock-out (D-KO). Our results showed that spatial memory was impaired when both Neur1 and Neur2 were deleted, but not in the individual knock-out of either Neur1 or Neur2. In addition, basal synaptic properties estimated by input-output relationships and paired-pulse facilitation did not change, but a form of long-term potentiation that requires protein synthesis was specifically impaired in the D-KO mice. These results collectively suggest that Neur1 and Neur2 are crucially involved in hippocampus-dependent spatial memory and synaptic plasticity.

Using machine learning to predict opioid misuse among U.S. adolescents.

This study evaluated prediction performance of three different machine learning (ML) techniques in predicting opioid misuse among U.S. adolescents. Data were drawn from the 2015-2017 National Survey on Drug Use and Health (N = 41,579 adolescents, ages 12-17 years) and analyzed in 2019. Prediction models were developed using three ML algorithms, including artificial neural networks, distributed random forest, and gradient boosting machine. The performance of the ML prediction models was compared with performance of the penalized logistic regression. The area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC) were used as metrics of prediction performance. We used the AUPRC as the primary measure of prediction performance given that it is considered more informative for assessing binary classifiers on imbalanced outcome variable than AUROC. The overall rate of opioid misuse among U.S. adolescents was 3.7% (n = 1521). Prediction performance was similar across the four models (AUROC values range from 0.809 to 0.815). In terms of the AUPRC, the distributed random forest showed the best performance in prediction (0.172) followed by penalized logistic regression (0.162), gradient boosting machine (0.160), and artificial neural networks (0.157). Findings suggest that machine learning techniques can be a promising technique especially in the prediction of outcomes with rare cases (i.e., when the binary outcome variable is heavily lopsided) such as adolescent opioid misuse.

Predicting opioid misuse at the population level is different from identifying opioid misuse in individual patients.

Tumin and Bhalla mentioned challenges associated with the use of population-based survey and machine learning (ML) results on adolescent opioid misuse to clinical settings. In a clinical setting, medical providers do know patient's identity. So, it is not surprising that drug misuse is rarely identified through patient's self-report especially if it involves illicit drug. Even though self-report is susceptible to bias, it is a valid and affordable tool to gather data on illicit drug use at the population level. Use of audio computer-assisted self-interviewing (ACASI) and computer-assisted personal interviewing (CAPI) in NSDUH provides the respondent with a highly private and confidential mode for responding to questions, which helps increase the level of honest reporting of illicit drug use and other sensitive behaviors. As acknowledged in the paper, opioid misuse should not be inferred at the individual level from our ML models. Such interpretations may lead to ecological fallacy. Predicting opioid misuse at the population level is different from identifying opioid misuse in individual patients. Nonetheless, we believe that coordinated multisectoral collaborations that leverage the expertise and resources of both public health and clinical sectors would offer a promising model for addressing the opioid crisis.