Kappa-opioid receptor antagonism in the nucleus accumbens shell distinguishes escalated alcohol consumption and negative affective-like behavior from physiological withdrawal in alcohol-dependence.

Alcohol use disorder (AUD) is a chronic relapsing disease that is deleterious at individual, familial, and societal levels. Although AUD is one of the highest preventable causes of death in the USA, therapies for the treatment of AUD are not sufficient given the heterogeneity of the disorder and the limited number of approved medications. To provide better pharmacological strategies, it is important to understand the neurological underpinnings of AUD. Evidence implicates the endogenous dynorphin (DYN)/κ-opioid receptor (KOR) system recruitment in dysphoric and negative emotional states in AUD to promote maladaptive behavioral regulation. The nucleus accumbens shell (AcbSh), mediating motivational and emotional processes that is a component of the mesolimbic dopamine system and the extended amygdala, is an important site related to alcohol's reinforcing actions (both positive and negative) and neuroadaptations in the AcbSh DYN/KOR system have been documented to induce maladaptive symptoms in AUD. We have previously shown that in other nodes of the extended amygdala, site-specific KOR antagonism can distinguish different symptoms of alcohol dependence and withdrawal. In the current study, we examined the role of the KOR signaling in the AcbSh of male Wistar rats in operant alcohol self-administration, measures of negative affective-like behavior, and physiological symptoms during acute alcohol withdrawal in alcohol-dependence. To induce alcohol dependence, rats were exposed to chronic intermittent ethanol vapor for 14 h/day for three months, during which stable escalation of alcohol self-administration was achieved and pharmacological AcbSh KOR antagonism ensued. The results showed that AcbSh KOR antagonism significantly reduced escalated alcohol intake and negative affective-like states but did not alter somatic symptoms of withdrawal. Understanding the relative contribution of these different drivers is important to understand and inform therapeutic efficacy approaches in alcohol dependence and further emphasis the importance of the KOR/DYN system as a target for AUD therapeutics.

Fatty Liver Education Promotes Physical Activity in Vulnerable Groups, Including Those With Unhealthy Alcohol Use.

BACKGROUND AND AIMS: Fatty liver disease (FLD), alcohol-associated and metabolically associated, often coexists. Increase in physical activity is associated with metabolic health and decreased FLD. We aimed to identify factors associated with physical activity and its improvement following FLD education in a racially diverse, vulnerable population. METHODS: From February 19, 2020 to December 30, 2022, 314 adults with FLD at safety-net hepatology clinics in San Francisco were surveyed at baseline, immediately after FLD education, and at 6-month follow-up. After collecting clinical and sociodemographic data, logistic regression (adjusted for age, sex, and race/ethnicity) assessed factors associated with physical activity at baseline and its improvement following education. RESULTS: Participant characteristics in those without vs with any physical activity were median age 49 vs 55 years, 64% vs 56% female, 66% vs 53% Hispanic race/ethnicity, 75% vs 55% obese, and 30% vs 22% consumed heavy alcohol, respectively. On multivariable analysis, older age was the only significant factor associated with physical activity at baseline (relative risk ratio 1.37 per decade increase, 95% confidence interval [CI] 1.07-1.75). Hispanic (vs non-Hispanic) participants had a significantly higher odds of improvement in physical activity (vs no change) 6 months after education (odds ratio 2.36, 95% CI 1.27-4.39). Among those with suboptimal or no physical activity at baseline, participants who consumed heavy alcohol (vs no drinking) had a significantly higher likelihood of achieving optimal physical activity following education (relative risk ratio 1.98, 95% CI 1.05-3.74). CONCLUSION: Despite social and structural barriers, FLD education increased uptake of physical activity in vulnerable populations, especially among Hispanic individuals and those consuming heavy alcohol. Implementation of patient-centered education is important for FLD management.

Bio-Based Epoxy Vitrimers with Excellent Properties of Self-Healing, Recyclability, and Welding.

The development of more recyclable materials is a key requirement for a transition towards a more circular economy. Thanks to exchange reactions, vitrimer, an attractive alternative for recyclable materials, is an innovative class of polymers that is able to change its topology without decreasing its connectivity. In this work, a bisphenol compound (VP) was prepared from saturated cardanol, i.e., 3-pentadecylphenol and vanillyl alcohol. Then, VP was epoxidized to obtain epoxide (VPGE). Finally, VPGE and citric acid (CA) were polymerized in the presence of catalyst TBD to prepare a fully bio-based vitrimer based on transesterification. The results from differential scanning calorimetry (DSC) showed that the VPGE/CA system could be crosslinked at around 163 °C. The cardanol-derived vitrimers had good network rearrangement properties. Meanwhile, because of the dynamic structural elements in the network, the material was endowed with excellent self-healing, welding, and recyclability.

Enhancing the Biodegradability, Water Solubility, and Thermal Properties of Polyvinyl Alcohol through Natural Polymer Blending: An Approach toward Sustainable Polymer Applications.

The escalating environmental crisis posed by single-use plastics underscores the urgent need for sustainable alternatives. This study provides an approach to introduce biodegradable polymer blends by blending synthetic polyvinyl alcohol (PVA) with natural polymers-corn starch (CS) and hydroxypropyl methylcellulose (HPMC)-to address this challenge. Through a comprehensive analysis, including of the structure, mechanical strength, water solubility, biodegradability, and thermal properties, we investigated the enhanced performance of PVA-CS and PVA-HPMC blends over conventional polymers. Scanning electron microscopy (SEM) findings of pure PVA and its blends were studied, and we found a complete homogeneity between the PVA and both types of natural polymers in the case of a high concentration of PVA, whereas at lower concentration of PVA, some granules of CS and HMPC appear in the SEM. Blending corn starch (CS) with PVA significantly boosts its biodegradability in soil environments, since adding starch of 50 w/w duplicates the rate of PVA biodegradation. Incorporating hydroxypropyl methylcellulose (HPMC) with PVA not only improves water solubility but also enhances biodegradation rates, as the addition of HPMC increases the biodegradation of pure PVA from 10 to 100% and raises the water solubility from 80 to 100%, highlighting the significant acceleration of the biodegradation process and water solubility caused by HPMC addition, making these blends suitable for a wide range of applications, from packaging and agricultural films to biomedical engineering. The thermal properties of pure PVA and its blends with natural were studied using diffraction scanning calorimetry (DSC). It is found that the glass transition temperature (Tg) increases after adding natural polymers to PVA, referring to an improvement in the molecular weight and intermolecular interactions between blend molecules. Moreover, the amorphous structure of natural polymers makes the melting temperature ™ lessen after adding natural polymer, so the blends require lower temperature to remelt and be recycled again. For the mechanical properties, both types of natural polymer decrease the tensile strength and elongation at break, which overall weakens the mechanical properties of PVA. Our findings offer a promising pathway for the development of environmentally friendly polymers that do not compromise on performance, marking a significant step forward in polymer science's contribution to sustainability. This work presents detailed experimental and theoretical insights into novel polymerization methods and the utilization of biological strategies for advanced material design.

Sustainable Electrically Conductive Bio-Based Composites via Radical-Induced Cationic Frontal Photopolymerization.

Diglycidylether of vanillyl alcohol (DGEVA), in combination with mechanically recycled carbon fibers (RCFs), was used to make, via Radical-Induced Cationic Frontal Photopolymerization (RICFP), fully sustainable and bio-based conductive composites with good electrical conductivity and consequent Joule effect proprieties. Three different fiber lengths, using three different sieve sizes during the mechanical recycling process (0.2, 0.5, and 2.0 mm), were used in five different amounts (ranging from 1 to 25 phr). The samples were first characterized by dynamic mechanical thermal analysis (DMTA), followed byelectrical conductivity and Joule heating tests. More specifically, the mechanical properties of the composites increased when increasing fiber content. Furthermore, the composites obtained with the longest fibers showed the highest electrical conductivity, reaching a maximum of 11 S/m, due to their higher aspect ratio. In this context, the temperature reached by Joule effect was directly related to the electrical conductivity, and was able to reach an average and maximum temperatures of 80 °C and 120 °C, respectively, just by applying 6 V.

Impact of sugar and sugar alcohol on the pasting and retrogradation properties of starch with distinct molecular structures.

The molecular structures of starch and sugar/sugar alcohol are recognized as critical determinants of starch pasting and retrogradation properties. However, their combined effects on these properties remain elusive. This study for the first time examined the pasting and retrogradation properties of nine starches with diverse molecular structures, both with and without the addition of glucose, sucrose, isomaltose, isomalt, and sorbitol. The presence of sugar/sugar alcohol significantly enhanced starch pasting viscosity. In particular, the variations of the peak viscosity of wheat starch were more pronounced than other starches, possibly due to its distinct molecular structures. The changes in melting temperatures and enthalpy of retrograded starches were complex, varying depending on the type of starch and sugar/sugar alcohol used. For example, the melting peak temperature ranged from 56.45 °C (TS) to 61.9 °C (WMS), and the melting enthalpy ranged from 0.16 J/g (TS) to 5.6 J/g (PES). The micromorphology of retrograded starch revealed agglomeration and needle-like structures, instead of a network structure, after the addition of glucose and sorbitol, respectively. Correlations between starch molecular structure and pasting properties remained largely unchanged, while the relationship between starch molecular structure and retrogradation properties exhibited notable variations after the addition of sugars or sugar alcohols. These findings help a better understanding of the effects of starch molecular structure and the presence of sugar/sugar alcohol on starch pasting and retrogradation properties.

Student experiences in a novel interprofessional neurodevelopmental clinic: a qualitative study.

BACKGROUND: Student-led clinics can provide low-cost speciality care and practical interprofessional education (IPE) opportunities. In Australia, there are currently limited speciality services available that provide neurodevelopmental assessments that consider fetal alcohol spectrum disorder (FASD) as one possible outcome. The aim of the current study was to understand student experiences in a novel interprofessional student-led clinic for children and adolescents with suspected or confirmed prenatal alcohol exposure. METHOD: Seventeen allied health university students (11 occupational therapy; 6 psychology) participated in individual semi-structured interviews following completion of a 10-week clinic placement. Reflexive thematic analysis was undertaken using NVivo12. RESULTS: Four main themes were generated: (1) Interprofessional practice a key for students' development as future healthcare professionals; (2) Meaningful relationships and students' belief they made a difference; (3) Novel challenges tested students' capabilities on placement; and (4) Supervisor attitude and approach to learning supported student development. CONCLUSIONS: The current study demonstrated that the interprofessional student-led neurodevelopmental clinic provided a valuable IPE opportunity for students.

Mild-moderate alcohol consumption and diabetes are associated with liver fibrosis in patients with biopsy-proven MASLD.

Background: It is unclear whether patients with metabolic dysfunction-associated steatotic liver disease (MASLD) are allowed variable low levels of alcohol. This study aimed to evaluate the effect of mild-moderate alcohol consumption on the biochemical and histological characteristics of patients with MASLD. Methods: Alcohol consumption was assessed in 713 patients with steatotic liver disease (SLD) who underwent liver biopsy. Non-drinking, mild-moderate drinking, and excessive drinking were defined as 0 g/day, 1-<20 g/day, and >20 g/day for women and 0 g/day, 1-<30 g/day, and >30 g/day for men, respectively. Liver biopsies were scored according to the NASH CRN system. Results: A total of 713 participants (median age 39.0 years and 77.1% male) with biopsy-proven SLD were enrolled, including 239 nondrinkers, 269 mild-moderate drinkers and 205 excessive drinkers. Excessive drinking was associated with increased risks for lobular inflammation and liver fibrosis compared to nondrinkers and mild-moderate drinkers. Compared with non-drinkers, mild-moderate drinkers had significantly lower odds for steatosis (OR = 0.60, 95% CI = 0.38-0.93, p = 0.025), hepatocellular ballooning (OR = 0.52, 95% CI = 0.29-0.91, p = 0.020) and fibrosis (OR = 0.50, 95% CI = 0.31-0.81, p = 0.005). However, in non-excessive drinkers with type 2 diabetes mellitus (T2DM), there was no association between mild-moderate alcohol consumption and liver fibrosis (OR = 0.562, 95% CI = 0.207-1.530, p = 0.257). Conclusions: Mild-moderate alcohol consumption might be protective against liver fibrosis in MASLD patients, which is modified by the presence of T2DM. However, further longitudinal studies are needed to determine the effect of ongoing alcohol consumption on disease severity.

Predictive factors of cognitive impairment in alcohol use disorder inpatients.

BACKGROUND: Cognitive impairments are common in patients with AUD and worsen the prognosis of addiction management. There are no clear guidelines for screening cognitive impairments in hospitalized patients with AUD. METHODS: Fifty-seven patients with an AUD history who were admitted to an acute hospital and assessed by the addiction care team were included. Those patients were screened for cognitive impairments using the Montreal Cognitive Assessment (MoCA) test. We collected clinical information regarding addiction history, comorbidities, and current treatments. Chi-square tests, t-tests, and Mann-Whitney tests were performed to determine factors associated with a pathological MoCA score (<26). RESULTS: A pathological MoCA score was positively associated with spatial-temporal disorientation, difficulty in recalling addiction history, patient underreporting of AUD and a date of last alcohol consumption lower than 11 days ago, and negatively associated with a reason for hospitalization due to alcohol-related health issues. No medication was associated with cognitive impairments. CONCLUSIONS: Clinical elements from assessment by the addiction care team allow for relevant indication for screening cognitive impairments.

Phosphatidylethanol is a promising tool for screening alcohol consumption during pregnancy.

BACKGROUND: Prenatal alcohol exposure (PAE) is one of the leading causes of preventable developmental disabilities. A lack of objective screening methods results in an under-recognition of the phenomenon. Phosphatidylethanol (PEth) is a specific ethanol biomarker that reveals alcohol intake up to several weeks after alcohol use. So far, PEth has mostly been a tool for detecting moderate and heavy drinking. With lower PEth cut-offs, revealing even minor prenatal alcohol consumption is possible. We aimed to find out if a sensitive method for PEth analysis would give additional information about PAE and to assess the cut-off value for a positive alcohol result in prenatal screening. METHODS: The study was an observational study of 3000 anonymous blood samples collected from the Helsinki University Hospital Diagnostic Center between June and September 2023. The Finnish Red Cross Blood Service received the samples originally for blood group typing and antibody screening as part of the prenatal blood screening program. We developed a sensitive PEth 16:0/18:1 analysis method using ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) equipment after liquid-liquid extraction of PEth from whole blood. The lower limit of quantification was 1 ng/mL. RESULTS: PEth was ≥2 ng/mL in 5.2% of the cases, ≥8 ng/mL in 2.0%, and ≥20 ng/mL in 1.0%. The detection time of PEth can be several weeks, especially with low PEth concentrations and after heavy alcohol consumption. It remained unknown whether the positive PEth tests resulted from drinking deliberately during pregnancy or before pregnancy recognition. CONCLUSIONS: We suggest adding PEth 16:0/18:1 to a routine prenatal blood screening program with a cut-off of 2 ng/mL-and in positive cases, clinical evaluation and retesting in 2-4 weeks. In clinical settings, information on gestational week and alcohol consumption before pregnancy is relevant and needs to be considered when interpreting low PEth concentrations.

Smoking, Alcohol Consumption, and Risk of Arterial Stiffness: A Two-Sample Mendelian Randomization Study.

Background: While observational studies have demonstrated connections between cigarette smoking, alcohol consumption, and arterial stiffness, establishing a causal relationship has proven challenging because of potential confounding factors. To address this problem, we employed a two-sample Mendelian randomization approach. Methods: We selected genetic instruments for these risk factors from genome-wide association studies encompassing 3,383,199 individuals at the genome-wide significance level (p < 5 × 10 - 9 ). Arterial stiffness data were acquired from the UK Biobank, which included 127,121 participants. Our primary analysis utilized the inverse variance-weighted method to explore causality. To confirm our results' robustness, we conducted sensitivity analyses using Egger regression, the weighted median method, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO). Results: Our analysis revealed a significant association between genetic inclination to smoking initiation and an increase in the arterial stiffness index ( ß = 0.11; 95% confidence interval [CI], 0.06 to 0.16; p = 1.95 × 10 - 5 ). Additionally, there was a suggestive connection between genetically predicted number of cigarettes per day and the arterial stiffness index ( ß = 0.05; 95% CI, 5.25 × 10 - 4 to 0.10; p = 4.75 × 10 - 2 ). No causal relationships were observed between the genetically predicted age of smoking initiation, smoking cessation, or alcohol consumption and the risk of arterial stiffness index. Conclusions: This Mendelian randomization study indicates that smoking initiation is likely a causative risk factor for arterial stiffness. However, further research is needed to determine if the quantity of daily cigarettes directly contributes to arterial stiffness development. Regarding alcohol consumption, age of smoking initiation, and smoking cessation, there was insufficient evidence to establish causality.

Effects of storage time on flavor characteristics of bran-free fermented Baijiu by using electronic sensory, descriptive sensory analysis, GC × GC-MS, and ICP-MS.

By examining and analyzing bran-free fermented Baijiu (BFB) with varying storage periods (0-20 years), it was observed that the overall concentration of volatile compounds initially increases and subsequently decreases over time. Furthermore, BFB exhibited more kinds of long chain esters, higher concentration of acetals, and reduced furfural content. The process of cellaring can enhance the aged, sweet, and fruity aroma of BFB. 16 flavor compounds, including 1,1-diethoxyethane, ethyl dodecanoate, and ethyl hexadecanoate, can be used as markers for vintage BFB, and electronic sensory technology was capable of discerning BFB in different years. The results of redundancy analysis (RDA) showed a positive correlation between metals and aldehydes, esters, and ketones, while indicating a negative correlation with acids and alcohols. Al, Fe, and Ca underwent the most significant changes during storage period, and they were positively correlated with differential substances, such as benzaldehyde, vanillin, ethyl isovalerate, and ethyl palmitate (P < 0.01).

A month in review: longitudinal dynamics between daily PTSD symptom networks, affect, and drinking behaviors in female college students.

Introduction: Sexual victimization (SV) is common among college women, with approximately half of those who have experienced SV meeting criteria for posttraumatic stress disorder (PTSD) within a year. Both SV and PTSD are associated with alcohol misuse among college women, often explained by the self-medication hypothesis. Existing literature focuses on overall PTSD severity rather than potential day-to-day fluctuations in specific symptoms, which might play a crucial role in understanding alcohol misuse risk. Studies also examine only same-day or next-day associations between PTSD and drinking, neglecting the potential for longer-term changes. Methods: This study explores the short-term longitudinal stability and time-lagged predictive dynamics of PTSD symptoms, affect, and drinking behavior among 174 female college heavy episodic drinkers over four weeks. Participants were categorized into three groups: those with a history of SV and PTSD (n = 77), women with SV but without PTSD (n = 59), and women without prior trauma history (n = 38) to be able to examine differences by trauma exposure, and PTSD. We compared the longitudinal stability of PTSD symptom networks, affect (arousal, positive affect, and negative affect), and drinking behavior across groups. Support vector regression determined which PTSD symptom networks and affect best predict drinking behavior at specific time lags within a 0-7 day range. Results: The PTSD group showed higher longitudinal stability for PTSD symptom networks (adjusted ps <.049) and arousal (adjusted ps <.048), but lower stability for negative affect (adjusted p =.013) and drinking behavior, including alcohol cravings (adjusted p =.019) and consumption (adjusted ps =.012), compared to the comparison groups. This suggests individuals with PTSD have more stable symptoms and arousal levels but greater fluctuations in negative affect and alcohol-related behaviors. Secondary analysis revealed PTSD symptom networks optimally predicted alcohol cravings with a three-day time lag (r=.88, p <.001) and consumption with a four-day time lag (r=.82, p <.001). Discussion: These findings challenge assumptions regarding immediate effects of PTSD and affect on drinking behavior and underscore the need for therapeutic approaches that consider longer-range effects. Future research should expand on these findings by incorporating longer-range assessments and exploring a broader range of symptom interactions.

Effect of hyperuricemia on paroxysmal atrial fibrillation after catheter ablation and influence of alcohol consumption.

Background: Evidence regarding the association between hyperuricemia and arrhythmia recurrence after catheter ablation for paroxysmal atrial fibrillation (AF) is scarce. We investigated whether hyperuricemia predicts arrhythmia recurrence after catheter ablation for paroxysmal AF and the relationship between hyperuricemia and alcohol consumption in AF recurrence. Methods: Patients who underwent catheter ablation for paroxysmal AF were divided into the hyperuricemia (index serum uric acid [UA] >7.0 mg/dL; n = 114) and control (UA ≤7.0 mg/dL; n = 609) groups and were followed for a median of 24 (12-48) months after ablation. Results: The hyperuricemia group had more patients with an alcohol intake of ≥20 g/day (33.3% vs. 22.7%, p = .017) and a lower incidence of AF-free survival (p = .019). Similarly, those with an alcohol intake of ≥20 g/day had a lower incidence of AF-free survival than other patients. Multivariate Cox regression analysis revealed the following independent predictors of AF recurrence (adjusted hazard ratio, 95% confidence interval): hyperuricemia (1.64, 1.12-2.40), female gender (1.91, 1.36-2.67), brain natriuretic peptide level >100 pg/mL (1.59, 1.14-2.22), and alcohol consumption ≥20 g/day (1.49, 1.03-2.15) (all p < .05). In addition, causal mediation analysis revealed that alcohol consumption of ≥20 g/day directly affected AF recurrence, independent of hyperuricemia. Conclusions: Patients with hyperuricemia may be at a high risk of arrhythmia recurrence after catheter ablation for paroxysmal AF. Although high alcohol consumption may contribute to increased UA levels, the presence of hyperuricemia may independently predict AF recurrence.

Brain dynamics supported by a hierarchy of complex correlation patterns defining a robust functional architecture.

Functional magnetic resonance imaging (fMRI) provides insights into cognitive processes with significant clinical potential. However, delays in brain region communication and dynamic variations are often overlooked in functional network studies. We demonstrate that networks extracted from fMRI cross-correlation matrices, considering time lags between signals, show remarkable reliability when focusing on statistical distributions of network properties. This reveals a robust brain functional connectivity pattern, featuring a sparse backbone of strong 0-lag correlations and weaker links capturing coordination at various time delays. This dynamic yet stable network architecture is consistent across rats, marmosets, and humans, as well as in electroencephalogram (EEG) data, indicating potential universality in brain dynamics. Second-order properties of the dynamic functional network reveal a remarkably stable hierarchy of functional correlations in both group-level comparisons and test-retest analyses. Validation using alcohol use disorder fMRI data uncovers broader shifts in network properties than previously reported, demonstrating the potential of this method for identifying disease biomarkers.

ChatGPT-4: Alcohol use disorder responses.

BACKGROUND AND AIMS: Alcohol use disorder (AUD) is characterized by low levels of engagement with effective treatments. Enhancing awareness of AUD treatments and how to navigate the treatment system is crucial. Many individuals use online sources (e.g. search engines) for answers to health-related questions; web-based results include a mix of high- and low-quality information. Artificial intelligence may improve access to quality health information by providing concise, high-quality responses to complex health-related questions. This study evaluated the quality of ChatGPT-4 responses to AUD-related queries. METHOD: A comprehensive list of 64 AUD-related questions was developed through a combination of Google Trends analysis and expert consultation. ChatGPT-4 was prompted with each question, followed by a request to provide 3-5 peer-reviewed scientific citations supporting each response. Responses were evaluated for whether they were evidence-based, provided a referral and provided supporting documentation. RESULTS: ChatGPT-4 responded to all AUD-related queries, with 92.2% (59/64) of responses being fully evidence-based. Although only 12.5% (8/64) of responses included referrals to external resources, all responses (100%; 5/5) to location-specific ('near me') queries directed individuals to appropriate resources like the NIAAA Treatment Navigator. Most (85.9%; 55/64) responses to the follow-up question provided supporting documentation. CONCLUSIONS: ChatGPT-4 responds to alcohol use disorder-related questions with evidence-based information and supporting documentation. ChatGPT-4 could be promoted as a reasonable resource for those looking online for alcohol use disorder-related information.

On the rise or a return to pre-pandemic levels? A cross-sectional online survey on nicotine, alcohol, and illicit drug use among youth.

OBJECTIVES: The COVID-19 pandemic has had unprecedented and deteriorating effects on the mental health of adolescents and young adults. Various studies have described changes regarding substance abuse, but findings are conflicting. STUDY DESIGN: We conducted a cross-sectional online survey on nicotine, alcohol, and illicit drug use. METHODS: From March to May 2023, 502 participants aged 14-24 from a community-based sample completed the questionnaire. RESULTS: We found a general trend of declining or stable substance use during the first 2 years of the pandemic; however, in the third year (i.e., 2022), substance use returned to pre-pandemic levels or exceeded it. Compared with young adults (age 19-24), adolescents' (age 14-18) use increased more clearly. Participants who scored above the cut-off on screening measures for problematic substance use showed a more pronounced increase in the use of cigarettes and illicit drugs but not of alcohol. Higher alcohol consumption during lockdowns was associated with increased likelihood of current problematic alcohol (odds ratio [OR]: 3.03) and cannabis use (OR: 2.60). Furthermore, individuals who reported increased usage of one psychotropic substance during lockdowns were more likely to have increased their use of other substances as well (OR: 2.66-4.87). CONCLUSIONS: Although not optimally generalizable due to the retrospective online format and convenience sampling, our results support the notion that special attention ought to be paid to certain subgroups such as younger people and those who already exhibit problematic substance use during the pandemic. Following up on post-pandemic trends in substance use is crucial for developing prevention measures and targeted interventions.

Enamine Synthesis via Regiocontrolled 6-endo-dig and 5-exo-dig Tethered Carboamination of Propargylic Alcohols.

Enamines are versatile building blocks for the synthesis of biologically active compounds. Nevertheless, only a limited number of strategies have been reported for preparing trisubstituted enamines in a regio- and stereoselective manner. Herein, we report a regiocontrolled 6-endo and 5-exo tethered carboamination of propargylic alcohols for the synthesis of trisubstituted enamines. High regioselectivity was achieved through fine-tuning of the amine protecting group during the Pd-catalyzed carboamination. The introduced trifluoromethylated tether enables further stereoselective functionalizations, such as hydrogenation and fluorination.

Population Pharmacokinetics of Loxoprofen and its alcoholic metabolites in healthy Korean men.

BACKGROUND: Loxoprofen has been actively used clinically to relieve musculoskeletal pain and inflammatory symptoms. However, there are few reports on quantitative pharmacokinetic (PK) prediction tools and diversity analyzes for loxoprofen within populations. OBJECTIVES: The aim of this study was to identify effective covariates associated with explaining inter-individual PK variability through a population pharmacokinetic (Pop-PK) modeling approach for loxoprofen, and to provide a starting point for establishing scientific dosing regimens. METHOD: The bioequivalence PK results of loxoprofen performed on 52 healthy Korean men and the physiological and biochemical parameters derived from each individual were used as base data for the development of a Pop-PK model of loxoprofen. In order to simultaneously predict the PKs of the active form according to loxoprofen exposure, previously reported PK results of trans-alcohol loxoprofen, an active metabolite of loxoprofen, were used to expand the model. RESULTS: The Pop-PK profiles of loxoprofen were described in terms of the basic structure of a non-sequential two absorption with 2-disposition compartment, and for inter-individual PK variations, peripheral compartment volume of distribution could be correlated with body surface area (BSA), and central compartment clearance with creatinine clearance (CrCL) and albumin levels. As a result of the model simulation, the concentrations of loxoprofen and its alcoholic metabolites in plasma significantly decreased as CrCL and albumin levels increased and decreased, respectively. On the other hand, it was confirmed that the higher the BSA, the greater the distribution of loxoprofen to the periphery, and the minimum concentrations of loxoprofen and alcoholic metabolites in plasma in steady-state increased by approximately 1.78-2 times, while the fluctuation between maximum and minimum concentrations decreased. The results suggest that patients with large BSA, impaired renal function, and high serum albumin levels may have significantly higher plasma exposure to loxoprofen and trans-alcohol loxoprofen. It was also suggested that the potential side effects in the gastrointestinal system and various tissues and the level of exposure in plasma due to long-term application of loxoprofen in this patient group could be causally explained. CONCLUSION: This study provides a very useful starting point for a scientific precision medicine approach to loxoprofen by discovering effective covariates and establishing a quantitative model that can explain the diversity of loxoprofen PKs within the population. CLINICAL TRIAL REGISTRATION: The clinical study protocol used in this study was thoroughly reviewed and approved by the Institutional Review Board of the Institute of Bioequivalence and Bridging Study, Chonnam National University, Gwangju, Republic of Korea. The bioequivalence study permit numbers are as follows: 041113; 10.15.2004.