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Coitus interruptus – colloquially referred to as withdrawal – is an attempt at contraception wherein the penis is removed from the vagina prior to ejaculation, with ejaculation occurring somewhere outside the vagina. Although withdrawal can reduce the risk of pregnancy, it is less efficacious than methods such as consistent condom use and hormonal birth control. Consequently, it is of public health importance to identify sociocultural influences that either increase or decrease the likelihood of withdrawal as a contraceptive technique. Multiple content analyses have identified external ejaculation as common in popular pornography, yet no study appears to have assessed whether more frequent pornography consumption increases the likelihood of withdrawal behavior. Using national probability data, the present study examined whether pornography use and withdrawal were correlated among U.S. women aged 15–49. Women who consumed pornography more frequently were more likely to report using withdrawal as a contraceptive method than women who consumed pornography less frequently, but this association was moderated by perceptions of pornography’s utility and women’s marital status. Results are discussed through the lens of the sexual script acquisition, activation, application model (3AM) of sexual media socialization. [ABSTRACT FROM AUTHOR]

Background and purpose: GABAergic neurons in mouse ventral tegmental area (VTA) exhibit elevated activity during withdrawal following chronic ethanol exposure. While increased glutamatergic input and decreased GABAA receptor sensitivity have been implicated, the impact of inhibitory signaling in VTA GABA neurons has not been fully addressed. Experimental approach: We used electrophysiological and ultrastructural approaches to assess the impact of chronic intermittent ethanol vapour exposure in mice on GABAergic transmission in VTA GABA neurons during withdrawal. We used CRISPR/Cas9 ablation to mimic a somatodendritic adaptation involving the GABAB receptor (GABABR) in ethanol‐naïve mice to investigate its impact on anxiety‐related behaviour. Key results: The frequency of spontaneous inhibitory postsynaptic currents was reduced in VTA GABA neurons following chronic ethanol treatment and this was reversed by GABABR inhibition, suggesting chronic ethanol strengthens the GABABR‐dependent suppression of GABAergic input to VTA GABA neurons. Similarly, paired‐pulse depression of GABAA receptor‐dependent responses evoked by optogenetic stimulation of nucleus accumbens inputs from ethanol‐treated mice was reversed by GABABR inhibition. Somatodendritic currents evoked in VTA GABA neurons by GABABR activation were reduced following ethanol exposure, attributable to the suppression of GIRK (Kir3) channel activity. Mimicking this adaptation enhanced anxiety‐related behaviour in ethanol‐naïve mice. Conclusions and implications: Chronic ethanol weakens the GABAergic regulation of VTA GABA neurons in mice via pre‐ and postsynaptic mechanisms, likely contributing to their elevated activity during withdrawal and expression of anxiety‐related behaviour. As anxiety can promote relapse during abstinence, interventions targeting VTA GABA neuron excitability could represent new therapeutic strategies for treatment of alcohol use disorder. [ABSTRACT FROM AUTHOR]

Despite progress in smoking reduction in the past several decades, cigarette smoking remains a significant public health concern world-wide, with many smokers attempting but ultimately failing to maintain abstinence. However, little is known about how decision-making evolves in quitting smokers. Based on preregistered hypotheses and analysis plan (https://osf.io/yq5th), we examined the evolution of reinforcement learning (RL), a key component of decision-making, in smokers during acute and extended nicotine abstinence. In a longitudinal, within-subject design, we used a probabilistic reward task (PRT) to assess RL in twenty smokers who successfully refrained from smoking for at least 30 days. We evaluated changes in reward-based decision-making using signal-detection analysis and five RL models across three sessions during 30 days of nicotine abstinence. Contrary to our preregistered hypothesis, punishment sensitivity emerged as the only parameter that changed during smoking cessation. While it is plausible that some changes in task performance could be attributed to task repetition effects, we observed a clear impact of the Nicotine Withdrawal Syndrome (NWS) on RL, and a dynamic relationship between craving and reward and punishment sensitivity over time, suggesting a significant recalibration of cognitive processes during abstinence. In this context, the heightened sensitivity to negative outcomes observed at the last session (30 days after quitting) compared to the previous sessions, may be interpreted as a cognitive adaptation aimed at fostering long-term abstinence. While further studies are needed to clarify the mechanisms underlying punishment sensitivity during nicotine abstinence, these results highlight the need for personalized treatment approaches tailored to individual needs. [ABSTRACT FROM AUTHOR]

The N-methyl-D-aspartate (NMDA) glutamate receptor is a major target of ethanol, and it is implicated in learning and memory formation, and other cognitive functions. Glycine acts as a co-agonist for this receptor. We examined whether Org24598, a selective inhibitor of glycine transporter1 (GlyT1), affects ethanol withdrawal-induced deficits in recognition memory (Novel Object Recognition (NOR) task) and spatial memory (Barnes Maze (BM) task) in rats, and whether the NMDA receptor glycine site participates in this phenomenon. Male Wistar rats were habituated to NOR or BM tasks, and then received binge-like intragastric ethanol administration (5 days, 5 g/kg). After ethanol withdrawal, Org24598 (0.1, 0.3, and 0.6 mg/kg) was administered 30 min before NOR (day 10 of withdrawal) or the reversal learning phase of BM (day 11–13 of withdrawal) task. The expression of GluN1 and GluN2B subunits of NMDA receptors were measured in the perirhinal cortex (PRC) and hippocampus (HIP) after termination of NOR. In the BM task, a glycine antagonist, L-701,324 (5 mg/kg), was administered 30 min before Org24598 to confirm the involvement of the NMDA receptor glycine site in the effects of Org24598. Our study showed that binge-like ethanol administration induced recognition and spatial memory impairments after withdrawal in rats. Additionally, an up-regulation of GluN1 and GluN2B subunits of the NMDA receptor was observed in the HIP and PRC on day 11 of abstinence. Org24598 ameliorated memory loss and normalized the expression of these subunits. L-701,324 reversed the effect of Org24598. Thus, NMDA receptor glycine sites are important in ethanol withdrawal-induced memory impairments. [ABSTRACT FROM AUTHOR]

Background Materials and methods Results Conclusion The present study aims to assess the therapeutic potential of vitamin C (Vit C) on anxiety‐ and depressive‐like behavior induced by abstinence from chronic nicotine‐ethanol co‐exposure in adolescent male rats.Adolescent male rats were divided into seven experimental groups with ten rats as follows: 1) vehicle, 2) Nicotine (Nic)‐Ethanol (Eth): received Nic (2 mg/kg) and Eth (20%) in drinking water from 21 to 42 days of age, 3–5) Nic‐Eth‐Vit C 100/200/400: received Nic and Eth from 21 to 42 days of age and received Vit C 100/200/400 mg/kg from 43 to 63 days of age, 6) Nic‐Eth‐Bupropion (Bup)‐ Naloxone (Nal): received Nic and Eth from 21 to 42 days of age and received Bup and Nal from 43 to 63 days of age, and 7) Vit C 400 mg/kg: received Vit C 400 mg/kg from 43 to 63 days of age. Behavioral assessments were done by elevated plus maze (EPM), forced swimming test (FST), marble burring test (MBT), and open field tests (OFT). Furthermore, specific biochemical variables associated with oxidative, inflammatory, and serotonergic profiles were quantified.According to the obtained results, Nic and Eth induced anxiety and depression in treated rats. We showed that two higher doses of Vit C increases the active struggling time in FST and decreases both the time spent in the peripheral zone of OFT and the time spent in the closed arms of EPM. In addition, animals treated by Vit C buried less number of marbles in MBT compared to their control counterparts. Nic and Eth induced oxidative stress and inflammation in cortical tissues of treated rats. Biochemical parameters were improved in the Nic‐Eth group receiving Vit C 200/400 mg/kg and Bup‐Nal through establishing a balance between oxidant/anti‐oxidant and inflammatory/anti‐inflammatory mediators. In addition, serotonin level was increased, while Monoamine oxidase (MAO) activity was notably decreased.The present findings support the beneficial effect of Vit C on anxiety‐ and depressive‐like behavior induced by Nic‐Eth withdrawal through various mechanisms such as the promotion of antioxidant defense, suppression of inflammatory mediators, and enhancement of serotoninergic function. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the demographic data and resolved-relapse rates in clinical follow-up of patients whose antiseizure medications (ASM) were discontinued after a minimum of 2 years of seizure freedom. Methods: The files of 1985 patients followed in the epilepsy outpatient clinic were evaluated retrospectively. The inclusion criteria for patients were between 18 and 65 years old, followed up at an epilepsy outpatient clinic, and having discontinued ASM after at least 2 years of seizure freedom under the supervision of a neurologist. Results: A total of 56 patients were included in the study. The age of onset of seizures was 13.9±10.04 years, the age of onset of ASM was 15.87±9.69 years, and the age of quitting ASM was 24.58±11.54 years. The patients had a mean seizure-free period of 64.46±32.27 months before drug discontinuation and 43.73±38.87 months after drug discontinuation. The EEGs of 49 patients were normal in the EEGs performed after drug discontinuation, and seven patients had epileptiform discharges. Relapse was observed in 23.2% of patients after drug discontinuation. It was observed that 69% of the recurrences in 13 patients occurred within the first 2 months. Conclusion: Although seizure recurrence probability is highest during the first 2 months after ASM discontinuation, it is still possible 6 years later in adults with inactive epilepsy. The time window without seizures before ASM discontinuation and follow-up EEGs afterwards may help in the prediction of seizure recurrence. [ABSTRACT FROM AUTHOR]

Alcohol use disorder (AUD) poses a significant public health challenge. Individuals with AUD engage in chronic and excessive alcohol consumption, leading to cycles of intoxication, withdrawal, and craving behaviors. This review explores the involvement of the cortical amygdala (CoA), a cortical brain region that has primarily been examined in relation to olfactory behavior, in the expression of alcohol dependence and excessive alcohol drinking. While extensive research has identified the involvement of numerous brain regions in AUD, the CoA has emerged as a relatively understudied yet promising candidate for future study. The CoA plays a vital role in rewarding and aversive signaling and olfactory-related behaviors and has recently been shown to be involved in alcohol-dependent drinking in mice. The CoA projects directly to brain regions that are critically important for AUD, such as the central amygdala, bed nucleus of the stria terminalis, and basolateral amygdala. These projections may convey key modulatory signaling that drives excessive alcohol drinking in alcohol-dependent subjects. This review summarizes existing knowledge on the structure and connectivity of the CoA and its potential involvement in AUD. Understanding the contribution of this region to excessive drinking behavior could offer novel insights into the etiology of AUD and potential therapeutic targets. • The cortical amygdala is involved in alcohol-dependent drinking. • The cortical amygdala connects to key brain regions involved in alcohol use disorder. Increased the cortical amygdala activity during alcohol withdrawal in dependent subjects may enhance glutamatergic signaling to the central amygdala, bed nucleus of the stria terminalis and basolateral amygdala. [ABSTRACT FROM AUTHOR]

Background: Social impairment has long been associated with psychosis, but recently a more nuanced understanding of how relationships are impacted by psychosis is emerging, taking into account both positive social changes (e.g. improved relationships, increased empathy for others) as well as challenges (e.g. stigma, shame). Methods: Ten participants were recruited from two early intervention services to participate in semi-structured interviews pertaining to their lived experience of psychosis. Thematic analysis was conducted on data related to social experiences during and after psychosis. Results: Participants reported a wide spectrum of experiences. Social withdrawal was common and sometimes enacted to protect oneself or others. Some participants reported feelings of confusion, shame, and guilt, resulting in internalized stigma and making it difficult to navigate relationships, especially after an experience of psychosis. Many participants reported positive social changes, including new, more meaningful, and closer relationships. Discussion: Recovery and adaptation following psychosis is not a linear process, and signs of both distress and growth may occur in parallel. Likewise, social withdrawal and connection may take place simultaneously or successively. More attention should be paid in both research and practice to the myriad ways in which psychosis impacts relationships and how this matters to service users. [ABSTRACT FROM AUTHOR]

Smoking rates in schizophrenia are exceptionally high; however, cessation rates remain low with limited research on effective interventions. A critical component of intervention development is identifying the effects of abstinence that are most salient and therefore may contribute to lapse and relapse. We conducted a systematic review and meta-analysis of controlled laboratory studies investigating acute smoking abstinence effects among people with schizophrenia and schizoaffective disorder. This review is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. OVID (MEDLINE, EMBASE, PsycINFO) and PubMed databases were searched from inception until November 2023. We identified (k = 16) articles meeting inclusion criteria; all assessed smoking abstinence (ranging 2–120 h). Acute abstinence resulted in large increases in reward-oriented craving and moderate increases in relief-oriented craving; these effects were greater in studies with longer abstinence duration (high certainty). We also observed significant increases in negative affect and global withdrawal symptoms, as well as memory disruption (moderate certainty). Qualitative synthesis suggests restlessness, irritability, anxiety, and visuospatial working memory may be additionally impacted. Findings with respect to negative symptoms and movement were mixed. Reward-oriented craving may constitute a key target of smoking cessation interventions for people with schizophrenia. In addition, identification of pharmacological and psychosocial interventions that address abstinence-induced changes in relief-oriented craving, memory, negative affect, restlessness, irritability, and anxiety may strengthen treatment outcomes. [ABSTRACT FROM AUTHOR]

Objective: Antipsychotics remain the first‐line treatment for people diagnosed with psychotic disorders despite adverse effects which lead many people to stop their medication. Many stop without the support of the prescriber, who may fear relapse. The objective of this study is to better understand the process of withdrawal from antipsychotics, from the perspective of people taking antipsychotics. Design: Online survey. Methods: An international online survey elicited quantitative responses about pre‐withdrawal planning (560) and qualitative responses about what was helpful and unhelpful when withdrawing from antipsychotics (443). Responses came from users of antipsychotics in 29 countries. Results: Forty‐seven per cent did not consult their psychiatrist before discontinuing. Only 40% made preparations, most commonly making a plan, gathering information and informing family. The most frequently reported helpful factors were focussing on the benefits of getting off the drugs (including ending adverse effects and feeling more alive), information about withdrawal symptoms and how to withdraw safely, withdrawing slowly, and support from psychologists, counsellors and psychotherapists. The most common unhelpful factor was the psychiatrist/doctor, largely because of their lack of knowledge, refusal to support the patient's wishes and the threat or use of coercion. Conclusions: Evidence‐based, respectful, collaborative responses to patients' concerns about adverse effects and desires to withdraw would probably reduce relapse rates and improve long‐term outcomes. It would definitely help end pervasive breaching of the principle of informed consent and human rights legislation. [ABSTRACT FROM AUTHOR]

Objective Management of neonatal abstinence syndrome includes nonpharmacological interventions, but their effectiveness may not be verified before implemented. The objective of this study is to evaluate the effectiveness of a type of bassinet in the treatment of infants with neonatal abstinence syndrome. Study Design This is a retrospective observational cohort study. Study setting involved a 24-bed open-bay Level III neonatal intensive care unit located in a metropolitan academic trauma facility. Participant inclusion criteria involved prenatally opioid-exposed infants ≥ 35 weeks with confirmed maternal opioid urine toxicology, required pharmacological treatment for withdrawal symptoms, and were admitted to the neonatal intensive care unit. Three subsets of study participants were analyzed over three different time periods: Group 1 were infants admitted during 2019 without nonpharmacological intervention, Group 2 who were admitted from September 2021 to February 2022 and received nonpharmacological interventions, and Group 3 included those admitted from February 2022 to March 2023 who received the same interventions as Group 2 but were managed in bassinets being used in other local facilities for neonatal abstinence syndrome. Results Group 3 had significant increases in length of stay compared with Group 1 (p = 0.006) and Group 2 (p = 0.013). Group 3 had a significantly greater length of treatment than Group 1 (p = 0.041) and a significantly higher total mg/kg morphine exposure than Group 1 (p = 0.006). Conclusion Addition of the bassinet for nonpharmacological management of infants with neonatal abstinence syndrome appeared to prolong length of stay, length of treatment, and increase total mg/kg morphine exposure. As a retrospective nonrandomized study, weakness of low certainty of causality is of concern but findings strongly warrant further research before devices such as the bassinet used in this study are adopted for routine neonatal abstinence syndrome care. Key Points Special bassinets are promoted to enhance sleep and decrease agitation. Such bassinets may assist infants undergoing drug withdrawal. Study of the bassinet failed to show benefit to this population. [ABSTRACT FROM AUTHOR]

Background: Phenobarbital (PHB) has been shown to be an effective treatment of alcohol withdrawal syndrome (AWS), with multiple dosing strategies used (e.g., single-dose and symptom-triggered). Studies have often used tapered doses, typically following a front-loaded dose, despite PHB's long half-life which should lead to an ability to auto-taper. Objective: The purpose of this study was to compare clinical outcomes associated with two PHB dosing strategies (taper [T], no taper [NT]) for AWS. Methods: This retrospective cohort study compared adult patients admitted to the ICU from October 2017 to May 2019 who received an initial loading dose of PHB for AWS. The use of PHB was at the discretion of the clinician per our institutional guidelines. Prior to November 2018, patients were prescribed a PHB taper, while after this period, the taper was no longer recommended. The primary outcome was the proportion of patients requiring rescue PHB or adjunctive medications for AWS. Secondary outcomes included number of adjunctive agents used, prevalence of severe manifestations of AWS, ICU and hospital lengths of stay, and incidence of potentially significant drug interactions. Results: A total of 172 patients were included (T: n = 81, NT: n = 91). Baseline characteristics were similar between groups, including history of severe AWS and cumulative benzodiazepine dose pre-PHB. There was no difference in the primary outcome between groups (T: 70.4% vs NT: 59.3%, P = 0.152). The median number of adjunctive agents per patient, severe manifestations, and ICU and hospital length of stay did not differ between groups. Twenty-five patients (14.5%) had potentially significant drug interactions. Conclusion and Relevance: The use of a PHB loading dose without a taper may be comparable to a taper strategy on clinical outcomes. Prospective studies are needed to further delineate the optimal dose of PHB for AWS. [ABSTRACT FROM AUTHOR]

Morphinan antagonists, which block opioid effects at mu-opioid receptors, have been studied for their analgesic potential. Previous studies have suggested that these antagonists elicit analgesia with fewer adverse effects in the presence of the mutant mu-opioid receptor (MOR; S196A). However, introducing a mutant receptor for medical applications represents significant challenges. We hypothesize that binding a chemical compound to the MOR may elicit a comparable effect to the S196A mutation. Through high-throughput screening and structure-activity relationship studies, we identified a modulator, 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (BPRMU191), which confers agonistic properties to small-molecule morphinan antagonists, which induce G protein-dependent MOR activation. Co-application of BPRMU191 and morphinan antagonists resulted in MOR-dependent analgesia with diminished side effects, including gastrointestinal dysfunction, antinociceptive tolerance, and physical and psychological dependence. Combining BPRMU191 and morphinan antagonists could serve as a potential therapeutic strategy for severe pain with reduced adverse effects and provide an avenue for studying G protein-coupled receptor modulation. [Display omitted] • BPRMU191 exemplifies an antagonist-to-agonist modulator of mu-opioid receptor (MOR) • BPRMU191 converts opioid antagonists to G protein-biased agonists of MOR • BPRMU191 /opioid antagonist combination induces analgesia while minimizing side effects • Antagonist-to-agonist modulators of GPCRs display strong therapeutic potential Huang, Lin, and Ou et al. identified BPRMU191 , a small molecule that endows morphinan antagonists of mu-opioid receptor with agonistic properties, thereby activating the receptor and inducing analgesia. This work demonstrates an effective approach for modulating the activity of G protein-coupled receptors by small molecules that modulate the receptor conformation. [ABSTRACT FROM AUTHOR]

Introduction: Tobacco use is highly addictive and the leading cause of premature mortality in the world. Long-access nicotine self-administration procedures in rats closely model human smoking behavior. However, significant gaps remain in our understanding of sex differences in the development of dependence and relapse in adult rats. Methods: In the present study, we investigated operant responding for both nicotine and saline and the development of dependence in adult rats of both sexes. The rats had daily access to nicotine or saline for 6 h per day, 7 days per week. Dependence was assessed by evaluating precipitated and spontaneous somatic withdrawal signs, measuring locomotor activity in the small open field test, and assessing anxiety-like behavior in the large open field and elevated plus maze test. The sucrose preference test was used to determine if cessation of nicotine intake leads to anhedonia. It was also investigated if a period of forced abstinence affects nicotine-seeking behavior. Results: This study showed that nicotine intake is higher in females than in males when given daily long access to nicotine. Daily nicotine self-administration led to more precipitated and spontaneous somatic withdrawal signs compared to saline self-administration, with no sex differences observed. In addition, cessation of nicotine intake led to a similar increase in activity in both males and females in the small open field test. However, cessation of nicotine intake did not increase anxiety-like behavior or cause anhedonia in either males or females. A time course analysis revealed that the nicotinic acetylcholine receptor antagonist mecamylamine affected nicotine intake differently in males and females, increasing intake in males and decreasing intake in females. Three weeks of forced abstinence led to an increase in nicotine and saline-seeking behavior. The rats exhibited more nicotine than saline seeking, and the females displayed more nicotine seeking than the males. Discussion: The present findings demonstrate that females self-administer more nicotine and display more nicotine-seeking behavior than males. Furthermore, there were no sex differences in somatic withdrawal signs or activity during abstinence from nicotine. This work underscores the importance of considering sex differences across various aspects of addiction, including intake and relapse, when developing novel treatments for tobacco use disorder. [ABSTRACT FROM AUTHOR]

The reinforcement of drug-seeking motivation following drug withdrawal is recognized as a significant factor contributing to relapse. The ventral pallidum (VP) plays a crucial role in encoding and translating motivational aspects of reward. However, current research lacks a clear understanding of how the VP mediates drug-seeking motivation and the feedback modulation between the VP and the nucleus accumbens (NAc) following drug withdrawal. Therefore, utilizing a rat model of cocaine self-administration, we investigated the circuitry mechanisms underlying drug-seeking behavior post-drug withdrawal involving the NAc-VP pathway. Initially, we observed a significant enhancement in drug-seeking behavior 14 days after cocaine withdrawal. Subsequently, we identified the feedback mechanism through which the NAc-VP regulates this behavior. Immunofluorescence results indicated an increase in c-Fos expression levels in the ventral pallidum ventromedial (VPvm) and ventrolateral ventral pallidum (VPvl) following drug withdrawal. Calcium fiber photometry further elucidated that during the expression of high motivational drug-seeking behavior, there was a specific enhancement in VPvm neuronal activity, and retrograde tracing techniques suggested a weakened transmission function in the NAc-VPm pathway. Additionally, chemical genetic techniques demonstrated that inhibiting the activity of the NAc-VP pathway could increase the motivational level of drug-seeking behavior. These findings indicate that the reduced inhibitory function of the NAc-VP pathway following prolonged cocaine withdrawal forms the basis for heightened reactivity in VPvm neurons, thus regulating the expression of high motivational behavior triggered by drug-related cues. Our study results suggest that maintaining normal NAc-VP pathway functionality may decrease drug-seeking motivation post long-term drug withdrawal, offering new insights for interventions targeting relapse. [ABSTRACT FROM AUTHOR]

Opioid-seeking behaviors depend on glutamatergic plasticity in the nucleus accumbens core (NAcc). Here we investigated whether the behavioral and synaptic effects of opioids are influenced by acid-sensing ion channel 1A (ASIC1A). We tested the effects of ASIC1A on responses to several opioids and found that Asic1a−/− mice had elevated behavioral responses to acute opioid administration as well as opioid seeking behavior in conditioned place preference (CPP). Region-restricted restoration of ASIC1A in NAcc was sufficient to reduce opioid CPP, suggesting NAcc is an important site of action. We next tested the effects of oxycodone withdrawal on dendritic spines in NAcc. We found effects of oxycodone and ASIC1A that contrasted with changes previously described following cocaine withdrawal. Finally, we examined α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated and N-methyl-D-aspartic acid (NMDA) receptor-mediated synaptic currents in NAcc. Oxycodone withdrawal, like morphine withdrawal, increased the AMPAR/NMDAR ratio in Asic1a+/+ mice, whereas oxycodone withdrawal reduced the AMPAR/NMDAR ratio in Asic1a−/− mice. A single dose of oxycodone was sufficient to induce this paradoxical effect in Asic1a−/− mice, suggesting an increased sensitivity to oxycodone. We conclude that ASIC1A plays an important role in the behavioral and synaptic effects of opioids and may constitute a potential future target for developing novel therapies. [ABSTRACT FROM AUTHOR]

A preclinical model of human adolescent binge drinking, adolescent intermittent ethanol exposure (AIE) recreates the heavy binge withdrawal consummatory patterns of adolescents and has identified the loss of basal forebrain cholinergic neurons as a pathological hallmark of this model. Cholinergic neurons of the nucleus basalis magnocellularis (NbM) that innervate the prefrontal cortex (PFC) are particularly vulnerable to alcohol related neurodegeneration. Target derived neurotrophins (nerve growth factor [NGF] and brain-derived neurotrophic factor [BDNF]) regulate cholinergic phenotype expression and survival. Evidence from other disease models implicates the role of immature neurotrophin, or proneurotrophins, activity at neurotrophic receptors in promoting cholinergic degeneration; however, it has yet to be explored in adolescent binge drinking. We sought to characterize the pro- and mature neurotrophin expression, alongside their cognate receptors and cholinergic markers in an AIE model. Male and female Sprague Dawley rats underwent 5 g/kg 20% EtOH or water gavage on two-day-on, two-day-off cycles from post-natal day 25–57. Rats were sacrificed 2 h, 24 h, or 3 weeks following the last gavage, and tissue were collected for protein measurement. Western blot analyses revealed that ethanol intoxication reduced the expression of BDNF and vesicular acetylcholine transporter (vAChT) in the PFC, while NGF was lower in the NbM of AIE treated animals. During acute alcohol withdrawal, proNGF in the PFC was increased while proBDNF decreased, and in the NbM proBDNF increased while NGF decreased. During AIE abstinence, the expression of neurotrophins, their receptors, and vAChT did not differ from controls in the PFC. In contrast, in the NbM the expression of both NGF and choline acetyltransferase (ChAT) were reduced long-term following AIE. Taken together these findings suggest that AIE alters the expression of proneurotrophins and neurotrophins during intoxication and withdrawal that favor prodegenerative mechanisms by increasing the expression of proNGF and proBDNF, while also reducing NGF and BDNF. • Adolescent ethanol exposure causes neurotrophin dysregulation. • There is disruption in the ratio of proNGF to mature NGF. • Cholinergic markers are also impacted by adolescent intermittent ethanol exposure. • Changes in pro- and mature NGF contributes to alcohol-related brain damage in an adolescent model. [ABSTRACT FROM AUTHOR]

The impact of thiopurine de-escalation while on vedolizumab versus continuing thiopurine therapy in ulcerative colitis (UC) is unclear. We aimed to determine the effect of thiopurine withdrawal for patients with UC in remission on vedolizumab. This multicenter randomized controlled trial recruited UC patients on vedolizumab 300 mg intravenously every 8 weeks and a thiopurine. Patients in steroid-free clinical remission for ≥6 months and endoscopic remission/improvement (Mayo endoscopic subscore ≤1) were randomized 2:1 to withdraw or continue thiopurine. Primary outcome was comparing week 48 vedolizumab trough concentrations. Secondary outcomes were clinical relapse (partial Mayo score ≥3 and fecal calprotectin >150 μg/g or increase in Mayo endoscopic subscore ≥1 from baseline), fecal calprotectin remission (<150 μg/g), C-reactive protein remission (<5 mg/L), centrally read endoscopic remission (Mayo endoscopic subscore = 0), histologic remission (Nancy index = 0), histo-endoscopic remission, and adverse events. In total, 62 patients were randomized to continue (n = 20) or withdraw (n = 42) thiopurine. At week 48, vedolizumab trough concentrations were not significantly different between continue and withdrawal groups (14.7 μg/mL, interquartile rate [IQR], 12.3–18.5 μg/mL versus 15.9 μg/mL, IQR, 10.1–22.7 μg/mL, respectively, P = 0.36). The continue group had significantly higher fecal calprotectin remission (95.0%, 19/20 versus 71.4%, 30/42; P =.03), histologic remission (80.0%, 16/20 versus 48.6%, 18/37; P =.02), and histo-endoscopic remission (75.0%, 15/20 versus 32.4%, 12/37; P =.002) than the withdrawal group. Histologic activity (hazard ratio [HR], 15.5; 95% confidence interval [CI], 1.6–146.5; P =.02) and prior anti-tumor necrosis factor exposure (HR, 6.5; 95% CI, 1.3–33.8; P =.03) predicted clinical relapse after thiopurine withdrawal. Thiopurine withdrawal did not affect vedolizumab trough concentrations. However, it may increase fecal calprotectin, histologic, and histo-endoscopic activity. Histologic activity and prior anti-tumor necrosis factor exposure may predict disease relapse on thiopurine withdrawal for patients using vedolizumab for UC. Australian and New Zealand Trial Registry, number ACTRN12618000812291. [Display omitted] [ABSTRACT FROM AUTHOR]

This article studies new reports released by the U.S. and China press from 30 August to 2 September 2021 on the United States' troops withdrawing from Afghanistan, aiming at investigating the difference of ideologies towards the evacuation. Comparing how China Daily and U.S. News & World Report reported the withdrawal, the study finds out that invidious terminology isn't presented in the U.S. reports but repugnant terms are presented in China reports in the headlines. Moreover, the chaotic withdrawal is just Biden's failure and there is no mention of the death of Afghans at all in the U.S. press, while the withdrawal is the U.S. failure but also their so-called "war on terror" is pointless from the beginning, moreover the "America First" policy is implied in China reports. Taoist philosophy (Tao Te Ching) has been reflected in China reports. [ABSTRACT FROM AUTHOR]

What happens to companies that file for an initial public offering (IPO), but withdraw and do not list? How long does the post‐IPO outcome take? These questions are investigated by analysing market, firm and offer characteristics of 334 withdrawn IPOs in Europe between 2001 and 2015. The majority of withdrawn IPOs is engaged in M&A, only few file for a second time IPO. These post‐IPO withdrawal outcomes happen shortly after the IPO filing. Private equity and venture capital‐backed firms are more frequently engaging in M&A or trading. The evidence suggests that the IPO may be used as a marketing mechanism, being one of several alternatives of exit. [ABSTRACT FROM AUTHOR]

The issue of the worldwide COVID-19 pandemic led to raising concerns about mental health issues. Research showed that changes in daily routines and life circumstances have brought negative feelings like stress and anxiety. Many individuals had to adapt their workout routines to lockdowns and restrictions. Evidence suggests during abstinence periods individuals with exercise addiction may experience withdrawal effects. The present study aimed to explore the serial mediating roles of difficulties in emotion regulation and state anxiety on the relationship between fear of COVID-19 and withdrawal effects in individuals with problematic exercise behaviour. The data (N = 160) was obtained using validated self-report measurements including the Fear of COVID-19 Scale, Difficulties in Emotion Regulation Scale-16, State-Trait Inventory for Cognitive and Somatic Anxiety, and Exercise Dependence Scale-21. To test the proposed model, a number of mediation analyses were performed via PROCESS Macro by Hayes for SPSS 27.0. The findings showed that when individuals with problematic exercise behaviour had increased levels of fear of COVID-19, they were likely to have difficulties in emotion regulation and that difficulties led to state anxiety, turning into withdrawal effects s. However, the mediating effect disappeared when controlling for age. The limitations, implications, and recommendations for further studies were discussed. [ABSTRACT FROM AUTHOR]

Abstract Despite progress in smoking reduction in the past several decades, cigarette smoking remains a significant public health concern world-wide, with many smokers attempting but ultimately failing to maintain abstinence. However, little is known about how decision-making evolves in quitting smokers. Based on preregistered hypotheses and analysis plan ( https://osf.io/yq5th ), we examined the evolution of reinforcement learning (RL), a key component of decision-making, in smokers during acute and extended nicotine abstinence. In a longitudinal, within-subject design, we used a probabilistic reward task (PRT) to assess RL in twenty smokers who successfully refrained from smoking for at least 30 days. We evaluated changes in reward-based decision-making using signal-detection analysis and five RL models across three sessions during 30 days of nicotine abstinence. Contrary to our preregistered hypothesis, punishment sensitivity emerged as the only parameter that changed during smoking cessation. While it is plausible that some changes in task performance could be attributed to task repetition effects, we observed a clear impact of the Nicotine Withdrawal Syndrome (NWS) on RL, and a dynamic relationship between craving and reward and punishment sensitivity over time, suggesting a significant recalibration of cognitive processes during abstinence. In this context, the heightened sensitivity to negative outcomes observed at the last session (30 days after quitting) compared to the previous sessions, may be interpreted as a cognitive adaptation aimed at fostering long-term abstinence. While further studies are needed to clarify the mechanisms underlying punishment sensitivity during nicotine abstinence, these results highlight the need for personalized treatment approaches tailored to individual needs.

The management of sedation in critically ill adults poses a unique challenge to clinicians. Dexmedetomidine, an α2 agonist, has a unique mechanism and favorable pharmacokinetics, making it an attractive intravenous option for sedation and delirium in the intensive care unit. However, patients may be at risk for withdrawal with prolonged use, adding to the complexity of sedation and agitation management in this patient population. Enteral α2 agents have the benefit of cost savings and ease of administration, thus playing a role in the ability to decrease intravenous sedative use and prevent dexmedetomidine withdrawal. Clonidine and guanfacine are the two most common enteral α2 agents utilized for this purpose, however, there is a paucity of evidence regarding the comparative benefit between the two agents. The decision to use one vs the other agent should be determined based on their differing pharmacology, pharmacokinetics, and side effect profile. The most effective dosing strategy for these agents is also unknown. Ultimately, more robust literature is required to determine enteral α2 agonists place in therapy. This narrative review evaluates the currently available literature on the use of α2 agonists in critically ill adults with an emphasis on sedation, delirium, and withdrawal. [ABSTRACT FROM AUTHOR]

Modulating role of circRNAs and microRNAs in neurobiological changes induced by drug exposure remains unclear. We examined alterations in some circRNAs and microRNAs in the striatum after morphine dependence and withdrawal and their associations with the changes in spatial working memory performance. Male Wistar rats were used in which 10 days morphine exposure induced dependence. Withdrawal effects were assessed 30 days after stopping morphine exposure. Spatial working memory was assessed using a Y maze test on days 1 and 10 of the drug exposure and 30 days after withdrawal. The gene and protein expression were assessed after dependence and withdrawal. The results revealed that 10 days morphine exposure impaired working memory, which partially reinstated after withdrawal. After 10 days morphine exposure, significant increases in Oprm1 gene and OPRM1 protein levels were detected, which persisted even after withdrawal. The expression of circOprm1 and miR-339-3p decreased in the morphine-dependent group, but they returned to normal levels after withdrawal. The expression of Tlr4 gene and TLR4 protein levels decreased after dependence. While Tlr4 mRNA levels returned to normal after withdrawal, TLR4 protein levels remained lower than the control group. In the morphine-dependent group, both Serpini1 and circSerpini expression significantly increased, but they restored after withdrawal. Expression of miR-181b-3p, miR-181b-5p, miR-181c-3p, and miR-181c-5p decreased after dependence, but they reinstated after withdrawal. It can be concluded that circOprm1 and circSerpini via regulating the OPRM1 and TLR4 expression in the striatum are associated with the neuroadaptation underlying spatial working memory after both morphine dependence and withdrawal. [ABSTRACT FROM AUTHOR]

Background: Dependence on gamma-hydroxybutyrate (GHB) is an emerging substance use disorder which can be life-threatening in overdose and withdrawal. The aim of this study was to describe rising GHB-related hospitalizations amidst the ongoing COVID-19 pandemic. Methods: A retrospective consecutive case series of adults admitted to hospitals in South Western Sydney Local Health District was identified with clinical coding of GHB-related disorder between March 20 2019 and March 20 2021. Morbidity outcomes and multivariable Kaplan–Meier survival analysis on length of hospital stay were described. Results: Sixty-nine of 84 included admissions, (82%) occurred in the 12 months following COVID-19 related border closure. Of 47 admissions for withdrawal, fifteen of 47 (32%) required intensive care, 6 (13%) intubation, 4 (9%) one-to-one ward observation, and 8 (17%) emergency calls for agitated delirium, fall, or seizure. Five cofactors were associated with longer hospital stay in the multivariable analysis: age 30 or older (p <.05), 6 months of regular GHB use (p <.01), and elective admission (p <.05), and diagnosis of psychosis rather than withdrawal (p <.05) or overdose (p <.001). Conclusions: Development of a validated GHB withdrawal severity scale based on these risk factors could help identify patients requiring close monitoring for complicated withdrawal and escalation of care. [ABSTRACT FROM AUTHOR]

Abstract Taking the perspective of career choice as a lifelong, iterative, constructive, and agentic process, the present study focuses on the development of vocational aspirations of nursing trainees; that is, thoughts about a long-term perspective in nursing (i.e., persistence), ideas of finishing the training but changing into another profession after some time (i.e., withdrawal), and decisions to terminate the training before completing the programme through a final examination (i.e., dropout). In order to generate detailed insights about the dynamics behind the development of such aspirations during the initial training phase, a qualitative, longitudinal, within-subject study design based on grounded theory was employed. The results mainly show that social interactions with more experienced nurses, practical work experiences, encounters with environments that are either conducive to learning or not, the satisfaction of different needs (e.g., autonomy, competence, belonging, sense of meaningfulness), as well as the associated feelings of well-being affect how vocational aspirations develop over the first year of training. In addition, the study identifies four different patterns of how trainees typically oscillate between thoughts of staying in nursing and leaving the profession in the short or long run: (a) arriving and wanting to stay, (b) staying as a transitional passage, (c) seeking to stay, and (d) exiting as a knee-jerk reaction. The patterns present evidence of a variety of approaches regarding how trainees deal with certain experiences during their training and how the combination of experiences might affect young professionals’ subsequent career choices.

Abstract Background Chronic cigarette smokers report withdrawal symptomology, including affective dysfunction and cognitive deficits. While there are studies demonstrating sex specific withdrawal symptomology in nicotine-dependent individuals, literature examining the underlying biological mediators of this is scant and not in complete agreement. Therefore, in this study, we evaluated the sex specific effects of nicotine and withdrawal on contextual fear memory, a hippocampally dependent aspect of cognition that is disrupted in nicotine withdrawal. Methods Male and female B6/129F1 mice (8–13 weeks old) were used in all experiments. For the acute nicotine experiment, mice received intraperitoneal saline or nicotine (0.5 mg/kg) prior to contextual fear conditioning and test. For the chronic nicotine experiment, mice received nicotine (18 mg/kg/day) or saline for 11 days, then underwent contextual fear conditioning and test. Following the test, mice underwent minipump removal to elicit withdrawal or sham surgery, followed by the fear extinction assay. Bulk cortical tissue was used to determine nicotinic acetylcholine receptor levels via single point [3H]Epibatidine binding assay. Gene expression levels in the dorsal and ventral hippocampus were quantified via RT-PCR. Results We found that female mice had a stronger expression of contextual fear memory than their male counterparts. Further, following acute nicotine treatment, male, but not female, subjects demonstrated augmented contextual fear memory expression. In contrast, no significant effects of chronic nicotine treatment on fear conditioning were observed in either sex. When examining extinction of fear learning, we observed that female mice withdrawn from nicotine displayed impaired extinction learning, but no effect was observed in males. Nicotine withdrawal caused similar suppression of fosb, cfos, and bdnf, our proxy for neuronal activation and plasticity changes, in the dorsal and ventral hippocampus of both sexes. Additionally, we found that ventral hippocampus erbb4 expression, a gene implicated in smoking cessation outcomes, was elevated in both sexes following nicotine withdrawal. Conclusions Despite the similar impacts of nicotine withdrawal on gene expression levels, fosb, cfos, bdnf and erbb4 levels in the ventral hippocampus were predictive of delays in female extinction learning alone. This suggests sex specific dysfunction in hippocampal circuitry may contribute to female specific nicotine withdrawal induced deficits in extinction learning.

Abstract Objective This prospective study aimed to delineate the demographics, natural progression, and treatment response of patients newly diagnosed with epilepsy with generalized tonic–clonic seizures alone (EGTCA). Furthermore, our objective includes assessing the seizure recurrence rate post antiseizure medication (ASM) discontinuation within this cohort, alongside exploring predictive factors for seizure relapse. Methods The study cohort, derived from an ongoing, prospective, multicenter investigation on children and adults with new‐onset unprovoked seizures, included consecutive patients enrolled between March 2010 and March 2020, and meeting mandatory ILAE criteria for EGTCA diagnosis. Participants underwent a 3‐h sleep‐deprived video‐EEG recording along with an epilepsy protocol brain magnetic resonance imaging (MRI) with repeat EEG at each follow‐up. Cumulative time‐dependent probabilities of seizure recurrence were calculated using Kaplan–Meier survival analysis. Logistic regression identified variables associated with seizure recurrence following ASM taper. Results Eighty‐nine patients with a median age of 16 years were included, constituting 31% of those diagnosed with an idiopathic generalized epilepsy. Regarding the circadian distribution of seizures, 59.6% of patients exclusively experienced diurnal seizures, 12.4% exclusively nocturnal, and 28.1% experienced both diurnal and nocturnal seizures. Generalized spike–wave discharges (GSWD) were present in the initial EEG of 88% of patients. A GTC recurred in 14% of patients treated with ASM compared with 73% of untreated patients (p

Abstract The existing literature on withdrawal from foreign markets leaves several questions unanswered. We propose alignment between cohesive learning from failure and the intrinsic motivation to reemerge after failure. The study contends that failure is not considered an ultimate demise but as a precursor to new birth. Interviews with eight firms that faced withdrawal from international markets demonstrate the importance of failure as rivaling that of success and as cultivating self-efficacy. We conclude that learning from failure enhances the perceived ability to reemerge in international markets, and entrepreneurs recommit themselves to businesses with new perspectives.

Introduction: Cannabis is the second most widely-used substance in India, after alcohol. Several researches show how cannabis use can impair emotion recognition capacity, but relatively few researchers have explored this among cannabis abstainers. Aims: The present study’s authors aimed at assessing emotion recognition, emotion differentiation, self-reported anxiety, depression, stress, withdrawal intensity and impact in a sample of men who abstain from cannabis. Methods: Heavy cannabis users (N = 70 males) were assessed via questionnaires regarding their cannabis use frequency, their age at onset of usage, anxiety, depression, and stress levels as well as their performance on computerised tasks of emotion recognition and discrimination within 24 hours of their admission (T0), then after 15 days of abstinence (T1), and finally after 30 days of abstinence (T2). At T1 and T2, they were also assessed for withdrawal intensity and the impact of withdrawal on daily activities. Results: Findings revealed that, with abstinence, successive improvement in emotion recognition and emotion differentiation developed, even after accounting for declines in psychological distress from T0 to T1. However, from T1 to T2, further declines in psychological distress and withdrawal impact mainly accounted for this improvement. Happiness was the best recognised and well-differentiated emotion while the poorest discrimination was observed for anger. Conclusions: This study’s findings corroborate and significantly add to the limited existing literature, demonstrating improved emotion recognition and differentiation due to initial cannabis abstinence, but later this improvement proceeds with a decline in distress and withdrawal impact.

Background: Chronic cigarette smokers report withdrawal symptomology, including affective dysfunction and cognitive deficits. While there are studies demonstrating sex specific withdrawal symptomology in nicotine-dependent individuals, literature examining the underlying biological mediators of this is scant and not in complete agreement. Therefore, in this study, we evaluated the sex specific effects of nicotine and withdrawal on contextual fear memory, a hippocampally dependent aspect of cognition that is disrupted in nicotine withdrawal. Methods: Male and female B6/129F1 mice (8–13 weeks old) were used in all experiments. For the acute nicotine experiment, mice received intraperitoneal saline or nicotine (0.5 mg/kg) prior to contextual fear conditioning and test. For the chronic nicotine experiment, mice received nicotine (18 mg/kg/day) or saline for 11 days, then underwent contextual fear conditioning and test. Following the test, mice underwent minipump removal to elicit withdrawal or sham surgery, followed by the fear extinction assay. Bulk cortical tissue was used to determine nicotinic acetylcholine receptor levels via single point [3H]Epibatidine binding assay. Gene expression levels in the dorsal and ventral hippocampus were quantified via RT-PCR. Results: We found that female mice had a stronger expression of contextual fear memory than their male counterparts. Further, following acute nicotine treatment, male, but not female, subjects demonstrated augmented contextual fear memory expression. In contrast, no significant effects of chronic nicotine treatment on fear conditioning were observed in either sex. When examining extinction of fear learning, we observed that female mice withdrawn from nicotine displayed impaired extinction learning, but no effect was observed in males. Nicotine withdrawal caused similar suppression of fosb, cfos, and bdnf, our proxy for neuronal activation and plasticity changes, in the dorsal and ventral hippocampus of both sexes. Additionally, we found that ventral hippocampus erbb4 expression, a gene implicated in smoking cessation outcomes, was elevated in both sexes following nicotine withdrawal. Conclusions: Despite the similar impacts of nicotine withdrawal on gene expression levels, fosb, cfos, bdnf and erbb4 levels in the ventral hippocampus were predictive of delays in female extinction learning alone. This suggests sex specific dysfunction in hippocampal circuitry may contribute to female specific nicotine withdrawal induced deficits in extinction learning. Plain text summary: Smokers undergoing nicotine withdrawal report increased feelings of anxiety, depression, and cognitive deficits. However, there are sex differences in these symptoms, with women reporting higher feelings of anxiety compared to men and men having worse cognitive deficits than women. The mechanisms underlying these sex differences in nicotine withdrawal symptoms are not well understood. The hippocampus is a brain region highly implicated in both the cognitive and anxiety-like symptoms of nicotine withdrawal. Therefore, we evaluated the effects of nicotine and withdrawal on contextual fear memory, a hippocampally dependent learning and memory task, in male and female mice. We found that female mice had a stronger contextual fear memory expression than their male counterparts. However, following acute nicotine treatment male mice had enhanced contextual fear memory compared to non-nicotine treated males, while acute nicotine had no impact on female mice. When examining extinction of contextual fear, we found female mice withdrawn from nicotine displayed impaired extinction learning, but no effect was observed in males. The female specific deficits in extinction learning due to nicotine withdrawal were correlated to hippocampal gene expression related to neuronal activity. This suggests hippocampal dysfunction may be driving the female specific nicotine withdrawal induced deficits in extinction learning. Highlights: Female mice, but not males, showed deficits in contextual fear extinction during forced nicotine withdrawal. Despite the sex specific impact of nicotine withdrawal on contextual extinction learning, with females alone showing deficits in extinction, we observed suppression of immediate early genes in the dorsal and ventral hippocampus and increased erbb4 mRNA in the ventral hippocampus in both sexes. The deficits in female extinction were predicted by specific alterations in gene expression in the ventral hippocampus, highlighting a potential sex specific mechanism of nicotine withdrawal induced endophenotypes. [ABSTRACT FROM AUTHOR]

Background and aims: Compulsive Sexual Behaviour (CSB), defined as a persistent failure to control repetitive sexual impulses, has been discussed as a pathological phenomenon for centuries. Various terms, such as excessive sexual behaviour, hyper-sexuality, compulsive sexual behaviour disorder (CSBD), or sexual addiction (SA), have been used to describe it, contributing to ongoing debates about its theoretical framework. The following three studies aim to empirically assess whether CSB exhibits key elements of behavioural addiction (mood-modification, sensitization/tolerance, and withdrawal). Method: Three studies, involving participants with and without CSB, were conducted. The mood-modification hypothesis was tested by exposing participants to short films inducing positive, negative, and emotionally neutral moods, followed by an evaluation of their craving for pornography. To test the sensitization hypothesis, participants viewed short films with varying levels of explicit sexual stimuli, and their level of actual wanting and liking were assessed through self-reports. For the withdrawal hypothesis, participants underwent a 10-day sexual abstinence, with self-reports of various symptoms, collected on pre-intervention, 3rd, 7th, and 10th days. Results: Contrary to previous studies of addiction, CSB participants didn't show increased craving to mood induction and negative mood actually decreased craving for pornography. Secondly, they showed wanting to explicit sexual stimuli although it was not increased with explicitness. Finally, they demonstrated reduced withdrawal symptom during abstinence. Conclusion: The results of this study provide conflicting results concerning the model of behavioural addiction. There is supporting evidence for wanting in response to explicit pornography stimuli although it was not associated with increased explicitness. There is also evidence for reduced withdrawal during abstinence. Finally, there was no evidence that mood modification increases craving for pornography, negative mood actually decreased craving. Further research is needed to test the various models of CSB. [ABSTRACT FROM AUTHOR]

The Indian summer monsoon supplies over 75% of the country's annual precipitation, profoundly impacting over a billion people. Variability in the timing of its onset and withdrawal has a direct impact on the agricultural sector and other users of water resources. Previous studies have shown that a wedge of mid‐tropospheric dry air emanating from the midlatitudes is present over India during the pre‐monsoon, which gradually retreats toward the northwest as the onset progresses. The withdrawal of the monsoon is observed to progress in a southeast direction during September–October, but there is a lack of a conceptual model. In this study, we use observations and the ERA5 reanalysis to understand the dynamics and thermodynamics of the withdrawal. We find that the climatological mid‐level dry intrusion appears over northwest India around mid‐September. Vertical profiles associated with this dry air show how the most unfavourable environment for deep convection occurs in the northwest, where the withdrawal occurs first. As the withdrawal progresses, the wedge of dry air deepens throughout its horizontal extent and descends, as well as pushing further across the country. This stabilises the troposphere, suppressing deep convection and ultimately driving the withdrawal toward the southeast. By mid‐October, the dry air engulfs most of India, causing the monsoon to withdraw from the entire country. Thus, the strengthening of the mid‐level dry advection from the midlatitudes can explain the withdrawal of the monsoon and its direction, in a reversal of the processes at work during progression of the onset. This work establishes a new paradigm for the withdrawal of the Indian summer monsoon in terms of midlatitude interactions, which could be tested for other monsoon regions. [ABSTRACT FROM AUTHOR]

Taking the perspective of career choice as a lifelong, iterative, constructive, and agentic process, the present study focuses on the development of vocational aspirations of nursing trainees; that is, thoughts about a long-term perspective in nursing (i.e., persistence), ideas of finishing the training but changing into another profession after some time (i.e., withdrawal), and decisions to terminate the training before completing the programme through a final examination (i.e., dropout). In order to generate detailed insights about the dynamics behind the development of such aspirations during the initial training phase, a qualitative, longitudinal, within-subject study design based on grounded theory was employed. The results mainly show that social interactions with more experienced nurses, practical work experiences, encounters with environments that are either conducive to learning or not, the satisfaction of different needs (e.g., autonomy, competence, belonging, sense of meaningfulness), as well as the associated feelings of well-being affect how vocational aspirations develop over the first year of training. In addition, the study identifies four different patterns of how trainees typically oscillate between thoughts of staying in nursing and leaving the profession in the short or long run: (a) arriving and wanting to stay, (b) staying as a transitional passage, (c) seeking to stay, and (d) exiting as a knee-jerk reaction. The patterns present evidence of a variety of approaches regarding how trainees deal with certain experiences during their training and how the combination of experiences might affect young professionals' subsequent career choices. [ABSTRACT FROM AUTHOR]

This study investigates the climatological characteristics of the withdrawal period of the southwest monsoon (henceforth, Habagat) season using daily rainfall records from 11 weather stations of the Philippine Atmospheric, Geophysical, and Astronomical Services Administration located along the west coast of the Philippines from 1979-2020. The withdrawal dates were objectively determined by iterative fitting of two-phase linear regression models on the cumulative time series of rainfall in each year and station. The cumulative time series were bootstrapped, and the withdrawal detection was applied in each bootstrap sample to estimate the lower (25th percentile) and upper (75th percentile) confidence limits. The average withdrawal date across the 11 stations was found to occur on 21 Oct, with confidence limits of -6 and 11 d. Using the same index, the average onset date was also obtained, and the average duration was estimated. The average duration of the Habagat season is about 148 d. No significant correlation was found between the onset and withdrawal dates, indicating that the duration of the Habagat season is mainly controlled by its withdrawal. The withdrawal period is characterized by a gradual decrease in rainfall and relative humidity along the western coastal stations, strengthening of the easterlies from the Pacific Ocean, as well as the southward migration of the monsoon trough and western North Pacific subtropical high. Further analysis showed that there is no clear relationship between ENSO and the withdrawal dates obtained in this study. However, there were notable years such as 2010 and 2020, both being La Niña years, when the withdrawal dates were delayed by at least 20 d. This study is the first attempt to characterize the withdrawal of the Habagat season, and the index used in this study may be useful for agricultural planning and management of hydrological resources in the Philippines. [ABSTRACT FROM AUTHOR]

Aim: Morphine is one of the important opioids used in chronic and acute pain management. However, it has many side effects, including the development of addiction, which seriously limits its use. Melatonin shows its physiological effects through melatonin receptor 1 (MT1), melatonin receptor 2 (MT2) and heterodimer receptors (MT1/MT2). No study has examined the presence of MT1/MT2 mRNA in the hypothalamus and hippocampus and its relationship with the addiction process. The aim of this study was to investigate the gene expression levels of MT1, MT2 and MT1/MT2 in rat hippocampus and hypothalamus during morphine addiction and morphine withdrawal. Materials and Methods: A total of 36 male Wistar rats were divided into 3 groups (n=12). Control (C) group received saline subcutaneously for 6 days. Morphine (M) and morphine+naloxone (M+N) groups received 10 mg/kg/day morphine subcutaneously for 6 days. On the seventh day, saline was injected intraperitoneally into C and M groups and 1 mg/kg naloxone was injected intraperitoneally into M+N group. 30 minutes later, hippocampus and hypothalamus tissues of rats were dissected. Melatonin receptor genes expression level were analysed by quantitative qPCR. Results: Both MT1 and MT1/MT2 gene expression levels in the hypothalamus were higher in the M+N group than in the C group (p<0.05). There was no difference between the expression levels of MT2 receptors in the hypothalamus (p>0.05). There was no difference in MT1, MT2 and MT1/MT2 gene expression in the hippocampus (p>0.05). Conclusion: This is the first study to show the presence of MT1/MT2 in the hypothalamus and hippocampus, and it is possible that MT1 and MT1/MT2 receptors, especially in the hypothalamus, play a role in the addiction process. [ABSTRACT FROM AUTHOR]

Objectives: The link between cannabis use and psychotic symptoms or disorders is well known. However, the relation between cannabis withdrawal and psychotic symptoms is less studied. Methods: To our knowledge, this is the first publication of an observational systematic report of cannabis-induced psychotic disorder with onset during withdrawal. Here, we review patients presenting to a major emergency room in Montreal between January 2020 and September 2023 in a context of psychotic symptoms following cannabis cessation. Results: In total, seven male and one female patients presented at the peak of cannabis withdrawal with acute psychotic symptoms, representing less than 1% of all emergency service admissions. Conclusions: We discuss current knowledge regarding the endocannabinoid system and dopamine homeostasis to formulate hypotheses regarding these observations. [ABSTRACT FROM AUTHOR]

Phenibut is a gamma aminobutyric acid derivative with activity at γ‐aminobutyric acid (GABA)B, A and β‐phenethylamine receptors. It was developed as a drug in the former Soviet Union to overcome anxiety and improve cognitive function in military personnel. In the last decade, it has made inroads into the European and U.S. markets, being marketed for purported nootropic properties. Here, we summarize the current knowledge on phenibut, its toxicology, pharmacology, adverse health effects, and patterns of use. Publications in peer‐reviewed journals were searched in PubMed, Web of Science, and Google Scholar databases. Available literature points to adverse side effects associated with intoxication, withdrawal, and addiction to phenibut. Some of these effects can be life‐threatening, requiring hospitalization and therapeutic interventions. Supportive efforts are often complicated by a lack of knowledge regarding phenibut's toxicology and pharmacology. Ingestion of phenibut was often associated with concomitant use of other substances of abuse. As control over its online marketing seems unrealistic, current efforts need to be focused on the addition of phenibut to current drug screening tests and the development of generally accepted treatment strategies for phenibut‐associated toxicities. [ABSTRACT FROM AUTHOR]

Alcohol use disorder (AUD) is the most common substance use disorder and poses a significant global health challenge. Despite pharmacological advances, no single drug effectively treats all AUD patients. This study explores the protective potential of hispidol, a 6,4′-dihydroxyaurone, for AUD using the Caenorhabditis elegans model system. Our findings demonstrate that hispidol-fed worms exhibited more pronounced impairments in thrashes, locomotory speed, and bending amplitude, indicating that hispidol exacerbated the detrimental effects of acute ethanol exposure. However, hispidol significantly improved ethanol withdrawal behaviors, such as locomotory speed and chemotaxis performance. These beneficial effects were absent in slo-1 worms (the ortholog of mammalian α-subunit of BK channel) but were restored with the slo-1(+) or hslo(+) transgene, suggesting the involvement of BK channel activity. Additionally, hispidol increased fluorescence intensity and puncta in the motor neurons of slo-1::mCherry-tagged worms, indicating enhanced BK channel expression and clustering. Notably, hispidol did not alter internal ethanol concentrations, suggesting that its action is independent of ethanol metabolism. In the mouse models, hispidol treatment also demonstrated anxiolytic activity against ethanol withdrawal. Overall, these findings suggest hispidol as a promising candidate for targeting the BK channel in AUD treatment. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to estimate health state utility values (HSUVs) for the key health states found in opioid use disorder (OUD) cost-effectiveness models in the published literature. Methods: Data obtained from six trials representing 1,777 individuals with OUD. We implemented mapping algorithms to harmonize data from different measures of quality of life (the SF-12 Versions 1 and 2 and the EQ-5D-3 L). We performed a regression analysis to quantify the relationship between HSUVs and the following variables: days of extra-medical opioid use in the past 30 days, injecting behaviors, treatment with medications for OUD, HIV status, and age. A secondary analysis explored the impact of opioid withdrawal symptoms. Results: There were statistically significant reductions in HSUVs associated with extra-medical opioid use (-0.002 (95% CI [-0.003,-0.0001]) to -0.003 (95% CI [-0.005,-0.002]) per additional day of heroin or other opiate use, respectively), drug injecting compared to not injecting (-0.043 (95% CI [-0.079,-0.006])), HIV-positive diagnosis compared to no diagnosis (-0.074 (95% CI [-0.143,-0.005])), and age (-0.001 per year (95% CI [-0.003,-0.0002])). Parameters associated with medications for OUD treatment were not statistically significant after controlling for extra-medical opioid use (0.0131 (95% CI [-0.0479,0.0769])), in line with prior studies. The secondary analysis revealed that withdrawal symptoms are a fundamental driver of HSUVs, with predictions of 0.817 (95% CI [0.768, 0.858]), 0.705 (95% CI [0.607, 0.786]), and 0.367 (95% CI [0.180, 0.575]) for moderate, severe, and worst level of symptoms, respectively. Conclusion: We observed HSUVs for OUD that were higher than those from previous studies that had been conducted without input from people living with the condition. Plain English Summary: Thus far, health-related quality of life estimates for patients with opioid use disorder in the United States are limited, and importantly, they were not generated from studies among people living with the condition. This study extracted data from six clinical trials providing data among 1,777 people with opioid use disorder, made publicly available by the National Institutes of Health, to produce estimates of health-related quality of life. Our study found higher health-related quality of life estimates as compared to previous studies, modest impact of medications for opioid use disorder and strong impact of withdrawal symptoms on this outcome. These higher values among people with opioid use disorder might reflect the very negative perception of this condition among members of the general population (among whom these estimates have been generated previously). However, these relatively high estimates could also reflect an adaptation to the condition or a lack of awareness of associated-health damage in the context of dependence. The low number of observations providing data on medications for opioid use disorder led to high uncertainty around related estimates of health-related quality of life, but our findings could also reflect real experiences by patients in the absence of the positive effects of non-medication opioids, which deserve more attention in clinical practice. Our study suggests that systematically measuring withdrawal symptoms and representing these in health economic models might provide a more accurate representation of health-related quality of life among people with opioid use disorder and therefore of the impact and cost-effectiveness of interventions. Clinical trial registration details: The information reported here results from secondary analyses of data from clinical trials conducted by the National Institute on Drug Abuse (NIDA). Specifically, data from NIDA-CTN-0001 (NCT00032955 and 'Buprenorphine/Naloxone versus Clonidine for Inpatient Opiate Detoxification'), NIDA-CTN-0002 (NCT00032968 and 'Buprenorphine/Naloxone versus Clonidine for Outpatient Opiate Detoxification'), NIDA-CTN-0009 (NCT00067158 and 'Smoking Cessation Treatment with Transdermal Nicotine Replacement Therapy in Substance Abuse Rehabilitation Programs'), NIDA-CTN-0030 (NCT00316277 and 'A Two-Phase Randomized Controlled Clinical Trial of Buprenorphine/Naloxone Treatment Plus Individual Drug Counseling for Opioid Analgesic Dependence'), NIDA-CTN-0049 (NCT01612169 and 'Project HOPE - Hospital Visit as Opportunity for Prevention and Engagement for HIV-Infected Drug Users'), NIDA-CTN-0051 (NCT02032433 and 'Extended-Release Naltrexone vs. Buprenorphine for Opioid Treatment') were included. NIDA databases and information are available at (https://datashare.nida.nih.gov). Additional observational data was used to equate different measures of health-related quality of life onto the same scale using psychometric methods. These data included the National Health Measurement Study (which is available at https://www.disc.wisc.edu/) and the Household Component files for the Medical Expenditure Panel Survey (which is available at https://meps.ahrq.gov/mepsweb/). [ABSTRACT FROM AUTHOR]

The persistent use of opioids leads to profound changes in neuroplasticity of the brain, contributing to the emergence and persistence of addiction. However, chronic opioid use disrupts the delicate balance of the reward system in the brain, leading to neuroadaptations that underlie addiction. Chronic cocaine usage leads to synchronized alterations in gene expression, causing modifications in the Nucleus Accumbens (NAc), a vital part of the reward system of the brain. These modifications assist in the development of maladaptive behaviors that resemble addiction. Neuroplasticity in the context of addiction involves changes in synaptic connectivity, neuronal morphology, and molecular signaling pathways. Drug-evoked neuroplasticity in opioid addiction and withdrawal represents a complicated interaction between environmental, genetic, and epigenetic factors. Identifying specific transcriptional and epigenetic targets that can be modulated to restore normal neuroplasticity without disrupting essential physiological processes is a critical consideration. The discussion in this article focuses on the transcriptional aspects of drug-evoked neuroplasticity, emphasizing the role of key transcription factors, including cAMP response element-binding protein (CREB), ΔFosB, NF-kB, Myocyte-enhancing factor 2 (MEF2), Methyl-CpG binding protein 2 (MeCP2), E2F3a, and FOXO3a. These factors regulate gene expression and lead to the neuroadaptive changes observed in addiction and withdrawal. Epigenetic regulation, which involves modifying gene accessibility by controlling these structures, has been identified as a critical component of addiction development. By unraveling these complex molecular processes, this study provides valuable insights that may pave the way for future therapeutic interventions targeting the mechanisms underlying addiction and withdrawal. [ABSTRACT FROM AUTHOR]

Background: Untreated pain is a source of significant physical and psychosocial distress in patients with cancer. While guidelines for prescribing opioids have improved the treatment of cancer-related pain, all patients who take opioids are at risk for developing opioid-induced respiratory depression (OIRD). The current treatment for OIRD is naloxone although guidelines are highly variable on initial dose and indication. Patients with cancer on chronic opioids are at risk for increased suffering due to naloxone-induced opioid withdrawal and loss of pain control. Aim: A review of the evidence for the safety and benefits of using buprenorphine instead of naloxone for reversal of OIRD in patients prescribed chronic opioids for cancer-related pain. Methods: A realist review of the literature was completed following the RAMSES Framework. An iterative literature search of electronic databases was used to identify appropriate literature relating to buprenorphine and naloxone safety and use as reversal agents in OIRD. Results: While naloxone does reverse OIRD it does have the risk of pulmonary edema and research has consistently shown that naloxone is usually given for the wrong indications and/or at an inappropriate dose for patients on chronic opioids for cancer-related pain. Buprenorphine has been shown to safely reverse OIRD with less incidence and severity of withdrawal and uncontrolled pain when compared to naloxone. Conclusions: Because of the potential for decreased opioid withdrawal-associated symptoms, this review argues that buprenorphine warrants additional study and consideration to replace naloxone as the first-line rescue medication for patients with cancer on chronic opioids who experience OIRD. [ABSTRACT FROM AUTHOR]

Using data from 11 institutions, the authors investigate enrollments in intermediate microeconomics to determine characteristics of successful and unsuccessful students and follow the retake behavior of unsuccessful students. Successful students are significantly different from unsuccessful ones, and unsuccessful students differ by type (unsuccessful completers vs. withdrawers). Aptitude is a strong predictor of success but not of retake. Having taken or concurrently taking intermediate macro reduces the likelihood of withdrawal and increases that of retake. Proficiency in calculus reduces the likelihood of unsuccessful completion but is uncorrelated with withdrawal and retake. Predictors of unsuccessful completion, withdrawal, and retake are similar in direction and significance for males and females, although magnitudes differ. URM students are more likely than white and Asian students to earn less than a C−. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusions In TRED‐HF, 40% of patients with recovered dilated cardiomyopathy (DCM) relapsed in the short term after therapy withdrawal. This follow‐up investigates the longer‐term effects of therapy withdrawal.TRED‐HF was a randomized trial investigating heart failure therapy withdrawal in patients with recovered DCM over 6 months. Those randomized to continue therapy subsequently withdrew treatment between 6 and 12 months. Participants were recommended to restart therapy post‐trial and were followed until May 2023. Clinical outcomes are reported in a non‐randomized fashion from enrolment and from the end of the trial. The primary outcome was relapse defined as ≥10% reduction in left ventricular ejection fraction to <50%, doubling in N‐terminal pro‐B‐type natriuretic peptide to >400 ng/L, or clinical features of heart failure. From enrolment to the last follow‐up (median 6 years, interquartile range 6–7), 33 of 51 patients (65%) relapsed. The 5‐year relapse rate from enrolment was 61% (95% confidence interval [CI] 45–73) and from the end of the trial was 39% (95% CI 19–54). Of 20 patients who relapsed during the trial, nine had a recurrent relapse during follow‐up. Thirteen relapsed for the first time after the trial; seven had restarted low intensity therapy, four had not restarted therapy and two did not have therapy withdrawn. The mean intensity of therapy was lower after the trial compared to enrolment (mean difference −6 [−8 to −4]; p < 0.001). One third of relapses during follow‐up had identifiable triggers (arrhythmia [n = 4], pregnancy [n = 1], hypertension [n = 1], infection [n = 1]). Corrected atrial fibrillation was associated with reduced risk of relapse (hazard ratio 0.33, 95% CI 0.12–0.96; p = 0.042).The risk of relapse in the 5 years following the TRED‐HF trial remained high. Restarting lower doses of heart failure medications at the end of the trial, external triggers and disease progression are likely to have contributed to relapse. [ABSTRACT FROM AUTHOR]

The ability of morphine to decrease cysteine transport into neurons by inhibition of excitatory amino acid transporter 3 (EAA3) may be a key molecular mechanism underlying the acquisition of physical and psychological dependence to morphine. This study examined whether co-administration of the cell-penetrant antioxidant D-thiol ester, D-cysteine ethyl ester (D-CYSee), with morphine, would diminish the development of physical dependence to morphine in male Sprague Dawley rats. Systemic administration of the opioid receptor antagonist, naloxone (NLX), elicited pronounced withdrawal signs (e.g., wet-dog shakes, jumps, rears, circling) in rats that received a subcutaneous depot of morphine (150 mg/kg, SC) for 36 h and continuous intravenous infusion of vehicle (20 µL/h, IV). The NLX-precipitated withdrawal signs were reduced in rats that received an infusion of D-CYSee, but not D-cysteine, (both at 20.8 µmol/kg/h, IV) for the full 36 h. NLX elicited pronounced withdrawal signs in rats treated for 48 h with morphine (150 mg/kg, SC), plus continuous infusion of vehicle (20 µL/h, IV) that began at the 36 h timepoint of morphine treatment. The NLX-precipitated withdrawal signs were reduced in rats that received a 12 h infusion of D-CYSee, but not D-cysteine, (both at 20.8 µmol/kg/h, IV) that began at the 36 h timepoint of morphine treatment. These findings suggest that D-CYSee may attenuate the development of physical dependence to morphine and reverse established dependence to the opioid in male Sprague Dawley rats. Alternatively, D-CYSee may simply suppress the processes responsible for NLX-precipitated withdrawal. Nonetheless, D-CYSee and analogues may be novel therapeutics for the treatment of opioid use disorders. [ABSTRACT FROM AUTHOR]