The need for smoking cessation counselling and nicotine withdrawal therapy for hospitalised patients: A smoking point prevalence study at Groote Schuur Hospital, Cape Town, South Africa.

Background: South Africa has high tobacco-attributable mortality and a smoking prevalence of 32.5% in males and 25.6% in females. There are limited data on smoking prevalence and desire to quit in hospitalised patients, who have limited access to smoking cessation services. Objectives: To determine smoking prevalence and the extent of nicotine withdrawal symptoms, using a hospital-wide inpatient survey. Methods: A 1-day point prevalence survey was conducted at Groote Schuur Hospital, Cape Town. All wards except the haematology isolation, active labour and psychiatry lock-up wards were evaluated. Smoking status, withdrawal symptoms and desire to quit were established. Results: Smoking status was confirmed in 85.8% of inpatients (n=501/584), of whom 31.9% (n=160) were current smokers; 43.5% (n=101/232) of male and 21.9% (n=59/269) of female inpatients were smokers. Documentation and confirmation of smoking status was highest in the maternity wards (100%) and lowest in the surgical wards (79.6%) and intensive care units (70.0%). Smoking prevalence ranged from 47.6% in male surgical patients to 15.2% in maternity patients. Of the smokers, 54.5% reported being motivated to quit, with a median (interquartile range) Fagerström test for nicotine dependence score of 4 (2 - 6), and 31.4% reported moderate to severe cravings to smoke, highest in the surgical wards. Conclusion: Smoking prevalence was higher in hospitalised patients than in the local general population. Many inpatients were not interested in quitting; however, a third had significant nicotine withdrawal symptoms. All inpatients who are active smokers should be identified and given universal brief smoking cessation advice. Patients with severe withdrawal symptoms should be allowed to smoke outside, and nicotine withdrawal pharmacotherapy should be provided to those who are bedbound or express a desire to stop smoking during the current admission. Study synopsis: What the study adds. A single data point prevalence study of active smokers at Groote Schuur Hospital, Cape Town, was conducted. The prevalence of smoking was higher in the hospitalised patients than in the general community, but not all smokers were identified by the clinicians. Although symptoms of nicotine withdrawal were severe in some patients, motivation to quit smoking was not related to the degree of withdrawal being experienced. Many patients were not motivated to quit smoking.Implications of the findings. Better identification of inpatient smokers is required, and all should be given smoking cessation advice. Withdrawal symptoms can be severe in some patients, and those who are not interested in stopping smoking should allowed to smoke outside or be provided with nicotine withdrawal pharmacotherapy while in hospital. Those who are willing to quit should be supported as well as possible, including provision of nicotine replacement therapy or varenicline, and followed up after discharge as best practice.

The effect of ostracism on social withdrawal behavior: the mediating role of self-esteem and the moderating role of rejection sensitivity.

Extant studies have empirically tested the main two behavior responses following ostracism: prosocial or antisocial. Few studies have investigated the relationship between ostracism and social withdrawal. According to the temporal need-threat model and the self-verification theory, the present study aimed to examine the influence mechanism of ostracism on social withdrawal, especially the mediating role of self-esteem and the moderating role of rejection sensitivity. A total of 1,315 Chinese high school students (52.6% female) completed a written questionnaire. Results showed that ostracism was positively correlated with social withdrawal. Ostracism not only directly predicted social withdrawal, but also indirectly affected social withdrawal by threatening adolescents' self-esteem. High rejection sensitivity may help aggravate adolescents' self-esteem threaten perceive from ostracism. Adolescents with high rejection sensitivity felt a greater threat to self-esteem when ostracized. Findings suggest a new direction for understanding individuals' responses to ostracism.

Estimation of withdrawal interval recommendations following administration of fenbendazole medicated feed to ring-necked pheasants (Phasianus colchicus).

Introduction: Prescribing fenbendazole medicated feed for pheasants in the USA is considered extra-label drug use under CPG Sec 615.115, and a safe estimated withdrawal interval (WDI) must be applied following administration to this minor food-producing species. This study sought to determine the pharmacokinetic and residue depletion profile for fenbendazole and its major metabolites to estimate a WDI for pheasants following fenbendazole administration as an oral medicated feed. Method: Pheasants (n = 32) were administered fenbendazole as an oral medicated feed (100 ppm) for 7 days. Fenbendazole, fenbendazole sulfoxide, and fenbendazole sulfone (FBZ-SO2) in liver and muscle samples were analyzed using HPLC-UV. Tissue WDIs were estimated using FDA, European Medicines Agency (EMA), and half-life multiplication methods for US poultry tolerances, EMA maximum residue limits, and the analytical limit of detection (LOD; 0.004 ppm). Terminal tissue elimination half-lives (T1/2) were estimated by non-compartmental analysis using a naïve pooled data approach. Results: The tissue T1/2 was 14.4 h for liver, 13.2 h for thigh muscle, and 14.1 h for pectoral muscle. The maximum estimated withdrawal interval was 153 h (7 days) for FBZ-SO2 in pectoral muscle using the FDA tolerance method (95% confidence interval for the 99th percentile of the population), and the LOD as the residue limit. Discussion: The results from this study support the use of FBZ-SO2 as the marker residue in the liver of pheasants and the provision of evidence based WDIs following the extra-label administration of fenbendazole medicated feed (100 ppm) for 7 days.

Microscopic ferning in human pre-ejaculate is highly correlated with the absence of sperm.

OBJECTIVE: We characterize microscopic ferning in pre-ejaculate samples with and without sperm. METHODS: Healthy, male, withdrawal-experienced participants provided up to three paired pre-ejaculate and ejaculate samples. We centrifuged ejaculate samples to obtain a supernatant without sperm. After sperm analysis, we dried and evaluated pre-ejaculate, ejaculate, and supernatants for microscopic ferning. RESULTS: Of 57 pre-ejaculate samples (N=24 men), seven (12.3%) contained sperm, none of which exhibited ferning. 66% (33/50) of pre-ejaculate samples without sperm exhibited ferning. Neither ejaculate nor supernatant samples exhibited ferning. CONCLUSION: Ferning may distinguish clinical pre-ejaculate with and without sperm. Ferning exhibited 100% specificity for pre-ejaculate without sperm.

Phenobarbital Dosing for the Treatment of Alcohol Withdrawal Syndrome: A Review of the Literature.

Objective: To determine the most appropriate phenobarbital dosing regimen by evaluating the safety and efficacy of the drug when specifically used in alcohol withdrawal syndrome (AWS). Data sources: A comprehensive literary search was conducted using PubMed and bibliographic mining in October 2023. Study selection and data extraction: An established monotherapy phenobarbital regimen needed to be established within the article to be included in analysis. Location of implementation was not a deterrent to evaluation, nor was the route of phenobarbital administration. Data synthesis: Six publications were evaluated in this review, and two main phenobarbital dosing regimens emerged. While fix-based dosing strategies and weight-based dosing strategies resulted, the dosing within the regimens resulted in the same or relatively similar doses employed, respectively. Each of the studies had a statistically significant decrease in their primary outcome being studied, and the use of phenobarbital as monotherapy was proven to improve AWS symptoms, significantly decrease intensive care unit and hospital length of stay, decrease the use of adjunctive medications, decrease the use of a ventilator, and prevent seizures. Conclusions: Despite benzodiazepines having been the clinical first-line therapy for AWS, research shows that the pharmacokinetic stability and clinical benefits of phenobarbital are in support creation of phenobarbital protocols, as monotherapy, in hospitals or institutions for patients with AWS.

The autoimmune nature of morphine addiction.

The onset of the disease as a morphine addiction is associated with the appearance in the patient's body of antibodies directed against opiate receptors (ORs). Once anti-opiate receptor antibodies (anti-OR antibodies) appear in the blood they will tend to bind to ORs. Such binding will cause blocking of physiological functions of OR. The blockage is felt by a morphine addict as withdrawal syndrome. To get rid of this harmful condition, the addict increases the dose of morphine taken. This is where tolerance manifests itself. The drug addict is forced to increase the dose of morphine from time to time because of the body responds by producing the more and more anti-OR antibodies. The immunological nature of morphine addiction is the reason for lifelong changes in the body's reactivity to the drug. An addict can be cured if he gets rid of B- and T-memory cells, which specifically react to ORs.

Safety of Phenobarbital Versus Benzodiazepines for Alcohol Withdrawal in Critically Ill Patients With Primary Neurologic Injuries.

BACKGROUND: Alcohol withdrawal syndrome (AWS) is a complication of alcohol use disorder that manifests as a range of symptoms. Symptom-triggered benzodiazepines (BZDs) are often used as first-line treatment of AWS. However, recent literature suggests phenobarbital (PHB) may be safer and more efficacious, but studies are limited by exclusion of patients with neurological injuries. OBJECTIVE: We aimed to evaluate the safety of PHB compared to BZDs for the management of AWS among patients with primary neurologic injuries. METHODS: Retrospective cohort study of patients with primary neurologic injuries admitted to an ICU who received PHB or symptom-triggered BZD for AWS between December 2013 and February 2020. The primary outcome was incidence of oversedation, defined as Richmond Agitation Sedation Scale (RASS) scores from -5 to -3 within 24 hours of initial PHB or BZD dose. Secondary outcomes included largest decrease in RASS, need for mechanical ventilation, and additional sedative use within 24 hours of initial PHB or BZD dose. A multivariable analysis was performed to evaluate the association of PHB administration with the primary outcome. RESULTS: Among 600 patients treated for AWS, 84 patients were included in our analysis (PHB, n = 56; BZD, n = 28). In the unadjusted analysis, there were no differences between the PHB and BZD groups for the primary outcome of oversedation (21.4 vs. 7.1%, P = 0.13), or secondary outcomes of decrease in RASS (P = 0.34), or new ventilator requirement (P = 0.55). Patients who received PHB had higher rates of additional sedative use (P < 0.01). Multivariable regression revealed an increase in oversedation among intubated patients (P = 0.014), while PHB administration was not independently associated with oversedation (P = 0.516). CONCLUSION AND RELEVANCE: Phenobarbital did not independently increase the risk of oversedation compared to BZD for AWS in patients with primary neurologic injuries. Future studies should determine optimal dosing of PHB in this population.

Understanding the relationship between smartphone distraction, social withdrawal, digital stress, and depression among college students: A cross-sectional study in Wuhan, China.

Background: Smartphone distraction considerably affects the depression level of college students. These two variables are highly associated with social withdrawal and digital distress. However, the underlying mechanisms of how social withdrawal and digital stress were involved in the relationship between smartphone distraction and depression remain unclear. Methods: A cross-sectional survey was conducted in seven colleges of Wuhan, Hubei Province, from September to November 2021. Participants were selected using convenience sampling. Smartphone distraction, social withdrawal, digital stress, and depression level were assessed using the Smartphone Distraction Scale (SDS), 25-item Hikikomori Questionnaire (HQ-25), Multidimensional Digital Stress Scale (DSS), and the Patient Health Questionnaire-9 (PHQ-9), respectively. All scales demonstrated good reliability in this study, the reliability of each scale was 0.920, 0.884, 0.959, and 0.942. Results: The final analysis included 1184 students (692 males and 492 females), aged between 17 and 37 years. Participants were from various academic disciplines, including medical and non-medical. The findings revealed that smartphone distraction had a significant direct effect on depression (c = 0.073, 95 % CI: 0.037 to 0.108, p < 0.001) and three significant indirect mediation effects: (1) social withdrawal (B = 0.083, 95 % CI: 0.066 to 0.101, p < 0.001), accounting for 27.76 % of the total effect; (2) digital stress (B = 0.109, 95 % CI: 0.088 to 0.132, p < 0.001), accounting for 36.45 % of the total effect; and (3) the chain mediating roles of social withdrawal and digital stress (B = 0.034, 95 % CI: 0.026 to 0.043, p < 0.001), accounting for 11.37 % of the total effect. The total mediating effect was 75.59 %. Limitations: This study is based on cross-sectional data, which limits the causality inference. Conclusions: These findings suggest that educational institutions should identify college students with excessive smartphone use early and provide timely interventions to minimize negative outcomes. It is also significant to reduce the risk of social withdrawal and digital stress to maintain the physical and mental health development of college students.

The chain mediating role of rumination and social withdrawal in the relationship between smartphone distraction and depression among Chinese nursing students.

Smartphone distraction (SD) is closely related to depression, and the prevalence of SD among nursing students is gradually increasing. However, the potential mechanism of the effect of SD on nursing students' depression is unclear. A total of 574 nursing students were assessed using Smartphone Distraction Scale, Ruminative Response Scale, Hikikomori Questionnaire, and Patient Health Questionnaire-9. The results indicated that SD among nursing students had an impact on depression through four pathways: (1) SD was positively associated with depression (ß = 0.353, P < 0.001); (2) Rumination (ß = 0.199, 95% CI: 0.081 to 0.162) and social withdrawal (ß = 0.061, 95% CI: 0.034 to 0.091) mediated the effects of SD on depression, respectively; and (3) Rumination and social withdrawal played a chain mediating role in the effect of SD on nursing students' depression (ß = 0.027, 95% CI: 0.015 to 0.042). The negative impact of SD on nursing students' mental health should not be taken lightly. Schools and hospitals should guide nursing students to use smartphones correctly, including providing mental health education and professional psychological counselling; families could play a supervisory role and communicate regularly to understand the psychological state and learning of nursing students. These measures can help nursing students cope with stress and reduce the risk of depression.

Chronic ethanol exposure produces long-lasting, subregion-specific physiological adaptations in RMTg-projecting mPFC neurons.

Chronic ethanol exposure produces neuroadaptations in the medial prefrontal cortex (mPFC) that are thought to facilitate maladaptive behaviors that interfere with recovery from alcohol use disorder. Despite evidence that different cortico-subcortical projections play distinct roles in behavior, few studies have examined the physiological effects of chronic ethanol at the circuit level. The rostromedial tegmental nucleus (RMTg) is functionally altered by chronic ethanol exposure. Our recent work identified dense input from the mPFC to the RMTg, yet the effects of chronic ethanol exposure on this circuitry is unknown. In the current study, we examined physiological changes after chronic ethanol exposure in prelimbic (PL) and infralimbic (IL) mPFC neurons projecting to the RMTg. Adult male Long-Evans rats were injected with fluorescent retrobeads into the RMTg and rendered dependent using a 14-day chronic intermittent ethanol (CIE) vapor exposure paradigm. Whole-cell patch-clamp electrophysiological recordings were performed in fluorescently-labeled (RMTg-projecting) and -unlabeled (projection-undefined) layer 5 pyramidal neurons 7-10 days following ethanol exposure. CIE exposure significantly increased intrinsic excitability as well as spontaneous excitatory and inhibitory postsynaptic currents (sE/IPSCs) in RMTg-projecting IL neurons. In contrast, no lasting changes in excitability were observed in RMTg-projecting PL neurons, although a CIE-induced reduction in excitability was observed in projection-undefined PL neurons. CIE exposure also increased the frequency of sEPSCs in RMTg-projecting PL neurons. These data uncover novel subregion- and circuit-specific neuroadaptations in the mPFC following chronic ethanol exposure and reveal that the IL mPFC-RMTg projection is uniquely vulnerable to long-lasting effects of chronic ethanol exposure.

Physicians' experiences and perceptions about withholding and withdrawal life-sustaining treatment in Chiang Mai University Hospital: a cross-sectional study.

BACKGROUND: Withholding or withdrawing life-sustaining treatment in end-of-life patients is a challenging ethical issue faced by physicians. Understanding physicians' experiences and factors influencing their decisions can lead to improvement in end-of-life care. OBJECTIVES: To investigate the experiences of Thai physicians when making decisions regarding the withholding or withdrawal of life-sustaining treatments in end-of-life situations. Additionally, the study aims to assess the consensus among physicians regarding the factors that influence these decisions and to explore the influence of families or surrogates on the decision-making process of physicians, utilizing case-based surveys. METHODS: A web-based survey was conducted among physicians practicing in Chiang Mai University Hospital (June - October 2022). RESULTS: Among 251 physicians (response rate 38.3%), most of the respondents (60.6%) reported that they experienced withholding or withdrawal treatment in end-of-life patients. Factors that influence their decision-making include patient's preferences (100%), prognosis (93.4%), patients' quality of life (92.8%), treatment burden (89.5%), and families' request (87.5%). For a chronic disease with comatose condition, the majority of the physicians (47%) chose to continue treatments, including cardiopulmonary resuscitation (CPR). In contrast, only 2 physicians (0.8%) would do everything, in cases when families or surrogates insisted on stopping the treatment. This increased to 78.1% if the families insisted on continuing treatment. CONCLUSION: Withholding and withdrawal of life-sustaining treatments are common in Thailand. The key factors influencing their decision-making process included patient's preferences and medical conditions and families' requests. Effective communication and early engagement in advanced care planning between physicians, patients, and families empower them to align treatment choices with personal values.

Educating Nurses to Improve Awareness and Use of a Human Milk Feeding Care Pathway for Opioid-Exposed Neonates.

OBJECTIVE: To increase nurses' awareness and use of a human milk feeding (HMF) and opioid use disorder (OUD) standardized care pathway to improve rates of HMF at discharge in opioid-exposed neonates (OENs). DESIGN: Quality improvement project. SETTING/LOCAL PROBLEM: Underutilizing an HMF and OUD standardized care pathway in an academic medical center led to declining HMF rates at discharge. PARTICIPANTS: Staff nurses in the women and infants department (N = 311). INTERVENTION/MEASUREMENTS: Nurses completed an asynchronous online educational module regarding awareness and use of the HMF and OUD standardized care pathway for supporting HMF in OENs. Monthly infographics were placed in each nursing unit to reinforce content. Nurses completed pre- and posteducation surveys to evaluate their knowledge and use of the pathway. After the education, rates of OENs receiving human milk at discharge were collected from the electronic health record. RESULTS: A total of 240 (77.2%) nurses participated in the educational module; awareness of the pathway increased from 91.5% to 97.3%. HMF rate at discharge significantly increased from 29.8% to 59.4% (p = .03). CONCLUSION: Improved awareness among nurses of a standardized HMF and OUD care pathway was associated with a doubling of HMF rates at discharge in OENs.

Vitamin B12 supplementation improved memory impairment following nicotine withdrawal in adolescent male rats: The role of oxidative stress, inflammatory, BDNF, GFAP, and AChE activity.

The present study aimed to assess the potential effect of vitamin B12 (Vit B12) on cognition impairment caused by nicotine (Nic) cessation in adolescent male rats. Adolescent male rats were categorized into two main groups as vehicle (normal saline, intraperitoneally), and Nic group in which received Nic (2 mg/kg) from 21 to 42 days of ages and then the Nic group were divided into three groups as withdrawal (the animals returned to regular diet without treatment), second and third groups received bupropion (20 mg/kg), and Vit B12 at three different doses including 0.5,1, and 1.5 mg/kg by oral gavage as treatments to attenuate Nic withdrawal symptoms. The last group including normal animals received the highest doses of Vit B12 just in the Nic abstinence period to compare the effect of that with vehicle. In MWM, Vit B12and bupropion increased the time spent in the target quadrant that is strongly associated with spatial memory as well as the more time spent with the NORT. Vit B12 and bupropion modulated both oxidant/antioxidant and inflammatory/anti-inflammatory balance, alongside inhibitory effect on AChE, and GFAP. However, BDNF and amyloid-B showed insignificant difference as compared to Vit B12 and bupropion. Considering the present results and similar related studies, Vit B12 can be introduced as a strong anti-oxidant, and anti-inflammatory agent by which probably improved memory impairment caused by Nic addiction accompanied by withdrawal. Further, other mechanisms including activity reduction of AChE, and GFAP should be considered; however, it needs further investigation and larger-scale evidences.

Issues and implications of the life-sustaining treatment decision act: comparing the data from the survey and clinical data of inpatients at the end-of-life process.

BACKGROUND: Health professionals had difficulty choosing the right time to discuss life-sustaining treatments (LSTs) since the Korean Act was passed in 2018. OBJECTIVE: This study aimed to understand how patients decide to undergo LSTs in clinical practice and to compare the perceptions of these decisions among health professionals, patients, and families with suggestions to support the self-directed decisions of patients. RESEARCH DESIGN: A retrospective observational study with electronic medical records (EMRs) and a descriptive survey was used. METHODS: The data obtained from the EMRs included all adult patients who died in end-of-life care at a university hospital in 2021. We also conducted a survey of 214 health professionals and 100 patients and their families (CNUH IRB approval no. 2022-07-006). RESULTS: Based on the EMR data of 916 patients in end-of-life care, 78.4% signed do-not-attempt-resuscitation consents, 5.6% completed the documents for LSTs, and 10.2% completed both forms. LST decisions were mostly made by family members (81.5%). Most survey participants agreed that meaningless LSTs should be suspended, and the decision should be made by patients. Patients and family members (42-56%) and health professionals (56-58%) recommended discussing LST suspension when the patient is still conscious but with predicted deterioration of their condition. The suffering experienced by the patient was considered to be a priority by most patients (58%) and families (54%) during the decision-making process, while health professionals considered "the possibility of the patient's recovery" to be the highest priority (43-55%). CONCLUSIONS: There is still a significant discrepancy in the perceptions of LST decisions among health professionals, patients, and their families despite high awareness of the Act. This situation makes it challenging to implement the Act to ensure respect for the rights of patients to self-determination and dignified end-of-life. Further effort is needed to improve the awareness of LSTs and to clarify the ambiguity of document preparation timing.

N-palmitoylethanolamide attenuates negative emotions induced by morphine withdrawal in mice.

Depression and anxiety are prominent symptoms of withdrawal syndrome, often caused by the abuse of addictive drugs like morphine. N-palmitoylethanolamide (PEA), a biologically active lipid, is utilized as an anti-inflammatory and analgesic medication. Recent studies have highlighted PEA's role in mitigating cognitive decline and easing depression resulting from chronic pain. However, it remains unknown whether PEA can influence negative emotions triggered by morphine withdrawal. This study seeks to explore the impact of PEA on such emotions and investigate the underlying mechanisms. Mice subjected to morphine treatment underwent a 10-day withdrawal period, followed by assessments of the effect of PEA on anxiety- and depression-like behaviors using various tests. Enzyme-linked immunosorbent assay was conducted to measure levels of monoamine neurotransmitters in specific brain regions. The findings indicate that PEA mitigated anxiety and depression symptoms and reduced 5-hydroxytryptamine, noradrenaline, and dopamine levels in the hippocampus and prefrontal cortex. In summary, PEA demonstrates a significant positive effect on negative emotions associated with morphine withdrawal, accompanied with the reduction in levels of monoamine neurotransmitters in key brain regions. These insights could be valuable for managing negative emotions arising from morphine withdrawal.

Analyzing quality of life among people with opioid use disorder from the National Institute on Drug Abuse Data Share initiative: implications for decision making.

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.

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.

The lived experience of withdrawal from Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants: A qualitative interview study.

BACKGROUND: Our knowledge of the broader impacts of antidepressant withdrawal, beyond physical side effects, is limited. Further research is needed to investigate the lived experiences of withdrawal, to aid clinicians on how to guide patients through the process. AIM: To explore antidepressant users' experiences and views on the withdrawal process and how it affected their quality of life across multiple life domains. DESIGN AND SETTING: We conducted in-depth qualitative interviews with 20 individuals from the community who had attempted to withdraw from Serotonin Reuptake Inhibitor antidepressants in the past year. METHOD: Semi-structured interviews were conducted online. A topic guide was used to ensure consistency across interviews. The interviews were audio-recorded and transcribed verbatim and analysed using inductive reflexive thematic analysis. RESULTS: Five themes were generated. The first highlighted the challenges of managing the release from emotional blunting and cognitive suppression following antidepressant discontinuation. The second related to the negative impact of withdrawal on close relationships and social interactions. The third showed that concurrent with negative physical symptoms, there was a positive impact on health (exercise was reported by some as a coping mechanism). The fourth theme focused on support from GPs and families, emphasising the importance of mental health literacy in others. The final theme underscored the importance of gradual and flexible tapering in enabling a manageable withdrawal experience, and the consideration of timing. CONCLUSION: The lived experience of withdrawal significantly impacts individuals' well-being. Participants emphasised that withdrawal is not just about physical side effects but also affects their emotional, cognitive, and social functioning. PATIENT AND PUBLIC INVOLVEMENT (PPI): Eight people attended individual online meetings to share their experiences of antidepressant withdrawal to help inform the study design and recruitment strategy. Insights from these meetings informed the development of the topic guide. Questions about GP involvement, family relationships, and mood and thinking changes were included based on this PPI work. This ensured the inclusion of topics important to antidepressant users and facilitated the researcher's questioning during the interviews.

Bottom-up PBPK modeling of phenytoin brain disposition in postpartum newborns after intrauterine dosing.

OBJECTIVES: The antiepileptic phenytoin has a narrow therapeutic window, nonlinear pharmacokinetics, and can cross the placenta causing apathy and jitteriness in postpartum newborns. Further, the sudden decay of phenytoin concentration can cause withdrawal seizures. This work aimed to assess the brain toxic exposure to phenytoin in newborns after transplacental transfer using neonatal saliva-brain correlations. METHODS: The phenytoin dose that the newborn receives transplacentally at birth was estimated using verified physiologically based pharmacokinetic (PBPK) model simulations in third-trimester pregnancy (pregnancy T3). Such doses were used as an input to the newborn PBPK model to estimate the neonatal levels of phenytoin and their correlations in brain extracellular fluid (bECF), plasma, and saliva. RESULTS: The PBPK model-estimated neonatal plasma and bECF concentrations of phenytoin were below the necessary thresholds for anticonvulsant and toxic effects. The neonatal salivary thresholds for phenytoin anticonvulsant and toxic effects were estimated to be 1.3 and 2.5 mg/L, respectively using the plasma-saliva-bECF correlations established herein. CONCLUSIONS: The salivary TDM of phenytoin can be a more convenient option for avoiding phenytoin brain toxicity in newborns of epileptic mothers. Still, the appropriateness of using the same adult values of phenytoin anticonvulsant and toxic effects for infants needs investigation.

Low to non-existent sperm content of pre-ejaculate in perfect-use contraceptive withdrawal, a pilot study.

OBJECTIVE: To assess pregnancy risk following perfect use of the withdrawal method by quantification of sperm in pre-ejaculate. STUDY DESIGN: We conducted a pilot study of sperm and factors linked to its presence in pre-ejaculate samples among healthy, reproductive-age, withdrawal-experienced men. Participants provided up to three paired pre-ejaculate and ejaculate specimens in 72-hour intervals. We analyzed samples for volume, consistency, sperm concentration, count, and motility. We set clinical pregnancy risk as our primary outcome, defined as sperm concentration >1million/mL. RESULTS: From 70 paired samples (N=24 participants, median age: 27 years), we identified sperm in 9 (12.9%) pre-ejaculate samples, from 6 (25.0%) participants. Only 7 samples contained sperm in concentrations of significant clinical pregnancy risk. All ejaculatory specimens contained motile sperm in concentrations of significant pregnancy risk. CONCLUSION: In this study of the pre-ejaculate of perfect-use withdrawal users, motile sperm were usually absent, or found inconsistently and in insufficient quantities to confer significant clinical pregnancy risk. IMPLICATIONS: While correct and consistent withdrawal use is likely to be highly effective, given that motile sperm in concentrations >1 million/mL are usually absent or inconsistently present in pre-ejaculate, clinical trial data is lacking.

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.