Withdrawal Symptoms Research Articles

The effect of Certificate‐of‐Need laws on substance use disorder care for vulnerable populations

AbstractSubstance use disorders are a prevalent and growing problem across the United States, especially for households that rely on publicly funded healthcare insurance plans. State Certificate‐of‐Need (CON) laws for substance use disorder (SUD) treatment facilities can worsen outcomes for these patients by restricting the supply of facilities and beds, leading to spillovers into the general hospital system. We present a choice theory for treatment facility patient admission and model the outcome as a function of the patient's insurance type. We then combine two datasets on state CON laws for SUD treatment facilities with Medicaid patient data from 2017 to 2020 to test the model using a three‐stage least squares design and provide some of the first evidence on Medicaid patient outcomes under CON laws for SUD treatment facilities. We find significant evidence that state CON laws for SUD treatment facilities are associated with higher rates of hospital bed utilization, increases in the number of infants born with Neonatal Abstinence Syndrome, and higher rates of emergency department visits. Our findings are robust to several specification tests, including a model of conditional mixed method endogeneity and incorporating timing of the Affordable Care Act.

Effectiveness assessment of sulfur-containing amino acids in rats with experimental “alcohol withdrawal syndrome” with modified zoosocial interaction methods

The aim of the work was to compare the effects of ademethionine, acetylcysteine and taurine on the zoosocial behavior of rats in a post-intoxicated state after an acute ethanol poisoning.Materials and methods. The study was conducted on male rats of the Wistar line. The post-intoxication state was modeled by a single injection of ethanol (3 g/kg, intraperitoneally). 30 min after awakening, the animals were injected with a physiological solution, acetylcysteine (1 g/kg), ademetionine (100 mg/kg) or taurine (40 mg/kg). A zoosocial interaction test was performed 30 min after the administration.Results. Among the behavioral indicators investigated, the following were validated: the number of acts of freezing, their duration, the number of acts of sniffing in front, the number of acts of avoidance and the number of vertical stances without support (p <0.05 between the values of the negative and positive control groups in all cases). The administration of acetylcysteine, ademetionine and taurine reduced the number of freezing acts by 53.64, 7.27 and 24.51%, respectively (p <0.05 when compared with the indicator index in the animals from the positive control group in all cases). The administration of acetylcysteine and taurine reduced the number of avoidance acts by 50 and 10%, respectively (p <0.05 when compared to that of the animals from the positive control group in both cases). All amino acids normalized the communicative performance, although it did not differ from that of the animals from the positive control group (p >0.05). Alcoholization reduced the number of vertical stances by 65% (p <0.001 when compared with that in the animals from the negative control group), and when followed by the administration of ademetionine and taurine, the reduction was 38 and 36%, respectively (p <0.05 when compared to that in the animals from the negative control group).Conclusion. According to the data obtained, sulfur-containing amino acids, primarily those that had central effects, normalized neuronal functions, positively influencing a complex behavior of rats. Taking into account the results of the previous studies, it was possible to conclude that the therapeutic effect of ademetionine and taurine in the context of a post-intoxication state is mediated by their central effects, which are not so pronounced in comparison with acetylcysteine.

Social media group support for antidepressant deprescribing: a mixed-methods survey of patient experiences.

Background Antidepressant use has continually increased in recent decades and although they are an effective treatment for moderate-to-severe depression, when there is no longer a clinical benefit, deprescribing should occur. Currently, routine deprescribing is not part of clinical practice and research shows that there has been an increase in antidepressant users seeking informal support online. This small scoping exercise used a mixed-methods online survey to investigate the motives antidepressant users have for joining social media deprescribing support groups, and what elements of the groups are most valuable to them. Methods Thirty members of two antidepressant deprescribing Facebook groups completed an online survey with quantitative and open-text response questions to determine participant characteristics and motivation for group membership. Quantitative data were analysed using descriptive statistics, and open-text responses were analysed thematically through NVivo. Results Two overarching themes were evident: first, clinician expertise , where participants repeatedly reported a perceived lack of skills around deprescribing by their clinician, not being included in shared decision-making about their treatment, and symptoms of withdrawal during deprescribing going unaddressed. Motivated by the lack of clinical support, peer support developed as the second theme. Here, people sought help online where they received education, knowledge sharing and lived experience guidance for tapering. The Facebook groups also provided validation and peer support, which motivated people to continue engaging with the group. Conclusions Antidepressant users who wish to cease their medication are increasingly subscribing to specialised online support groups due to the lack of information and support from clinicians. This study highlights the ongoing need for such support groups. Improved clinician understanding about the complexities of antidepressant deprescribing is needed to enable them to effectively engage in shared decision-making with their patients.

Efficacy of the QuitSure App for Smoking Cessation in Adult Smokers: Cross-Sectional Web Survey.

Cigarette smoking remains one of the leading causes of preventable death worldwide. A worldwide study by the World Health Organization concluded that more than 8 million people die every year from smoking, tobacco consumption, and secondhand smoke. The most effective tobacco cessation programs require personalized human intervention combined with costly pharmaceutical supplementation, making them unaffordable or inaccessible to most tobacco users. Thus, digital interventions offer a promising alternative to these traditional methods. However, the leading smartphone apps available in the market today have either not been studied in a clinical setting or are unable to match the smoking cessation success rates of their expensive offline counterparts. We would like to understand whether QuitSure, a novel smoking cessation app built by Rapidkart Online Private Limited, is able to bridge this efficacy gap and deliver affordable and effective smoking cessation at scale. Our objective was to do an initial exploration into the engagement, efficacy, and safety of QuitSure based on the self-reported experiences of its users. Outcomes measured were program completion, the effect of program completion on smoking behavior, including self-reported cessation outcomes, and negative health events from using the app. All QuitSure registered users who created their accounts on the QuitSure app between April 1, 2021, and February 28, 2022, were sent an anonymized web-based survey. The survey results were added to their engagement data on the app to evaluate the feasibility and efficacy of the app as a smoking cessation intervention. The data were analyzed using descriptive statistics (frequencies and percentages) and the χ2 test of independence. In total, 1299 users who had completed the QuitSure program submitted the survey and satisfied the inclusion criteria of the study. Of these, 1286 participants had completed the program more than 30 days before filling out the survey, and 1040 (80.1%, 95% CI 79.1%-82.6%) of them had maintained prolonged abstinence for at least 30 days after program completion. A majority of participants (770/891, 86.4%) who were still maintaining abstinence at the time of submitting the survey did not experience any severe nicotine withdrawal symptoms, while 41.9% (373/891) experienced no mild withdrawal symptoms either. Smoking quantity prior to completing the program significantly affected quit rates (P<.001), with heavy smokers (>20 cigarettes per day) having a lower 30-day prolonged abstinence rate (relative risk=0.91; 95% CI 90.0%-96.2%) compared to lighter smokers. No additional adverse events outside of known nicotine withdrawal symptoms were reported. The nature of web-based surveys and cohort selection allows for extensive unknown biases. However, the efficacy rates of survey respondents who completed the program were high and provide a case for further investigation in the form of randomized controlled trials on the QuitSure tobacco cessation program.

Pharmacologic profile of ITI-333: a novel molecule for treatment of substance use disorders.

Medications are urgently needed to treat symptoms of drug withdrawal and mitigate dysphoria and psychiatric comorbidities that drive opioid abuse and relapse. ITI-333 is a novel molecule in development for treatment of substance use disorders, psychiatric comorbidities, and pain. Characterize the preclinical profile of ITI-333 using pharmacological, behavioral, and physiological assays. Cell-based assays were used to measure receptor binding and intrinsic efficacy of ITI-333; animal models were employed to assess effects on opioid reinstatement, precipitated oxycodone withdrawal, and drug abuse liability. In vitro, ITI-333 is a potent 5-HT2A receptor antagonist (Ki = 8nM) and a biased, partial agonist atμ-opioid (MOP) receptors (Ki = 11nM; lacking β-arrestin agonism) with lesser antagonist activity at adrenergic α1A (Ki = 28nM) and dopamine D1 (Ki = 50nM) receptors. In vivo, ITI-333 blocks 5-HT2A receptor-mediated head twitch and MOP receptor-mediated effects on motor hyperactivity in mice. ITI-333 alone is a naloxone-sensitive analgesic (mice) which suppresses somatic signs of naloxone-precipitated oxycodone withdrawal (mice) and heroin cue-induced reinstatement responding without apparent tolerance or physical dependence after chronic dosing (rats). ITI-333 did not acutely impair gastrointestinal or pulmonary function (rats) and was not intravenously self-administered by heroin-maintained rats or rhesus monkeys. ITI-333 acts as a potent 5-HT2A receptor antagonist, as well a biased MOP receptor partial agonist with low intrinsic efficacy. ITI-333 mitigates opioid withdrawal/reinstatement, supporting its potential utility as a treatment for OUD.

ANK3 rs10994336 and ZNF804A rs7597593 polymorphisms: genetic interaction for emotional and behavioral symptoms of alcohol withdrawal syndrome

ObjectiveAlcohol withdrawal syndrome (AWS) is a complex condition associated with alcohol use disorder (AUD), characterized by significant variations in symptom severity among patients. The psychological and emotional symptoms accompanying AWS significantly contribute to withdrawal distress and relapse risk. Despite the importance of neural adaptation processes in AWS, limited genetic investigations have been conducted. This study primarily focuses on exploring the single and interaction effects of single-nucleotide polymorphisms in the ANK3 and ZNF804A genes on anxiety and aggression severity manifested in AWS. By examining genetic associations with withdrawal-related psychopathology, we ultimately aim to advance understanding the genetic underpinnings that modulate AWS severity.MethodsThe study involved 449 male patients diagnosed with alcohol use disorder. The Self-Rating Anxiety Scale (SAS) and Buss-Perry Aggression Questionnaire (BPAQ) were used to assess emotional and behavioral symptoms related to AWS. Genomic DNA was extracted from peripheral blood, and genotyping was performed using PCR.ResultsSingle-gene analysis revealed that naturally occurring allelic variants in ANK3 rs10994336 (CC homozygous vs. T allele carriers) were associated with mood and behavioral symptoms related to AWS. Furthermore, the interaction between ANK3 and ZNF804A was significantly associated with the severity of psychiatric symptoms related to AWS, as indicated by MANOVA. Two-way ANOVA further demonstrated a significant interaction effect between ANK3 rs10994336 and ZNF804A rs7597593 on anxiety, physical aggression, verbal aggression, anger, and hostility. Hierarchical regression analyses confirmed these findings. Additionally, simple effects analysis and multiple comparisons revealed that carriers of the ANK3 rs10994336 T allele experienced more severe AWS, while the ZNF804A rs7597593 T allele appeared to provide protection against the risk associated with the ANK3 rs10994336 mutation.ConclusionThis study highlights the gene-gene interaction between ANK3 and ZNF804A, which plays a crucial role in modulating emotional and behavioral symptoms related to AWS. The ANK3 rs10994336 T allele is identified as a risk allele, while the ZNF804A rs7597593 T allele offers protection against the risk associated with the ANK3 rs10994336 mutation. These findings provide initial support for gene-gene interactions as an explanation for psychiatric risk, offering valuable insights into the pathophysiological mechanisms involved in AWS.

Alcohol-related posterior reversible encephalopathy syndrome: a case report of a patient managed with a benzodiazepine-sparing regimen for alcohol withdrawal

ABSTRACT We report a case of posterior reversible encephalopathy syndrome (PRES) during treatment for alcohol withdrawal syndrome with gabapentin and clonidine. The patient developed severe hypertension, confusion and tremor, culminating in bilateral vision loss and a seizure. Imaging revealed posterior cerebral edema. Treatment with benzodiazepines, antihypertensives, and anti-seizure medications led to resolution. One year later, imaging showed resolution of the findings. We review the associated literature and propose the recognition of a PRES sub-entity, Alcohol-Related PRES (ARPRES), which can appear in the setting of alcohol withdrawal syndrome, chronic alcohol use, and acute alcohol intoxication, with or without hypertension.

The Health Costs of Cost-Sharing

Abstract What happens when patients suddenly stop their medications? We study the health consequences of drug interruptions caused by large, abrupt, and arbitrary changes in price. Medicare’s prescription drug benefit as-if-randomly assigns 65-year-olds a drug budget as a function of their birth month, beyond which out-of-pocket costs suddenly increase. Those facing smaller budgets consume fewer drugs and die more: mortality increases 0.0164 percentage points per month (13.9%) for each ${\$}$100 per month budget decrease (24.4%). This estimate is robust to a range of falsification checks, and lies in the 97.8th percentile of 544 placebo estimates from similar populations that lack the same idiosyncratic budget policy. Several facts help make sense of this large effect. First, patients stop taking drugs that are both ‘high-value,’ and suspected to cause life-threatening withdrawal syndromes when stopped. Second, using machine learning, we identify patients at the highest risk of drug-preventable adverse events. Contrary to the predictions of standard economic models, high-risk patients (e.g., those most likely to have a heart attack) cut back more than low-risk patients on exactly those drugs that would benefit them the most (e.g., statins). Finally, patients appear unaware of these risks. In a survey of 65-year-olds, only one-third believe that stopping their drugs for up to a month could have any serious consequences. We conclude that, far from curbing waste, cost-sharing is itself highly inefficient, resulting in missed opportunities to buy health at very low cost (${\$}$11,321 per life-year).

Maternal opioid use during pregnancy and the risk of neonatal opioid withdrawal syndrome in the offspring.

Neonatal opioid withdrawal syndrome (NOWS) is caused by sudden cessation from in utero exposure to opioids. The indications for opioid use during pregnancy are diverse including medication for opioid use disorder and analgesia. The opioid dose typically depends on the indication, with higher doses used for medication for opioid use disorder and lower doses used for analgesia. The aim of this study was to investigate the relationship between maternal opioid dose during pregnancy and the risk of NOWS. We conducted a historical multicenter cohort study of neonates prenatally exposed to opioids in Eastern Denmark during a six-year period from 2013 to 2018. The data was extracted from reviewing the individual's medical record(s), which were identified through a search of the Danish National Patient Register. Four groups (quartiles) according to maternal opioid dose during the last four weeks prior to delivery were compared. Unadjusted and adjusted logistic regression analyses were conducted to examine the risk of NOWS while controlling for relevant covariates. A total of 130 in utero opioid exposed neonates were included. The majority of the pregnant patients (88%) were treated with opioids for analgesic purposes. Overall, 52% of neonates developed NOWS. The cumulative incidence of NOWS was 21%, 28%, 67% and 91% at maternal average daily dose of morphine milligram equivalent during the last four weeks prior to delivery of 0.7-14 (group I), 14.3-38.6 (group II), 40-90 (group III) and 90.9-1440 (group IV), respectively. Compared to group I the adjusted odds (aOR) of NOWS increased significantly in group III (aOR 10.6 [2.9-39.1]) and group IV (aOR 37.8 [7.6-188.2]) but not in group II (aOR 1.5 [0.4-5.2]). No cases of NOWS were reported at maternal dose less than an average daily dose of five morphine milligram equivalent during the last four weeks prior to delivery. No significant changes in the incidence of NOWS were observed between 2013 and 2018. The odds of neonatal opioid withdrawal syndrome increased significantly as the maternal average daily dose of morphine milligram equivalent during the last four weeks prior to delivery surpassed 40.

Abstract PS12-03: p53 loss enables HR+ breast cancer escape from CDK4/6 inhibitor-induced quiescence via CDK2

Abstract Background: Inhibition of CDK4/6 kinases has led to improved clinical outcomes in hormone receptor positive (HR+) breast cancer. While these are highly effective therapies, only a minority of patients experience long-term disease control. We sought to determine the genomic configurations and underlying mechanisms associated with long-term response. Methods: To identify genomic patterns associated with clinical outcomes, we analyzed a cohort of 447 patients with metastatic HR+ breast cancer treated at MSK with first-line CDK4/6 inhibitors (CDK4/6i) for which tumor-normal sequencing and long-term clinical follow up were available. To identify the pattern of genomic features associated with longer, intermediate, and short response, we implemented an elastic net Cox regression on binary pathogenic variant status of each gene as well as select clinical features (prior endocrine therapy, endocrine therapy partner, de novo metastatic status). Our principal aim was variable interpretability over pure predictive accuracy. Human HR+ breast cancer models including human breast cancer organoids and cell lines were utilized for mechanistic studies. For validation in a clinical setting, we analyzed the association between Ki67 score after neoadjuvant ribociclib plus endocrine therapy and pre-treatment gene mutation from the FELINE trial [NCT02712723] using a Fisher exact test. Results: Our model identified a “longer response” group (n = 124, 27.7%) from patients with a median progression free survival (PFS) of 32.5 months, compared with an “intermediate” (n = 224, 50.1%, median PFS = 13.7 months) and “short response” group (n = 99, 22.1%, median PFS = 5.84 months). TP53 and MDM2 pathogenic variant status were the most important variables to stratify between these groups, obtaining variable selection frequencies of 1.0 and 0.93 and mean hazard ratios of 2.02 and 1.38, respectively. To elucidate the mechanisms whereby the p53 pathway supports long term response, we generated isogenic and patient derived models of TP53 loss or MDM2 overexpression. Using immunoblotting and cell cycle assays, we found that drug-treated p53 KO cells and MDM2 overexpressing cells effectively suppressed RB1 phosphorylation and blocked in G1 after 24-48 hours. However, upon drug withdrawal, these cells could reenter the cell cycle and promote long-term tumor outgrowth. These effects we observed both in vitro and in vivo. Measures of long-term CDK4/6i response such as expression of senescence associated secretory phenotype genes was abrogated by TP53 loss. Mechanistically, we found persistent phosphorylation of the p130 RB1-like protein in the p53 KO cells. Phosphorylation of p130 impaired its interaction with E2F4, thereby blocking DREAM complex assembly and promoting cell cycle reentry. Inhibition of phosphorylation of p130 via p21 overexpression or by selective CDK2 inhibitors could restore irreversible cell cycle arrest in p53 KO cells. The combination of CDK2 and CDK4/6 inhibition led to long-term tumor growth suppression in models with mutant TP53. To validate the human relevance of TP53 mediating CDK4/6i response, we analyzed longitudinal samples from the FELINE trial that evaluated efficacy and feasibility of neoadjuvant ribociclib plus endocrine therapy. Of 45 evaluable patients, 13 (28.9%) harbored a pre-treatment TP53 loss of function variant. Of these 13 cases, 7 (53.8%) did not achieve a low ( &amp;lt; 10%) Ki-67 upon surgical resection as compared to TP53 wildtype tumors (n=32), only one (3.2%) of which did not achieve a low Ki-67 [OR 32.1, 95% CI 3.28 – 1660.3, p = 0.00026]. Conclusion: Loss of p53 was strongly associated with lack of long-term response to CDK4/6i in patients. Complete inhibition of both CDK4/6 and CDK2 appears to be necessary in order to convert quiescent HR+ tumors cells into durably inhibited and effectively dormant cancers. Citation Format: Rei Kudo, Anton Safonov, Edaise M. da Silva, Qing Li, Hong Shao, Marie Will, Harikrishna Nakshatri, Jorge Reis-Filho, Shom Goel, Andrew Koff, Britta Weigelt, Qamar Khan, Pedram Razavi, Sarat Chandarlapaty. p53 loss enables HR+ breast cancer escape from CDK4/6 inhibitor-induced quiescence via CDK2 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS12-03.

European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and therapy of glucocorticoid-induced adrenal insufficiency.

Glucocorticoids are widely prescribed as anti-inflammatory and immunosuppressive agents. This results in at least 1% of the population using chronic glucocorticoid therapy, being at risk for glucocorticoid-induced adrenal insufficiency. This risk is dependent on the dose, duration and potency of the glucocorticoid, route of administration, and individual susceptibility. Once glucocorticoid-induced adrenal insufficiency develops or is suspected, it necessitates careful education and management of affected patients. Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency. In general, tapering of glucocorticoids can be more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing. The degree and persistence of HPA axis suppression after cessation of glucocorticoid therapy are dependent on overall exposure and recovery of adrenal function varies greatly amongst individuals. This first European Society of Endocrinology/Endocrine Society joint clinical practice guideline provides guidance on this clinically relevant condition to aid clinicians involved in the care of patients on chronic glucocorticoid therapy.

Tailor-Made Doses of Pharmaceuticals by Tunable Modular Design: A Case Study on Tapering Antidepressant Medication.

An abrupt cessation of antidepressant medication can be challenging due to the appearance of withdrawal symptoms. A slow hyperbolic tapering of an antidepressant, such as citalopram hydrobromide (CHB), can mitigate the withdrawal syndrome. However, there are no viable dosage forms on the market to implement the tapering scheme. A solution using a tunable modular design (TMD) approach to produce flexible and accurate doses of CHB is proposed. This design consists of two parts: 1) a module with a fixed amount of preloaded CHB in a freeze-dried polymer matrix, and 2) fine-tuning the CHB dose by inkjet printing. A noncontact food-grade printer, used for the first time for printing pharmaceuticals, is modified to allow for accurate printing of the highly concentrated CHB ink on the porous CHB-free or CHB-preloaded modules. The produced modules with submilligram precision are bench-marked with commercially available CHB tablets that are manually divided. The TMD covers the entire range of doses needed for the tapering (0.5-23.8mg). The greatest variance is 13% and 88% when comparing the TMD and self-tapering, respectively. Self-tapering is proven inaccurate and showcases the need for the TMD to make available accurate and personalized doses to wean off treatment with CHB.

Kratom addiction per DSM-5 SUD criteria, and kratom physical dependence: Insights from dosing amount versus frequency

BackgroundKratom products are widely used in the United States, with inadequate understanding of how dosing amounts/frequencies relate to outcomes. MethodsBetween July-November 2022, we enrolled 395 active US adult kratom consumers into a remote study with a baseline survey. We examined self-reported typical dose amounts and frequencies across people and product types, and their associations with outcomes: multiple regression was used to examine whether amounts and frequencies (doses/day) were associated with acute effects, withdrawal symptoms, scores on the Subjective Opioid Withdrawal Scale (SOWS), and addiction (operationalized as DSM-5-based symptoms of kratom-use disorder, KUD). ResultsParticipants were 54.9% male, aged 38.1 on average, and 81.3% White. Mean length of kratom use was 5.7 years. Most (95.9%) reported regularly using whole-leaf kratom products; 16 (4.1%) reported regular extract use. SOWS scores were mild to moderate on average (13.5, SD 11.9). KUD symptom counts were mostly in the mild/moderate range (80.7%). Withdrawal and KUD symptoms were more closely associated with dose frequency than dose amount. Men reported more acute effects, withdrawal symptoms with cessation, and KUD symptoms than women. ConclusionsGreater dose amount and frequency were systematically related to the number of withdrawal symptoms upon cessation and to KUD symptoms; the relationship was stronger for dose frequency than amount. Men may have more acute effects and more withdrawal and KUD symptoms than women. Although kratom may be used nonproblematically by some consumers, physical dependence (tolerance, withdrawal, or use to avoid withdrawal) and KUD become more likely with increasing dose frequency.

Detecting Substance Use Disorder Using Social Media Data and the Dark Web: Time- and Knowledge-Aware Study.

Opioid and substance misuse has become a widespread problem in the United States, leading to the "opioid crisis." The relationship between substance misuse and mental health has been extensively studied, with one possible relationship being that substance misuse causes poor mental health. However, the lack of evidence on the relationship has resulted in opioids being largely inaccessible through legal means. This study aims to analyze social media posts related to substance use and opioids being sold through cryptomarket listings. The study aims to use state-of-the-art deep learning models to generate sentiment and emotion from social media posts to understand users' perceptions of social media. The study also aims to investigate questions such as which synthetic opioids people are optimistic, neutral, or negative about; what kind of drugs induced fear and sorrow; what kind of drugs people love or are thankful about; which drugs people think negatively about; and which opioids cause little to no sentimental reaction. The study used the drug abuse ontology and state-of-the-art deep learning models, including knowledge-aware Bidirectional Encoder Representations From Transformers-based models, to generate sentiment and emotion from social media posts related to substance use and opioids being sold through cryptomarket listings. The study crawled cryptomarket data and extracted posts for fentanyl, fentanyl analogs, and other novel synthetic opioids. The study performed topic analysis associated with the generated sentiments and emotions to understand which topics correlate with people's responses to various drugs. Additionally, the study analyzed time-aware neural models built on these features while considering historical sentiment and emotional activity of posts related to a drug. The study found that the most effective model performed well (statistically significant, with a macro-F1-score of 82.12 and recall of 83.58) in identifying substance use disorder. The study also found that there were varying levels of sentiment and emotion associated with different synthetic opioids, with some drugs eliciting more positive or negative responses than others. The study identified topics that correlated with people's responses to various drugs, such as pain relief, addiction, and withdrawal symptoms. The study provides insight into users' perceptions of synthetic opioids based on sentiment and emotion expressed in social media posts. The study's findings can be used to inform interventions and policies aimed at reducing substance misuse and addressing the opioid crisis. The study demonstrates the potential of deep learning models for analyzing social media data to gain insights into public health issues.

Opioid Use Disorder among Hospitalized Adults in North Carolina: Analysis from the 2000-2020 NC State Inpatient Database.

Opioid use disorder (OUD) is characterized as a chronic condition that was first outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and now the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision. It encompasses frequent opioid usage, cravings, the development of tolerance, withdrawal symptoms upon discontinuation, unsuccessful attempts to quit or reduce use, and recurrent use even when faced with negative consequences. Both national- and state-level data show that overdose deaths associated with prescription opioids are increasing at an alarming rate. The increasing overdose deaths from illicitly manufactured fentanyl and other synthetic opioids compound this epidemic's burden. The present study sought to determine the prevalence and potential factors associated with OUD in North Carolina. Using the State Inpatient Database, a retrospective cross-sectional study was conducted to identify OUD-related discharges between 2000 and 2020. Descriptive statistics and rates of OUD per 1000 discharges were calculated. Simple and multivariable logistic regression models were used to identify factors associated with increased odds of having an opioid use disorder diagnosis at discharge. The deviance-Pearson goodness of fit statistic was also used. Variables were identified using International Classification of Diseases, Ninth Revision, Clinical Modification, and International Classification of Diseases, Tenth Revision, Clinical Modification, codes in the discharge records. Of 19,370,483 hospitalizations that occurred between 2000 and 2020 in North Carolina, 483,250 were associated with OUD, a prevalence rate of 24.9 cases per 1000 discharges. The highest OUD rates were seen among adults who self-paid for their hospitalization, those with Medicaid, and those with other types of payors such as Workers' Compensation and the Indian Health Service; individuals between 25 and 54 years old; tobacco and alcohol users; Native American patients; patients located in urban areas; patients with lower household income; White patients; and female patients. OUD also was associated with increased odds of having one or more comorbid psychiatric disorders when controlling for other factors. Although preventive measures are crucial, including policies that discourage prescribing opioids for noncancer pain and those that target the manufacturing and distribution of synthetic opioids, providing integrated care for patients with OUD and co-occurring psychiatric and/or physical disorders is equally important. These findings suggest the need for a system-wide public health response focused on the expansion of primary prevention and treatment efforts, including crisis services, harm reduction services, and recovery programs.

Molecular and functional characterization of reversible-sunitinib-tolerance state in human renal cell carcinoma.

Therapy failure with the tyrosine kinase inhibitor (TKI) sunitinib remains a great challenge in metastatic renal cell carcinoma (mRCC). Growing evidence indicates that the tumour subpopulation can enter a transient, non-mutagenic drug-tolerant state to endure the treatment underlying the minimal residual disease and tumour relapse. Drug tolerance to sunitinib remains largely unexplored in RCC. Here, we show that sunitinib-tolerant 786-O/S and Caki-2/S cells are induced by prolonged drug treatment showing reduced drug sensitivity, enhanced clonogenicity, and DNA synthesis. Sunitinib-tolerance developed via dynamic processes, including (i) engagement of c-MET and AXL pathways, (ii) alteration of stress-induced p38 kinase and pro-survival BCL-2 signalling, (iii) extensive actin remodelling, which was correlated with activation of focal adhesion proteins. Remarkably, the acute drug response in both sensitive and sunitinib-tolerant cell lines led to dramatic fine-tuning of the actin-cytoskeleton and boosted cellular migration and invasion, indicating that the drug-response might depend on cell state transition rather than pre-existing mutations. The drug-tolerant state was transiently acquired, as the cells resumed initial drug sensitivity after >10 passages under drug withdrawal, reinforcing the concept of dynamic regulation and phenotypic heterogeneity. Our study described molecular events contributing to the reversible switch into sunitinib-tolerance, providing possible novel therapeutic opportunities in RCC.

Evaluation of multitarget drugs on the expression of cocaine-induced locomotor sensitization in male rats: A comparative study

Purpose— Cocaine use disorder (CUD) is a complex disease. Several studies have shown the efficacy of multitarget drugs used to treat CUD. Here we compare the efficacy of mirtazapine (MIR), pindolol (PIN), fluoxetine (FLX), risperidone (RIS), trazodone (TRZ), ziprasidone (ZPR), ondansetron (OND), yohimbine (YOH), or prazosin (PRZ), to reduce long-term cocaine-induced locomotor activity and the expression of cocaine-induced locomotor sensitization in rats. Methods— The study consists of four experiments, which were divided into four experimental phases. Induction (10 days), cocaine withdrawal (30 days), expression (10 days), and post-expression phase (10 days). Male Wistar rats were daily dosed with cocaine (10 mg/kg; i.p.) during the induction and post-expression phases. During drug withdrawal, the MIR, PIN, FLX, RIS, TRZ, ZPR, OND, YOH, or PRZ were administered 30 min before saline. In the expression, the multitarget drugs were administered 30 min before cocaine. After each administration, locomotor activity for each animal was recorded for 30 min.During the agonism phase, in experiment four, 8-OH-DPAT, DOI, CP-809-101, SR-57227A, or clonidine (CLO) was administered 30 min before MIR and 60 min before cocaine. After each administration, locomotor activity for each animal was recorded for 30 min. Results—MIR, FLX, RIS, ZPR, OND, or PRZ attenuated the cocaine-induced locomotor activity and cocaine locomotor sensitization. PIN, TRZ, and YOH failed to decrease cocaine locomotor sensitization. At the optimal doses used, PIN, FLX, RIS, TRZ, ZPR, OND, YOH, or PRZ failed to attenuate long-term cocaine locomotor activation. MIR generated a decrease in cocaine-induced locomotor activity of greater magnitude and duration than the other multitarget drugs evaluated. Conclusion— At the optimal doses of multitarget drugs evaluated, MIR was the multitarget drug that showed the greatest long-term cocaine-induced behavior effects compared to other multitarget drugs.

Study of the Level of Sports Addiction Among Students at the Faculty of Sports Science

The aim of this study was to investigate the exercise addiction of the students of the School of Physical Education and Sport and to determine the differences according to the type of exercise, age of exercise and load dynamics. The Exercise Addiction Scale (EBÖ-21) developed by Housenblas and Downs (2002) and the Turkish Validity and Reliability Study by Yeltepe and İkizler (2007) and the Personal Information Form were applied to the sample group. The sample of the study consisted of 245 athletes who regularly train at Afyon Kocatepe University School of Physical Education and Sports. Studies on this subject indicate that addiction to sports is similar to addiction to chemical substances due to the presence of withdrawal and tolerance symptoms. The results of the study presented show that self-confidence and athletic performance increase as the students' level increases. When evaluating exercise addiction by gender, it was found that female students were more likely than male students to consider physical problems and show self-control and interruption of exercise behaviour. When evaluated by age, exercise addiction was found to have decreased and been brought under control in older individuals, indicating progress in self-control of addiction.

Adverse effects of criminal legal system involvement: a qualitative study examining the role of incarceration and reentry on substance use trajectories among women with opioid use disorders

BackgroundWomen with substance use disorders (SUDs) often experience adversity related to incarceration and reentry that can impact their substance use outcomes. This study aims to examine the adverse effects of incarceration and reentry on substance use outcomes among women with a history of opioid use disorder (OUD).MethodsWe carried out 42 semi-structured interviews (May–July 2022) with women with a history of criminal legal involvement and OUD (n = 20), criminal legal professionals (n = 10), and SUD treatment professionals (n = 12). The interviews focused on women’s substance use trajectories, barriers to treatment, and the intersection of the criminal legal system and treatment. None of the women were presently incarcerated during their interviews.ResultsParticipants expressed the severe adverse impact of criminal legal involvement on women with OUD. Many women felt traumatized by experiencing detox while incarcerated, especially as they received minimal aid for withdrawal symptoms. Women seeking recovery while incarcerated felt unsupported, being afforded few treatment options, and experiencing stigma. Reentering society after incarceration also posed significant challenges to women’s individual recovery goals. Reentry-related challenges such as returning to unsupportive environments, facing difficulties finding employment, lacking secure housing, and facing the stigma of incarceration triggered adverse outcomes, such as relapse among those who were seeking to avoid illicit substances.ConclusionsFindings suggest a need to evaluate detox protocols, medication for opioid use disorder (MOUD) access, and stigma in the criminal legal system. Interventions facilitating women’s reentry, reducing the combined stigma of incarceration and OUD, and restoring agency for women with OUD are also needed.

Clomiphene citrate and optional human chorionic gonadotropin for treating male hypogonadism arising from long-term anabolic-androgenic steroid use—A pilot study

IntroductionLong-term anabolic-androgenic steroid (AAS) use poses several health risks, including secondary hypogonadism. There is a knowledge gap on treatment targeting the hypothalamic-pituitary-gonadal (HPG) axis among men with anabolic steroid-induced hypogonadism (ASIH). This study aims to gain insights into the potential utility of endocrine therapy to restore endogenous testosterone levels and alleviate ASIH symptoms in AAS dependent men. MethodsIn this proof-of-concept, single-site, open longitudinal pilot study, AAS dependent men with continuous AAS use and a desire to permanently discontinue use, were given endocrine therapy. The treatment included 25 mg clomiphene citrate (CC) every second day for 16 weeks, transdermal testosterone daily during the first four weeks, and if indicated, human chorionic gonadotropin (hCG) injections for a maximum of eight weeks. Physical exams including blood collection and online questionnaires were completed every four and two weeks, respectively. ResultsTen participants, with median age 32 years (interquartile range 30–45), with mean ± standard deviation AAS use of 11 ± 4 years, completed the CC intervention. Seven participants received hCG as part of their treatment protocol. Mild adverse events included headaches, dizziness, and mood swings, and no serious adverse events occurred. During the intervention, there was a decrease in levels of hematocrit, hemoglobin and ALT (alanine aminotransferase), as well as an increase in serum FSH (follicle stimulating hormone), LH (luteinizing hormone) and SHBG (sex hormone binding globulin). Five of ten participants reached a total testosterone level within normal range (9–30 nmol/l). The HPG axis response varied greatly among participants, and was not aligned with the severity of ASIH related withdrawal symptoms. ConclusionsThe findings from this proof-of-concept study may guide future randomized controlled trials aiming to investigate potential endocrine therapeutic approaches to ASIH.