Withdrawal Symptoms Research Articles

Efficacy of Lemborexant in Adults ≥ 65 Years of Age with Insomnia Disorder.

Pharmacologic treatments are available to treat insomnia, a common and burdensome sleep disorder, but may be contraindicated in older adults who are prone to side effects from sleep-promoting drugs. These analyses of sleep diary data from Study E2006-G000-303 (Study 303) investigated the benefits of lemborexant 5mg (LEM5) and 10mg (LEM10) in the subgroup age ≥ 65years with insomnia. Study 303, a 12-month, double-blind study of LEM5 and LEM10 in adults (age ≥ 18years) with insomnia disorder (sleep onset and/or maintenance difficulties) assessed subject-reported (subjective) sleep-onset latency (sSOL), sleep efficiency (sSE), wake after sleep onset (sWASO), and total sleep time (sTST). Morning sleepiness/alertness, insomnia severity (Insomnia Severity Index [ISI]), fatigue (Fatigue Severity Scale [FSS]), perceptions of sleep-related medication effects (Patient Global Impression-Insomnia [PGI-I] questionnaire), and safety were also evaluated. In this subgroup of older adults (≥ 65years; n = 262), there were significantly larger changes from baseline for sSOL, sSE, sTST, and sWASO with LEM5 and LEM10 versus placebo through month 6 (except sWASO month 1), indicating improvement; these improvements were sustained through month 12. Subject-reported increases in morning alertness were significantly greater with one or both LEM doses versus placebo through month 6 and sustained through month 12. There were significantly larger ISI total and daytime functioning score decreases (improvement) from baseline with LEM versus placebo at months 1, 3, and 6 (total score: both doses; daytime functioning: LEM5 month 1 and both doses months 3 and 6) and decreases from baseline FSS at months 1 and 3 (LEM5) and month 6 (both doses), sustained to month 12. Compared with placebo, more subjects reported that LEM (both doses) positively impacted ability to sleep, time to fall asleep, and TST through month 6, sustained to month 12, with no rebound after drug withdrawal. LEM was well tolerated to month 12; mild somnolence was the most common treatment-emergent adverse event. Improvements in subject-reported efficacy in LEM-treated adults age ≥ 65years with insomnia were observed as early as the first week of treatment and sustained through end of month 12. LEM was well tolerated. ClinicalTrials.gov identifier NCT02952820: E2006-G000-303; Study 303; SUNRISE-2 (First posted: October 2016); EudraCT 2015-001463-39 (First posted: November 2016).

Protein kinase C epsilon-mediated modulation of T-type calcium channels underlies alcohol withdrawal hyperexcitability in the midline thalamus.

Millions of people struggle with alcohol use disorder (AUD). Abrupt abstinence after a period of chronic alcohol use can precipitate the alcohol withdrawal syndrome (AWS), which includes hyperexcitability and, potentially, seizures. We have shown that T-type Ca2+ channels are novel, sensitive targets of alcohol, an effect that is dependent upon protein kinase C (PKC). The purpose of this study was to (1) understand midline thalamic neuronal hyperexcitability during alcohol withdrawal and its dependence on PKC; (2) characterize T channel functional changes using both current clamp and voltage clamp methods; and (3) determine which PKC isoform may be responsible for alcohol withdrawal (WD) effects. Whole-cell patch clamp recordings were performed in midline thalamic neurons in brain slices prepared from C57bl/6 mice that underwent chronic intermittent alcohol exposure in a standard vapor chamber model. The recordings were compared to those from air-exposed controls. T-channel inactivation curves and burst responses were acquired through voltage-clamp and current-clamp recordings, respectively. Whole-cell voltage clamp recordings of native T-type current exhibited a depolarizing shift in the voltage-dependency of inactivation during alcohol withdrawal compared to air-exposed controls. A PKCε translocation inhibitor peptide mitigated this change. Current clamp recordings demonstrated more spikes per burst during alcohol withdrawal. Consistent with voltage clamp findings, the PKCɛ translocation inhibitor peptide reduced the number of spikes per burst after WD. We found that alcohol WD produces T channel-mediated hyperexcitability in the midline thalamus, produced in part by a shift in the inactivation curve consistent with greater availability of T current. WD effects on T current inactivation were reduced to control levels by blocking PKCε translocation. Our results demonstrate that PKCε translocation plays an important role in the regulation of alcohol withdrawal-induced hyperexcitability in midline thalamic circuitry.

Staged Bilateral MRI-Guided Focused Ultrasound Subthalamotomy for Parkinson Disease.

Unilateral magnetic resonance imaging (MRI)-guided focused ultrasound subthalamotomy (FUS-STN) improves cardinal motor features among patients with asymmetrical Parkinson disease (PD). The feasibility of bilateral FUS-STN is as yet unexplored. To assess the safety and effectiveness of staged bilateral FUS-STN to treat PD. This prospective, open-label, case series study was conducted between June 18, 2019, and November 7, 2023, at HM-CINAC, Puerta del Sur University Hospital, Madrid, Spain, and included 6 patients with PD who had been treated with unilateral FUS-STN contralateral to their most affected body side and whose parkinsonism on the untreated side had progressed and was not optimally controlled with medication. Staged bilateral FUS-STN. Primary outcomes were assessed 6 months after the second treatment and included safety (incidence and severity of adverse events after second treatment) and effectiveness in terms of motor change (measured with the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III [MDS-UPDRS III]) in the off-medication state (ie, after at least 12 hours of antiparkinsonian drug withdrawal) compared with baseline (ie, prior to the first side ablation). Secondary outcomes included motor change in patients in the on-medication state (ie, after usual antiparkinsonian medication intake), motor complications (measured with the MDS-UPDRS IV), daily living activities (measured with the MDS-UPDRS I-II), quality of life (measured with the 39-item Parkinson's Disease Questionnaire), change in dopaminergic treatment, patient's global impression of change (measured with the Global Impression of Change [PGI-C] scale), and long-term (24-month) follow-up. Of 45 patients previously treated with unilateral FUS-STN, 7 were lost to follow-up, and 4 were excluded due to adverse events. Of the remaining 34 patients, 6 (median age at first FUS-STN, 52.6 years [IQR, 49.0-57.3 years]; 3 women [50%]) experienced progression of parkinsonism on the untreated body side and were included. At the time of the first FUS-STN, patients' median duration of disease was 5.7 years (IQR, 4.7-7.3 years). The median time between procedures was 3.2 years (IQR, 1.9-3.5 years). After the second FUS-STN, 4 patients presented with contralateral choreic dyskinesia, which resolved by 3 months. Four patients developed speech disturbances, which gradually improved but remained in a mild form for 2 patients at 6 months; 1 patient experienced mild imbalance and dysphagia during the first week after treatment, which subsided by 3 months. No behavioral or cognitive disturbances were found on neuropsychological testing. For patients in the off-medication state, MDS-UPDRS III scores improved by 52.6% between baseline and 6 months after the second FUS-STN (from 37.5 [IQR, 34.2-40.0] to 20.5 [IQR, 8.7-24.0]; median difference, 23.0 [95% CI, 7.0-33.7]; P = .03). The second treated side improved by 64.3% (MDS-UPDRS III score, 17.0 [IQR, 16.0-19.5] prior to the second treatment vs 5.5 [IQR, 3.0-10.2]; median difference, 9.5 [95% CI, 3.2-17.7]; P = .02). After the second procedure, all self-reported PGI-C scores were positive. Findings of this pilot study suggest that staged bilateral FUS-STN was safe and effective for the treatment of PD, although mild but persistent speech-related adverse events were observed among a small number of patients.

Knowledge, Perception, and Associated Factors of Electronic Cigarette Consumption Among the Saudi Population in Jeddah City.

Introduction Electronic cigarettes(e-cigarettes) are rising in popularity among young adults and teenagers. Previous studies have shown that among high and middle schoolers, the percentage of e-cigarette smokers was noticeably higher than tobacco cigarette smokers. Various research papers focusing on different communities have reported a low-to-moderate level of knowledge and awareness of e-cigarette's effects on health. E-cigarettes were initially advertised as devices to help people quit smoking, but the use of e-cigarettes in modern days has changed considerably. A big chunk of the population perceivedthat e-cigarettes have no harmful effects because they are nicotine-free and thus are used as a replacement for regular cigarettes rather than as a way to quit smoking. Objectives The study aimed to assess the perception of e-cigarette consumption and associated factors among the Saudi population in Jeddah city. Methodology A cross-sectional study was conducted on the Saudi population in Jeddah, Saudi Arabia, during the year 2023. The study assessed the participant's perceptions of e-cigarette consumption and its risk factors. A pre-existing online questionnaire created by Google Forms was distributed among the population through social media applications to collect data after obtaining their informed consent. Results A total of 515 participants were included in this study. Relatives and friends were the most common sources (54%) for information about e-cigarettes. Of the sample, 17.5% thought that e-cigarettes were safer than conventional cigarettes, 13.4% used e-cigarettes on a regular basis, and 65% had not smoked electronically before. Vaping pushed only 17.2% to try traditional tobacco cigarettes, and 25% stopped using traditional tobacco products after starting to smoke e-cigarettes. Gender, age group, and total family salary were the associated factors with the use of e-cigarettes. In addition, an association between the perception of e-smoking and its use was noticed, as well as a significant association between gender and withdrawal symptoms. Conclusion A minority of the participants perceived that e-cigarette smoking is safer than conventional methods of smoking. The majority did not practice e-smoking at all. Furthermore, results showed that relatives and friends were the most common sources of information. The findings from the correlation testing underscore several noteworthy associations within the studied population. Notably, gender, age, total family salary, and occupation exhibited statistically significant correlations with e-cigarette usage.

Post-Overdose Extended-Release Buprenorphine Initiation Facilitated by a Partnership Between Emergency Medical Services and an Outpatient Substance Use Disorder Observation Unit.

People who experience a nonfatal opioid overdose and receive naloxone are at high risk of subsequent overdose death but experience gaps in access to medications for opioid use disorder. The immediate post-naloxone period offers an opportunity for buprenorphine initiation. Limited data indicate that buprenorphine administration by emergency medical services (EMS) after naloxone overdose reversal is safe and feasible. We describe a case in which a partnership between a low-barrier substance use disorder (SUD) observation unit and EMS allowed for buprenorphine initiation with extended-release injectable buprenorphine after naloxone overdose reversal. A man in his 40's with severe opioid use disorder and numerous prior opioid overdoses experienced overdose in the community. EMS was activated and he was successfully resuscitated with intranasal naloxone, administered by bystanders and EMS. He declined emergency department (ED) transport and consented to transport to a 24/7 SUD observation unit. The patient elected to start buprenorphine due to barriers attending opioid treatment programs daily. His largest barrier was unsheltered homelessness. His severe opioid withdrawal symptoms were successfully treated with 16/4 mg sublingual buprenorphine/naloxone and 300 mg extended-release injectable buprenorphine (XR-buprenorphine), without precipitated withdrawal. Two weeks later, he reported no interval fentanyl use. We describe the case of a patient successfully initiated onto XR-buprenorphine in the immediate post-naloxone period via a partnership between an outpatient low-barrier addiction programs and EMS. Such partnerships offer promise in expanding buprenorphine access and medication choice, particularly for the high-risk population of patients who decline ED transport.

Gradually tapering off antipsychotics: lessons for practice from case studies and neurobiological principles.

There has been an increasing focus on deprescribing in psychiatry recently, particularly of antipsychotic medication, with recognition that not all patients with psychotic disorders require lifelong medication. We summarize some empirical and theoretical papers, and examine case studies to provide instruction on this topic. Recent studies have found that slower tapering (over months or longer) of antipsychotics is associated with a lower relapse rate than quicker tapering (weeks). Case studies presented suggest that the process of reduction is associated with the precipitation or exacerbation of psychotic symptoms and that a slower process of reduction may minimize this effect. This may be because faster reductions cause greater disruption of homeostatic equilibria, provoking psychotic symptoms either as direct withdrawal symptoms or consequences of nonpsychotic withdrawal symptoms (e.g. insomnia) - although not all patients will experience withdrawal symptoms. This suggests that smaller dose reductions, especially at lower doses, made very gradually, may minimize the risk of psychotic symptoms. Slower tapering of antipsychotics may provide time for adaptations made to the presence of the medications to resolve, thus reducing the disruption to homeostatic equilibrium caused by dose reduction, potentially reducing the risk of relapse. Exacerbation of psychotic symptoms on antipsychotic reduction may not represent evidence of the need for a higher dose of antipsychotic on a long-term basis but may indicate the need for more gradual reduction. Gradual reduction of antipsychotics, especially after long-term use in clinical practice is prudent.

Substance Addiction Rehabilitation Drugs

The relapse rate of substance abusers is high, and addiction rehabilitation adjunct drugs need to be developed urgently. There have been numerous reports on blocking the formation of substance addiction, but studies on drugs that can alleviate withdrawal symptoms are very limited. Both the dopamine transporter (DAT) hypothesis and D3 dopamine receptor (D3R) hypothesis are proposed. DAT activators reduce the extracellular dopamine level, and D3R antagonists reduce the neuron’s sensitivity to dopamine, both of which may exacerbate the withdrawal symptoms subsequently. The D3R partial agonist SK608 has biased signaling properties via the G-protein-dependent pathway but did not induce D3R desensitization and, thus, may be a promising drug for the withdrawal symptoms. Drugs for serotoninergic neurons or GABAergic neurons and anti-inflammatory drugs may have auxiliary effects to addiction treatments. Drugs that promote structural synaptic plasticity are also discussed.

Current Therapeutic Strategies for the Management of Benzodiazepine (BZD) Withdrawal Syndrome: A Review.

Benzodiazepines are commonly prescribed drugs for numerous indications such as epilepsy, anti-anxiety, sleep aids, sedatives, and hypnotics. Although the well-tolerated effects of benzodiazepine are seen in many clinical instances, the severity of side effects reduces its quantifiable use. Benzodiazepines, which are medically useful but theoretically unsafe, are frequently recommended by medical practitioners for psychotic patients but have misuse and dependence liabilities. It is impelled as a debateable topic globally about which no one talks. These drugs are also known as silent killers because abruptly stopping them can result in tremors, muscle spasticity, and life-frightening seizures. These drugs are beneficial as well as risky. Nonclinical treatment is simple and well suited and provides support for patients suffering from side effects generated by benzodiazepine withdrawal. This review mainly focuses on antipsychotic drugs and their mechanisms, mortality, withdrawal, abuse, and management via clinical and nonclinical therapies.

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.

Prenatal opioid exposure by likelihood of exposure and risk to prenatal development: Medicaid-covered births in Wisconsin, 2010-2019.

Prenatal opioid exposure is an established public health problem, in particular among Medicaid-covered births. Yet, existing prevalence rates are plausibly underestimated. We leverage extensive linked longitudinal administrative data for all Medicaid-covered live births in Wisconsin from 2010 to 2019 to estimate a range of prevalence rates using an innovative strategy that jointly accounts for both likelihood of exposure and potential risk to prenatal development. We find that 20.8% of infants may have been prenatally exposed to opioids, with 1.7% diagnosed with neonatal abstinence syndrome and an additional 1.2% having a high combined likelihood of exposure and potential risk to prenatal development, 2.6% a moderate combined likelihood and risk, and 15.3% a low or uncertain combined likelihood and risk. We assess improvements in prevalence estimates based on our nuanced classification relative to those of prior studies. Our strategy could be broadly used to quantify the scope of the opioid crisis for pregnant populations, target interventions, and promote child health and development.

Treatment for Neonatal Abstinence Syndrome using Nonpharmacological Interventions.

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. 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. 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). 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. · 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..

A Comprehensive Review on Weight Gain following Discontinuation of Glucagon-Like Peptide-1 Receptor Agonists for Obesity

Obesity is considered the leading public health problem in the medical sector. The phenotype includes overweight conditions that lead to several other comorbidities that drastically decrease health. Glucagon-like receptor agonists (GLP-1RAs) initially designed for treating type 2 diabetes mellitus (T2DM) had demonstrated weight loss benefits in several clinical trials. In vivo studies showed that GLP-1RA encourages reduced food consumption and consequent weight reduction by stimulating brown fat and enhancing energy outlay through the action of the sympathetic nervous system (SNS) pathways. Additionally, GLP-1RAs were found to regulate food intake through stimulation of sensory neurons in the vagus, interaction with the hypothalamus and hindbrain, and through inflammation and intestinal microbiota. However, the main concern with the use of GLP-1RA treatment was weight gain after withdrawal or discontinuation. We could identify three different ways that could lead to weight gain. Potential factors might include temporary hormonal adjustment in response to weight reduction, the central nervous system’s (CNS) incompetence in regulating weight augmentation owing to the lack of GLP-1RA, and β-cell malfunction due to sustained exposure to GLP-1RA. Here, we also review the data from clinical studies that reported withdrawal symptoms. Although the use of GLP-1RA could be beneficial in multiple ways, withdrawal after years has the symptoms reversed. Clinical studies should emphasize the downside of these views we highlighted, and mechanistic studies must be carried out for a better outcome with GLP-1RA from the laboratory to the bedside.

Recent insights in the correlation between social media use, personality traits and exercise addiction: a literature review

Introduction and aimThe excessive involvement in physical activity without stopping in between sessions despite injuries, the continuous thinking to exercise feeling insane thoughts and experiencing withdrawal symptoms are all characteristics of the Exercise Addiction (EA), an addictive behavior. While the primary exercise addiction is directly caused by compulsive exercise, many studies highlighted the relationship between Eating Disorders (ED) and EA, defining the secondary EA. The correlation between EA, social media use (SMU) and other individual traits remains a relatively underexplored domain. Therefore, this review aimed to examine the latest evidence on the relationship between EA, SMU, and some personality traits such as perfectionism and body image.MethodsElectronic databases including PubMed, Medline, PsycARTICLES, Embase, Web of Science were searched from January 2019 to October 2023, following the PRISMA guidelines.ResultsA total of 15 articles were examined and consolidated in this review. EA was found to be related to different individual traits such perfectionism, body dissatisfaction, depression, obsessive-compulsive personality disorders. While controversial results were found regarding the relationship between EA and SMU.ConclusionThe interaction between mental health, exercise addiction and social media use is complex. Excessive engagement in these latter may result in negative mental health consequences despite their potential benefits. Understanding individual differences and developing effective interventions is crucial to promoting healthy habits and mitigating the EA risks, ultimately enhancing mental well-being. Further research should focus on the identification of risks and protective factors with the eventual aim of developing and implementing effective prevention strategies.

Predictors of cocaine use disorder treatment outcomes: a systematic review

BackgroundPsychosocial approaches are the first-line treatments for cocaine dependence, although they still present high dropout and relapse rates. Thus, there is a pressing need to understand which variables influence treatment outcomes to improve current treatments and prevent dropout and relapse rates. The aim of this study is to explore predictors of treatment retention and abstinence in CUD.MethodsThis systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We searched three databases—PubMed, PsychINFO and Web of Science—for randomized clinical trials (RCTs) published in English and Spanish from database inception through April 1, 2023. We selected all studies that met the inclusion criteria (adults aged ≥ 18, outpatient treatment, CUD as main addiction, and no severe mental illness) to obtain data for the narrative synthesis addressing cocaine abstinence and treatment retention as main outcome variables. After data extraction was completed, risk of bias was assessed using the Cochrane risk-of-bias tool for randomized trials (RoB-2).ResultsA total of 566 studies were screened, and, of those, 32 RCTs were included in the synthesis. Younger age, more years of cocaine use, and craving levels were significant predictors of relapse and treatment dropout. Fewer withdrawal symptoms, greater baseline abstinence, greater treatment engagement, and more self-efficacy were all predictors of longer duration of abstinence. The role of impulsivity as a predictor of CUD is unclear due to conflicting data, although the evidence generally suggests that higher impulsivity scores can predict more severe addiction and withdrawal symptoms, and earlier discontinuation of treatment.ConclusionCurrent evidence indicates which variables have a direct influence on treatment outcomes, including well-studied cocaine use-related variables. However, additional variables, such as genetic markers, appear to have a high impact on treatment outcomes and need further study.Systematic review registrationThis systematic review is registered at PROSPERO (ID: CRD42021271847). This study was funded by the Spanish Ministry of Science, Innovation and Universities, Instituto Carlos III (ISCIII) (FIS PI20/00929) and FEDER funds and Fundació Privada Hospital de la Santa Creu i Sant Pau (Pla d’acció social 2020).

The impact of methamphetamine on psychosocial variables in patients from Iraq

BackgroundThe current work reviews the psychosocial factors associated with different urinary methamphetamine concentration levels.MethodsFrom April to November 2023, 243 participants from Baghdad’s Al-Ataa Hospital were the subjects of a cross-sectional descriptive analysis study. We included 73 patients in this study.ResultThe urinary methamphetamine concentration levels were from 3 to 92,274 ng/ml, with a mean ± SD of 10,873.6 ± 18,641. Patients diagnosed with major depression disorder exhibited higher scores on GHQ-30, UCLA, MOAS, and BDI-II with a significant P-value of 0.0001, 0.001, 0.0001, and 0.0001, consequently with an effect size of 0.015, 0.001, 1.05, and 3.24, respectively.ConclusionsThe multi-screening test can produce a false positive. It frequently interferes with other drugs, especially antidepressants. This will result in patients being stigmatized and accused. On the other hand, those who accidentally come into contact with crystal smoke will experience the same withdrawal symptoms as the addicted patients. Their urinary methamphetamine level (titer) could have negative results. Urinary methamphetamine levels should be zero in healthy patients. In this situation, screening tests, expert opinion, and urine methamphetamine testing are strongly recommended.

Biochemical, Hematological, Inflammatory, and Gut Permeability Biomarkers in Patients with Alcohol Withdrawal Syndrome with and without Delirium Tremens

Background: Delirium Tremens (DT) is known to be a serious complication of alcohol withdrawal syndrome (AWS). Neurotransmitter abnormalities, inflammation, and increased permeability are associated with the pathogenesis of AWS and DT. However, the biomarkers of these conditions are still poorly understood. Methods: In this work, biochemical, hematologic, inflammatory, and gut permeability biomarkers were investigated in the following three groups: healthy controls (n = 75), severe AWS patients with DT (n = 28), and mild/moderate AWS without DT (n = 97). Blood sampling was performed after resolution of the acute condition (on 5 ± 1 day after admission) to collect clinical information from patients and to investigate associations with clinical scales. Biomarker analysis was performed using automated analyzers and ELISA. Inflammatory biomarkers included the erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (hsCRP), and platelet-to-lymphocyte ratio (PLR). Results: Among the biochemical biomarkers, only glucose, total cholesterol, and alanine aminotransferase (ALT) changed significantly in the analyzed groups. A multiple regression analysis showed that age and ALT were independent predictors of the CIWA-Ar score. Hematologic biomarker analysis showed an increased white blood cell count, and the elevated size and greater size variability of red blood cells and platelets (MCV, RDWc, and PDWc) in two groups of patients. Gut permeability biomarkers (FABP2, LBP, and zonulin) did not change, but were associated with comorbid pathologies (alcohol liver disease and pancreatitis). The increase in inflammatory biomarkers (ESR and PLR) was more evident in AWS patients with DT. Cluster analysis confirmed the existence of a subgroup of patients with evidence of high inflammation, and such a subgroup was more frequent in DT patients. Conclusions: These findings contribute to the understanding of biomarker variability in AWS patients with and without DT and support the heterogeneity of patients by the level of inflammation.

Evaluation of enrofloxacin in the Chinese soft-shelled turtle (Pelodiscus sinensis) based on the biochemical, histopathological and intestinal microbiota responses

Enrofloxacin (ENR) is a veterinary medicine extensively used in aquatic farming, the abuses of antibacterials can lead to drug residues and toxicity to aquatic animals. Nevertheless, its toxicological effects on the Pelodiscus sinensis remain unclear. The objective of this work was to study the toxic effects of ENR on male P. sinensis following multiple oral administration. For hematological, antioxidant status, histological and ultrastructural analyzed, male P. sinensis were orally administrated with ENR for 5 consecutive days, each at the dose of 15 (recommended dose, 1×), 45 (3 times the recommended dose, 3×), and 75 (5 times the recommended dose, 5×) mg/kg body weight (BW) daily. The effect of ENR on P. sinensis by changes in the intestinal microbiota using high-throughput sequencing technology was also investigated. Samples of blood and fresh tissue (liver, spleen, intestine, muscle, spermary, testes, heart, lung, and kidney) were collected after 24 h of drug withdrawal. The results showed that multiple oral administration of ENR induced immunosuppression (lowered total proteins, alkaline phosphatase, and albumin), hepatic-renal dysfunction (elevated aspartate transaminase, alanine aminotransferase, urea nitrogen, K+ and Ca2+), and lowering the hepatic and splenic antioxidant functions (higher MDA, and declines in the activities of SOD, CAT, and NOS) in 3× ENR-dosed or 5× ENR-dosed groups. Noteworthy, histopathological and ultrastructural examination of tissue samples revealed adverse effects with increasing oral dosage of ENR. The 16S sequencing analysis showed that the ENR treatment can greatly change the intestinal microbial diversity and abundance in P. sinensis, but more probiotics such as Cetobacterium, Lactococcus, and Paraclostridium were retained in the short-term period. The findings may provide new insights into the toxicity of ENR to P. sinensis, and help to determine the dose to ensure the safety of aquatic food products.

A Comprehensive Study to Determine the Residual Elimination Pattern of Major Metabolites of Amoxicillin–Sulbactam Hybrid Molecules in Rats by UPLC–MS/MS

Amoxicillin and sulbactam are widely used in animal food compounding. Amoxicillin–sulbactam hybrid molecules are bicester compounds made by linking amoxicillin and sulbactam with methylene groups and have good application prospects. However, the residual elimination pattern of these hybrid molecules in animals needs to be explored. In the present study, the amoxicillin–sulbactam hybrid molecule (AS group) and a mixture of amoxicillin and sulbactam (mixture group) were administered to rats by gavage, and the levels of the major metabolites of amoxicillin, amoxicilloic acid, amoxicillin diketopiperazine, and sulbactam were determined by UPLC–MS/MS. The residue elimination patterns of the major metabolites in the liver, kidney, urine, and feces of rats in the AS group and the mixture group were compared. The results showed that the total amount of amoxicillin, amoxicilloic acid, amoxicillin diketopiperazine, and the highest concentration of sulbactam in the liver and kidney samples of the AS group and the mixture group appeared at 1 h after drug withdrawal. Between 1 h and 12 h post discontinuation, the total amount of amoxicillin, amoxicilloic acid, and amoxicillin diketopiperazine in the two tissues decreased rapidly, and the elimination half-life of the AS group was significantly higher than that in the mixture group (p < 0.05); the residual amount of sulbactam also decreased rapidly, and the elimination half-life was not significantly different (p > 0.05). In 72 h urine samples, the total excretion rates were 60.61 ± 2.13% and 62.62 ± 1.73% in the AS group and mixture group, respectively. The total excretion rates of fecal samples (at 72 h) for the AS group and mixture group were 9.54 ± 0.26% and 10.60 ± 0.24%, respectively. These results showed that the total quantity of amoxicillin, amoxicilloic acid, and amoxicillin diketopiperazine was eliminated more slowly in the liver and kidney of the AS group than those of the mixture group and that the excretion rate through urine and feces was essentially the same for both groups. The residual elimination pattern of the hybrid molecule in rats determined in this study provides a theoretical basis for the in-depth development and application of hybrid molecules, as well as guidelines for the development of similar drugs.

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.

Clinically defining the opioid-exposed birthing person and infant as a dyad to support bedside care, surveillance, and research

IntroductionAn increased incidence of maternal opioid use disorder (OUD) and neonatal abstinence syndrome (NAS) has prompted recommendations supporting a dyadic approach to care for birthing persons and their infants. However, there are no consensus guidelines outlining how the dyad is clinically defined.MethodsTo examine how the opioid-exposed birthing person-infant dyad has been defined for purposes of data collection and research, a literature review applying the RAND/UCLA Appropriateness Method was conducted.ResultsThe search yielded 320 abstracts, with 110 articles identified as having a dyadic focus. While no articles included a specific definition for the dyad, 33 (30%) contained a descriptive reference to the birthing person-infant dyad. Thematic analysis revealed eight recurring elements characteristic of the dyad: (1) engagement, (2) communication, (3) bonding, (4) attachment, (5) mutual responsiveness, (6) reciprocity, (7) synchrony, and (8) attunement. Integrating these elements revealed the interactional relationship between the opioid-exposed birthing person and infant as the foundational principle that defines the dyad.DiscussionThis definition shifts the focus of the opioid-exposed dyad from two individual patient populations to an interactional relationship that has broad applicability for clinical use, public health data collection, and research considerations.