Influence of age and co-medication on dolutegravir glucuronidation in paediatric patients.

Dolutegravir (DTG) is primarily metabolized by uridine diphosphate glucuronosyltransferases, forming the pharmacologically inactive DTG glucuronide (DTG-gluc). We described the dolutegravir metabolic ratio (DTG-MR; DTG-gluc AUC0-24h divided by DTG AUC0-24h) in 85 children with HIV aged 3 months to 18 years receiving DTG in the CHAPAS-4 (ISRCTN22964075) and ODYSSEY (NCT02259127) trials. Additionally, we assessed the influence of age, body weight, nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone, rifampicin use and kidney function on DTG-MR. The overall geometric mean (CV%) DTG-MR was 0.054 (52%). Rifampicin use was the only significant factor associated with DTG-MR (P < .001) in multiple linear regression. DTG-MR geometric mean ratio was 1.81 (95% CI: 1.57-2.08) for children while on vs. off rifampicin. This study showed that overall DTG-MR in children was similar to adults, unaffected by age or NRTI backbone, and increased with rifampicin co-administration. These findings support future paediatric pharmacokinetic modelling and extrapolation from adult data.

Pharmacokinetics of once-daily darunavir/ritonavir in second-line treatment in African children with HIV.

BACKGROUND: Darunavir is a potent HIV protease inhibitor with a high barrier to resistance. We conducted a nested pharmacokinetic sub-study within CHAPAS-4 to evaluate darunavir exposure in African children with HIV, taking once-daily darunavir/ritonavir for second-line treatment. METHODS: We used data from the CHAPAS-4 pharmacokinetic sub-study treating children with once-daily darunavir/ritonavir (600/100 mg if 14-24.9 kg and 800/100 mg if ≥25 kg) with either tenofovir alafenamide fumarate (TAF)/emtricitabine (FTC), abacavir/lamivudine or zidovudine/lamivudine. Steady-state pharmacokinetic sampling was done at 0, 1, 2, 4, 6, 8, 12 and 24 hours after observed darunavir/ritonavir intake. Non-compartmental and population pharmacokinetic analyses were used to describe the data and identify significant covariates. Reference adult pharmacokinetic data were used for comparison. We simulated the World Health Organization (WHO) recommended 600/100 mg darunavir/ritonavir dose for the 25-34.9 kg weight band. RESULTS: Data from 59 children with median age and weight 10.9 (range 3.8-14.7) years and 26.0 (14.5-47.0) kg, respectively, were available. A two-compartment disposition model with transit absorption compartments and weight-based allometric scaling of clearance and volume best described darunavir data. Our population achieved geometric mean (%CV) darunavir AUC0-24h, 94.3(50) mg·h/L and Cmax, 9.1(35) mg/L, above adult reference values and Ctrough, 1.5(111) mg/L, like adult values. The nucleoside reverse-transcriptase inhibitor backbone was not found to affect darunavir concentrations. Simulated WHO-recommended darunavir/ritonavir doses showed exposures equivalent to adults. Higher alpha-1-acid glycoprotein increased binding to darunavir and decreased apparent clearance of darunavir. CONCLUSIONS: Darunavir exposures achieved in our trial are within safe range. Darunavir/ritonavir can safely be co-administered with TAF/FTC. Both WHO-recommended 600/100 mg and CHAPAS-4 800/100 mg darunavir/ritonavir doses for the 25-34.9 kg weight band offer favourable exposures. The choice between them can depend on tablet availability.

Cannabis expectancies and associations with cannabis use and health functioning among adults with chronic pain.

INTRODUCTION: Cannabis is increasingly available to individuals in the United States, with the majority of states legalizing medical or recreational cannabis use. Cannabis expectancies (e.g., positive expectations from cannabis use) are related to more frequent cannabis use and associated with greater odds of lapse following a cessation attempt. METHODS: To evaluate the relationship between expectancies and cannabis- and health-related outcomes, we surveyed adults who used medical cannabis for chronic pain (n = 633; 52.2 % female; 82.1 % white) over a two-year period. Then, we performed a principal components analysis (PCA) on the Cannabis Expectancies Questionnaire to derive components of cannabis expectancies. We performed k-means clustering to identify subgroups with similar expectancies. The relationship between subgroup assignment and cannabis use outcomes (frequency, quantity), and physical and mental health functioning were evaluated. RESULTS: The PCA identified a three-component solution and k-means clustering identified four subgroups: low expectancies, negative expectancies, amotivation expectancies, and positive expectancies. Participants' cannabis expectancies were dynamic over time. After adjusting for demographics, expectancy subgroup was able to predict six-month cannabis use frequency (χ2(3) = 11.244; p = 0.010) and mental health functioning (χ2(3) = 24.926; p < 0.001), but not quantity (χ2(3) = 2.741, p = 0.433) or physical health functioning (χ2(3) = 5.110, p = 0.164). CONCLUSION: In a large cohort of individuals who use medical cannabis, four subgroups with differing cannabis expectancies emerged: low expectancies, negative expectancies, amotivation expectancies, and positive expectancies. These subgroups predicted subsequent outcomes and may be important for targeted intervention approaches to reduce cannabis use and improve functioning.

Prevention and management of venous thrombosis in patients with cirrhosis.

Venous thromboembolism (VTE), particularly portal vein thrombosis, is common in patients with cirrhosis. Misconceptions around the increased bleeding risk in this patient group may lead to delayed and/or inadequate anticoagulation. This nutshell review focusses on the approach to management including the role of direct oral anticoagulants in the treatment of VTE in patients with cirrhosis.

Can edoxaban be used at extremes of bodyweight and in patients with a creatinine clearance ≥95 ml/min? - A population pharmacokinetic analysis.

BACKGROUND: Clinical evidence surrounding edoxaban use in patients weighing <50 kg and >120 kg is lacking. The International Society of Thrombosis and Haemostasis Scientific and Standardisation Committee suggests avoiding edoxaban in patients >120 kg. Additionally, concerns exist regarding decreased efficacy in patients prescribed edoxaban for atrial fibrillation with a creatinine clearance (CrCl) >95 ml/min, a finding of the ENGAGE AF-TIMI 48 trial when edoxaban was compared to warfarin. OBJECTIVE: To derive a population pharmacokinetic (PopPK) model using clinical practice data, to understand the impact of bodyweight and renal function on edoxaban pharmacokinetics. METHOD: Edoxaban plasma concentrations and patient characteristics were collated from King's College Hospital anticoagulation clinics between 11/2016 and 08/2022. A PopPK model was developed using non-linear mixed effects modelling and used to simulate edoxaban concentrations at the extremes of bodyweight and with varying renal function. RESULTS: Data from 409 patients (46 < 50 kg, 34 > 120 kg and 123 with a CrCl > 95 ml/min) provided 455 edoxaban plasma concentrations. A one-compartment model with between-subject variability on clearance with a proportional error model best described the data. The most significant covariates impacting on edoxaban exposure were CrCl and bodyweight. Our work suggests that edoxaban exposure in patients weighing up to 140 kg is comparable to those weighing 75 kg. Edoxaban exposure is reduced in patients weighing <50 kg due to the recommended dose reductions. There is also a reduction in AUCss when CrCl > 95 ml/min compared to CrCl 80 ml/min. CONCLUSIONS: Our population PK model for edoxaban suggests that renal function is a key driver for overall edoxaban exposure. Further clinical outcome data is required to understand clinical effectiveness and adverse outcomes.

A mobile health intervention for emerging adults with regular cannabis use: A micro-randomized pilot trial design protocol.

BACKGROUND: Emerging adult (EA) cannabis use is associated with increased risk for health consequences. Just-in-time adaptive interventions (JITAIs) provide potential for preventing the escalation and consequences of cannabis use. Powered by mobile devices, JITAIs use decision rules that take the person's state and context as input, and output a recommended intervention (e.g., alternative activities, coping strategies). The mHealth literature on JITAIs is nascent, with additional research needed to identify what intervention content to deliver when and to whom. METHODS: Herein we describe the protocol for a pilot study testing the feasibility and acceptability of a micro-randomized trial for optimizing MiWaves mobile intervention app for EAs (ages 18-25; target N = 120) with regular cannabis use (≥3 times per week). Micro-randomizations will be determined by a reinforcement learning algorithm that continually learns and improves the decision rules as participants experience the intervention. MiWaves will prompt participants to complete an in-app twice-daily survey over 30 days and participants will be micro-randomized twice daily to either: no message or a message [1 of 6 types varying in length (short, long) and interaction type (acknowledge message, acknowledge message + click additional resources, acknowledge message + fill in the blank/select an option)]. Participants recruited via social media will download the MiWaves app, and complete screening, baseline, weekly, post-intervention, and 2-month follow-up assessments. Primary outcomes include feasibility and acceptability, with additional exploratory behavioral outcomes. CONCLUSION: This study represents a critical first step in developing an effective mHealth intervention for reducing cannabis use and associated harms in EAs.

Treatment for Co-Occurring Stimulant and Opioid Use Disorders: Overcoming Barriers in the Era of Polysubstance Use.

This Viewpoint explores the current barriers to implementing contingency management treatment for individuals experiencing both opioid use and stimulant use disorders in the context of high numbers of US overdoses.

Histone H3K18 & H3K23 acetylation directs establishment of MLL-mediated H3K4 methylation.

In an unmodified state, positively charged histone N-terminal tails engage nucleosomal DNA in a manner which restricts access to not only the underlying DNA but also key tail residues subject to binding and/or modification. Charge-neutralizing modifications, such as histone acetylation, serve to disrupt this DNA-tail interaction, facilitating access to such residues. We previously showed that a polyacetylation-mediated chromatin "switch" governs the read-write capability of H3K4me3 by the MLL1 methyltransferase complex. Here, we discern the relative contributions of site-specific acetylation states along the H3 tail and extend our interrogation to other chromatin modifiers. We show that the contributions of H3 tail acetylation to H3K4 methylation by MLL1 are highly variable, with H3K18 and H3K23 acetylation exhibiting robust stimulatory effects and that this extends to the related H3K4 methyltransferase complex, MLL4. We show that H3K4me1 and H3K4me3 are found preferentially co-enriched with H3 N-terminal tail proteoforms bearing dual H3K18 and H3K23 acetylation (H3{K18acK23ac}). We further show that this effect is specific to H3K4 methylation, while methyltransferases targeting other H3 tail residues (H3K9, H3K27, & H3K36), a methyltransferase targeting the nucleosome core (H3K79), and a kinase targeting a residue directly adjacent to H3K4 (H3T3) are insensitive to tail acetylation. Together, these findings indicate a unique and robust stimulation of H3K4 methylation by H3K18 and H3K23 acetylation and provide key insight into why H3K4 methylation is often associated with histone acetylation in the context of active gene expression.

Anticoagulation for stroke prevention in atrial fibrillation and treatment of venous thromboembolism and portal vein thrombosis in cirrhosis: guidance from the SSC of the ISTH.

While advanced liver disease was previously considered to be an acquired bleeding disorder, there is increasing recognition of an associated prothrombotic state with patients being at higher risk of atrial fibrillation (AF) and stroke and venous thromboembolism (VTE) including portal vein thrombosis (PVT). We review the available literature on epidemiology, pathophysiology, and risk factors and provide guidance on anticoagulant management of these conditions in adults with cirrhosis. In patients with Child-Pugh A or B cirrhosis and AF, we recommend anticoagulation with standard-dose direct oral anticoagulants (DOACs) in accordance with cardiology guideline recommendations for patients without liver disease. In those with Child-Pugh C cirrhosis, there is inadequate evidence with respect to the benefit and risk of anticoagulation for stroke prevention in AF. In patients with cirrhosis and acute deep vein thrombosis or pulmonary embolism, we recommend anticoagulation and suggest use of either a DOAC or low-molecular-weight heparin (LMWH)/vitamin K antagonist (VKA) in Child-Pugh A or B cirrhosis and LMWH alone (or as a bridge to VKA in patients with a normal baseline international normalized ratio) in Child-Pugh C cirrhosis. We recommend anticoagulation for patients with cirrhosis and symptomatic PVT. We suggest anticoagulation for those with asymptomatic, progressing PVT and recommend continuing extended anticoagulation for liver transplant candidates with PVT.

Comparison of Treatment Receipt and Hospitalization Among Patients With Stimulant Use Disorder and/or Opioid Use Disorder in the Veterans Health Administration.

OBJECTIVES: Stimulant use is a growing problem, but little is known about service utilization among patients with stimulant use disorder (StUD). In the context of the overdose crisis, much research has focused on patients with opioid use disorder (OUD). It is unclear how the characteristics, treatment receipt, and hospitalization of patients with StUD differ from patients with OUD. METHODS: Electronic health record data were extracted for national Veterans Health Administration patients with a visit from March 1, 2020, to February 28, 2021 with StUD and/or OUD (N = 132,273). We compared patients with StUD without OUD to those with (1) co-occurring StUD + OUD and (2) OUD without StUD. Patient characteristics, substance use disorder treatment, and hospitalizations in the year following patients' first study period visit were descriptively compared. Treatment and hospitalization were also compared in adjusted regression models. RESULTS: Compared with patients with OUD + StUD, those with StUD without OUD were less likely to receive outpatient (adjusted odds ratio [aOR] 0.49, 95% confidence interval [CI] 0.47-0.50) or any treatment (aOR 0.47, 95% CI 0.46-0.49). Compared with patients with OUD without StUD, those with StUD without OUD were less likely to receive outpatient (aOR 0.51, 95% CI 0.49-0.52) or any treatment (aOR 0.56, 95% CI 0.54-0.58) and more likely to receive residential treatment (aOR 2.18, 95% 2.05-2.30) and to be hospitalized (aOR 1.62, 95% 1.56-1.69). CONCLUSIONS: Patients with StUD may be less likely to receive treatment and more likely to be hospitalized than patients with OUD. Efforts focused on mitigating hospitalization and increasing treatment receipt for patients with StUD are needed.

H3K18 & H3K23 acetylation directs establishment of MLL-mediated H3K4 methylation.

In an unmodified state, positively charged histone N-terminal tails engage nucleosomal DNA in a manner which restricts access to not only the underlying DNA, but also key tail residues subject to binding and/or modification. Charge-neutralizing modifications, such as histone acetylation, serve to disrupt this DNA-tail interaction, facilitating access to such residues. We previously showed that a polyacetylation-mediated chromatin "switch" governs the read-write capability of H3K4me3 by the MLL1 methyltransferase complex. Here, we discern the relative contributions of site-specific acetylation states along the H3 tail and extend our interrogation to other chromatin modifiers. We show that the contributions of H3 tail acetylation to H3K4 methylation by MLL1 are highly variable, with H3K18 and H3K23 acetylation exhibiting robust stimulatory effects, and that this extends to the related H3K4 methyltransferase complex, MLL4. We show that H3K4me1 and H3K4me3 are found preferentially co-enriched with H3 N-terminal tail proteoforms bearing dual H3K18 and H3K23 acetylation (H3{K18acK23ac}). We further show that this effect is specific to H3K4 methylation, while methyltransferases targeting other H3 tail residues (H3K9, H3K27, & H3K36), a methyltransferase targeting the nucleosome core (H3K79), and a kinase targeting a residue directly adjacent to H3K4 (H3T3) are insensitive to tail acetylation. Together, these findings indicate a unique and robust stimulation of H3K4 methylation by H3K18 and H3K23 acetylation and provide key insight into why H3K4 methylation is often associated with histone acetylation in the context of active gene expression.

Contingency management for substance use disorders in the U.S. Veterans Health Administration: 2018-2022.

INTRODUCTION: Contingency management (CM) is one of the most effective interventions for substance use disorders (SUDs), including stimulant use disorder. In the United States, the Veterans Health Administration (VHA) led the largest-scale rollout of CM in the US to date, but little is known about characteristics of patients treated and CM clinical practices. METHODS: In this retrospective cohort study, we used VHA electronic health records data to descriptively examine CM treatment course (e.g., number of visits, time between visits, duration of treatment episode) and characteristics of patients receiving CM for SUDs from 2018 to 2022. RESULTS: From January 2018 to September 2022, 2844 patients received CM at 90 VA Health Systems (including 98 VA Medical Center, 7 community-based outpatient clinics, and 15 other sites). The median number of CM visits was 8 (mean = 10.17, SD = 8.12) visits over the course of 1.5 months (median = 45 days, mean = 57.46 days, SD = 62.65). The target substance was stimulants in 86.42 % of visits. Average age of patients was 52.29 years (SD = 12.10), with 55.06 % of patients experiencing homelessness or housing instability, and 97.50 % of patients diagnosed with more than one SUD. Compared to the year prior to the COVID-19 pandemic (03/2019-02/2020; mean = 957.33, SD = 157.71 visits/month), CM visits declined by 83.20 % in the year following the pandemic (03/2020-02/2021; mean = 160.83, SD = 164.14), and have yet to return to pre-pandemic levels. CONCLUSIONS: The CM rollout has been markedly successful in the VHA, with adoption across multiple VHA sites within a complex patient population, indicating the potential for effective, more widespread CM implementation. At the same time, there was a considerable reduction in CM care during the COVID-19 pandemic and CM has not yet returned to pre-pandemic levels. Moreover, only a small minority of VA patients with stimulant use disorder have received CM. Given increasing rates of overdose, including stimulant-involved overdose, it is important to increase CM provision in VHA and non-VHA settings.

Advances and current research in primary thromboprophylaxis to prevent hospital-associated venous thromboembolism.

Hospital-associated venous thromboembolism (VTE) is defined as any case of VTE occurring during hospital admission and for up to 90 days post discharge. It accounts for over 50% of all cases of VTE internationally; indeed, there are an estimated 10 million cases of hospital-associated VTE annually. Over the last decade, there has been increasing interest in improving VTE risk assessment and thromboprophylaxis. This review summarises all the recent and ongoing major research studies and future challenges in the different areas, including medical, surgical and obstetric patients, as well as special areas such as lower limb immobilisation. We include sections on both pharmacological and mechanical thromboprophylaxis.

Acceptability and feasibility of a mobile behavioral economic health intervention to reduce alcohol use in adults in rural areas.

Background: At-risk alcohol use is associated with increased adverse health consequences, yet is undertreated in healthcare settings. People residing in rural areas need improved access to services; however, few interventions are designed to meet the needs of rural populations. Mobile interventions can provide feasible, low-cost, and scalable means for reaching this population and improving health, and behavioral economic approaches are promising. Methods: We conducted a pilot randomized controlled trial focused on acceptability and feasibility of a mobile behavioral economic intervention for 75 rural-residing adults with at-risk alcohol use. We recruited participants from a large healthcare system and randomized them to one of four virtually-delivered conditions reflecting behavioral economic approaches: episodic future thinking (EFT), volitional choice (VC), both EFT and VC, or enhanced usual care control (EUC). The intervention included a telephone-delivered induction session followed by two weeks of condition-consistent ecological momentary interventions (EMIs; 2x/day) and ecological momentary assessments (EMAs; 1x/day). Participants completed assessments at baseline, post-intervention, and two-month follow-up, and provided intervention feedback. Results: All participants completed the telephone-delivered session and elected to receive EMI messages. Average completion rate of EMAs across conditions was 92.9%. Among participants in active intervention conditions, 89.3% reported the induction session was helpful and 80.0% reported it influenced their future drinking. We also report initial alcohol use outcomes. Discussion: The behavioral economic intervention components and trial procedures evaluated here appear to be feasible and acceptable. Next steps include determination of their efficacy to reduce alcohol use and public health harms.

Distinguishing Clinical From Statistical Significances in Contemporary Comparative Effectiveness Research.

OBJECTIVE: To determine the prevalence of clinical significance reporting in contemporary comparative effectiveness research (CER). BACKGROUND: In CER, a statistically significant difference between study groups may or may not be clinically significant. Misinterpreting statistically significant results could lead to inappropriate recommendations that increase health care costs and treatment toxicity. METHODS: CER studies from 2022 issues of the Annals of Surgery , Journal of the American Medical Association , Journal of Clinical Oncology , Journal of Surgical Research , and Journal of the American College of Surgeons were systematically reviewed by 2 different investigators. The primary outcome of interest was whether the authors specified what they considered to be a clinically significant difference in the "Methods." RESULTS: Of 307 reviewed studies, 162 were clinical trials and 145 were observational studies. Authors specified what they considered to be a clinically significant difference in 26 studies (8.5%). Clinical significance was defined using clinically validated standards in 25 studies and subjectively in 1 study. Seven studies (2.3%) recommended a change in clinical decision-making, all with primary outcomes achieving statistical significance. Five (71.4%) of these studies did not have clinical significance defined in their methods. In randomized controlled trials with statistically significant results, sample size was inversely correlated with effect size ( r = -0.30, P = 0.038). CONCLUSIONS: In contemporary CER, most authors do not specify what they consider to be a clinically significant difference in study outcome. Most studies recommending a change in clinical decision-making did so based on statistical significance alone, and clinical significance was usually defined with clinically validated standards.