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.

Myeloid PTP1B deficiency protects against atherosclerosis by improving cholesterol homeostasis through an AMPK-dependent mechanism.

OBJECTIVE: Atherosclerosis is a chronic inflammatory process induced by the influx and entrapment of excess lipoproteins into the intima media of arteries. Previously, our lab demonstrated that systemic PTP1B inhibition protects against atherosclerosis in preclinical LDLR-/- models. Similarly, it was shown that myeloid-specific PTP1B ablation decreases plaque formation and ameliorates dyslipidaemia in the ApoE-/- model of atherosclerosis. We hypothesized that the relevant improvements in dyslipidaemia following modification of PTP1B activation may either result from changes in hepatic cholesterol biosynthesis and/or increased uptake and degradation by liver-resident macrophages. We examined this in animal models and patients with coronary artery disease. METHODS: In this study, we determined the cholesterol-lowering effect of myeloid-PTP1B deletion in mice fed a high-fat high-cholesterol diet and examined effects on total cholesterol levels and lipoprotein profiles. We also determined the effects of PTP1B inhibition to oxLDL-C challenge on foam cell formation and cholesterol efflux in human monocytes/macrophages. RESULTS: We present evidence that myeloid-PTP1B deficiency significantly increases the affinity of Kupffer cells for ApoB containing lipoproteins, in an IL10-dependent manner. We also demonstrate that PTP1B inhibitor, MSI-1436, treatment decreased foam cell formation in Thp1-derived macrophages and increased macrophage cholesterol efflux to HDL in an AMPK-dependent manner. We present evidence of three novel and distinct mechanisms regulated by PTP1B: an increase in cholesterol efflux from foam cells, decreased uptake of lipoproteins into intra-lesion macrophages in vitro and a decrease of circulating LDL-C and VLDL-C in vivo. CONCLUSIONS: Overall, these results suggest that myeloid-PTP1B inhibition has atheroprotective effects through improved cholesterol handling in atherosclerotic lesions, as well as increased reverse cholesterol transport. Trial registration Research registry, researchregistry 3235. Registered 07 November 2017, https://www.researchregistry.com/browse-the-registry#home/registrationdetails/5a01d0fce7e1904e93e0aac5/ .

Implementing contingency management for stimulant use in opioid treatment programs: protocol of a type III hybrid effectiveness-stepped-wedge trial.

BACKGROUND: Contingency management (CM) is an evidence-based intervention for stimulant use and is highly effective in combination with medication for opioid use disorder. Yet, uptake of CM in opioid treatment programs that provide medication for opioid use disorder remains low. This paradox in which CM is one of the most effective interventions, yet one of the least available, represents one of the greatest research-to-practice gaps in the addiction health services field. Multi-level implementation strategies are needed to address barriers to CM implementation at both the provider- and organization-level. This type III hybrid effectiveness-implementation trial was funded by the National Institute on Drug Abuse to evaluate whether a multi-level implementation strategy, the Science of Service Laboratory (SSL), can effectively promote CM implementation in opioid treatment programs. Specific aims will test the effectiveness of the SSL on implementation outcomes (primary aim) and patient outcomes (secondary aim), as well as test putative mediators of implementation outcomes (exploratory aim). METHODS: Utilizing a fully powered type III hybrid effectiveness-implementation trial with a stepped wedge design, we propose to randomize a cohort of 10 opioid treatment programs to receive the SSL across four steps. Each step, an additional 2-3 opioid treatment programs will receive the SSL implementation strategy, which has three core components: didactic training, performance feedback, and external facilitation. At six intervals, each of the 10 opioid treatment programs will provide de-identified electronic medical record data from all available patient charts on CM delivery and patient outcomes. Staff from each opioid treatment program will provide feedback on contextual determinants influencing implementation at three timepoints. DISCUSSION: Between planning of this protocol and receipt of funding, the landscape for CM in the USA changed dramatically, with multiple Departments of Health launching state-wide CM initiatives. We therefore accelerated the protocol timeline and offered some cursory training resources to all sites as a preparation activity. We also began partnering with multiple Departments of Health to evaluate their rollout of CM using the measures outlined in this protocol. TRIAL REGISTRATION: This study protocol is registered via ClinicalTrials.gov Identifier: NCT05702021. Date of registration: January 27, 2023.

Fenretinide inhibits obesity and fatty liver disease but induces Smpd3 to increase serum ceramides and worsen atherosclerosis in LDLR-/- mice.

Fenretinide is a synthetic retinoid that can prevent obesity and improve insulin sensitivity in mice by directly altering retinol/retinoic acid homeostasis and inhibiting excess ceramide biosynthesis. We determined the effects of Fenretinide on LDLR-/- mice fed high-fat/high-cholesterol diet ± Fenretinide, a model of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Fenretinide prevented obesity, improved insulin sensitivity and completely inhibited hepatic triglyceride accumulation, ballooning and steatosis. Moreover, Fenretinide decreased the expression of hepatic genes driving NAFLD, inflammation and fibrosis e.g. Hsd17b13, Cd68 and Col1a1. The mechanisms of Fenretinide's beneficial effects in association with decreased adiposity were mediated by inhibition of ceramide synthesis, via hepatic DES1 protein, leading to increased dihydroceramide precursors. However, Fenretinide treatment in LDLR-/- mice enhanced circulating triglycerides and worsened aortic plaque formation. Interestingly, Fenretinide led to a fourfold increase in hepatic sphingomyelinase Smpd3 expression, via a retinoic acid-mediated mechanism and a further increase in circulating ceramide levels, linking induction of ceramide generation via sphingomyelin hydrolysis to a novel mechanism of increased atherosclerosis. Thus, despite beneficial metabolic effects, Fenretinide treatment may under certain circumstances enhance the development of atherosclerosis. However, targeting both DES1 and Smpd3 may be a novel, more potent therapeutic approach for the treatment of metabolic syndrome.

A systematic review of remotely delivered contingency management treatment for substance use.

BACKGROUND: Substance use and related consequences (e.g., impaired driving, injuries, disease transmission) continue to be major public health concerns. Contingency management (CM) is a highly effective treatment for substance use disorders. Yet CM remains vastly underutilized, in large part due to implementation barriers to in-person delivery. If feasible and effective, remote delivery of CM may reduce barriers at both the clinic- and patient-level, thus increasing reach and access to effective care. Here, we summarize data from a systematic review of studies reporting remote delivery of CM for substance use treatment. METHODS: We conducted a systematic review, reported according to PRISMA guidelines. The study team identified a total of 4358 articles after deduplication. Following title and abstract screening, full-text screening, and reference tracking, 39 studies met the eligibility criteria. We evaluated the methodological quality of the included studies using the Effective Public Health Practice Project Quality tool. RESULTS: Of 39 articles included in the review, most (n = 26) targeted cigarette smoking, with others focusing on alcohol (n = 9) or other substance use or targeting multiple substances (n = 4). Most remotely delivered CM studies focused on abstinence (n = 29), with others targeting substance use reduction (n = 2), intervention engagement (n = 5), and both abstinence and intervention engagement (n = 3). CM was associated with better outcomes (either abstinence, use reduction, or engagement), with increasingly more remotely delivered CM studies published in more recent years. Studies ranged from moderate to strong quality, with the majority (57.5 %) of studies being strong quality. CONCLUSIONS: Consistent with in-person CM, remotely delivered CM focusing on abstinence or use reduction from substances or engagement in substance use treatment services improves outcomes at the end of treatment compared to control conditions. Moreover, remotely delivered CM is feasible across a variety of digital delivery platforms (e.g., web, mobile, and wearable), with acceptability and reduced clinic and patient burden as technological advancements streamline monitoring and reinforcer delivery.

Induction of experimental diabetes and diabetic nephropathy using anomer-equilibrated streptozotocin in male C57Bl/6J mice.

Streptozotocin (STZ) is widely used to induce experimental diabetes in murine models. However, the ability to induce diabetic nephropathy (DN) is more challenging. It has been recommended to inject STZ at multiple low doses within 15 min after dissolution due to its alleged instability. However, some studies suggest that STZ is stable for days due to equilibration of its two anomers (α and ß), 90 min after dissolution, and that this anomer-equilibrated STZ leads to higher survival rates and persistent hyperglycaemia with minimal weight loss. The aim of this study was to determine an optimal dose of anomer-equilibrated STZ to induce kidney tubular damage and compare it with the more commonly used freshly prepared STZ. We hypothesised that anomer-equilibrated STZ provides a better, reproducible experimental model of diabetes-induced kidney damage with improved animal welfare. Body measurements, fasting glycaemia, insulinemia and renal histology were assessed in male C57Bl/6J at two and six months of age treated with fresh (50 mg/kg) or anomer-equilibrated (dose ranging 35-50 mg/kg) STZ or vehicle control. We demonstrated a dose-dependent effect of anomer-equilibrated STZ on the induction of hypo-insulinaemia and hyperglycaemia, as well as body weight in two-month-old mice. Interestingly, in six-month-old mice STZ leads to body weight loss, independently of STZ preparation mode. Anomer-equilibrated STZ provoked moderate to severe kidney tubule structural damage, resulting in significant kidney hypertrophy, whereas freshly prepared STZ only caused mild alterations. In conclusion, our study proposes that anomer-equilibrated STZ provides a robust murine model of diabetes and early-stage diabetic nephropathy, which can be used to test therapeutic approaches to treat and/or prevent renal damage.

The BACE1 inhibitor LY2886721 improves diabetic phenotypes of BACE1 knock-in mice.

AIM: The ß-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) has been identified as the central initiator of amyloid ß (Aß) generation in the brain, the key hallmark of Alzheimer's disease (AD). However, recent studies provided evidence that BACE1 also plays a crucial role in metabolic regulation, and we have shown that neuronal human BACE1 knock-in mice (PLB4) display type 2 diabetes mellitus (T2DM)-like symptoms alongside AD-like impairments. Hence, we here investigated if targeted BACE1 inhibition using LY2886721, an active site BACE1 inhibitor, would improve glucose homeostasis, insulin sensitivity and motor performance in PLB4 mice. MATERIALS AND METHODS: LY2886721 was administered as a dietary supplement (0.02% wt/wt) for six consecutive weeks. Physiological, metabolic and motor assessments were performed during the last two weeks of treatment, followed by molecular tissue analyses post-mortem. RESULTS: LY2886721 treatment improved glucose homeostasis and hepatic gluconeogenesis in diabetic PLB4 mice, as determined by improvements in basal glucose and glucose/pyruvate tolerance tests. Furthermore, LY2886721 improved hepatic insulin sensitivity, as indicated by enhanced basal hyperphosphorylation of insulin receptors. In PLB4 brains, we detected altered basal conditions of APP expression and processing, with beneficial effects on APP processing achieved by LY2886721 treatment. No improvements in motor coordination were found. CONCLUSIONS: Our data provide support for a role of BACE1 as a regulator of systemic glucose homeostasis and suggest BACE1 inhibitors for the treatment of T2DM-associated pathologies, especially in cases where diabetes is comorbid to AD.

NLRP3 inflammasome inhibition with MCC950 improves insulin sensitivity and inflammation in a mouse model of frontotemporal dementia.

The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome has been implicated as a crucial component in both neurodegeneration and diabetes. However, the role of metabolic signalling pathways and the NLRP3 inflammasome in frontotemporal dementia remain largely elusive. We therefore investigated the effects of an NLRP3 inhibitor (MCC950) in a murine tau knock-in (PLB2TAU) model vs. wild-type (PLBWT) control mice. In male PLB2TAU mice (4 months at start of study), MCC950 treatment (20 mg/kg, for 12 weeks) improved insulin sensitivity and reduced circulating plasma insulin levels. Further molecular analysis suggested normalisation in insulin signalling pathways in both liver and muscle tissue. Treatment also resulted in improvements in inflammation and ER stress signalling, both peripherally and centrally, alongside a partial normalisation of phospho-tau levels. Overall, we provide evidence that MCC950 improved metabolic, inflammatory and frontotemporal dementia (FTD) relevant phenotypes in multiple tissues. NLRP3 inhibition may therefore offer a therapeutic approach to ameliorate FTD pathology.

Effects of Liraglutide and Fenretinide treatments on the diabetic phenotype of neuronal human BACE1 knock-in mice.

We recently reported that brain-specific human ß-secretase 1 (BACE1) knock-in (PLB4), a mouse model of sporadic Alzheimer's disease (AD), also develops a severe diabetic phenotype characterised by impaired glucose homeostasis, decreased insulin sensitivity and a fatty liver phenotype. Hence, we here aimed to assess if targeted anti-diabetic therapies (Liraglutide and Fenretinide) would attenuate the diabetic and behavioural phenotype of these mice. PLB4 mice and wild-type (WT) controls were administered Liraglutide or Fenretinide for ten consecutive weeks alongside vehicle-treated mice. Physiological (body weight and mass composition, glucose tolerance, serum hormone concentration), behavioural (locomotor activity) and molecular assessments were performed in mice pre- and post-treatment. Liraglutide and Fenretinide treatments inhibited adiposity gain and decreased circulating serum triglyceride (with Liraglutide) and leptin (with Fenretinide) levels in PLB4 mice. We also found that PLB4 mice exhibited increased levels of serum dipeptidyl peptidase 4 (DPP4), together with up-regulated hepatic expression of Dpp4, retinol binding protein 4 (Rbp4) and sterol regulatory element-binding 1c (Srebp1c), which was normalised by both treatments. Interestingly, Liraglutide treatment slowed down habituation to a novel environment and increased secondary night activity peak in WT mice, suggesting an impact on circadian activity regulation. However, neither treatment improved glucose homeostasis in PLB4 mice, implying that impaired glucose metabolism in this genotype may not be associated with glucagon like peptide 1 (GLP-1) and/or RBP4-mediated pathways. In summary, this study provides new insights into molecular mechanisms underlying neuronal BACE1-mediated metabolic regulation and implicates BACE1 as a putative regulator of systemic DPP4 levels.