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Yuliang Shi,1,2 Yuxian Yang,1,2 Miaoling Feng,1,2 Weihan Ling,1,2 Tongguo Wei,1,2 Yumin Cao,1,2 Rui Zhong,1,2 Heming Wu2 1Department of Neurology, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China; 2Center for Precision Medicine, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of ChinaCorrespondence: Heming Wu, Center for Precision Medicine, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, No. 63 Huangtang Road, Meijiang District, Meizhou, People’s Republic of China, Email wuheming1986@126.comBackground: Cytochrome P450 2C19 (CYP2C19) genotypes and metabolic phenotypes (extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM)) are related to the metabolism of therapeutic drugs for cardiovascular and cerebrovascular diseases. This study aimed to investigate the differences of CYP2C19 gene polymorphism distribution between coronary artery disease (CAD) patients and cerebral infarction (CI) patients.Methods: We identified 413 CI patients, 509 CAD patients, and 241 CI+CAD patients from 2016 to 2020 and studied genotypes of CYP2C19 rs4986893 (636G>A) and rs4244285 (681G>A) polymorphisms using PCR-gene chip detection method. Differences in CYP2C19 genotypes and metabolic phenotypes between the groups were compared. To analyze the efficacy of CYP2C19 metabolic phenotypes in discriminating between cerebral infarction and coronary artery disease, multiple logistic regression analysis was conducted after adjusting for gender, age, smoking history, drinking history, hypertension, and diabetes.Results: There were significant differences in the distribution of CYP2C19 genotypes and metabolic phenotypes between CI and CAD patients. The results of multivariate logistic regression (adjusted for sex, age, smoking, drinking, hypertension, and diabetes) indicated that CYP2C19 IM phenotype (IM vs EM: OR 1.443, 95% CI: 1.086– 1.918, P=0.011) and CYP2C19 IM+PM phenotype (IM or PM vs EM: OR 1.440, 95% CI: 1.100– 1.885, P=0.008) may be indicators of CI from CAD.Conclusion: CYP2C19 EM metabolic phenotype was dominant in CAD patients, and CYP2C19 IM metabolic phenotype was dominant in CI patients. After adjusting for other confounding factors, patients with the CYP2C19 IM metabolic phenotype were more likely to develop CI than CAD.Keywords: CYP2C19, genotype, metabolic phenotype, cerebral infarction, coronary artery disease

The μ-opioid receptor (MOR) is the primary target of methadone and buprenorphine. The primary neuronal transcript of the OPRM1 gene, MOR-1, contains a ~13 kb 3' untranslated region with five common haplotypes in European-Americans. We analyzed the effects of these haplotypes on the percentage of opioid positive urine tests in European-Americans (n=582) during a 24-week, randomized, open-label trial of methadone or buprenorphine/naloxone (Suboxone) for the treatment of opioid dependence. A single haplotype, tagged by rs10485058, was significantly associated with patient urinalysis data in the methadone treatment group. Methadone patients with the A/A genotype at rs10485058 were less likely to have opioid-positive urine drug screens than those in the combined A/G and G/G genotypes group (relative risk=0.76, 95% confidence intervals=0.73-0.80, P=0.0064). Genotype at rs10485058 also predicted self-reported relapse rates in an independent population of Australian patients of European descent (n=1215) who were receiving opioid substitution therapy (P=0.003). In silico analysis predicted that miR-95-3p would interact with the G, but not the A allele of rs10485058. Luciferase assays indicated miR-95-3p decreased reporter activity of constructs containing the G, but not the A allele of rs10485058, suggesting a potential mechanism for the observed pharmacogenetic effect. These findings suggest that selection of a medication for opioid dependence based on rs10485058 genotype might improve outcomes in this ethnic group.

Guilin Ye, Wu Zhou, Jiawu Li, Wenwu Ling, Yan Luo Department of Ultrasound, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Yan LuoDepartment of Ultrasound, West China Hospital, Sichuan University, No, 37, Guoxue Xiang, Chengdu 610041, People’s Republic of ChinaEmail luoyanddoc@163.comRationale: The most common complications of vacuum-assisted removal (VAR) for benign breast masses are hematoma, infection, and occasionally pseudoaneurysms. To the best of our knowledge, this is the first report of a true aneurysm following VAR for breast fibroadenomas.Case Presentation: A 50-year-old woman underwent VAR of bilateral benign breast masses under ultrasonic guidance. Routine breast ultrasound examination was performed 3 months later, and no discomfort was observed during follow-up.Diagnoses and Interventions: Physical examination revealed a slightly palpable, arterial-like pulsation in the lateral part of the right breast. The two-dimensional ultrasound showed that there was a well-defined anechoic nodule in the right breast at the 9 o’clock position 3 cm from the nipple, measuring 6 mm × 4 mm. Color Doppler sonography demonstrated that it was a localized dilated intramammary arteriole within the colorful flow. Spectral Doppler illustrated a high-velocity turbulent arterial flow component inside. Based on these findings, the patient was diagnosed with an iatrogenic true aneurysm of the breast. Given her overall good condition, conservative treatment with regular imaging surveillance was adopted.Outcomes: Up to now, the patient remains asymptomatic, and the size of the aneurysm has not changed.Lessons: With the increasing use of interventional diagnosis and treatment techniques, iatrogenic vascular complications are likely to occur more frequently. Careful duplex ultrasound examination prior to or following the procedure is strongly recommended. In the absence of risk factors, we recommend a conservative approach to small, stable aneurysms.Keywords: ultrasound, breast, true aneurysm, conservative treatment

Wei Xue,1 Juhua Mao,2 Qingjie Chen,1 Weide Ling,1 Yuqi Sun3 1Department of Pharmacy, Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, Guangxi 530011, People’s Republic of China; 2Center for Drug Control, Lishui Institute for Quality Inspection and Testing, Lishui, Zhejiang 323000, People’s Republic of China; 3Department of Anesthesiology, Guangzhou 12th People’s Hospital, Guangzhou, Guangdong 510620, People’s Republic of ChinaCorrespondence: Yuqi SunGuangzhou 12th People’s Hospital, No. 1 Tianqiang Road, Tianhe District, Guangzhou, Guangdong 510620, People’s Republic of ChinaEmail yuqisunhh@163.comBackground: Diabetic nephropathy (DN) is the leading cause of impaired renal function. The purpose of this study was to investigate the effects of Mogroside IIIE (MG IIIE), a cucurbitane-type compound isolated from Siraitia grosvenorii, in high glucose (HG)-induced podocytes and the possible mechanisms.Methods: MPC-5 cells were cultured under normal glucose or HG conditions. After treatment with MG IIIE, cell viability was examined using a cell counting kit-8 assay. The contents of inflammatory factors and oxidative stress-related markers were determined using the corresponding kits. Additionally, apoptosis of MPC-5 cells was determined using flow cytometry assay and the levels of apoptosis-associated proteins were evaluated by Western blot analysis. Moreover, the expression of proteins in AMPK/SIRT1 signaling was tested and the compound C, an AMPK inhibitor, was used to study whether the effects of MG IIIE on HG-induced MPC-5 cells were mediated by activation of the AMPK/SIRT1 signaling pathway.Results: MG IIIE elevated the cell viability of HG-induced MPC-5 cells, reduced the concentrations of inflammatory cytokines and decreased the levels of oxidative stress-related markers. What’s more, the apoptosis of podocytes induced by HG was inhibited after MG IIIE intervention, accompanied by the upregulated expression of Bcl-2 and downregulated expression of Bax, cleaved caspase-3 and cleaved caspase-9. It was also found that MG IIIE could activate the AMPK/SIRT1 signaling, but compound C inhibited this pathway and reversed the inhibitory effects of MG IIIE on inflammation, oxidative stress and apoptosis in HG-stimulated podocytes.Conclusion: MG IIIE can alleviate HG-induced inflammation and oxidative stress of podocytes by the activation of AMPK-SIRT1 signaling.Keywords: podocytes, inflammation, oxidative stress, apoptosis, AMPK

Liping Yang,1,2 Zhaomin Liu,2 Wenhua Ling,2 Li Wang,1 Changyi Wang,1 Jianping Ma,1 Xiaolin Peng,1 Jianying Chen3 1Center for Chronic Disease Control, Nanshan, Shenzhen, People’s Republic of China; 2Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, People’s Republic of China; 3Internal Medicine Department, BaiYun Hospital, GuangZhou, GuangDong Province, People’s Republic of ChinaCorrespondence: Liping YangCenter for Chronic Disease Control, NanShan, ShenZhen 518000, People’s Republic of ChinaTel +86-755-26403300Email yanglp6@mail2.sysu.edu.cnBackground: Insulin-like growth factor binding protein-4 (IGFBP-4) fragments have been shown to be associated with cardiometabolic diseases. Anthocyanins as a subgroup of natural polyphenols could have benefits on treating cardiometabolic diseases. The aim of this study was to examine the effects of purified anthocyanins on serum IGFBP-4 fragments and glycemic control in patients with fasting hyperglycemia.Methods: A set of 121 participants with elevated fasting glucose (≥ 5.6 mmol/L), who were originally randomly assigned to anthocyanins (320 mg/day) or placebo groups, were included in this study. Serum IGFBP-4 fragments, fasting and postload glucose, insulin, and C-peptide after a three-hour oral glucose tolerance test (OGTT) were measured at baseline and at the end of 12 weeks.Results: Compared with placebo, anthocyanins increased serum IGFBP-4 fragments (net change 8.33 ng/mL, 95% CI [1.2, 15.47], p=0.023) and decreased fasting glucose (− 0.4 mmol/L [− 0.71, -0.1], p=0.01), 2-hour C-peptide (− 1.02 ng/mL [− 1.99, − 0.04], p=0.041) and the 3-hour area under the curve (AUC) of C-peptide (− 2.19 [− 4.11, − 0.27], p=0.026). No other significant difference in parameters for glycemic control and insulin resistance was observed.Conclusion: Anthocyanins supplementation for 12 weeks improved serum IGFBP-4 fragments and decreased fasting glucose and postload C-peptide in patients with fasting hyperglycemia. Further studies are needed to confirm our findings and clarify the potential mechanism.Trial Registration: ClinicalTrials.gov, NCT02689765. Registered on 6 February 2016, https://clinicaltrials.gov/ct2/show/NCT02689765.Keywords: IGFBP-4 fragments, anthocyanin, oral glucose tolerance test, insulin resistance, C-peptide

BackgroundOpioid dependence is associated with high levels of morbidity, yet sparse data exists regarding the health-related quality of life (HRQoL) of individuals with opioid dependence, particularly following treatment initiation. To inform cost-effectiveness analyses of treatment modalities, this study investigates short-term changes in HRQoL following enrollment into opioid agonist treatment (OAT), across treatment modalities and patient subgroups.MethodsData was analyzed from the Starting Treatment with Agonist Replacement Therapies (START) and Prescription Opioid Addiction Treatment Studies (POATS) randomized controlled trials. Participants included individuals dependent on prescription opioids (POs) or heroin, receiving limited-term or time-unlimited treatment. PO- or heroin-users in START received buprenorphine/naloxone (BUP/NX) or methadone (MET) over 24 weeks. PO-users in POATS received psychosocial care and short-term (4-week) taper with BUP/NX, with non-responders offered subsequent extended (12-week) stabilization and taper. HRQoL was assessed using the short-form SF-6D while in and out of OAT, with distinction between MMT and BUP/NX in START. Linear mixed effects regression models were fitted to determine the independent effects of OAT on HRQoL and characterize HRQoL trajectories.ResultsTreatment had a similar immediate and modest positive association with HRQoL in each patient subgroup. The association of OAT on HRQoL was statistically significant in each model, with effect sizes between 0.039 (heroin-users receiving BUP/NX) and 0.071 (PO-users receiving MET). After initial improvement, HRQoL decreased slightly, or increased at a diminished rate.ConclusionsOAT, whether delivered in time-limited or unlimited form, using BUP/NX or MET, is associated with modest immediate HRQoL improvements, with diminishing benefits thereafter.

We examined risk factors associated with hepatitis C virus (HCV) infection among opioid-dependent patients enrolled into medication-assisted therapy (buprenorphine or methadone) to determine factors affecting chronic infection. Patients (N = 1039) were randomized as part of a larger, multisite clinical trial sponsored by the National Drug Abuse Treatment Clinical Trials Network assessing liver function. HCV status was first assessed with an antibody screen; if positive, then current infection was determined with an antigen screen testing for detectable virus. Patients were classified as HCV negative, HCV positive but have cleared the virus, or as having chronic HCV. Logistic regression analysis was used to examine demographic and behavioral correlates of the three groups. Thirty-four percent of patients were classified with chronic infection and 14% had evidence of prior infection with apparent clearing of the virus. Chronic infection was associated with recent injection drug use and cocaine use. Chronic HCV infection was also associated with being older and Hispanic. Age, ethnicity, and current drug use increase the likelihood of being chronically infected with HCV. Strategies targeting high risk subgroups can aid in preventing further disease escalation.

Multiple-step nucleation pathways have been observed during mineral formation in both inorganic and biomineral systems. These pathways can involve precursor aqueous species, amorphous intermediates, or metastable phases. Despite the widespread occurrence of these processes, elucidating the precise nucleation steps and the transformation mechanisms between each step remains a challenging task. Using a suite of potentiometric, microscopic, and spectroscopic tools, we studied the nucleation pathway of SrSO4 as a function of the physico-chemical solution parameters. Our observations reveal that below a threshold supersaturation, nucleation is driven by bound species, akin to the prenucleation cluster model, which directly leads to the formation of the stable phase celestine, SrSO4. At higher supersaturations, this situation is altered, with nucleation dominated by the consumption of free ions. Importantly, this change in nucleation mechanism is coupled to the formation of a hemihydrate metastable phase, SrSO4 · 1/2H2O, which eventually transforms into celestine, adhering to Ostwald's rule of stages. This transformation is a solution-mediated process, also occurring in the presence of a fluid film and is controlled by the physico-chemical parameters of the surrounding environment. It proceeds through the dissolution of the metastable phase and the de novo crystallization of the final phase. Overall, our results reveal that ion association taking place during the prenucleation stage dictates whether the nucleation pathway goes through an intermediate phase or not. This also underlines that although Ostwald's rule of stages is a common process, it is not a prerequisite for mineral formation—even in systems where it can occur. [ABSTRACT FROM AUTHOR]

Two commonly prescribed treatments for opioid addiction are methadone and buprenorphine. Although these drugs show some efficacy in treating opioid dependence, treatment response varies among individuals. It is likely that genetic factors have a role in determining treatment outcome. This study analyses the pharmacogenetic association of six polymorphisms in OPRD1, the gene encoding the delta-opioid receptor, on treatment outcome in 582 opioid addicted European Americans randomized to either methadone or buprenorphine/naloxone (Suboxone) over the course of a 24-week open-label clinical trial. Treatment outcome was assessed as the number of missed or opioid-positive urine drug screens over the 24 weeks. In the total sample, no single-nucleotide polymorphisms (SNPs) in OPRD1 were significantly associated with treatment outcome in either treatment arm. However, sex-specific analyses revealed two intronic SNPs (rs581111 and rs529520) that predicted treatment outcome in females treated with buprenorphine. Females with the AA or AG genotypes at rs581111 had significantly worse outcomes than those with the GG genotype when treated with buprenorphine (P=0.03, relative risk (RR)=1.67, 95% confidence interval (CI) 1.06-2.1). For rs529520, females with the AA genotype had a significantly worse outcome than those with the CC genotype when (P=0.006, RR=2.15, 95% CI 1.3-2.29). No significant associations were detected in males. These findings suggest that rs581111 and rs52920 may be useful when considering treatment options for female opioid addicts, however, confirmation in an independent sample is warranted.

The Space Plasma Environment Research Facility (SPERF) was built in Harbin to study the three-dimensional magnetic reconnection and wave–particle interactions relevant to space physics in laboratory settings. A 2.45 GHz Electron Cyclotron Resonance (ECR) plasma source is adopted in the device to simulate the Earth's magnetosphere and achieve the scientific goals. In this paper, the design of the ECR plasma source is presented. The structures of the microwave source, the microwave transfer system, and the antenna are introduced. Additionally, the resonant surfaces are computed to predict the locations of microwave absorption. The absorption mechanisms of the microwave in the SPERF are also discussed. The discharge experiment demonstrates the utility of the ECR source in simulating the Earth's magnetosphere. The successful operation of the source indicates that the ECR discharge is a powerful tool for creating a plasma environment in a large plasma experimental device. [ABSTRACT FROM AUTHOR]

Walter Ling,1 Steve Shoptaw,1 David Goodman-Meza2 1UCLA Department of Family Medicine, Center for Behavioral and Addiction Medicine, Los Angeles, CA, USA; 2UCLA Department of Medicine, Division of Infectious Diseases, Los Angeles, CA, USACorrespondence: Walter Ling Email lwalter@ucla.eduAbstract: Buprenorphine has pharmacologic advantages over methadone, especially buprenorphine’s better safety profile. The true significance of buprenorphine’s introduction lies in returning the care of those suffering from opioid use disorder (OUD) to the hands of the physician. The clinical success of buprenorphine has been meager, in part because most physicians have not been exposed to treating these patients. For physicians inclined to treat OUD, the barriers to buprenorphine’s implementation have been onerous and largely counter to the norms of medical practice. Some notable concerns pertain to buprenorphine’s clinical pharmacology like street diversion, unintended use and accidental poisoning. Recently, injectable buprenorphine preparations have been introduced to mitigate these latter shortcomings. Yet, the injectable preparations’ clinical and commercial success has fallen far short of expectation. Here, we review the clinical pharmacology of these products and their expected clinical advantages for the manufacturers, clinicians, policy makers and patients, and offer our perspective, as clinicians and researchers, on how things can improve. Questions remain whether clinicians are willing to overcome barriers to treat OUD using these medications.Keywords: opioid use disorder, injectable buprenorphine, treatment barriers, stakeholders

Walter Ling,1 Vijay R Nadipelli,2 Caitlyn T Solem,3 David Farabee,1,4 Naoko A Ronquest,2 Brian Perrochet,1,5 Susan M Learned,6 Chinmay G Deshpande,3 Christian Heidbreder71UCLA Department of Family Medicine, Center for Behavioral and Addiction Medicine, Los Angeles, CA, USA; 2Global Health Economics and Outcomes Research, Indivior Inc, Richmond, VA, USA; 3Patient-centered outcomes Center of Excellence, Pharmerit International, Bethesda, ML, USA; 4Department of Population Health, School of Medicine,, New York, NY, USA; 5Marron Institute of Urban Management, Marron Institute, New York University, New York, NY, USA; 6Global Medicines Development, Indivior Inc, Richmond, VA, USA; 7Global Research and Development, Indivior Inc, Richmond, VA, USAPurpose: The Treatment Effectiveness Assessment (TEA) is a patient-centered instrument for evaluating treatment progress and recovery from substance use disorders, including opioid use disorder (OUD). We assessed the TEA’s reliability and validity and determined minimal clinically important differences (MIDs) in participants with moderate to severe OUD.Patients and methods: The TEA measures change in four single-item domains (substance use, health, lifestyle, community involvement) from treatment initiation across the duration of a treatment program. Self-reported responses range from 1 (“none or not much”) to 10 (“much better”) with items summed to a total score ranging from 4–40. We assessed floor and ceiling effects, internal consistency, test-retest reliability, known-groups validity (ANOVA stratified by current health status [36-Item Short Form Health Survey item 1]), convergent/divergent validity, and MIDs using data from a phase 3, open-label clinical trial of buprenorphine extended-release monthly injection for subcutaneous use (BUP-XR). Participants with OUD completed the TEA at screening and before monthly injections for up to 12 months.Results: Among 410 participants (mean age 38 years; 64% male), the mean baseline (pre-injection 1) TEA total score was 25.4 (SD 9.7), with

1. The ferritin heavy chain (FHC) has a vital impact on follicular development in geese, due to its ability to regulate apoptosis of granulosa cells (GCs) and follicular atresia. However, its specific regulatory mechanisms remain unclear. The present study characterised how FHC regulates oxidative stress, cell proliferation and apoptosis in goose GCs by interfering with and overexpressing the FHC gene. 2. After 72 h of interference with FHC expression, the activity of GCs decreased remarkably (p < 0.05), reactive oxygen species (ROS) levels and the expression levels of antioxidant enzyme genes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) increased significantly (p < 0.05). The overexpression of FHC for 72 h was found to significantly reduce the expression of CAT and SOD genes (p < 0.05). 3. Interfering with FHC expression revealed that the expression levels of the cell proliferation gene Aurora kinase A (AURORA-A) were significantly decreased (p < 0.05), while the expression levels of the apoptosis genes B-cell lymphoma-2 (BCL-2) and cysteine aspartate-specific protease 8 (CASPASE 8) increased (p < 0.05). Further research has shown that, when interfering with FHC expression for 72 h, apoptosis rate increased by 1.19-fold (p < 0.05), but the current data showed a lower apoptosis rate after FHC overexpression by 59.41%, 63.39%, and 52.31% at three different treatment times (p < 0.05). 4. In conclusion, FHC improved the antioxidant capacity of GCs, promotes GCs proliferation, and inhibits GCs apoptosis of ovarian follicles in Sichuan white geese. [ABSTRACT FROM AUTHOR]

Background: Methamphetamine (MA) abusers have cognitive deficits, abnormal metabolic activity and structural deficits in limbic and paralimbic cortices, and reduced hippocampal volume. The links between cognitive impairment and these cerebral abnormalities are not established. Methods: We assessed cerebral glucose metabolism with [F-18]fluorodeoxyglucose positron emission tomography in 17 abstinent (4 to 7 days) methamphetamine users and 16 control subjects performing an auditory vigilance task and obtained structural magnetic resonance brain scans. Regional brain radioactivity served as a marker for relative glucose metabolism. Error rates on the task were related to regional radioactivity and hippocampal morphology Results. Methamphetamine users bad higher error rate than control subjects on the vigilance task. The groups showed different relationships between error rates and relative activity), in the anterior and middle cingulate gyrus and the insula. Whereas the MA user group showed negative correlations involving these regions, the control group showed positive correlations involving the cingulate cortex. Across groups, hippocampal metabolic and structural measures were negatively correlated with error rates. Conclusions: Dysfunction in the cingulate and insular cortices of recently abstinent MA abusers contribute to impaired vigilance and other cognitive functions requiring sustained attention. Hippocampal integrity predicts task performance in methamphetamine users as well as control subjects.

Our earth is immersed in the near-earth space plasma environment, which plays a vital role in protecting our planet against the solar-wind impact and influencing space activities. It is significant to investigate the physical processes dominating the environment, for deepening our scientific understanding of it and improving the ability to forecast the space weather. As a crucial part of the National Major Scientific and Technological Infrastructure–Space Environment Simulation Research Infrastructure (SESRI) in Harbin, the Space Plasma Environment Research Facility (SPERF) builds a system to replicate the near-earth space plasma environment in the laboratory. The system aims to simulate the three-dimensional (3-D) structure and processes of the terrestrial magnetosphere for the first time in the world, providing a unique platform to reveal the physics of the 3-D asymmetric magnetic reconnection relevant to the earth's magnetopause, wave–particle interaction in the earth's radiation belt, particles' dynamics during the geomagnetic storm, etc. The paper will present the engineering design and construction of the near-earth space plasma simulation system of the SPERF, with a focus on the critical technologies that have been resolved to achieve the scientific goals. Meanwhile, the possible physical issues that can be studied based on the apparatus are sketched briefly. The earth-based system is of great value in understanding the space plasma environment and supporting space exploration. [ABSTRACT FROM AUTHOR]

Walter Ling,1 David Farabee,2,3 Vijay R Nadipelli,4 Brian Perrochet3 On behalf of the TEA Development Group1Department of Family Medicine, Center for Behavioral and Addiction Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; 2Department of Population Health, New York University School of Medicine, New York, NY, USA; 3Department of Psychiatry and Biobehavioral Sciences Semel Institute, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA; 4Global Health Economics and Outcome Research, Indivior Inc., Richmond, VA, USACorrespondence: Walter Ling Tel +1 310 993 8111Email lwalter@ucla.edu The authors are pleased to provide this updated version of the TEA to the community of clinicians and researchers using the TEA. Previous to its original publication in 2012,1 the TEA had been used for five years by clinicians in office-based and hospital-based treatment settings, as well as by researchers in pilot projects. The TEA’s utility and psychometrics were recently studied in a large clinical trial of extended-release buprenorphine for opioid use disorder, demonstrating moderate to strong reliability and validity.3 The TEA has been widely adopted by researchers and clinicians in the United States and around the world. It has been translated into Spanish, Chinese, Lithuanian, and Arabic, and is being used in Europe, Asia, the Americas, and the Middle-East.View the original paper by Ling and colleagues

Ling W, Shoptaw S, Goodman-Meza D. Subst Abuse Rehabil. 2019;10:69–78.The authors of this paper have advised that Table 1 is incorrect. The authors advised that they had listed values for Cmax and Ctrough after a single dose of Brixadi (CAM2038) and not steady state, as it was provided for Sublocade. The new Table 1 reflects the Brixadi steady state concentrations for a more direct comparison with Sublocade.Read the original article

The powers against the higher-order differential cryptanalysis of the single-SP(substitution-permutation) model and the double-SP model are studied in the type-1 Feistel network by analyzing the growths of algebraic degrees. Combining the higher-order integral and the higher-order difference, a new method is exploited to estimate the upper bounds of algebraic degrees for the 4-line type-1 Feistel-SP scheme and the 4-line type-1 Feistel-SPSP scheme. Applying the new method, distinguishers of the two schemes are constructed with four common parameters. As a result, the dou-ble-SP model is weaker than the single-SP model against the higher-order differential attack under the 4-line type-1 Feis-tel structure.

A nascent line of research aimed at elucidating the neurocognitive mechanisms of mindfulness has consistently identified a relationship between mindfulness and error monitoring. However, the exact nature of this relationship is unclear, with studies reporting divergent outcomes. The current study sought to clarify the ambiguity by addressing issues related to construct heterogeneity and technical variation in mindfulness training. Specifically, we examined the effects of a brief open monitoring (OM) meditation on neural (error-related negativity (ERN) and error positivity (Pe)) and behavioral indices of error monitoring in one of the largest novice non-meditating samples to date (N = 212). Results revealed that the OM meditation enhanced Pe amplitude relative to active controls but did not modulate the ERN or behavioral performance. Moreover, exploratory analyses yielded no relationships between trait mindfulness and the ERN or Pe across either group. Broadly, our findings suggest that technical variation in scope and object of awareness during mindfulness training may differentially modulate the ERN and Pe. Conceptual and methodological implications pertaining to the operationalization of mindfulness and its training are discussed.

Walter Ling,1 David Farabee,1 Dagmar Liepa,2 Li-Tzy Wu31Integrated Substance Abuse Programs, University of California, Los Angeles, CA, USA; 2Valley Care Medical Center, Panorama City, CA, USA; 3Department of Psychiatry and Behavioral Sciences, School of Medicine, Duke University Medical Center, Durham, NC, USAAbstract: The fields of addiction medicine and addiction research have long sought an efficient yet comprehensive instrument to assess patient progress in treatment and recovery. Traditional tools are expensive, time consuming, complex, and based on topics that clinicians or researchers think are important. Thus, they typically do not provide patient-centered information that is meaningful and relevant to the lives of patients with substance use disorders. To improve our ability to understand patients’ progress in treatment from their perspectives, the authors and colleagues developed a patient-oriented assessment instrument that has considerable advantages over existing instruments: brevity, simplicity, ease of administration, orientation to the patient, and cost (none). The resulting Treatment Effectiveness Assessment (TEA) elicits patient responses that help the patient and the clinician quickly gauge patient progress in treatment and in recovery, according to the patients’ sense of what is important within four domains established by prior research. Patients provide both numerical responses and representative details on their substance use, health, lifestyle, and community. No software is required for data entry or scoring, and no formal training is required to administer the TEA. This article describes the development of the TEA and the initial phases of its application in clinical practice and in research.Keywords: substance use disorders, global treatment progress, brief instrument, patient-centered

Ji Jun, Ji Shang-Yi, Yang Jian-An, He Xia, Yang Xiao-Han, Ling Wen-Ping, Chen Xiao-LingDepartment of Pathology and Cardiovascular Surgery, Shenzhen Sun Yat-Sen Cardiovascular Hospital, Shenzhen, Guangdong, People's Republic of ChinaBackground: There are more than 300,000 prosthetic heart valve replacements each year worldwide. These patients are faced with a higher risk of thromboembolic events after heart valve surgery and long-term or even life-long anticoagulative and antiplatelet therapies are necessary. Some severe complications such as hemorrhaging or rebound thrombosis can occur when the therapy ceases. Tissue-type plasminogen activator (t-PA) is a thrombolytic agent. One of the best strategies is gene therapy, which offers a local high expression of t-PA over a prolonged time period to avoid both systemic hemorrhaging and local rebound thrombosis. There are some issues with t-PA that need to be addressed: currently, there is no up-to-date report on how the t-PA gene targets the heart in vivo and the gene vector for t-PA needs to be determined.Aims: To fabricate an albumin nano-t-PA gene ultrasound-targeted agent and investigate its targeting effect on prevention of thrombosis after heart mechanic valve replacement under therapeutic ultrasound.Methods: A dog model of mechanical tricuspid valve replacement was constructed. A highly expressive t-PA gene plasmid was constructed and packaged by nanoparticles prepared with bovine serum albumin. This nanopackaged t-PA gene plasmid was further cross-linked to ultrasonic microbubbles prepared with sucrose and bovine serum albumin to form the ultrasonic-targeted agent for t-PA gene transfection. The agent was given intravenously followed by a therapeutic ultrasound treatment (1 MHz, 1.5 w/cm2, 10 minutes) of the heart soon after valve replacement had been performed. The expression of t-PA in myocardium was detected with multiclonal antibodies to t-PA by the indirect immunohistochemical method. Venous blood t-PA and D-dimer contents were tested before and 1, 2, 4, and 8 weeks after the operation.Results: The high expression of t-PA could be seen in myocardium with increases in blood t-PA and D-dimer contents and thrombosis was prevented 8 weeks after operation.Conclusion: We successfully fabricated an albumin nano-t-PA gene ultrasound-targeted agent that could prevent dog thrombosis after mechanical heart valve replacement. Our study provides an experimental basis for prevention of human thrombosis-related diseases.Keywords: albumin nanoparticles, ultrasonic microbubbles, valve replacement

Walter Ling1, Larissa Mooney1, Min Zhao2, Suzanne Nielsen1, Matthew Torrington1, Karen Miotto1 1Integrated Substance Abuse Programs, University of California, Los Angeles, CA, USA; 2Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China Abstract: Pharmacotherapies for opioid addiction under active development in the US include lofexidine (primarily for managing withdrawal symptoms) and Probuphine®, a distinctive mode of delivering buprenorphine for six months, thus relieving patients, clinicians, and regulatory personnel from most concerns about diversion, misuse, and unintended exposure in children. In addition, two recently approved formulations of previously proven medications are in early phases of implementation. The sublingual film form of buprenorphine + naloxone (Suboxone®) provides a less divertible, more quickly administered, more child-proof version than the buprenorphine + naloxone sublingual tablet. The injectable depot form of naltrexone (Vivitrol®) ensures consistent opioid receptor blockade for one month between administrations, removing concerns about medication compliance. The clinical implications of these developments have attracted increasing attention from clinicians and policymakers in the US and around the world, especially given that human immunodeficiency virus/acquired immunodeficiency syndrome and other infectious diseases are recognized as companions to opioid addiction, commanding more efforts to reduce opioid addiction. While research and practice improvement efforts continue, reluctance to adopt new medications and procedures can be expected, especially considerations in the regulatory process and in the course of implementation. Best practices and improved outcomes will ultimately emerge from continued development efforts that reflect input from many quarters. Keywords: buprenorphine, naltrexone, probuphine, lofexidine, implant buprenorphine, buprenorphine film

Daniel J Pilowsky1, Li-Tzy Wu2, Bruce Burchett2, Dan G Blazer2, George E Woody3, Walter Ling41Departments of Epidemiology and Psychiatry, Columbia University, and the New York State Psychiatric Institute, New York City, NY; 2Department of Psychiatry and Behavioral Sciences, School of Medicine, Duke University Medical Center, Durham, NC; 3Department of Psychiatry, School of Medicine, University of Pennsylvania and Treatment Research Institute, Philadelphia, PA; 4David Geffen School of Medicine, NPI/Integrated Substance Abuse Programs, University of California, Los Angeles, CA, USABackground: In response to the rising rate of treatment admissions related to illicit use of amphetamines (eg, methamphetamine), we examined the prevalence of amphetamine use among treatment-seeking, opioid-dependent adults, explored whether amphetamine users were as likely as nonamphetamine users to enroll in opioid-dependence treatment trials, and determined whether amphetamine users manifested greater levels of medical and psychiatric comorbidity than nonusers.Methods: The sample included 1257 opioid-dependent adults screened for participation in threemultisite studies of the National Drug Abuse Treatment Clinical Trials Network (CTN001-003), which studied the effectiveness of buprenorphine for opioid detoxification under varying treatment conditions. Patients were recruited from 23 addiction treatment programs across the US. Medical and psychiatric comorbidity were examined by past-month amphetamine use (current vs former) and route of administration. Five mutually exclusive groups were examined, ie, nonusers, current amphetamine injectors, current amphetamine noninjectors, former amphetamine injectors, and former amphetamine noninjectors.Results: Of the sample (n = 1257), 22.3% had a history of regular amphetamine use. Of the 280 amphetamine users, 30.3% reported injection as their primary route. Amphetamine users were more likely than nonusers to be white and use more substances. Amphetamine users were as likely as nonusers to enroll in treatment trials. Bivariate analyses indicated elevated rates of psychiatric problems (depression, anxiety, hallucinations, cognitive impairment, violence, suicidal thoughts/attempts) and medical illnesses (dermatological, hepatic, cardiovascular, respiratory, neurological, seizure, allergy conditions) among amphetamine users. After adjusting for demographic variables and lifetime use of other substances: current amphetamine users and former injectors showed an increased likelihood of having medical illnesses and hospitalizations; current injectors had elevated odds of suicidal thoughts or attempts; current noninjectors exhibited elevated odds of anxiety, cognitive impairment, and violent behaviors; and former noninjectors had increased odds of depression.Conclusion: Treatment-seeking, amphetamine-using, opioid-dependent adults manifest greater levels of medical and psychiatric morbidity than treatment-seeking, opioid-dependent adults who have not used amphetamines, indicating a greater need for intensive clinical management.Keywords: amphetamine use, buprenorphine, clinical trials network, injection drug use, methamphetamine use, opioid dependence, rehabilitation