Fouling of virus filtration membranes by monoclonal antibody feeds with low aggregate content.

Membrane fouling by monoclonal antibodies (mAbs) is one of the main challenges in virus-filtration processes. Previous publications attributed membrane fouling to the presence of mAb aggregates in the solution, which block the membrane pores. This fouling mechanism can be solved by a prefilter; however, it was shown that there are mAbs that severely foul the membranes (reduce permeability by 90% and more) even after prefiltering the aggregates, while other mAbs foul the membrane weakly (reduce permeability by ~10% and less). Unfortunately, the differences between the fouling- and the nonfouling mAbs have never been convincingly explained. To get a deeper insight on these differences, we measured the fouling of chemically modified Isoprene-Styrene-4-vinylpyridine (ISV) membranes (TeraPore Technologies) by 8 mAbs exhibiting different hydrophobicity and charge. The results show that mAb solutions with low concentration of aggregates foul ISV membranes via an adsorptive mechanism, and the adsorption is driven mainly by hydrophobic forces between the mAb and the membrane. The charge of the mAbs plays a secondary role in fouling. We want to emphasize that the conclusions pertain to ISV membranes; the insights presented in this paper can potentially be used to engineer new surface chemistries to mitigate fouling of other virus-filtration and/or ultrafiltration membranes.

Are there non-linear relationships between alcohol consumption and long-term health?: a systematic review of observational studies employing approaches to improve causal inference.

BACKGROUND: Research has long found 'J-shaped' relationships between alcohol consumption and certain health outcomes, indicating a protective effect of moderate consumption. However, methodological limitations in most studies hinder causal inference. This review aimed to identify all observational studies employing improved approaches to mitigate confounding in characterizing alcohol-long-term health relationships, and to qualitatively synthesize their findings. METHODS: Eligible studies met the above description, were longitudinal (with pre-defined exceptions), discretized alcohol consumption, and were conducted with human populations. MEDLINE, PsycINFO, Embase and SCOPUS were searched in May 2020, yielding 16 published manuscripts reporting on cancer, diabetes, dementia, mental health, cardiovascular health, mortality, HIV seroconversion, and musculoskeletal health. Risk of bias of cohort studies was evaluated using the Newcastle-Ottawa Scale, and a recently developed tool was used for Mendelian Randomization studies. RESULTS: A variety of functional forms were found, including reverse J/J-shaped relationships for prostate cancer and related mortality, dementia risk, mental health, and certain lipids. However, most outcomes were only evaluated by a single study, and few studies provided information on the role of alcohol consumption pattern. CONCLUSIONS: More research employing enhanced causal inference methods is urgently required to accurately characterize alcohol-long-term health relationships. Those studies that have been conducted find a variety of linear and non-linear functional forms, with results tending to be discrepant even within specific health outcomes. TRIAL REGISTRATION: PROSPERO registration number CRD42020185861.

Potential evidence of peripheral learning and memory in the arms of dwarf cuttlefish, Sepia bandensis.

CREB (cAMP response element-binding) transcription factors are conserved markers of memory formation in the brain and peripheral circuits. We provide immunohistochemical evidence of CREB phosphorylation in the dwarf cuttlefish, Sepia bandensis, following the inaccessible prey (IP) memory experiment. During the IP experiment, cuttlefish are shown prey enclosed in a transparent tube, and tentacle strikes against the tube decrease over time as the cuttlefish learns the prey is inaccessible. The cues driving IP learning are unclear but may include sensory inputs from arms touching the tube. The neural activity marker, anti-phospho-CREB (anti-pCREB) was used to determine whether IP training stimulated cuttlefish arm sensory neurons. pCREB immunoreactivity occurred along the oral surface of the arms, including the suckers and epithelial folds surrounding the suckers. pCREB increased in the epithelial folds and suckers of trained cuttlefish. We found differential pCREB immunoreactivity along the distal-proximal axis of trained arms, with pCREB concentrated distally. Unequal CREB phosphorylation occurred among the 4 trained arm pairs, with arm pairs 1 and 2 containing more pCREB. The resulting patterns of pCREB in trained arms suggest that the arms obtain cues that may be salient for learning and memory of the IP experiment.

Evidence of learning and memory in the juvenile dwarf cuttlefish Sepia bandensis.

Measuring behavior in the form of numerical data is difficult, especially for studies involving complex actions. DanioVision is a closed-chamber system that utilizes subject tracking to comprehensively record behavior, while also mitigating the influence of environmental conditions. We used DanioVision to record activity of juvenile dwarf cuttlefish (Sepia bandensis) during the inaccessible prey (IP) procedure, a memory experiment in which cuttlefish learn to inhibit capture attempts towards inaccessible prey. By quantifying total movement and orientation of the body, we found that cuttlefish show memory by selectively inhibiting tentacle strikes without reducing total movement, or orientation towards the prey. We show that DanioVision can be used to assess multiple components of dynamic responses that are not measurable by direct observation alone and provide new evidence that strike inhibition is the product of learning, and not motor fatigue.

Mechanisms of output interference in cued recall.

The primary aim of this paper is to elucidate the mechanisms governing output interference in cued recall. Output interference describes the phenomenon where accuracy decrease over the course of an episodic memory test. Output inference in cued recall takes the form of a decrease in correct and intrusion responses and an increase in failures to response across the test. This pattern can only be accounted for by a model with two complementary mechanisms: learning during retrieval and a response filter that prevents repeated recall of the same item. We investigate how a retrieval filter might operate by manipulating the similarity of words. The data are consistent with a retrieval filter that does not operate by a global match of a potential target to previously recalled items. Results are discussed within the search of associative memory theory.

Fracture rate in women with oestrogen deficiency - Comparison of Turner syndrome and premature ovarian insufficiency.

OBJECTIVE: Women with early-onset oestrogen deficiency are at risk of reduced bone mineral density (BMD). We sought to assess fracture history and BMD in women with Turner syndrome (TS) and premature ovarian insufficiency (POI). DESIGN: A cross-sectional observational study. PATIENTS: Two hundred and sixty seven women with TS (median age 34.3 years) and 67 women with POI (median age 28.1 years). MEASUREMENTS: A questionnaire was used to collect data on fracture history, co-morbidities and drug history including age at first oestrogen exposure. Clinical data included height, weight, serum vitamin D and hip and spine T-scores, which were adjusted for height and age. Fractures were subdivided into major osteoporotic fractures (MOF) and 'other' fracture types. RESULTS: Overall fracture rate was similar in women with TS and POI (82 [30.5%] vs 22 [32.8%] respectively, P = .74). Compared to women with POI, those with TS had more fractures at MOF sites (30.2% vs 52.7%, P = .012) and fewer phalangeal fractures (27.9% vs 9.8%, P = .005). There was no difference in BMD between women who sustained a fracture compared to those who did not. Women with TS who fractured were more likely to suffer from hearing impairment compared to those with no fracture (62.2% vs 48.1%, P = .045). CONCLUSIONS: TS is not associated with an overall excess risk of bone fracture. The higher rate of fractures at MOF sites in women with TS may be secondary to hearing impairment, thin cortical bone and abnormal bone remodelling.

Reactivation of Goodpasture Disease During the Third Trimester of Pregnancy: A Case Report.

BACKGROUND: Active Goodpasture disease (GD) in pregnancy is extremely rare and can result in significant maternal and fetal morbidity. Relapse of GD in a subsequent pregnancy has not been reported. Factors associated with a relapse of GD are unknown. CASE: A woman in her second pregnancy presented with clinical findings of preeclampsia and biopsy evidence of GD in the third trimester. Her first puerperium was also complicated by GD, requiring temporary hemodialysis. After her second pregnancy she developed terminal renal failure. CONCLUSION: Active GD is extremely rare in pregnancy and has never been reported in 2 successive pregnancies in the same patient. Pregnancy and preeclampsia may be risk factors for a GD relapse, and women with GD contemplating pregnancy should be counseled accordingly.

The Long-Term Relationship Between Cannabis and Heroin Use: An 18- to 20-year Follow-Up of the Australian Treatment Outcome Study (ATOS).

OBJECTIVE: Cannabis use is common among individuals with opioid use disorder, but it remains unclear whether cannabis use is associated with an increase or a reduction in illicit opioid use. To overcome limitations identified in previous longitudinal studies with limited follow-ups, the authors examined a within-person reciprocal relationship between cannabis and heroin use at several follow-ups over 18 to 20 years. METHODS: The Australian Treatment Outcome Study (ATOS) recruited 615 people with heroin dependence in 2001 and 2002 and reinterviewed them at 3, 12, 24, and 36 months as well as 11 and 18-20 years after baseline. Heroin and cannabis use were assessed at each time point using the Opiate Treatment Index. A random-intercept cross-lagged panel model analysis was conducted to identify within-person relationships between cannabis use and heroin use at subsequent follow-ups. RESULTS: After accounting for a range of demographic variables, other substance use, and mental and physical health measures, an increase in cannabis use 24 months after baseline was significantly associated with an increase in heroin use at 36 months (estimate=0.21, SE=0.10). Additionally, an increase in heroin use at 3 months and 24 months was significantly associated with a decrease in cannabis use at 12 months (estimate=-0.27, SE=0.09) and 36 months (estimate=-0.22, SE=0.08). All other cross-lagged associations were not significant. CONCLUSIONS: Although there was some evidence of a significant relationship between cannabis and heroin use at earlier follow-ups, this was sparse and inconsistent across time points. Overall, there was insufficient evidence to suggest a unidirectional or bidirectional relationship between the use of these substances.

Biomarkers of neurodegeneration in schizophrenia: systematic review and meta-analysis.

QUESTION: Does neurodegenerative disease underlie the increased rate of dementia observed in older people with schizophrenia? Several studies have reported a higher prevalence of dementia in people with schizophrenia compared with the general population. This may reflect a higher risk of developing neurodegenerative diseases such as vascular dementia or Alzheimer's disease (AD). Alternatively, this may reflect non-pathological, age-related cognitive decline in a population with low cognitive reserve. STUDY SELECTION AND ANALYSIS: We reviewed papers that compared postmortem findings, hippocampal MRI volume or cerebrospinal fluid (CSF) markers of AD, between patients with schizophrenia with evidence of cognitive impairment (age ≥45 years) with controls. We subsequently performed a meta-analysis of postmortem studies that compared amyloid-ß plaques (APs) or neurofibrillary tangles (NFTs) in cognitively impaired patients with schizophrenia to normal controls or an AD group. FINDINGS: No studies found a significant increase of APs or NFTs in cognitively impaired patients with schizophrenia compared with controls. All postmortem studies that compared APs or NFTs in patients with schizophrenia to an AD group found significantly more APs or NFTs in AD. No studies found a significant differences in CSF total tau or phosphorylated tau between patients with schizophrenia and controls. The two studies which compared CSF Aß42 between patients with schizophrenia and controls found significantly decreased CSF Aß42 in schizophrenia compared with controls. Hippocampal volume findings were mixed. CONCLUSIONS: Studies have not found higher rates of AD-related pathology in cognitively impaired individuals with schizophrenia compared with controls. Higher rates of dementia identified in population studies may reflect a lack of specificity in clinical diagnostic tools used to diagnose dementia.

Is post-traumatic stress disorder a risk factor for development of opioid use disorder among individuals with chronic non-cancer pain? A systematic review.

Introduction: There is emerging evidence that posttraumatic-stress disorder may have mediating effects in development of chronic-non-cancer-pain and opioid-use-disorder independently, but its impact on the development of opioid-use-disorder in people with chronic-non-cancer pain is still unclear. Objectives: (i) Estimate the risk of opioid-use-disorder among individuals with chronic-non-cancer-pain and posttraumatic-stress disorder, relative to those with chronic-non-cancer-pain only, and (ii) identify potential correlates of opioid-use-disorder among people with chronic-non-cancer-pain and posttraumatic-stress disorder. Methods: This systematic review was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Longitudinal, epidemiological, cohort, follow-up, retrospective, prospective and cross-sectional studies reporting measures of variance on the likelihood of developing opioid-use-disorder with posttraumatic-stress disorder among individuals with chronic-non-cancer-pain were identified from six-electronic databases (Medline, Embase, Evidence-based Medicine reviews, PsycINFO, Scopus and Web of Science) until December 2022. Results: Three out of the four studies, which met the selection criteria for this analysis reported statistically significant positive association between risk of developing opioid-use-disorder with posttraumatic-stress disorder among chronic-non-cancer-pain cohort (unadjusted Relative-Risk range: 1.51-5.27) but this association was not evident in the fourth study (adjusted Relative-Risk: 0.96; statistically non-significant), when adjusted for sociodemographic variables. The increased risk was noted particularly with females and chronic musculoskeletal pain conditions. Conclusions: Posttraumatic-stress disorder can increase the risk of development of opioid-use-disorder among people with chronic-non-cancer-pain and a better understanding of this relationship will help to predict and prevent the development of opioid-use-disorder and may also help in reducing the disability and burden associated with chronic-non-cancer-pain. Perspective: This review quantifies the risk of developing opioid-use-disorder in the context of posttraumatic-stress disorder among individuals with chronic-non-cancer-pain. Awareness and subsequent practice change will reduce the increasing global burden associated with the chronic-non-cancer-pain.

Prevalence of comorbid substance use disorders among people with opioid use disorder: A systematic review & meta-analysis.

BACKGROUND: Comorbid substance use disorders (SUDs) among people with opioid use disorder (OUD) contribute to poor clinical outcomes, including overdose and mortality. We present the first systematic review and meta-analysis to estimate the prevalence of specific non-opioid SUDs among people with OUD. METHODS: We searched Embase, PsycINFO, and MEDLINE from 1990 to 2022 for studies that used Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) criteria to assess the prevalence of non-opioid SUDs among individuals with OUD. We used random-effects meta-analyses with 95% Confidence Intervals (CIs) to pool current and lifetime prevalence estimates separately. Meta-regressions and stratified meta-analyses were used to examine differences in prevalence estimates by sample characteristics and methodological factors. RESULTS: Of the 36,971 publications identified, we included data from 194 studies and 77,212 participants with OUD. The prevalence of any comorbid SUD among people with OUD was 59.5% (95%CI 49.1-69.5%) for current non-opioid SUDs, with 72.0% (95%CI 52.5-87.9%) experiencing a comorbid SUD in their lifetime. Of the studies that examined current comorbid SUDs, cocaine use disorder (30.5%, 95%CI 23.0-38.7%) was most common, followed by alcohol (27.1%, 95%CI 24.4- 30.0%), cannabis (22.7%, 95%CI 19.0-26.6%), sedative (16.1%, 95%CI 13.1-19.3%), and methamphetamine (11.4%, 95%CI 6.8-17.1%) use disorders. Substantial heterogeneity (I2>90%) across estimates was observed. Substantial heterogeneity (I2>90%) was observed across estimates, with significant variations in prevalence identified across geographic locations, recruitment settings, and other study-level factors. CONCLUSION: Findings from this study emphasize the importance of comorbid SUD treatment access for people with OUD. Our estimates can inform the provision of treatment and harm reduction strategies for people with OUD and specific subpopulations.

Low Risk of Cardiac Complications during Long-Term Follow-Up of Opioid Dependence.

OBJECTIVES: To prospectively assess rates of QT prolongation, arrhythmia, syncope, and sudden cardiac death (SCD) in a cohort of people with heroin dependence. METHODS: To estimate rates of QT prolongation, arrhythmia, and syncope, a subcohort (n = 130) from the Australian Treatment Outcomes Study, a prospective longitudinal cohort study of 615 people with heroin dependence, underwent medical history, venepuncture, and ECG at the 18- to 20-year follow-up.To estimate rates of SCD, probabilistic matching for the entire cohort was undertaken with the Australian Institute of Health and Welfare National Death Index. Deaths were classified into suicide, accidental overdose, trauma, unknown, and disease, which were then further subclassified by probability of SCD. SCD rate was the number of possible or probable SCDs divided by total patient years from the cohort. RESULTS: From the subcohort, 4 participants (3%) met the criteria for QT prolongation; 3 were prescribed methadone. Seven participants (5%) reported history of arrhythmia, including 2 transferred from methadone to buprenorphine. Thirty participants (23%) reported a previous syncopal event-14 diagnosed as nonarrhythmic syncope and 13 not investigated. In the previous 12 months, 66 participants (51%) reported heroin use; 55 participants (42%) were prescribed methadone. No participant had QTc greater than 500 milliseconds.There were 3 possible SCDs, translating to an estimated SCD rate of 0.29 (CI: 0.05, 0.8) events per 1000 patient years. More cohort members died of overdose (n = 50), suicide (n = 11), and hepatitis C (n = 4). CONCLUSIONS: Low rates of QT prolongation, arrhythmia, syncope, and SCD in the cohort despite high rates of heroin use and methadone treatment.

Cannabidiol does not attenuate acute delta-9-tetrahydrocannabinol-induced attentional bias in healthy volunteers: A randomised, double-blind, cross-over study.

AIMS: To test how attentional bias and explicit liking are influenced by delta-9-tetrahydrocannabinol (THC) and whether these effects are moderated by cannabidiol (CBD). DESIGN: Double-blind, randomised, within-subjects cross-over study. SETTING: NIHR Wellcome Trust Clinical Research Facility at King's College Hospital, London, United Kingdom. PARTICIPANTS/CASES: Forty-six infrequent cannabis users (cannabis use <1 per week). INTERVENTION(S): Across four sessions, participants inhaled vaporised cannabis containing 10 mg of THC and either 0 mg (0:1 CBD:THC), 10 mg (1:1), 20 mg (2:1) or 30 mg (3:1) of CBD, administered in a randomised order and counter-balanced across participants (a total of 24 order groups). MEASUREMENTS: Participants completed two tasks: (1) Attentional Bias (AB), comparing reaction times toward visual probes presented behind 28 target stimuli (cannabis/food) compared with probes behind corresponding non-target (neutral) stimuli. Participants responding more quickly to probes behind target than non-target stimuli would indicate greater attentional bias to cannabis/food; (2) Picture Rating (PR), where all AB stimuli were rated on a 7-point pleasantness scale, measuring explicit liking. FINDINGS: During the AB task, participants were more biased toward cannabis stimuli in the 0:1 condition compared with baseline (mean difference = 12.2, 95% confidence intervals [CIs] = 1.20-23.3, d = 0.41, P = 0.03). No other significant AB or PR differences were found between cannabis and food stimuli between baseline and 0:1 condition (P > 0.05). No significant CBD effect was found on AB or PR task performance at any dose (P > 0.05). There was additionally no cumulative effect of THC exposure on AB or PR outcomes (P > 0.05). CONCLUSIONS: A double-blind, randomised, cross-over study among infrequent cannabis users found that inhaled delta-9-tetrahydrocannabinol increased attentional bias toward cannabis in the absence of explicit liking, a marker of liability toward cannabis use disorder. At the concentrations normally found in legal and illegal cannabis, cannabidiol had no influence on this effect.

Applications of Thermochemical Modeling in Molten Salt Reactors.

The extensively evaluated and consistent thermodynamic database, the Molten Salt Thermal Properties Database-Thermochemical (MSTDB-TC), was used along with additional thermodynamic values from other sources as examples of ways to examine molten salt reactor (MSR) fuel behavior. Relative stability with respect to halide potential and temperature for likely fuel and fission product components were mapped in Ellingham diagrams for the chloride and fluoride systems. The Ellingham diagrams provide a rich, visual means for identifying halide-forming components in proposed fuel/solvent salt systems. Thermochemical models and values from MSTDB-TC and ancillary sources were used in global equilibrium calculations to provide compositions for a close analysis of the behavior of a possible Molten Chloride Salt Fast Reactor and a Molten Salt Reactor Experiment-type system at high burnup (100 GWd/t). The results illustrated the oxidative nature of burnup in MSRs and provided information about redox behavior and possible control.

Long-term patterns of treatment use for opioid use disorder (OUD): Findings from the 18-20-year Australian Treatment Outcome Study.

BACKGROUND: Opioid-related deaths continue to increase to unprecedented rates in many regions of the world. While long-term stable treatment has been shown to reduce associated morbidity and mortality, discontinuation and numerous treatment episodes are common, limiting our understanding of the common course of treatment and associated characteristics. Therefore, using an 18-20-year follow-up of people with heroin dependence, we aimed to identify i) distinct trajectories of treatment use, ii) whether baseline characteristics predict treatment trajectory group membership, and ii) if group membership is associated with characteristics at 18-20-years post-baseline. METHODS: A total of 615 people with heroin dependence were recruited from maintenance therapy, detoxification, residential rehabilitation, or needle and syringe programs as part of the Australian Treatment Outcome Study (ATOS), a longitudinal cohort followed up on seven occasions over 18-20-years between 2001 and 2021. Of those who had complete data (n = 393), group-based trajectory modelling and a series of multinomial logistical regressions were conducted. RESULTS: Five trajectories of treatment use were identified: i) 'long-term low treatment' (17.2%), ii) 'rapid increase with gradual decrease' (13.9%), iii) 'late increase' (17.8%), (iv) 'long-term treatment' (27.7%), and (v) 'reduced treatment' (23.5%). Entering maintenance treatment at baseline predicted trajectory group membership, while trajectory group membership was associated with demographics and the use of heroin, methamphetamine, alcohol, and benzodiazepines at 18-20-years. CONCLUSIONS: In one of the longest cohort studies of its kind, we characterised distinct trajectories of treatment use in people with heroin dependence over 18-20-years. Clinicians should be aware of the potential impact of demographics and substance use on long-term treatment use. Despite the well-documented benefits of long-term treatment, some patients may be able to achieve abstinence from opioids without engaging in treatment over the life-course.

Incidence of new-onset in-hospital and persistent diabetes in COVID-19 patients: comparison with influenza.

BACKGROUND: This study investigated the incidences and risk factors associated with new-onset persistent type-2 diabetes during COVID-19 hospitalization and at 3-months follow-up compared to influenza. METHODS: This retrospective study consisted of 8216 hospitalized, 2998 non-hospitalized COVID-19 patients, and 2988 hospitalized influenza patients without history of pre-diabetes or diabetes in the Montefiore Health System in Bronx, New York. The primary outcomes were incidences of new-onset in-hospital type-2 diabetes mellitus (I-DM) and persistent diabetes mellitus (P-DM) at 3 months (average) follow-up. Predictive models used 80%/20% of data for training/testing with five-fold cross-validation. FINDINGS: I-DM was diagnosed in 22.6% of patients with COVID-19 compared to only 3.3% of patients with influenza (95% CI of difference [0.18, 0.20]). COVID-19 patients with I-DM compared to those without I-DM were older, more likely male, more likely to be treated with steroids and had more comorbidities. P-DM was diagnosed in 16.7% of hospitalized COVID-19 patients versus 12% of hospitalized influenza patients (95% CI of difference [0.03,0.065]) but only 7.3% of non-hospitalized COVID-19 patients (95% CI of difference [0.078,0.11]). The rates of P-DM significantly decreased from 23.9% to 4.0% over the studied period. Logistic regression identified similar risk factors predictive of P-DM for COVID-19 and influenza. The adjusted odds ratio (0.90 [95% CI 0.64,1.28]) for developing P-DM was not significantly different between the two viruses. INTERPRETATION: The incidence of new-onset type-2 diabetes was higher in patients with COVID-19 than influenza. Increased risk of diabetes associated with COVID-19 is mediated through disease severity, which plays a dominant role in the development of this post-acute infection sequela. FUNDING: None.

Different Tokes for Different Folks: Use of Cannabis Products Among a Longitudinal Cohort of People with Heroin Dependence.

Co-occurring cannabis use is common among those with opioid use disorder (OUD), but the extent to which it is harmful may be due to its preparation and concentration of various cannabinoids. The current study aimed to examine the prevalence of, and long-term associations with, the use of varying cannabis products among a naturalistic longitudinal cohort of people with heroin dependence. A total of 615 people, most of whom were entering treatment, were recruited to the Australian Treatment Outcome Study (ATOS) in 2001-2002. This analysis focuses on the 401 participants followed up at 18-20 years post baseline. Structured interviews assessed the use of cannabis products, as well as demographic and health covariates. High-potency/indoor-grown cannabis was the most common type ever used (68.8%), and in the past 12 months (80.4%), followed by low potency/outdoor grown (22.4%; 14.4%), and less so for other types of cannabis. After controlling for covariates, older age at baseline was associated with lower odds of high-potency cannabis being used as the primary type in the past 12 months. In contrast to studies of non-opioid dependent populations, common use of high-potency cannabis was not associated with more severe health outcomes. Supplementary Information: The online version contains supplementary material available at 10.1007/s11469-023-01071-5.

Patterns and Predictors of Heroin Use, Remission, and Psychiatric Health Among People with Heroin Dependence: Key Findings from the 18-20-Year Follow-Up of the Australian Treatment Outcome Study (ATOS).

This study aimed to investigate the long-term patterns and predictors of heroin use, dependence, and psychiatric health over 18-20 years among a cohort of Australians with heroin dependence, using a prospective longitudinal cohort study conducted in Sydney, Australia. The original cohort consisted of 615 participants, who were followed up at 3 months and 1, 2, 3, 11, and 18-20 years post-baseline; 401 (65.2%) were re-interviewed at 18-20 years. The Australian Treatment Outcome Study structured interview with established psychometric properties was administered to participants at each follow-up, addressing demographics, treatment and drug use history, overdose, crime, and physical and mental health. Overall, 96.7% completed at least one follow-up interview. At 18-20 years, 109 participants (17.7%) were deceased. Past-month heroin use decreased significantly over the study period (from 98.7 to 24.4%), with one in four using heroin at 18-20 years. Just under half were receiving treatment. Reductions in heroin use were accompanied by reductions in heroin dependence, other substance use, needle sharing, injection-related health, overdose, crime, and improvements in general physical and mental health. Major depression and borderline personality disorder (BPD) were consistently associated with poorer outcome. At 18-20 years, there is strong evidence that clinically significant levels of improvement can be maintained over the long term. The mortality rate over 18-20 years was devastating, with over one in six participants deceased. More sustained and targeted efforts are needed in relation to major depression and BPD to ensure evidence-based treatments are delivered to people with heroin dependence. Supplementary Information: The online version contains supplementary material available at 10.1007/s11469-022-01006-6.

Does cannabidiol make cannabis safer? A randomised, double-blind, cross-over trial of cannabis with four different CBD:THC ratios.

As countries adopt more permissive cannabis policies, it is increasingly important to identify strategies that can reduce the harmful effects of cannabis use. This study aimed to determine if increasing the CBD content of cannabis can reduce its harmful effects. Forty-six healthy, infrequent cannabis users participated in a double-blind, within-subject, randomised trial of cannabis preparations varying in CBD content. There was an initial baseline visit followed by four drug administration visits, in which participants inhaled vaporised cannabis containing 10 mg THC and either 0 mg (0:1 CBD:THC), 10 mg (1:1), 20 mg (2:1), or 30 mg (3:1) CBD, in a randomised, counter-balanced order. The primary outcome was change in delayed verbal recall on the Hopkins Verbal Learning Task. Secondary outcomes included change in severity of psychotic symptoms (e.g., Positive and Negative Syndrome Scale [PANSS] positive subscale), plus further cognitive, subjective, pleasurable, pharmacological and physiological effects. Serial plasma concentrations of THC and CBD were measured. THC (0:1) was associated with impaired delayed verbal recall (t(45) = 3.399, d = 0.50, p = 0.001) and induced positive psychotic symptoms on the PANSS (t(45) = -4.709, d = 0.69, p = 2.41 × 10-5). These effects were not significantly modulated by any dose of CBD. Furthermore, there was no evidence of CBD modulating the effects of THC on other cognitive, psychotic, subjective, pleasurable, and physiological measures. There was a dose-response relationship between CBD dose and plasma CBD concentration, with no effect on plasma THC concentrations. At CBD:THC ratios most common in medicinal and recreational cannabis products, we found no evidence that CBD protects against the acute adverse effects of cannabis. This should be considered in health policy and safety decisions about medicinal and recreational cannabis.