A phase III multisite randomised controlled trial to compare the efficacy of cannabidiol to placebo in the treatment of cannabis use disorder: the CBD-CUD study protocol.

BACKGROUND: Cannabis use disorder (CUD) is increasingly common and contributes to a range of health and social problems. Cannabidiol (CBD) is a non-intoxicating cannabinoid recognised for its anticonvulsant, anxiolytic and antipsychotic effects with no habit-forming qualities. Results from a Phase IIa randomised clinical trial suggest that treatment with CBD for four weeks reduced non-prescribed cannabis use in people with CUD. This study examines the efficacy, safety and quality of life of longer-term CBD treatment for patients with moderate-to-severe CUD. METHODS/DESIGN: A phase III multi-site, randomised, double-blinded, placebo controlled parallel design of a 12-week course of CBD to placebo, with follow-up at 24 weeks after enrolment. Two hundred and fifty adults with moderate-to-severe CUD (target 20% Aboriginal), with no significant medical, psychiatric or other substance use disorders from seven drug and alcohol clinics across NSW and VIC, Australia will be enrolled. Participants will be administered a daily dose of either 4 mL (100 mg/mL) of CBD or a placebo dispensed every 3-weeks. All participants will receive four-sessions of Cognitive Behavioural Therapy (CBT) based counselling. Primary endpoints are self-reported cannabis use days and analysis of cannabis metabolites in urine. Secondary endpoints include severity of CUD, withdrawal severity, cravings, quantity of use, motivation to stop and abstinence, medication safety, quality of life, physical/mental health, cognitive functioning, and patient treatment satisfaction. Qualitative research interviews will be conducted with Aboriginal participants to explore their perspectives on treatment. DISCUSSION: Current psychosocial and behavioural treatments for CUD indicate that over 80% of patients relapse within 1-6 months of treatment. Pharmacological treatments are highly effective with other substance use disorders but there are no approved pharmacological treatments for CUD. CBD is a promising candidate for CUD treatment due to its potential efficacy for this indication and excellent safety profile. The anxiolytic, antipsychotic and neuroprotective effects of CBD may have added benefits by reducing many of the mental health and cognitive impairments reported in people with regular cannabis use. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry: ACTRN12623000526673 (Registered 19 May 2023).

Development of an Australian FASD Indigenous Framework: Aboriginal Healing-Informed and Strengths-Based Ways of Knowing, Being and Doing.

Aboriginal culture intuitively embodies and interconnects the threads of life that are known to be intrinsic to human wellbeing: connection. Therefore, Aboriginal wisdom and practices are inherently strengths-based and healing-informed. Underpinned by an Indigenist research methodology, this article presents findings from a collaboration of Aboriginal and non-Aboriginal peoples to develop an Australian Fetal Alcohol Spectrum Disorder (FASD) Indigenous Framework during 2021 to 2023. The FASD Indigenous Framework unfolds the changes that non-Aboriginal clinicians and Aboriginal peoples each need to make in their respective ways of knowing, being and doing in order to facilitate access to healing-informed, strengths-based and culturally responsive FASD knowledge, assessment, diagnosis and support services among Aboriginal peoples. Drawing on the Aboriginal practices of yarning and Dadirri, written and oral knowledges were gathered. These knowledges were mapped against Aboriginal cultural responsiveness and wellbeing frameworks and collaboratively and iteratively reflected upon throughout. This article brings together Aboriginal wisdom (strengths-based, healing-informed approaches grounded in holistic and integrated support) and Western wisdom (biomedicine and therapeutic models) in relation to FASD. From a place of still awareness (Dadirri), both forms of wisdom were drawn upon to create Australia's first FASD Indigenous Framework, a new practice in the assessment and diagnosis of FASD, which offers immense benefit to equity, justice, support and healing for Aboriginal families with a lived experience of FASD.

Factors to be considered as part of a holistic assessment for fetal alcohol spectrum disorder: A scoping review.

We undertook a scoping review to identify the factors outside of current fetal alcohol spectrum disorder (FASD) diagnostic criteria to be considered as part of a holistic assessment process. This included physical, social, cultural, mental health and wellbeing factors to inform targeted recommendations and supports to improve outcomes for individuals with FASD. Evidence from this review will be used to inform the revision of the Australian Guide to the Diagnosis of FASD. Six electronic databases were searched. Studies were eligible if they included factors outside of the diagnostic criteria that cover dysmorphology, growth restriction, neurodevelopmental impairments. Data charting and content analysis were performed to synthesize the results. One hundred twenty-one studies were included that spanned 12 key areas These included physical health, sleep, adverse postnatal experiences, substance use/other risk-taking behaviors, contact with the criminal justice system, mental health, First Nations cultural considerations, transition to adult roles, involvement with the out-of-home care system, feeding and eating, strengths/interests/external resources and incontinence. Areas to be considered as part of a holistic assessment and diagnostic process spanned individual, family, and system level factors. Results provide guidance for clinicians on the wide range of factors that could influence long-term health, development, and wellbeing for individuals with prenatal alcohol exposure and FASD. In practice, this guidance can be used to inform an individualized assessment process to facilitate tailored recommendations and supports to best meet the complex needs of individuals living with FASD and their families.

Onset and trajectory of alcohol and other drug use among Aboriginal men entering a prison treatment program: A qualitative study.

INTRODUCTION: Aboriginal and Torres Strait Islander people are vastly over-represented in Australian prisons. Many people in prison attribute in some way their offences to alcohol and/or other drug (AOD) use. This paper aims to understand AOD use before first and between terms in prison, among a group of Aboriginal men enrolled in a prison-based AOD treatment program. It examines opportunities for prevention or treatment that might interrupt the cycle of alcohol consumption, offending and imprisonment. METHODS: A thematic analysis of in-depth interviews with 14 Aboriginal men in an urban prison. RESULTS: Participants had low levels of formal education, none having completed high school and had spent limited or no time in the workforce. All 14 spoke of being negatively affected by AOD use within their families. First alcohol and cannabis use were around age 12-14 years, first amphetamines and/or heroin use was around age 15. As adults, they had unstable accommodation and when released from prison returned to the same situation they had been in previously. Most believed they would not have offended and subsequently imprisoned if they did not have a substance use disorder. DISCUSSION AND CONCLUSION: Without further support post-prison, the men in this study are likely to return to the same situation and continue their AOD use. Further efforts are needed to support families with substance use disorders and to give young Aboriginal and Torres Strait Islander people better education and training opportunities.

Radical-Mediated Strategies for the Functionalization of Alkenes with Diazo Compounds.

One of the most common reactions of diazo compounds with alkenes is cyclopropanation, which occurs through metal carbene or free carbene intermediates. Alternative functionalization of alkenes with diazo compounds is limited, and a methodology for the addition of the elements of Z-CHR2 (with Z = H or heteroatom, and CHR2 originates from N2═CR2) across a carbon-carbon double bond has not been reported. Here we report a novel reaction of diazo compounds utilizing a radical-mediated addition strategy to achieve difunctionalization of diverse alkenes. Diazo compounds are transformed to carbon radicals with a photocatalyst or an iron catalyst through PCET processes. The carbon radical selectively adds to diverse alkenes, delivering new carbon radical species, and then forms products through hydroalkylation by thiol-assisted hydrogen atom transfer (HAT), or forms azidoalkylation products through an iron catalytic cycle. These two processes are highly complementary, proceed under mild reaction conditions, and show high functional group tolerance. Furthermore, both transformations are successfully performed on a gram-scale, and diverse γ-amino esters, γ-amino alcohols, and complex spirolactams are easily prepared with commercially available reagents. Mechanistic studies reveal the plausible pathways that link the two processes and explain the unique advantages of each.

Hydrogen/deuterium exchange mass spectrometry applied to IL-23 interaction characteristics: potential impact for therapeutics.

IL-23 is an important therapeutic target for the treatment of inflammatory diseases. Adnectins are targeted protein therapeutics that are derived from domain III of human fibronectin and have a similar protein scaffold to antibodies. Adnectin 2 was found to bind to IL-23 and compete with the IL-23/IL-23R interaction, posing a potential protein therapeutic. Hydrogen/deuterium exchange mass spectrometry and computational methods were applied to probe the binding interactions between IL-23 and Adnectin 2 and to determine the correlation between the two orthogonal methods. This review summarizes the current structural knowledge about IL-23 and focuses on the applicability of hydrogen/deuterium exchange mass spectrometry to investigate the higher order structure of proteins, which plays an important role in the discovery of new and improved biotherapeutics.

Offending, custody and opioid substitution therapy treatment utilisation among opioid-dependent people in contact with the criminal justice system: comparison of Indigenous and non-Indigenous Australians.

BACKGROUND: Although Indigenous Australians are over-represented among heroin users, there has been no study examining offending, time in custody, and opioid substitution therapy (OST) treatment utilisation among Indigenous opioid-dependent (including heroin) people at the population level, nor comparing these to non-Indigenous opioid-dependent people. The aims of this study were to compare the nature and types of charges, time in custody and OST treatment utilisation between opioid-dependent Indigenous and non-Indigenous Australians in contact with the criminal justice system. METHODS: This was a population-based, retrospective data linkage study using records of OST entrants in New South Wales, Australia (1985-2010), court appearances (1993-2011) and custody episodes (2000-2012). Charge rates per 100 person-years were compared between Indigenous and non-Indigenous Australians by sex, age and calendar year. Statistical comparisons were made for variables describing the cumulative time and percentage of follow-up time spent in custody, as well as characteristics of OST initiation and overall OST treatment utilisation. RESULTS: Of the 34,962 people in the cohort, 6,830 (19.5%) were Indigenous and 28,132 (80.5%) non-Indigenous. Among the 6,830 Indigenous people, 4,615 (67.6%) were male and 2,215 (32.4%) female. The median number of charges per person against Indigenous people (25, IQR 31) was significantly greater than non-Indigenous people (9, IQR 16) (p < 0.001). Overall, Indigenous people were charged with 33.2% of the total number of charges against the cohort and 44.0% of all violent offences. The median percentage of follow-up time that Indigenous males and females spent in custody was twice that of non-Indigenous males (21.7% vs. 10.1%, p < 0.001) and females (6.0% vs. 2.9%, p < 0.001). The percentage of Indigenous people who first commenced OST in prison (30.2%) was three times that of non-Indigenous people (11.2%) (p < 0.001). Indigenous males spent less time in OST compared to non-Indigenous males (median percentage of follow-up time in treatment: 40.5% vs. 43.1%, p < 0.001). CONCLUSIONS: Compared to non-Indigenous opioid-dependent people, Indigenous opioid-dependent people in contact with the criminal justice system are charged with a greater number of offences, spend longer in custody and commonly initiate OST in prison. Hence, contact with the criminal justice system provides an important opportunity to engage Indigenous people in OST.

Opportunities for mitigating pathogen contamination during on-farm food production.

Fruits, vegetables, and meat are susceptible to contamination by foodborne pathogens at many points from production through preparation in the home. This review will largely highlight approaches and progress made in the last five years to address strategies to reduce pathogen contamination in animal production but will also touch on the emerging field of preharvest produce food safety. Mitigation strategies can be divided into those that address pathogen reduction in the environment and those that target reduction/elimination of pathogen contamination in animals or plants. The former strategy has been encompassed in studies evaluating sanitation treatments of facilities as well as in numerous epidemiologic risk assessment studies (both on-farm assessments and computer simulation models) that identify management practices that impact pathogen prevalence in animals. Interventions to significantly reduce pathogen exposure via feed or water are dependent on their role as a significant contributor to pathogen contamination in the animal production system. In addition, inconsistent results obtained with interventions of dietary additives or formulation modifications (grain versus forage; inclusion of distiller's grains) on pathogen prevalence in animals have been attributed to a range of factors including target organism, grain type, level of inclusion, the animal's health or stress level, and ability to survive the gastric acidic conditions. Recent attempts to microencapsulate organic acids or bacteriophage within feed have met with only marginal improvements in reducing pathogen carriage in animals but this approach may have greater potential with other antimicrobial additives (i.e., essential oils). Bacteriophage therapy, in general, can significantly reduce pathogen carriage in animals but based on its transient nature and the potential for development of phage-resistant subpopulations, this approach should be administered to animals just prior to slaughter and preferably to animals that are suspected "super-shedders". Other promising on-farm intervention approaches have included breeding for pathogen resistance, vaccines, and dietary bacteriocins. To optimize interventions on a cost basis, studies have also determined that application of dietary interventions at specific time points in the animal's production cycle is a useful strategy to reduce pathogen carriage (e.g., probiotics to fertilized eggs and acidified feed to fattening swine). In conclusion, applicable management and intervention strategies may vary depending on the type of food under production; however, it is important to consider from a holistic view how any new intervention strategies will affect the overall production system in order to maintain a successful, efficient food production environment.

Structural mass spectrometry in protein therapeutics discovery.

The protein therapeutics market is one of the highest growing segments of the pharmaceutical industry with an estimated global market value of $77 billion by 2011 (Global Protein Therapeutics Market report by RNCOS: Delhi, India, 2009). This growth has been fueled by several advantages that protein drugs can offer such as higher specificity, reduced side effects, and faster development time compared to small molecule drugs. Major pharmaceutical companies are strategically shifting gears toward protein therapeutics and gradually increasing the biologics portion of their pipelines. Consequently, in the present pharmaceutical industry, there is a rapid growth in the number and types of protein structural mass spectrometry analyses, particularly during the discovery phase where an abundance of new drug candidates are being investigated. This perspective article discusses the role of protein structural mass spectrometry during the discovery of protein therapeutics with focus on recombinant protein production quality control and structural biology applications. The current challenges in technologies associated with this field and the analytical prospects for the future direction will be also discussed.

Inhibitors of Helicobacter pylori ATPase Cagalpha block CagA transport and cag virulence.

With the steadily increasing occurrence of antibiotic resistance in bacteria, there is a great need for new antibacterial compounds. The approach described here involves targeting virulence-related bacterial type IV secretion systems (TFSSs) with small-molecule inhibitors. The cag TFSS of Helicobacter pylori was chosen as a model, and novel inhibitors directed against the cag VirB11-type ATPase Cagalpha were identified. The cag genes encode proteins that are components of a contact-dependent secretion system used by the bacterium to translocate the effector molecule CagA into host cells. Translocated CagA is associated with severe gastritis, and carcinoma. Furthermore, functional TFSSs and immunodominant CagA play a role in interleukin (IL)-8 induction, which is an important factor for chronic inflammation. Inhibitors of Cagalpha were identified by high-throughput screening of chemical libraries that comprised 524 400 small molecules. The ATPase activity of Cagalpha was inhibited by the selected compounds in an in vitro enzymic assay using the purified enzyme. The most active compound, CHIR-1, reduced TFSS function to an extent that cellular effects on AGS cells mediated by CagA were virtually undetectable, while reduced levels of IL-8 induction were observed. Gastric colonization by CHIR-1-pre-treated bacteria was found to be impaired in a dose-dependent manner using a mouse model of infection. Small-molecule Cagalpha inhibitors, the first described inhibitors of a TFSS, are potential candidates for the development of new antibacterial compounds that may lead to alternative medical treatments. The compounds are expected to impose weak selective pressure, since they target virulence functions. Moreover, the targeted virulence protein is conserved in a variety of bacterial pathogens. Additionally, TFSS inhibitors are potent tools to study the biology of TFSSs.

Fate of Escherichia coli O157:H7 in manure compost-amended soil and on carrots and onions grown in an environmentally controlled growth chamber.

Studies were done to determine the fate of Escherichia coli O157:H7 in manure compost-amended soil and on carrots and green onions grown in an environmentally controlled growth chamber. Commercial dairy cattle manure compost was inoculated with a five-strain mixture of green fluorescent protein-labeled E. coli O157:H7 at 10(7) CFU g(-1) and mixed with unsterilized Tifton sandy loam soil at a ratio of 1:5. Baby carrot or green onion seedlings were planted into the manure compost-amended soil in pots, and soil samples surrounding the plant, edible carrot roots and onion bulb samples, and soil immediately beneath the roots were assayed for E. coli O157:H7 in triplicate at weekly intervals for the first 4 weeks, and every 2 weeks for the remainder of the plant growth cycle (up to 3 months). E. coli O157:H7 cell numbers decreased within 64 days by 3 log CFU/g in soil and soil beneath the roots of green onions and by more than 2 log CFU/g on onions. E. coli O157:H7 survived better during the production of carrots, with a 2.3-log CFU/g reduction in soil and a 1.7-log CFU/g reduction on carrots within 84 days. These results indicate that the type of plant grown is an important factor influencing the survival of E. coli O157:H7 both on the vegetable and in the soil in which the vegetable is grown.

Total synthesis of (S)-(+)-imperanene. Effective use of regio- and enantioselective intramolecular carbon-hydrogen insertion reactions catalyzed by chiral dirhodium(II) carboxamidates.

The total synthesis of (S)-(+)-imperanene, a natural product found in Chinese medicine, has been completed in 12 steps from a commercially available cinnamic acid. The key step is highly enantioselective carbon-hydrogen insertion from a diazoacetate using a chiral dirhodium(II) carboxamidate catalyst. An elimination process essential to the construction has been optimized to avoid intramolecular Friedel-Crafts alkylation.