A snapshot of injecting drug consumption from the analysis of used syringes within the Medically Supervised Injecting Centre in Sydney, Australia.

INTRODUCTION: The administration of illicit drugs by injection is associated with considerable harm, including an increased risk of overdose. The chemical analysis of used syringes can enhance knowledge on injecting drug consumption beyond traditional data sources (self-report surveys). This additional information may be useful during significant global events like the COVID-19 pandemic. This study aimed to examine a snapshot of the drugs injected at the Medically Supervised Injecting Centre (MSIC) in Sydney, Australia, in 2019-2020. METHODS: Used syringes were collected from MSIC across three periods throughout 2019 and 2020 (February 2019, March-April 2020 and June-September 2020). Drug residues were extracted from used syringes using methanol before detection by gas chromatography-mass spectrometry and ultra-performance liquid chromatography-tandem mass spectrometry. The chemical analysis results were compared to self-report data obtained from MSIC clients. RESULTS: Heroin (46-53%), methamphetamine (24-34%) and pharmaceutical opioids (15-27%) were the most common drug residues detected. The chemically detected drugs had declining coherence with the drugs self-reported by MSIC clients across the time periods examined. DISCUSSION AND CONCLUSIONS: There was no significant change in the drugs injected (heroin, methamphetamine and pharmaceutical opioids) across the three periods collected throughout varying COVID-19 lockdown restrictions. Changes in the frequency of other drugs injected and discrepancies between chemical analysis and self-report were potentially related to regulatory changes, degradation or misinformed sales. Routine chemical analysis of used syringes has provided an alternative information source to promote awareness of current drug trends and aid harm reduction.

Outrage and algorithms: Shifting drug-related stigma in a digital world.

Illicit drug dependence is one of the most stigmatised health conditions worldwide and the harmful impacts of stigma for people who use drugs are well documented. The use of stigmatising language about drugs in traditional media is also well documented. The increasing use of digital media platforms has revolutionised the way we communicate, and extended the reach of our messages. However, there are issues specific to the ways in which these platforms operate that have the potential to increase drug-related stigma. This paper outlines the importance of language, narrative, and imagery in reducing this stigma. It discusses the challenges digital media platforms present to achieving this goal, including the use of engagement strategies that trigger fear and increase stigma, the potential for amplifying stigmatising messages by using algorithms, and the potential for dissemination of misinformation. Key strategies to frame conversations about drug use are presented including 1) appeal to values of fairness and equity rather than scaring people; 2) avoid correcting misinformation as it strengthens unhelpful stigmatising frames of drug use; and 3) create a new narrative, focusing on the diversity of experiences of people who use drugs. Internationally we are at a critical juncture with respect to drug policy reform, and efforts to reduce drug-related stigma are central to building support for these reforms. The extensive reach of digital media platforms represents an important opportunity to communicate about illicit drug use. The challenge is to do so in a way that minimises stigma. If we are to achieve change, a narrative that puts values, people, health care and equity at the centre of the conversation is critical.

Monitoring for fentanyl within Australian supervised injecting facilities: Findings from feasibility testing of novel methods and collaborative workshops.

BACKGROUND: Australia is yet to see widespread fentanyl-contaminated heroin, despite the established presence of fentanyl in other countries. International mortality trends alongside a local cluster of fentanyl-related deaths prompted interest in developing methods to monitor for fentanyl and other potentially harmful novel psychoactive substances (NPS) in Australia. METHODS: We tested novel methods to monitor for fentanyl and other NPS. From 2017-2021, clients from supervised injecting facilities (SIFs) in Melbourne and Sydney, Australia, contributed urine screens (UDS) with BTNX Rapid Response™ fentanyl test strips (FTS) paired with surveys, and injecting equipment associated with opioid overdoses for laboratory analysis. A single site piloted drug checking using FTS with laboratory confirmation. Two workshops were conducted with SIF staff, content experts and people with lived experience to determine how results can inform practices within SIFs. RESULTS: Of the 911 UDS with FTS conducted, less than 1% (n=8) yielded positive results that were not explained by self-reported pharmaceutical fentanyl use, with two laboratory confirmed fentanyl positive results. Injecting equipment from 59 overdoses was tested and neither fentanyl nor other NPS were identified. Drug checking with FTS (n=34) indicated the presence of fentanyl on three tests. Two specimens were subsequently sent for laboratory testing and classified as false positives as the presence of fentanyl was not confirmed. Workshop participants (n=21) felt routine monitoring with FTS currently had limited value. A process for using pre-defined signals to trigger surveillance was developed. CONCLUSION: The high false positive rates with FTS, relative to the small number of positive results and potential for them to undermine confidence in FTS emphasised the need for confirmatory testing. The role of routine surveillance was unclear within the current low-fentanyl context, however, a process was developed to upscale testing should signals of increased fentanyl prevalence in the Australian heroin market emerge.

Cyanidin and delphinidin restore colon physiology in high fat diet-fed mice: Involvement of TLR-4 and redox-regulated signaling.

Consumption of high fat diets (HFD) mimics a modern or "Western style" diet pattern and can impair intestinal barrier integrity, leading to endotoxemia and associated unhealthy conditions. This study investigated if supplementation with an anthocyanin (cyanidin and delphinidin glucosides)-rich extract (CDRE) could revert or mitigate HFD-induced alterations of colonic physiology in part through the regulation of Toll-Like Receptor 4 (TLR-4)- and redox-regulated signaling. C57BL/6J male mice were fed for 4 weeks with a control or an HFD. Then, mice were divided in four groups fed either control or HFD, or these diets supplemented with CDRE for the subsequent 4 weeks. After 8 weeks on the HFD we observed in the colon: i) disruption of tight junction structure and function; ii) increased TLR-4 expression; iii) increased NADPH oxidase NOX1 expression, and iv) activation of redox-sensitive and TLR-4-triggered pathways, i.e. NF-κB, ERK1/2, JNK1/2, PI3K/Akt. All these events were prevented or reverted by CDRE supplementation. Supporting the relevance of CDRE-mediated downregulation of TLR-4 on its colon beneficial effect; in vitro (Caco-2 cell monolayers), cyanidin, delphinidin and their metabolites protocatechuic and gallic acid, mitigated lipopolysaccharide (LPS)-induced monolayer permeabilization by restoring tight junction structure and dynamics and preventing lipid/protein oxidation. The CDRE also mitigated HFD-mediated alterations in parameters of goblet cell differentiation and function, including the downregulation of markers of goblet cell differentiation (Klf4), and intestinal mucosa healing (Tff3). Results show that a short-term supplementation with cyanidin and delphinidin, protect from HFD-induced alterations in colon physiology in part through the modulation of TLR-4- and redox-regulated signaling.

A Novel Herbal Extract Blend Product Prevents Particulate Matters-Induced Inflammation by Improving Gut Microbiota and Maintaining the Integrity of the Intestinal Barrier.

Air pollutants of PM2.5 can alter the composition of gut microbiota and lead to inflammation in the lung and gastrointestinal tract. The aim of this study was to evaluate the protective effect of a novel herbal extract blend, FC, composed of Lonicera japonica extract, Momordica grosvenori extract, and broccoli seed extract, on PM2.5-induced inflammation in the respiratory and intestinal tract. A549 cells and THP-1 cells, as well as C57BL/6 mice, were stimulated with PM2.5 to establish in vitro and in vivo exposure models. The models were treated with or without FC. The expression of inflammatory cytokines and tight junction proteins were studied. Proteomic analysis was performed to elucidate mechanisms. Mouse feces were collected for gut microbiota analysis. FC was shown to modulate the upregulation of pro-inflammatory cytokines mRNA expression in A549 and THP-1 cells and downregulated tight junction proteins mRNA expression in A549 cells due to PM2.5 stimulation. In animal models, the decreased expression of the anti-inflammatory factor il-10, tight junction protein ZO-1, and the elevated expression of COX-2 induced by PM2.5 were improved by FC intervention, which may be associated with zo-1 and cox-2 signaling pathways. In addition, FC was shown to improve the gut microbiota by increasing the abundance of beneficial bacteria.

Infrequent detection of unintentional fentanyl use via urinalysis among people who regularly inject opioids in Sydney and Melbourne, Australia.

BACKGROUND AND AIM: The current phase of the North American 'opioid crisis' is characterised by illicit fentanyl use; however, the presence of illicit fentanyl in Australia is unknown. This study aimed to monitor unintentional fentanyl consumption in Australia. DESIGN: Rapid urine drug screens (UDS) paired with surveys conducted within supervised injecting facilities (SIFs) and confirmatory laboratory testing. SETTING: Sydney and Melbourne, Australia. PARTICIPANTS: Clients who used heroin within the past 2 days (n = 911 tests, 2017-2021). Participants were demographically similar to the overall client base (median age 43, 72% male). MEASUREMENTS: UDS were conducted using BTNX Rapid Response fentanyl urine strip tests with cross-reactivity to numerous fentanyl analogues. Positive urine samples were analysed using liquid chromatography coupled with tandem mass spectrometry. Surveys covered past 3 day drug use and lifetime report of fentanyl in heroin. FINDINGS: Two percent of participants reported intentional use of fentanyl, mostly through fentanyl patches. Of the 911 rapid UDS conducted, 17 (1.9%) yielded positive results. Eight of these (all from Melbourne) were not explained by survey-reported fentanyl use in the past 3 days. Of these 8 unexplained positives, confirmatory laboratory analysis was conducted on 6, with 4 deemed to be false positives, and 2 confirmed for the presence of fentanyl. This represents the first confirmation of unintended use of fentanyl type substances in this population. CONCLUSION: There is limited evidence of unintentional fentanyl use among people in Sydney and Melbourne, Australia who regularly inject heroin, suggesting that, currently, there is very little illicit fentanyl in Australian drug markets accessed by supervised injecting facilities attendees. This study demonstrates the feasibility of quick onsite testing to cost-effectively screen large samples for fentanyl; however, the high false positive rate emphasises the need for confirmation of positive tests through advanced analytical techniques.

Supplementation with cyanidin and delphinidin mitigates high fat diet-induced endotoxemia and associated liver inflammation in mice.

Consumption of high fat diets (HFD) and the associated metabolic endotoxemia can initiate liver inflammation and lipid deposition that with time can progress to non-alcoholic fatty liver disease (NAFLD). We previously observed that 14 weeks supplementation with the anthocyanidins cyanidin and delphinidin mitigated HFD-induced metabolic endotoxemia and liver insulin resistance, steatosis, inflammation and oxidative stress. This work investigated if a 4-week supplementation of mice with a cyanidin- and delphinidin-rich extract (CDRE) could mitigate or reverse HFD (60% calories from lard fat)-induced liver steatosis and inflammation. After a first 4-weeks period on the HFD, mice showed increased endotoxemia and activation of liver proinflammatory signaling cascades. Supplementation with CDRE between weeks 4 and 8 did not mitigate liver steatosis or the altered lipid and glucose plasma levels. However, CDRE supplementation reverted HFD-induced metabolic endotoxemia, in parallel with the mitigation of the overexpression of hepatic TLR2 and TLR4, and of the activation of: (i) NF-κB, (ii) AP-1 and upstream mitogen-activated kinases p38 and ERK1/2, and (iii) HIF-1. Thus, even a short-term consumption of cyanidin and delphinidin could help mitigate the adverse consequences, i.e. metabolic endotoxemia and associated liver inflammation, triggered by the regular consumption of diets rich in fat.

Detailed breast cancer pathology data for large-scale studies - access and completeness in NSW, Australia.

OBJECTIVES: We sought to determine the ease with which breast cancer pathology data could be ascertained for a large cohort of Australian women, to support epidemiological research. METHOD: We assessed a range of options for accessing breast cancer pathology data. Manual review of the pathology report provided to the New South Wales Cancer Registry (NSWCR) was considered most feasible, complete and reliable. Incident breast cancers (ICD-10 C50) in female 45 and Up Study participants, resident in NSW, were identified from linked NSWCR data for the period 2006-2012. Data not routinely available in the NSWCR, including hormone receptor status, were extracted from the pathology report provided to the registry. RESULTS: Among 143 079 eligible women, 2051 had a first registration of breast cancer following cohort recruitment. The mean age at cancer diagnosis was 64.5 years. Based on cancer registry data, the cancers were predominantly ductal (74.1%), 54.4% were localised to the breast at diagnosis and 24.2% were >50 mm in size. Based on manually extracted data from pathology records, 23.9% of cancers were histological grade 1, 79.6% were oestrogen receptor positive and 71.2% were progestogen receptor positive. These data were mostly complete (<10% missing). HER2 receptor status was less well reported, with 31.9% of cancers having indeterminate or missing data, while 11.3% were reported as positive. Data on lymph node status was missing in 16.1% of breast cancer reports, 33.7% were node positive. 8.0% of breast cancers had involved surgical margins, and this data was missing for 14.1% of cases. CONCLUSION: Pathology information, in addition to that available from routine registry data, is required both for breast cancer research and for monitoring trends in the types of breast cancer occurring over time in Australia. All the important additional data items required are recorded on the pathology report, which is provided to the NSWCR as part of cancer notification but is not routinely coded, and are generally fairly complete. However, access to these data for large-scale studies requires substantial effort. Coding the pathology data and making it routinely available would substantially improve cancer research and enable proper monitoring of breast cancer trends in Australia.

Antioxidant Blend of Curcumin and Broccoli Seed Extract Exhibits Protective Effect on Neurodegeneration and Promotes Drosophila Lifespan.

Antioxidants and related compounds are anti-inflammatory and exhibit great potential in promoting human health. They are also often considered to be important elements in the process of neurodegeneration. Here we describe a antioxidant blend of Curcumin and Broccoli Seed Extract (BSE). Flies treated with the blend exhibit extended lifespan. RNA-seq analysis of samples from adult fly brains reveals a wide array of new genes with differential expression upon treatment with the blend. Interestingly, abolishing expression of some of the identified genes in dopaminergic (DA) neurons does not affect DA neuron number. Taken together, our findings reveal an antioxidant blend that promotes fly longevity and exhibits protective effect over neurodegeneration, demonstrating the importance of antioxidants in health and pathology.

Adapting harm reduction services during COVID-19: lessons from the supervised injecting facilities in Australia.

The COVID-19 crisis has had profound impacts on health service provision, particularly those providing client facing services. Supervised injecting facilities and drug consumption rooms across the world have been particularly challenged during the pandemic, as have their client group-people who consume drugs. Several services across Europe and North America closed due to difficulties complying with physical distancing requirements. In contrast, the two supervised injecting facilities in Australia (the Uniting Medically Supervised Injecting Centre-MSIC-in Sydney and the North Richmond Community Health Medically Supervised Injecting Room-MSIR-in Melbourne) remained open (as at the time of writing-December 2020). Both services have implemented a comprehensive range of strategies to continue providing safer injecting spaces as well as communicating crucial health information and facilitating access to ancillary services (such as accommodation) and drug treatment for their clients. This paper documents these strategies and the challenges both services are facing during the pandemic. Remaining open poses potential risks relating to COVID-19 transmission for both staff and clients. However, given the harms associated with closing these services, which include the potential loss of life from injecting in unsafe/unsupervised environments, the public and individual health benefits of remaining open are greater. Both services are deemed 'essential health services', and their continued operation has important benefits for people who inject drugs in Sydney and Melbourne.

Modelling nonlinear dynamics of Crassulacean acid metabolism productivity and water use for global predictions.

Crassulacean acid metabolism (CAM) crops are important agricultural commodities in water-limited environments across the globe, yet modelling of CAM productivity lacks the sophistication of widely used C3 and C4 crop models, in part due to the complex responses of the CAM cycle to environmental conditions. This work builds on recent advances in CAM modelling to provide a framework for estimating CAM biomass yield and water use efficiency from basic principles. These advances, which integrate the CAM circadian rhythm with established models of carbon fixation, stomatal conductance and the soil-plant-atmosphere continuum, are coupled to models of light attenuation, plant respiration and biomass partitioning. Resulting biomass yield and transpiration for Opuntia ficus-indica and Agave tequilana are validated against field data and compared with predictions of CAM productivity obtained using the empirically based environmental productivity index. By representing regulation of the circadian state as a nonlinear oscillator, the modelling approach captures the diurnal dynamics of CAM stomatal conductance, allowing the prediction of CAM transpiration and water use efficiency for the first time at the plot scale. This approach may improve estimates of CAM productivity under light-limiting conditions when compared with previous methods.

"How are you?" Estimation of anxiety, sleep quality, and mood using computational voice analysis.

We developed a method of estimating impactors of cognitive function (ICF) - such as anxiety, sleep quality, and mood - using computational voice analysis. Clinically validated questionnaires (VQs) were used to score anxiety, sleep and mood while salient voice features were extracted to train regression models with deep neural networks. Experiments with 203 subjects showed promising results with significant concordance correlation coefficients (CCC) between actual VQ scores and the predicted scores (0.46 = anxiety, 0.50 = sleep quality, 0.45 = mood).

A Novel Micronutrient Blend Mimics Calorie Restriction Transcriptomics in Multiple Tissues of Mice and Increases Lifespan and Mobility in C. elegans.

BACKGROUND: We previously described a novel micronutrient blend that behaves like a putative calorie restriction mimetic. The aim of this paper was to analyze the beneficial effects of our micronutrient blend in mice and C. elegans, and compare them with calorie restriction. METHODS: Whole transcriptomic analysis was performed in the brain cortex, skeletal muscle and heart in three groups of mice: old controls (30 months), old + calorie restriction and old + novel micronutrient blend. Longevity and vitality were tested in C. elegans. RESULTS: The micronutrient blend elicited transcriptomic changes in a manner similar to those in the calorie-restricted group and different from those in the control group. Subgroup analysis revealed that nuclear hormone receptor, proteasome complex and angiotensinogen genes, all of which are known to be directly related to aging, were the most affected. Furthermore, a functional analysis in C. elegans was used. We found that feeding C. elegans the micronutrient blend increased longevity as well as vitality. CONCLUSIONS: We describe a micronutrient supplement that causes similar changes (transcriptomic and promoting longevity and vitality) as a calorie restriction in mice and C. elegans, respectively, but further studies are required to confirm these effects in humans.

Efficacy of Fecal Microbiota Transplantation for Clostridium difficile Infection in Children.

BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) is commonly used to treat Clostridium difficile infection (CDI). CDI is an increasing cause of diarrheal illness in pediatric patients, but the effects of FMT have not been well studied in children. We performed a multi-center retrospective cohort study of pediatric and young adult patients to evaluate the efficacy, safety, and factors associated with a successful FMT for the treatment of CDI. METHODS: We performed a retrospective study of 372 patients, 11 months to 23 years old, who underwent FMT at 18 pediatric centers, from February 1, 2004, to February 28, 2017; 2-month outcome data were available from 335 patients. Successful FMT was defined as no recurrence of CDI in the 2 months following FMT. We performed stepwise logistic regression to identify factors associated with successful FMT. RESULTS: Of 335 patients who underwent FMT and were followed for 2 months or more, 271 (81%) had a successful outcome following a single FMT and 86.6% had a successful outcome following a first or repeated FMT. Patients who received FMT with fresh donor stool (odds ratio [OR], 2.66; 95% CI, 1.39-5.08), underwent FMT via colonoscopy (OR, 2.41; 95% CI, 1.26-4.61), did not have a feeding tube (OR, 2.08; 95% CI, 1.05-4.11), or had 1 less episode of CDI before FMT (OR, 1.20; 95% CI, 1.04-1.39) had increased odds for successful FMT. Seventeen patients (4.7%) had a severe adverse event during the 3-month follow-up period, including 10 hospitalizations. CONCLUSIONS: Based on the findings from a large multi-center retrospective cohort, FMT is effective and safe for the treatment of CDI in children and young adults. Further studies are required to optimize the timing and method of FMT for pediatric patients-factors associated with success differ from those of adult patients.

Effectiveness of Acellular Pertussis Vaccine in Older Adults: Nested Matched Case-control Study.

BACKGROUND: Despite recommendations that older adults receive acellular pertussis vaccines, data on direct effectiveness in adults aged over 50 years are sparse. METHODS: A case-control study nested within an adult cohort. Cases were identified from linked pertussis notifications and each matched to 3 controls on age, sex, and cohort recruitment date. Cases and controls were invited to complete a questionnaire, with verification of vaccination status by their primary care provider. Vaccine effectiveness (VE) was estimated by conditional logistic regression, with adjustment for reported contact with children and area of residence. RESULTS: Of 1112 notified cases in the cohort, we had complete data for 333 cases and 506 controls. Among 172 PCR-diagnosed cases (mean age, 61 years), 11.2% versus 19.5% of controls had provider-verified pertussis vaccination, on average, 3.2 years earlier. Adjusted VE against PCR-diagnosed pertussis was 52% (95% CI, 15-73%), nonsignificantly higher if vaccinated within 2 years (63%; -5-87%). Adjusted VE was similar in adults born before 1950, presumed primed by natural infection (51%; -8-77%) versus those born 1950 or later who may have received whole-cell pertussis vaccine (53%; -11-80%) (P-heterogeneity = 0.9). Among 156 cases identified by single-point serology, adjusted VE was -55% (-177-13%). CONCLUSIONS: We found modest protection against PCR-confirmed pertussis among older adults (mean age, 61 years; range, 46-81 years) within 5 years after acellular vaccine. The most likely explanation for the markedly divergent VE estimate from cases identified by single-titer serology is misclassification arising from limited diagnostic specificity in our setting.

Jump processes with deterministic and stochastic controls.

We consider the dynamics of a one-dimensional system evolving according to a deterministic drift and randomly forced by two types of jump processes, one representing an external, uncontrolled forcing and the other one a control that instantaneously resets the system according to specified protocols (either deterministic or stochastic). We develop a general theory, which includes a different formulation of the master equation using antecedent and posterior jump states, and obtain an analytical solution for steady state. The relevance of the theory is illustrated with reference to stochastic irrigation to assess crop-failure risk, a problem of interest for environmental geophysics.

Low Cure Rates in Controlled Trials of Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection: A Systematic Review and Meta-analysis.

BACKGROUND: Fecal microbiota transplantation (FMT) is highly effective for treating recurrent Clostridium difficile infection (CDI) in observational studies (>90%), but cure rates in clinical trials are lower. We performed a systematic review and meta-analysis to assess the efficacy of FMT for recurrent CDI in open-label studies and clinical trials . METHODS: A systematic search from January 1978 to March 2017 was performed to include clinical trials of FMT for CDI. We analyzed CDI resolution by calculating weighted pooled rates (WPRs). RESULTS: Thirteen trials were included, comprising 610 patients with CDI treated with single FMT. Overall, 439 patients had clinical cure (WPR, 76.1%; 95% confidence interval (CI), 66.4%-85.7%). There was significant heterogeneity among studies (I2 = 91.35%). Cure rates were lower in randomized trials (139/216 patients; WPR, 67.7%; 95% CI, 54.2%-81.3%) than in open-label studies (300/394 patients; WPR, 82.7%; 71.1%-94.3%) (P < .001). Subgroup analysis by FMT delivery modality showed lower cure rates with enema than colonoscopy (WPR, 66.3% vs 87.4%; P < .001) but no difference between colonoscopy and oral delivery (WPR, 87.4% vs 81.4%; P = .17). Lower rates were seen for studies including both recurrent and refractory CDI than for those including only recurrent CDI (WPR, 63.9% vs 79%; P < .001). CONCLUSIONS: FMT was associated with lower cure rates in randomized trials than in open-label and in observational studies. Colonoscopy and oral route are more effective than enema for stool delivery. The efficacy also seems to be higher for recurrent than for refractory CDI.