Analysis of the effect of hypusination in myeloid cells on colitis and colitis-associated cancer.

Hypusine is an amino acid synthesized by the enzyme deoxyhypusine synthase (DHPS). It is critical for the activity of eukaryotic translation initiation factor 5A (EIF5A). We reported that hypusination i) in macrophages supports the innate response towards pathogenic bacteria and ii) in epithelial cells maintains intestinal homeostasis. Herein, we investigated the effect of myeloid hypusination on the outcome of colitis and colitis-associated cancer. We found that patients with Crohn's disease exhibit increased levels of DHPS and EIF5AHyp in cells infiltrating the colon lamina propria. However, the specific deletion of Dhps in myeloid cells had no impact on clinical, histological, or inflammatory parameters in mice treated with dextran sulfate sodium (DSS). Further, tumorigenesis and level of dysplasia were not affected by myeloid deletion of Dhps in the azoxymethane-DSS model. The composition of the fecal and the mucosa-associated microbiome was similar in animals lacking or not DHPS in myeloid cells. Thus, hypusination in myeloid cells does not regulate colitis associated with epithelial injury and colitis-associated cancer. Enhancement of the DHPS/hypusine pathway in patients with inflammatory bowel disease could have therapeutic impact through epithelial effects, but modulation of hypusination in myeloid cells will be unlikely to affect the disease.

High Expression of ENO1 and Low Levels of Circulating Anti-ENO1 Autoantibodies in Patients with Myelodysplastic Neoplasms and Acute Myeloid Leukaemia.

In solid tumours, high expression of the glycolytic enzyme, α-enolase (ENO1), predicts for poor patient overall survival (OS), and circulating autoantibodies to ENO1 correlate positively with diagnosis and negatively with advanced disease. Although ENO1 is one of the most highly expressed genes in acute myeloid leukaemia (AML), its potential role as a biomarker in AML or its precursor, myelodysplastic neoplasms (MDS), has not been investigated. A meta-analysis of nine AML online datasets (n = 1419 patients) revealed that high ENO1 expression predicts for poor OS (HR = 1.22, 95% CI: 1.10-1.34, p < 0.001). Additionally, when compared to AML in remission (n = 5), ENO1 protein detected by immunohistochemistry was significantly higher at diagnosis in bone marrow from both AML (n = 5, p < 0.01) and MDS patients (n = 12, p < 0.05), and did not correlate with percentage of blasts (r = 0.28, p = 0.21). AML patients (n = 34) had lower circulating levels of ENO1 autoantibodies detected by ELISA compared to 26 MDS and 18 controls (p = 0.003). However, there was no difference in OS between AML patients with high vs. low levels of anti-ENO1 autoantibodies (p = 0.77). BM immunostaining for ENO1 and patient monitoring of anti-ENO1 autoantibody levels may be useful biomarkers for MDS and AML.

Monitoring the use of novel psychoactive substances in Australia by wastewater-based epidemiology.

Users of novel psychoactive substances (NPS) are at risk, due to limited information about the toxicity and unpredictable effects of these compounds. Wastewater-based epidemiology (WBE) has been used as a tool to provide insight into NPS use at the population level. To understand the preferences and trends of NPS use in Australia, this study involved liquid chromatography mass spectrometry analysis of wastewater collected from Australian states and territories from February 2022 to February 2023. In total, 59 different NPS were included across two complementary analytical methods and covered up to 57 wastewater catchments over the study. The NPS detected in wastewater were 25-B-NBOMe, buphedrone, 1-benzylpiperazine (BZP), 3-chloromethcathinone, N,N-dimethylpentylone (N,N-DMP), N-ethylheptedrone, N-ethylpentylone, eutylone, 4F-phenibut, 2-fluoro deschloroketamine, hydroxetamine, mephedrone, methoxetamine, methylone, mitragynine, pentylone, phenibut, para-methoxyamphetamine (PMA), alpha-pyrrolidinovalerophenone (α-PVP) and valeryl fentanyl. The detection frequency for these NPS ranged from 3 % to 100 % of the sites analysed. A noticeable decreasing trend in eutylone detection frequency and mass loads was observed whilst simultaneously N,N-DMP and pentylone increased over the study period. The emergence of some NPS in wastewater pre-dates other sources of monitoring and provides further evidence that WBE can be used as an additional early warning system for alerting potential NPS use.

Myeloid deletion of talin-1 reduces mucosal macrophages and protects mice from colonic inflammation.

The intestinal immune response is crucial in maintaining a healthy gut, but the enhanced migration of macrophages in response to pathogens is a major contributor to disease pathogenesis. Integrins are ubiquitously expressed cellular receptors that are highly involved in immune cell adhesion to endothelial cells while in the circulation and help facilitate extravasation into tissues. Here we show that specific deletion of the Tln1 gene encoding the protein talin-1, an integrin-activating scaffold protein, from cells of the myeloid lineage using the Lyz2-cre driver mouse reduces epithelial damage, attenuates colitis, downregulates the expression of macrophage markers, decreases the number of differentiated colonic mucosal macrophages, and diminishes the presence of CD68-positive cells in the colonic mucosa of mice infected with the enteric pathogen Citrobacter rodentium. Bone marrow-derived macrophages lacking expression of Tln1 did not exhibit a cell-autonomous phenotype; there was no impaired proinflammatory gene expression, nitric oxide production, phagocytic ability, or surface expression of CD11b, CD86, or major histocompatibility complex II in response to C. rodentium. Thus, we demonstrate that talin-1 plays a role in the manifestation of infectious colitis by increasing mucosal macrophages, with an effect that is independent of macrophage activation.

A too-good-to-be-true prior to reduce shortcut reliance.

Despite their impressive performance in object recognition and other tasks under standard testing conditions, deep networks often fail to generalize to out-of-distribution (o.o.d.) samples. One cause for this shortcoming is that modern architectures tend to rely on ǣshortcutsǥ superficial features that correlate with categories without capturing deeper invariants that hold across contexts. Real-world concepts often possess a complex structure that can vary superficially across contexts, which can make the most intuitive and promising solutions in one context not generalize to others. One potential way to improve o.o.d. generalization is to assume simple solutions are unlikely to be valid across contexts and avoid them, which we refer to as the too-good-to-be-true prior. A low-capacity network (LCN) with a shallow architecture should only be able to learn surface relationships, including shortcuts. We find that LCNs can serve as shortcut detectors. Furthermore, an LCN's predictions can be used in a two-stage approach to encourage a high-capacity network (HCN) to rely on deeper invariant features that should generalize broadly. In particular, items that the LCN can master are downweighted when training the HCN. Using a modified version of the CIFAR-10 dataset in which we introduced shortcuts, we found that the two-stage LCN-HCN approach reduced reliance on shortcuts and facilitated o.o.d. generalization.

Hypusination Maintains Intestinal Homeostasis and Prevents Colitis and Carcinogenesis by Enhancing Aldehyde Detoxification.

BACKGROUND & AIMS: The amino acid hypusine, synthesized from the polyamine spermidine by the enzyme deoxyhypusine synthase (DHPS), is essential for the activity of eukaryotic translation initiation factor 5A (EIF5A). The role of hypusinated EIF5A (EIF5AHyp) remains unknown in intestinal homeostasis. Our aim was to investigate EIF5AHyp in the gut epithelium in inflammation and carcinogenesis. METHODS: We used human colon tissue messenger RNA samples and publicly available transcriptomic datasets, tissue microarrays, and patient-derived colon organoids. Mice with intestinal epithelial-specific deletion of Dhps were investigated at baseline and in models of colitis and colon carcinogenesis. RESULTS: We found that patients with ulcerative colitis and Crohn's disease exhibit reduced colon levels of DHPS messenger RNA and DHPS protein and reduced levels of EIF5AHyp. Similarly, colonic organoids from colitis patients also show down-regulated DHPS expression. Mice with intestinal epithelial-specific deletion of Dhps develop spontaneous colon hyperplasia, epithelial proliferation, crypt distortion, and inflammation. Furthermore, these mice are highly susceptible to experimental colitis and show exacerbated colon tumorigenesis when treated with a carcinogen. Transcriptomic and proteomic analysis on colonic epithelial cells demonstrated that loss of hypusination induces multiple pathways related to cancer and immune response. Moreover, we found that hypusination enhances translation of numerous enzymes involved in aldehyde detoxification, including glutathione S-transferases and aldehyde dehydrogenases. Accordingly, hypusination-deficient mice exhibit increased levels of aldehyde adducts in the colon, and their treatment with a scavenger of electrophiles reduces colitis. CONCLUSIONS: Hypusination in intestinal epithelial cells has a key role in the prevention of colitis and colorectal cancer, and enhancement of this pathway via supplementation of spermidine could have a therapeutic impact.

Electrophilic reactive aldehydes as a therapeutic target in colorectal cancer prevention and treatment.

Colorectal cancer (CRC) is a major health problem worldwide. Dicarbonyl electrophiles, such as isolevuglandins (isoLGs), are generated from lipid peroxidation and form covalent adducts with amine-containing macromolecules. We have shown high levels of adducts of isoLGs in colonic epithelial cells of patients with CRC. We thus investigated the role of these reactive aldehydes in colorectal cancer development. We found that 2-hydroxybenzylamine (2-HOBA), a natural compound derived from buckwheat seeds that acts as a potent scavenger of electrophiles, is bioavailable in the colon of mice after supplementation in the drinking water and does not affect the colonic microbiome. 2-HOBA reduced the level of isoLG adducts to lysine as well as tumorigenesis in models of colitis-associated carcinogenesis and of sporadic CRC driven by specific deletion of the adenomatous polyposis coli gene in colonic epithelial cells. In parallel, we found that oncogenic NRF2 activation and signaling were decreased in the colon of 2-HOBA-treated mice. Additionally, the growth of xenografted human HCT116 CRC cells in nude mice was significantly attenuated by 2-HOBA supplementation. In conclusion, 2-HOBA represents a promising natural compound for the prevention and treatment of CRC.

Epithelial talin-1 protects mice from citrobacter rodentium-induced colitis by restricting bacterial crypt intrusion and enhancing t cell immunity.

Pathogenic enteric Escherichia coli present a significant burden to global health. Food-borne enteropathogenic E. coli (EPEC) and Shiga toxin-producing E. coli (STEC) utilize attaching and effacing (A/E) lesions and actin-dense pedestal formation to colonize the gastrointestinal tract. Talin-1 is a large structural protein that links the actin cytoskeleton to the extracellular matrix though direct influence on integrins. Here we show that mice lacking talin-1 in intestinal epithelial cells (Tln1Δepi) have heightened susceptibility to colonic disease caused by the A/E murine pathogen Citrobacter rodentium. Tln1Δepi mice exhibit decreased survival, and increased colonization, colon weight, and histologic colitis compared to littermate Tln1fl/fl controls. These findings were associated with decreased actin polymerization and increased infiltration of innate myeloperoxidase-expressing immune cells, confirmed as neutrophils by flow cytometry, but more bacterial dissemination deep into colonic crypts. Further evaluation of the immune population recruited to the mucosa in response to C. rodentium revealed that loss of Tln1 in colonic epithelial cells (CECs) results in impaired recruitment and activation of T cells. C. rodentium infection-induced colonic mucosal hyperplasia was exacerbated in Tln1Δepi mice compared to littermate controls. We demonstrate that this is associated with decreased CEC apoptosis and crowding of proliferating cells in the base of the glands. Taken together, talin-1 expression by CECs is important in the regulation of both epithelial renewal and the inflammatory T cell response in the setting of colitis caused by C. rodentium, suggesting that this protein functions in CECs to limit, rather than contribute to the pathogenesis of this enteric infection.

The nutraceutical electrophile scavenger 2-hydroxybenzylamine (2-HOBA) attenuates gastric cancer development caused by Helicobacter pylori.

Stomach cancer is a leading cause of cancer death. Helicobacter pylori is a bacterial gastric pathogen that is the primary risk factor for carcinogenesis, associated with its induction of inflammation and DNA damage. Dicarbonyl electrophiles are generated from lipid peroxidation during the inflammatory response and form covalent adducts with amine-containing macromolecules. 2-hydroxybenzylamine (2-HOBA) is a natural compound derived from buckwheat seeds and acts as a potent scavenger of reactive aldehydes. Our goal was to investigate the effect of 2-HOBA on the pathogenesis of H. pylori infection. We used transgenic FVB/N insulin-gastrin (INS-GAS) mice as a model of gastric cancer. First, we found that 2-HOBA is bioavailable in the gastric tissues of these mice after supplementation in the drinking water. Moreover, 2-HOBA reduced the development of gastritis in H. pylori-infected INS-GAS mice without affecting the bacterial colonization level in the stomach. Further, we show that the development of gastric dysplasia and carcinoma was significantly reduced by 2-HOBA. Concomitantly, DNA damage were also inhibited by 2-HOBA treatment in H. pylori-infected mice. In parallel, DNA damage was inhibited by 2-HOBA in H. pylori-infected gastric epithelial cells in vitro. In conclusion, 2-HOBA, which has been shown to be safe in human clinical trials, represents a promising nutritional compound for the chemoprevention of the more severe effects of H. pylori infection.

Content validity of patient-reported outcome measures for patients with chronic pain: considering the patient's perspective.

ABSTRACT: Understanding chronic pain and disability requires a consideration of the lived experience of the patient. There is limited evaluation of the content validity of patient-reported outcome measures (PROMs) in chronic pain using a comprehensive biopsychosocial view of the patient's experience. To address this gap, this study aimed to evaluate the content validity of PROMs for patients with chronic pain. A literature review was performed to identify PROMs for patients with chronic pain. Concepts from PROMs were linked to the International Classification of Functioning, Disability, and Health (ICF); the ICF Core Set for Chronic Widespread Pain; and the International Classification of Diseases-11 Functioning Properties of Chronic Pain (FP). Concepts were compared with published "attributes'' of chronic pain. 62 PROMs (1336 items total) were identified and linked to 560 unique second-level ICF categories. The greatest number of items across PROMs were represented in the activities and participation category (44% of all total items), followed by body functions (41%), environmental factors (9%), personal factors (5%), and body structures (0.3%). There was a 41% to 78% match with the Core Set for Chronic Widespread Pain and the International Classification of Diseases-11 FP, respectively. 20% of items reflected the pain-experience attributes with the most items reflecting the concept of "control over pain." Content validity analysis suggests chronic widespread pain patient-reported outcome measures poorly address attributes of living with chronic pain that matter most to patients. Future development or refinement should consider a more comprehensive view of the patients' lived experience.

Doxycycline-Induced Intracranial Hypertension Presenting as Unilateral Pulsatile Tinnitus.

Background: Pulsatile tinnitus (PT) is increasingly recognized as a cardinal symptom of idiopathic intracranial hypertension (IIH). However, clinicians should remain aware of other causes of nonidiopathic or secondary intracranial hypertension manifesting as PT. We present 2 patients with isolated PT (without accompanying headache, blurred vision, and papilledema) thought to be secondary to tetracycline-induced intracranial hypertension. To our knowledge, these are the first cases of PT as the presenting symptom of this condition. Cases: A 41-year-old female (body mass index [BMI] 29 kg/m2) with ocular rosacea was initially treated with minocycline. Shortly after transitioning to oral doxycycline and erythromycin eye ointment, she noted left-sided PT. Her PT resolved after discontinuing doxycycline. In a second case, a 39-year-old female (BMI 19 kg/m2) with acne presented with a three-year history of left-sided PT while on long-term oral doxycycline for many years. She denied visual or auditory changes and atypical headaches. MRI findings were concerning for intracranial hypertension. Three months later, the patient was seen by neuro-ophthalmology, with findings suggesting prior papilledema. The patient reported PT improvement after discontinuing doxycycline. Conclusions: This case series highlights 2 cases of isolated PT as the sole symptom of intracranial hypertension that resolved with tetracycline cessation. The presentation and unexpected improvement following tetracycline discontinuation are atypical compared with previous reports of tetracycline-induced intracranial hypertension. Clinicians should maintain a high index of suspicion for all types of intracranial hypertension (idiopathic and secondary), even in patients with a lower BMI. Current and prior medications should be reviewed when considering the etiology of intracranial hypertension.

Targeting the two-pore channel 2 in cancer progression and metastasis.

The importance of Ca2+ signaling, and particularly Ca2+ channels, in key events of cancer cell function such as proliferation, metastasis, autophagy and angiogenesis, has recently begun to be appreciated. Of particular note are two-pore channels (TPCs), a group of recently identified Ca2+-channels, located within the endolysosomal system. TPC2 has recently emerged as an intracellular ion channel of significant pathophysiological relevance, specifically in cancer, and interest in its role as an anti-cancer drug target has begun to be explored. Herein, an overview of the cancer-related functions of TPC2 and a discussion of its potential as a target for therapeutic intervention, including a summary of clinical trials examining the TPC2 inhibitors, naringenin, tetrandrine, and verapamil for the treatment of various cancers is provided.

Ornithine Decarboxylase in Gastric Epithelial Cells Promotes the Immunopathogenesis of Helicobacter pylori Infection.

Colonization by Helicobacter pylori is associated with gastric diseases, ranging from superficial gastritis to more severe pathologies, including intestinal metaplasia and adenocarcinoma. The interplay of the host response and the pathogen affect the outcome of disease. One major component of the mucosal response to H. pylori is the activation of a strong but inefficient immune response that fails to control the infection and frequently causes tissue damage. We have shown that polyamines can regulate H. pylori-induced inflammation. Chemical inhibition of ornithine decarboxylase (ODC), which generates the polyamine putrescine from l-ornithine, reduces gastritis in mice and adenocarcinoma incidence in gerbils infected with H. pylori However, we have also demonstrated that Odc deletion in myeloid cells enhances M1 macrophage activation and gastritis. Here we used a genetic approach to assess the specific role of gastric epithelial ODC during H. pylori infection. Specific deletion of the gene encoding for ODC in gastric epithelial cells reduces gastritis, attenuates epithelial proliferation, alters the metabolome, and downregulates the expression of immune mediators induced by H. pylori Inhibition of ODC activity or ODC knockdown in human gastric epithelial cells dampens H. pylori-induced NF-κB activation, CXCL8 mRNA expression, and IL-8 production. Chronic inflammation is a major risk factor for the progression to more severe pathologies associated with H. pylori infection, and we now show that epithelial ODC plays an important role in mediating this inflammatory response.

Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy.

Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5'-monophosphate-mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid-sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5'-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite Plasmodium falciparum, namely tyrosine RS (PfYRS). ML901 exerts whole-life-cycle-killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901.

Cystathionine γ-lyase exacerbates Helicobacter pylori immunopathogenesis by promoting macrophage metabolic remodeling and activation.

Macrophages play a crucial role in the inflammatory response to the human stomach pathogen Helicobacter pylori, which infects half of the world's population and causes gastric cancer. Recent studies have highlighted the importance of macrophage immunometabolism in their activation state and function. We have demonstrated that the cysteine-producing enzyme cystathionine γ-lyase (CTH) is upregulated in humans and mice with H. pylori infection. Here, we show that induction of CTH in macrophages by H. pylori promoted persistent inflammation. Cth-/- mice had reduced macrophage and T cell activation in H. pylori-infected tissues, an altered metabolome, and decreased enrichment of immune-associated gene networks, culminating in decreased H. pylori-induced gastritis. CTH is downstream of the proposed antiinflammatory molecule, S-adenosylmethionine (SAM). Whereas Cth-/- mice exhibited gastric SAM accumulation, WT mice treated with SAM did not display protection against H. pylori-induced inflammation. Instead, we demonstrated that Cth-deficient macrophages exhibited alterations in the proteome, decreased NF-κB activation, diminished expression of macrophage activation markers, and impaired oxidative phosphorylation and glycolysis. Thus, through altering cellular respiration, CTH is a key enhancer of macrophage activation, contributing to a pathogenic inflammatory response that is the universal precursor for the development of H. pylori-induced gastric disease.

Sickle cell disease and fat embolism: a rare complication of vaso-occlusive crisis.

A 61-year-old woman was admitted to the hospital for management of a painful vaso-occlusive crisis. She had a history of sickle cell beta-thalassaemia and end-stage renal disease managed with intermittent haemodialysis. While hospitalised, she became lethargic and unresponsive and developed acute chest syndrome. Initial MR scan of brain, cerebrospinal fluid examination and continuous electroencephalogram were unremarkable, but subsequent MR scan of brain identified a right transverse venous sinus thrombosis and extensive supratentorial and infratentorial microhaemorrhages consistent with fat emboli. We; therefore, discuss a case of non-traumatic fat embolism syndrome, a rare complication of sickle cell disease.

A neural network account of memory replay and knowledge consolidation.

Replay can consolidate memories through offline neural reactivation related to past experiences. Category knowledge is learned across multiple experiences, and its subsequent generalization is promoted by consolidation and replay during rest and sleep. However, aspects of replay are difficult to determine from neuroimaging studies. We provided insights into category knowledge replay by simulating these processes in a neural network which approximated the roles of the human ventral visual stream and hippocampus. Generative replay, akin to imagining new category instances, facilitated generalization to new experiences. Consolidation-related replay may therefore help to prepare us for the future as much as remember the past. Generative replay was more effective in later network layers functionally similar to the lateral occipital cortex than layers corresponding to early visual cortex, drawing a distinction between neural replay and its relevance to consolidation. Category replay was most beneficial for newly acquired knowledge, suggesting replay helps us adapt to changes in our environment. Finally, we present a novel mechanism for the observation that the brain selectively consolidates weaker information, namely a reinforcement learning process in which categories were replayed according to their contribution to network performance. This reinforces the idea of consolidation-related replay as an active rather than passive process.

Bone Marrow Microenvironment as a Source of New Drug Targets for the Treatment of Acute Myeloid Leukaemia.

Acute myeloid leukaemia (AML) is a heterogeneous disease with one of the worst survival rates of all cancers. The bone marrow microenvironment is increasingly being recognised as an important mediator of AML chemoresistance and relapse, supporting leukaemia stem cell survival through interactions among stromal, haematopoietic progenitor and leukaemic cells. Traditional therapies targeting leukaemic cells have failed to improve long term survival rates, and as such, the bone marrow niche has become a promising new source of potential therapeutic targets, particularly for relapsed and refractory AML. This review briefly discusses the role of the bone marrow microenvironment in AML development and progression, and as a source of novel therapeutic targets for AML. The main focus of this review is on drugs that modulate/target this bone marrow microenvironment and have been examined in in vivo models or clinically.

Protective Role of Spermidine in Colitis and Colon Carcinogenesis.

BACKGROUND & AIMS: Because inflammatory bowel disease is increasing worldwide and can lead to colitis-associated carcinoma (CAC), new interventions are needed. We have shown that spermine oxidase (SMOX), which generates spermidine (Spd), regulates colitis. Here we determined whether Spd treatment reduces colitis and carcinogenesis. METHODS: SMOX was quantified in human colitis and associated dysplasia using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. We used wild-type (WT) and Smox-/- C57BL/6 mice treated with dextran sulfate sodium (DSS) or azoxymethane (AOM)-DSS as models of colitis and CAC, respectively. Mice with epithelial-specific deletion of Apc were used as a model of sporadic colon cancer. Animals were supplemented or not with Spd in the drinking water. Colonic polyamines, inflammation, tumorigenesis, transcriptomes, and microbiomes were assessed. RESULTS: SMOX messenger RNA levels were decreased in human ulcerative colitis tissues and inversely correlated with disease activity, and SMOX protein was reduced in colitis-associated dysplasia. DSS colitis and AOM-DSS-induced dysplasia and tumorigenesis were worsened in Smox-/- vs WT mice and improved in both genotypes with Spd. Tumor development caused by Apc deletion was also reduced by Spd. Smox deletion and AOM-DSS treatment were both strongly associated with increased expression of α-defensins, which was reduced by Spd. A shift in the microbiome, with reduced abundance of Prevotella and increased Proteobacteria and Deferribacteres, occurred in Smox-/- mice and was reversed with Spd. CONCLUSIONS: Loss of SMOX is associated with exacerbated colitis and CAC, increased α-defensin expression, and dysbiosis of the microbiome. Spd supplementation reverses these phenotypes, indicating that it has potential as an adjunctive treatment for colitis and chemopreventive for colon carcinogenesis.

A quantitative analysis of MDMA seized at New South Wales music festivals over the 2019/2020 season: Form, purity, dose and adulterants.

INTRODUCTION: This research aims to understand the content and nature, and to explore the harm potential, of suspected 3,4-methylenedioxymethamphetamine (MDMA) substances circulating at music festivals in New South Wales. METHODS: Across 19 music festivals held between October 2019 and March 2020, 302 substances detected and suspected by police to contain MDMA were selected for quantitative analysis. RESULTS: Five percent of substances contained a drug other than MDMA (n = 13) or no drug (n = 2). The remaining 95.0% (n = 287) contained MDMA. Of this sub-sample, capsule was the commonest form (83.3%), followed by tablet (7.7%), crystal (6.3%) and powder (2.8%). The median MDMA base-purity of non-tablet forms ranged between 73.5% and 75.0%. The median MDMA base-dose per tablet (116 mg) was higher than per capsule (68 mg). The dose range varied substantially for capsules (14-146 mg) and tablets (24-201 mg). A higher dose (130 mg or greater) was found in 3.5% of MDMA tablets or capsules. Adulterants were identified in 14.1% of MDMA substances but only 1.6% contained a psychoactive adulterant and none presented as dangerous due to their nature or low concentration. DISCUSSION AND CONCLUSIONS: Dangerous MDMA adulterants or new psychoactive substances in tablet, capsule, powder or crystal forms (whether misrepresented as MDMA or not) were unlikely to be in circulation during the study period. Harm reduction messaging should inform that a key risk-factor for MDMA-related harm is the high and wide variation of purity and dose across forms. Market changes may have occurred since COVID-19, but continued monitoring will ensure messaging remains current.