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Background: Cutibacterium acnes is a commensal intradermal microorganism that is commonly isolated at revision shoulder arthroplasty. Standard practice chlorhexidine gluconate (CHG) skin preparation agents have limited effectiveness at eradicating C. acnes in the dermis. Benzoyl peroxide (BPO) has demonstrated effectiveness against C. acnes. This meta-analysis compares the efficacy of at-home shoulder decolonization before surgery using CHG vs. BPO to reduce shoulder C. acnes burden. Methods: This was a Preferred Reporting Items for Systematic Reviews and Meta-Analyses systematic review. PubMed and MEDLINE databases were searched for studies evaluating the effects of CHG and BPO in reducing C. acnes at the shoulder. Trial results were extracted and pooled using a random effects model, separating data from randomized controlled trials (RCTs) and non-RCTs. Methodologic quality of studies was assessed using the Cochrane Risk of Bias Assessment Tools. Results: Ten studies (589 patients) were included. RCTs showed that both BPO and CHG led to significant reductions in culture positivity compared with negative controls (risk ratio [RR] with 95% confidence interval [CI] = 0.20 [0.13, 0.30], P < .0001 and 0.46 [0.37, 0.57], P < .0001, respectively). Non-RCT data demonstrated similar results comparing BPO and CHG to the control (RR with 95% CI = 0.34 [0.21, 0.57], P < .0001 and 0.31 [0.20, 0.49], P < .0001, respectively). Comparing BPO and CHG, RCT data showed a significant reduction in culture positivity with BPO (RR with 95% CI = 0.46 [0.27, 0.77], P < .009). Of RCTs, 5 were low and one was of moderate risk of bias. Of non-RCTs, 3 had low risk of bias, whereas one had moderate risk of bias. Conclusion: This review demonstrated that preoperative CHG and BPO can reduce C. acnes at the shoulder. However, BPO exhibits greater efficacy than CHG, potentially because of the compound’s ability to penetrate the dermis. BPO is a simple and economical agent that may reduce joint exposure to C. acnes in shoulder surgery.

Objective . To compare the effects of a group-mediated cognitive behavioral (GMCB) exercise and dietary (EX+D) intervention with those of standard-of-care (SC) treatment on select social cognitive outcomes in prostate cancer (PCa) patients undergoing androgen deprivation therapy (ADT). Methods . In the single-blind, 2-arm, randomized controlled Individualized Diet and Exercise Adherence–Pilot (IDEA-P) trial, 32 PCa patients (mean age = 66.2 years; SD = 7.8) undergoing ADT were randomly assigned to a 12-week EX+D intervention (n = 16) or SC treatment (n = 16). The exercise component of the personalized EX+D intervention integrated a combination of supervised resistance and aerobic exercise performed twice per week. The dietary component involved counseling and education to modify dietary intake and composition. Blinded assessments of social cognitive outcomes were obtained at baseline and 2-month and 3-month follow-up. Results . Intent-to-treat analysis of covariance demonstrated that the EX+D intervention resulted in significantly greater improvements in scheduling ( P < .05), coping ( P < .01), and exercise self-efficacy ( P < .05), and satisfaction with function ( P < .01) at 3 months relative to SC. Results of partial correlation analysis also demonstrated that select social cognitive outcomes were significantly correlated with primary trial outcomes of mobility performance and exercise participation ( P < .05) at 3-month follow-up. Conclusions : The GMCB lifestyle intervention yielded more favorable improvements in relevant social cognitive outcomes relative to SC among PCa patients undergoing ADT. Additionally, more favorable social cognitive outcomes were associated with superior mobility performance and exercise participation following the independent maintenance phase of the EX+D intervention.

Knowledge of the number of people present in a catchment is fundamental for the assessment of spatio-temporal trends in wastewater-based epidemiology (WBE). Accurately estimating the number of people connected to wastewater catchments is challenging however, because populations are dynamic. Methods used to estimate population size can significantly influence the calculation and interpretation of population-normalised wastewater data (PNWD). This paper systematically reviews the reporting of population data in 339 WBE studies. Studies were evaluated based on their reporting of population size, the source of population data, the population calculation methods, and the uncertainties in population estimates. Most papers reported population size (96 %) and the source of population data (60 %). Fewer studies reported the uncertainties in their population data (50 %) and the methods used to calculate these estimates (28 %). This is relevant because different methods have unique strengths and limitations which can affect the accuracy of PNWD. Only 64 studies (19 %) reported all four components of population data. The reporting of population data has remained consistent in the past decade. Based on the findings, we recommend generalised reporting criteria for population data in WBE. As WBE is further mainstreamed and applied, the clear and comprehensive reporting of population data will only become increasingly important., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Methamphetamine is the illicit stimulant of choice in Australia. Countless initiatives have been employed to reduce methamphetamine use and drug-related harm. Wastewater analysis (WWA) has been used effectively as an objective measure of drug use at a population level and can be compared to indicators of harm, such as the number of drug-related fatalities. This paper attempts to describe methamphetamine use in the context of changes in levels measured in wastewater in South Australia whilst recognising considerable interventions over an 8-year period. Validated liquid chromatography-mass spectrometry methods were used to determine methamphetamine (and MDMA) levels in wastewater over an 8-year interval. The number of drug-induced deaths and driver fatalities involving methamphetamine (and MDMA) was presented and described in the context of changes in use measured by WWA. A rise in methamphetamine use according to WWA was evident up to 2017, followed by a gradual decrease to 2020 back to 2015 levels. Both driver fatalities and drug-induced deaths correlated well with use measured by WWA over the 8-year period. Multiple initiatives to curb supply, distribution and harm within the state and nationally have been implemented. The decrease in methamphetamine use after 2017 suggests that timely interventions have successfully reduced overall drug use and has led to fewer fatalities. This study shows that the response to increasing methamphetamine use in South Australia has resulted in a reversal of the upward trend in consumption and fewer drug-related fatalities., (© 2024 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

Opioids are widely distributed, potent prescription analgesics that are known to be diverted for illicit use. Their prevalence of use is reflected by high concentrations of parent compounds and/or metabolites found in samples collected from wastewater treatment plants. Given that treatment byproducts enter the environment through several routes, the consequences of insufficient removal by treatment methods include unwanted environmental exposure and potential to disrupt ecosystems. Activated sludge treatment has been widely investigated for a large suite of prescription opioids but the same cannot be said for UV and chlorination. Additionally, the biosolid cycle of opioids has been overlooked previously. This study aimed to determine the extent to which secondary and tertiary wastewater treatment methods remove opioids from influent, and the associated environmental exposure for those persistent, as well as the fate of opioids in biosolids. Membrane bioreactor treatment proved effective for natural and semi-synthetic opioids while the effect of UV treatment was negligible. Chlorination was the most effective treatment method resulting in effluent with concentrations below theoretical predicted no-effect concentration. Biosolids are not subjected to any additional biological or chemical treatment after membrane bioreactor treatment and the levels detected in biosolid used as fertiliser had several opioids at potentially hazardous concentrations, indicated by a QSAR theoretical model. This data indicates a potential issue regarding the treatment process of biosolids and reliance on chlorination for effluent treatment that should be investigated in other treatment plants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Between 2018 and 2020, Australia implemented major policy changes to improve the quality and safety of opioid prescribing, with a specific focus on oxycodone. This study used wastewater-based epidemiology to assess the efficacy of Australia's regulatory reforms by measuring change in consumption of oxycodone via exploratory analysis., Design, Setting, Participants, Measurements: Wastewater analysis data on oxycodone consumption was from the National Wastewater Drug Monitoring Program. The program captures data from more than 50 wastewater treatment plant catchments across Australia, equivalent to more than 50% of the national population. Geographic trend analyses were conducted for both major cities and regional areas within all states and territories of Australia over a 6-year period between 2017 and 2023., Findings: Oxycodone consumption showed a statistically significant increase nationally from 78 mg/day/1000 people (95% confidence interval [CI] = 71, 84) in 2017 to 120 mg/day/1000 people in August 2019 (95% CI = 110, 120), an increase of 52% (95% CI = 42, 62, P < 0.0001). From August 2019 to December 2020, there was a statistically significant decrease from 120 to 65 mg/day/1000 people (95% CI = 60, 71), a decrease of 45% (95% CI = 40, 51), followed by a modest 2.4% increase to the end of the study period in April 2023 (95% CI [2.0,2.7])., Conclusions: A 45% reduction in oxycodone consumption in Australia from 2019 to 2020 coincided with national policy changes that aimed to reduce consumption of prescription opioids. The overall declining trend in consumption was suggestive of the effectiveness of national interventions in reducing pharmaceutical opioid use. Wastewater-based epidemiology provides an effective approach for assessing the effectiveness of controlled substances policy changes., (© 2024 The Author(s). Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Objective: To update and add to the first report commissioned by the Blue Ribbon Committee about 20 years prior., Summary of Background Data: Following a summit in late 2022 commissioned by the American Board of Surgery regarding competency-based reforms in surgical education and via a partnership with the American College of Surgeons (ACS) and other stakeholders, a Blue Ribbon Committee (BRC-II) on surgical education was formed. The BRC-II would have seven subcommittees. This paper details the work of the Medical Student Subcommittee within the BRC- II., Methods: The subcommittee's work, supported by staff from the ACS, entailed a thorough literature review, which involved collating and aggregating the findings, identifying key challenges and opportunities, and committing to draft recommendations. These recommendations were then presented and refined via discussions with the Blue Ribbon Committee at large in multiple virtual and in-person settings., Results: The subcommittee's work is detailed below and further summarized in table format. The section below elucidates the medical student education continuum and discusses the pertinent topics of recruitment, surgical engagement in medical student training and the surgical image, training for the current surgical practice model, trainee selection for graduate medical education (GME), and optimizing the transition from undergraduate medical education (UME) to GME., Conclusions: The last two decades have shown significant changes and shifts in medical education and surgical practice. The findings of BRC-II in this manuscript help to structure the current and future necessary improvements, focusing on different aspects of medical student education., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Wastewater analysis provides a complementary measure of alcohol use in whole communities. We assessed absolute differences and temporal trends in alcohol consumption by degree of remoteness and socioeconomics indicators in Australia from 2016 to 2023., Methods: Alcohol consumption estimates from 50 wastewater treatment plants (WWTP) in the Australian National Wastewater Drug Monitoring Program were used. Trends were analysed based on 1) site remoteness: Major Cities, Inner Regional and a combined remoteness category of Outer Regional and Remote, and 2) using two socioeconomic indexes from the Australian Bureau of Statistics (ABS) relating to advantage and disadvantage for Income, education, occupation, and housing., Results: Consumption estimates were similar for Major Cities and Inner Regional areas (14.3 and 14.4L/day/1000 people), but significantly higher in Outer Regional and Remote sites (18.6L/day/1000 people). Consumption was decreasing in Major cities by 4.5% annually, Inner Regional by 2.4%, and 3.5% in the combined Outer Regional and Remote category. Consumption estimates were higher in socioeconomically advantaged quartiles than those of lower advantage (0%-25% mean = 13.0, 75%-100% mean = 17.4). Consumption in all quartiles decreased significantly over the 7 year period with annual rates of decrease of 0.9%, 3.7%, 3.6%, and 3.0% for the lowest to highest quartile, respectively., Conclusions: Declines in Australian alcohol consumption have been steeper in large urban areas than regional and remote areas. There were smaller annual decreases in the most socioeconomically disadvantaged areas. If continued, these trends may increase Australian health inequalities. Policy and prevention work should be appropriately targeted to produce more equitable long-term outcomes., Competing Interests: Declaration of Competing Interest The study sponsor had no role in analysis and interpretation of data; writing the report; and the decision to submit the report for publication., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The solid product of wastewater treatment plants is commonly used as a fertiliser to increase sustainability and waste reuse. It has undergone extensive treatment to remove high nutrient loads, pathogens and heavy metals but the extensive matrix of household chemicals, pesticides and pharmaceuticals remains, untargeted by most treatment technologies. These compounds, particularly pharmaceuticals, have been detected in biosolids with there being evidence of uptake by plants. With the current opioid pandemic in North America and overprescription, a simple method is required for the extraction of opioids from a solid medium as to ascertain the concentrations the environment is exposed to. A sonication-liquid-liquid extracted method was developed where biosolids were suspended in water and extracted using ethyl acetate before analysis on LC MS/MS. Sodium and potassium chloride were compared along with acidic and alkaline conditions. The optimised method utilised NaCl at a pH of 12 and was validated for 17 opioids, achieving linearity >0.987, 86-113% matrix effect and 0.1-10 μg/kg limits of detection. Upon analysis of biosolids destined for agriculture, 14 opioids were detected across all samples in a concentration range of 1-289 μg/kg., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cobus Gerber reports financial support was provided by Drug and Alcohol Services South Australia. Cobus Gerber reports financial support was provided by Australian Criminal Intelligence Commission., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Neoantigens, mutated tumour-specific antigens, are key targets of anti-tumour immunity during checkpoint inhibitor (CPI) treatment. Their identification is fundamental to designing neoantigen-directed therapy. Non-canonical neoantigens arising from the untranslated regions (UTR) of the genome are an overlooked source of immunogenic neoantigens. Here, we describe the landscape of UTR-derived neoantigens and release a computational tool, PrimeCUTR, to predict UTR neoantigens generated by start-gain and stop-loss mutations., Methods: We applied PrimeCUTR to a whole genome sequencing dataset of pre-treatment tumour samples from CPI-treated patients (n = 341). Cancer immunopeptidomic datasets were interrogated to identify MHC class I presentation of UTR neoantigens., Results: Start-gain neoantigens were predicted in 72.7% of patients, while stop-loss mutations were found in 19.3% of patients. While UTR neoantigens only accounted 2.6% of total predicted neoantigen burden, they contributed 12.4% of neoantigens with high dissimilarity to self-proteome. More start-gain neoantigens were found in CPI responders, but this relationship was not significant when correcting for tumour mutational burden. While most UTR neoantigens are private, we identified two recurrent start-gain mutations in melanoma. Using immunopeptidomic datasets, we identify two distinct MHC class I-presented UTR neoantigens: one from a recurrent start-gain mutation in melanoma, and one private to Jurkat cells., Conclusion: PrimeCUTR is a novel tool which complements existing neoantigen discovery approaches and has potential to increase the detection yield of neoantigens in personalised therapeutics, particularly for neoantigens with high dissimilarity to self. Further studies are warranted to confirm the expression and immunogenicity of UTR neoantigens., Competing Interests: KL reports personal fees from Kynos Therapeutics, Monopteros Therapeutics, Ellipses Pharma, Tempus Labs and Roche Tissue Diagnostics, and grants from Genesis Therapeutics and Cancer Research UK/Ono Pharmaceutical Co., Ltd./LifeArc IO Alliance, and is an employee of Isomorphic Labs, all outside the submitted work. BS is an employee of DIOSynVax Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sng, Kallor, Simpson, Bedran, Alfaro and Litchfield.)

Wastewater analysis (WWA) has been used as a tool to monitor population drug use, both pharmaceutical and illicit, for over 15 years. Policymakers, law enforcement and treatment services may use WWA-derived data to seek an objective understanding of the extent of drug use in specific areas. Therefore, wastewater data should best be reported in a meaningful form to allow those that are not experts in the field to compare the scale within and between drug classes. Excreted drug loads quantified in wastewater describe the mass of drug present in the sewer. Normalisation for wastewater flow and population is standard practice and critical for comparing drug loads between different catchments and indicates a transition to an epidemiological approach (wastewater-based epidemiology (WBE)). A further consideration is necessary to accurately compare the measured level of one drug to another. The standard dose of a drug taken to elicit a therapeutic effect will vary, with some compounds requiring microgram amounts, while others are administered in the gram range. When WBE data is expressed with units representing excreted or consumed loads without considering dose amounts, the scale of drug use when comparing multiple compounds becomes distorted. To demonstrate the utility and significance of including known excretion rates, potency and typical dose amounts into back-calculations of the measured drug load, this paper compares the levels of 5 prescribed (codeine, morphine, oxycodone, fentanyl and methadone) and 1 illicit (heroin) opioid from South Australian wastewater. The data is presented at each stage of the back-calculation starting with the total mass load measured, to consumed amounts factoring in excretion rates and finally the number of doses the load equates to. This is the first paper to describe the levels of 6 opioids measured in wastewater over a 4-year period in South Australia that demonstrate the relative scale of use., Competing Interests: Declaration of competing interest None declared., (Copyright © 2023. Published by Elsevier B.V.)

Pluripotency defines the unlimited potential of individual cells of vertebrate embryos, from which all adult somatic cells and germ cells are derived. Understanding how the programming of pluripotency evolved has been obscured in part by a lack of data from lower vertebrates; in model systems such as frogs and zebrafish, the function of the pluripotency genes NANOG and POU5F1 have diverged. Here, we investigated how the axolotl ortholog of NANOG programs pluripotency during development. Axolotl NANOG is absolutely required for gastrulation and germ-layer commitment. We show that in axolotl primitive ectoderm (animal caps; ACs) NANOG and NODAL activity, as well as the epigenetic modifying enzyme DPY30, are required for the mass deposition of H3K4me3 in pluripotent chromatin. We also demonstrate that all 3 protein activities are required for ACs to establish the competency to differentiate toward mesoderm. Our results suggest the ancient function of NANOG may be establishing the competence for lineage differentiation in early cells. These observations provide insights into embryonic development in the tetrapod ancestor from which terrestrial vertebrates evolved., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Simpson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Addressing continued inequities in medicine, and especially in dermatology, requires a strategic approach and meaningful actions that will yield and result in sustainable change in our medical, clinical, and learning environments. Heretofore, most solutions-based actions and programs in DEI have focused on developing and edifying the diverse learner or faculty member. Alternatively, accountability rests with the entities that wield the power and ability and authority to shift culture change such that the diverse learner, faculty member, and patient can receive equitable access to care and educational resources in environments within a culture of belonging., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Ameloblastoma is a benign, locally invasive epithelial odontogenic neoplasm of the jaw. Treatment of choice is jaw resection, often resulting in significant morbidity. The aim of this study was to recapitulate ameloblastoma in a completely humanised 3D disease model containing ameloblastoma cells, osteoblasts and activated osteoclasts to investigate the RANKL pathway within the ameloblastoma stromal environment and its response to the RANKL antibody denosumab. In vitro bone was engineered by culturing human osteoblasts (hOB) in a biomimetic, dense collagen type I matrix, resulting in extensive mineral deposits by day 21 forming alizarin red positive bone like nodules throughout the 3D model. Activated TRAP + human osteoclasts were confirmed through the differentiation of human CD14+ monocytes after 10 days within the model. Lastly, the ameloblastoma cell lines AM-1 and AM-3 were incorporated into the 3D model. RANKL release was validated through TACE/ADAM17 activation chemically or through hOB co-culture. Denosumab treatment resulted in decreased osteoclast activation in the presence of hOB and ameloblastoma cells. These findings stress the importance of accurately modelling tumour and stromal populations as a preclinical testing platform., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Wastewater-based epidemiology is a tool incorporating biomarker analysis that can be used to monitor the health status of a population. Indicators of health include endogenous oxidative stress biomarkers and hormones, or exogenous such as alcohol and nicotine. 8-Iso-prostaglandin F 2α/β is a biomarker of endogenous metabolism that can be used to measure oxidative stress in a community. Benzodiazepines are a harmful subclass of anxiolytics either prescribed or sourced illegally. The analysis of oxidative stress markers and uptake of benzodiazepines in wastewater may provide information about distress in the community. A method has been applied to detect 8-isoPGF 2α/β and the illicit benzodiazepines clonazolam, flubromazolam and flualprazolam in addition to other prescribed benzodiazepines in wastewater. These substances have been sold as counterfeit pharmaceutical products, such as Xanax, which was formulated to include alprazolam. Deconjugation was initially performed on wastewater samples, followed by liquid-liquid extraction for isoprostanes and solid phase extraction for benzodiazepines to determine the total levels of these analytes. Limits of quantification were in the range of 0.5-2 ng/L for all the analytes except 8-isoPGF 2α/β which was 50 ng/L. Stability, recovery and matrix effect studies were also conducted. Finally, this method was applied to influent wastewater from South Australia which showed the prevalence of 8-isoPGF 2α/β and benzodiazepines., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cobus Gerber reports financial support was provided by the Australian Criminal and Intelligence Commission and South Australia Dept. Health., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Chronic inflammation is known to be a predominant factor in the development of many age-related conditions including CVD, type II diabetes and neurodegenerative diseases. Previous studies have demonstrated that during the ageing process there is an increase in inflammatory biomarkers, which may be partially brought about by detrimental changes in the gut microbiota. The Mediterranean diet (MedDiet) and physical activity (PA) are protective against inflammation and chronic disease, and emerging evidence has shown that these effects may be partially mediated through favourable changes in the gut microbiota. In this review, we have evaluated the published literature on the effect of a MedDiet and PA on the gut microbiota. We also discuss the relationship between the gut microbiota and inflammation with a focus on healthy ageing. While inconsistent study designs make forming definitive conclusions challenging, the current evidence suggests that both a MedDiet and PA are capable of modifying the gut microbiota in a way that is beneficial to host health. For example, the increases in the relative abundance of SCFA producing bacteria that are considered to possess anti-inflammatory properties. Modification of the gut microbiota through a MedDiet and PA presents as a potential method to attenuate age-related increases in inflammation, and additional studies utilising older individuals are needed to fill the knowledge gaps existing in current literature.

Methcathinone is a prevalent Novel Psychoactive Substance (NPS) used illicitly in some countries. Routine analysis of wastewater sampled from catchments in South Australia has shown a consistent low-level presence of the compound, inconsistent with NPS use. This raised the question was the occurrence due to regular use as a drug of choice or was it an artefact being produced from other sources in the sewer system? NPS consumption is generally sporadic and would therefore point to the origin of methcathinone in wastewater being due to in-sewer oxidation of its legal precursor, pseudoephedrine. The present study tested this hypothesis by comparing the levels of pseudoephedrine and methcathinone in wastewater samples collected bimonthly from 8 catchment sites in South Australia. Laboratory experiments exposing pseudoephedrine to common household oxidizing agents (hypochlorite and percarbonate) were also performed and the production of methcathinone was demonstrated and monitored. The results of this study showed that the level of pseudoephedrine and methcathinone measured in wastewater followed a similar pattern. However, there were periods when the levels of each compound diverged. Laboratory experiments showed that when exposed to various oxidizing agents, pseudoephedrine is oxidised to non-stoichiometric quantities of methcathinone. Although the use of methcathinone as a drug of choice remains possible, the results of this study indicate that the low and persistent level of methcathinone found in wastewater may arise in part from the oxidation of pseudoephedrine in the sewer system., Competing Interests: Declaration of competing interest Cobus Gerber reports financial support was provided by Drug and Alcohol Services South Australia., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Multiparametric magnetic-resonance imaging (mpMRI) has proven utility in diagnosing primary prostate cancer. However, the diagnostic potential of prostate-specific membrane antigen positron-emission tomography (PSMA PET) has yet to be established. This study aims to systematically review the current literature comparing the diagnostic performance of mpMRI and PSMA PET imaging to diagnose primary prostate cancer. A systematic literature search was performed up to December 2021. Quality analyses were conducted using the QUADAS-2 tool. The reference standard was whole-mount prostatectomy or prostate biopsy. Statistical analysis involved the pooling of the reported diagnostic performances of each modality, and differences in per-patient and per-lesion analysis were compared using a Fisher’s exact test. Ten articles were included in the meta-analysis. At a per-patient level, the pooled values of sensitivity, specificity, and area under the curve (AUC) for mpMRI and PSMA PET/CT were 0.87 (95% CI: 0.83−0.91) vs. 0.93 (95% CI: 0.90−0.96, p < 0.01); 0.47 (95% CI: 0.23−0.71) vs. 0.54 (95% CI: 0.23−0.84, p > 0.05); and 0.84 vs. 0.91, respectively. At a per-lesion level, the pooled sensitivity, specificity, and AUC value for mpMRI and PSMA PET/CT were lower, at 0.63 (95% CI: 0.52−0.74) vs. 0.79 (95% CI: 0.62−0.92, p < 0.001); 0.88 (95% CI: 0.81−0.95) vs. 0.71 (95% CI: 0.47−0.90, p < 0.05); and 0.83 vs. 0.84, respectively. High heterogeneity was observed between studies. PSMA PET/CT may better confirm the presence of prostate cancer than mpMRI. However, both modalities appear comparable in determining the localisation of the lesions.

The accurate segregation of sister chromatids is complex, and errors that arise throughout this process can drive chromosomal instability and tumorigenesis. We recently showed that methylglyoxal (MGO), a glycolytic by-product, can cause chromosome missegregation events in lymphocytes. However, the underlying mechanisms of this were not explored. Therefore, in this study, we utilised shotgun proteomics to identify MGO-modified proteins, and label-free quantitation to measure changes in protein abundance following exposure to MGO. We identified numerous mitotic proteins that were modified by MGO, including those involved in the separation and cohesion of sister chromatids. Furthermore, the protein abundance of Securin, an inhibitor of sister chromatid separation, was increased following treatment with MGO. Cytological examination of chromosome spreads showed MGO prevented sister chromatid separation, which was associated with the formation of complex nuclear anomalies. Therefore, results from this study suggest MGO may drive chromosomal instability by preventing sister chromatid separation.

Type 2 diabetes (T2D) is associated with elevated frequencies of micronuclei (MNi) and other DNA damage biomarkers. Interestingly, individuals with T2D are more likely to be deficient in micronutrients (folic acid, pyridoxal-phosphate, cobalamin) that play key roles in one-carbon metabolism and maintaining genomic integrity. Furthermore, it has recently been shown that deficiencies in these nutrients, in particular folic acid leaves cells susceptible to glucose-induced DNA damage. Therefore, we sought to investigate if the B lymphoblastoid WIL2-NS cell line cultured under folic acid-deficient conditions was more sensitive to DNA damage induced by glucose, or the reactive glycolytic byproduct methylglyoxal (MGO) and subsequent advanced glycation endproduct formation. Here, we show that only WIL2-NS cultured under folic acid-deficient conditions (23 nmol/l) experience an increase in MNi frequency when exposed to high concentrations of glucose (45 mmol/l) or MGO (100 µmol/l). Furthermore, we showed aminoguanidine, a well-validated MGO and free radical scavenger was able to prevent further MNi formation in folic acid-deficient cells exposed to high glucose, which may be due to a reduction in MGO-induced oxidative stress. Interestingly, we also observed an increase in MGO and other dicarbonyl stress biomarkers in folic acid-deficient cells, irrespective of glucose concentrations. Overall, our evidence shows that folic acid-deficient WIL2-NS cells are more susceptible to glucose and/or MGO-induced MNi formation. These results suggest that individuals with T2D experiencing hyperglycemia and folic acid deficiency may be at higher risk of chromosomal instability., (© The Author(s) 2022. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Methylglyoxal (MGO) is a highly reactive cellular metabolite that glycates lysine and arginine residues to form post-translational modifications known as advanced glycation end products. Because of their low abundance and low stoichiometry, few studies have reported their occurrence and site-specific locations in proteins. Proteomic analysis of WIL2-NS B lymphoblastoid cells in the absence and presence of exogenous MGO was conducted to investigate the extent of MGO modifications. We found over 500 MGO modified proteins, revealing an over-representation of these modifications on many glycolytic enzymes, as well as ribosomal and spliceosome proteins. Moreover, MGO modifications were observed on the active site residues of glycolytic enzymes that could alter their activity. We similarly observed modification of glycolytic enzymes across several epithelial cell lines and peripheral blood lymphocytes, with modification of fructose bisphosphate aldolase being observed in all samples. These results indicate that glycolytic proteins could be particularly prone to the formation of MGO adducts.

Objective: We designed, prototyped, and tested a system that measures the viscoelastic response of tissue using nondestructive mechanical probing, with the goal of aiding clinical providers during epidural needle placement. This system is meant to alert clinicians when an epidural needle is about to strike bone during insertion. Methods: During needle insertion, the system periodically mechanically stimulates and collects viscoelastic response information data from the tissue at the needle's tip using an intra-needle probe. A machine-learning algorithm detects when the needle is close to bone using the series of observed stimulations. Results: Tests run on ex vivo pig spine show that the system can reliably determine if the needle is pointed at and within 3 mm of bone. Conclusion: Our technique can successfully differentiate materials at and in front of the needle's tip. However, it does not provide the 5 mm of forewarning that we believe would be necessary for use in clinical epidural needle placement. The technique may be of use in other applications requiring tissue differentiation during needle placement or in the intended application with further technical advances. Clinical and Translational Impact Statement: This Early/Pre-Clinical Research evaluates the feasibility of a method for helping clinical providers receive feedback during epidural needle insertion-thereby reducing complication rates-without significant alterations from current workflow.

Non-invasive promotion of myogenic regulatory factors (MRFs), through photobiomodulation therapy (PBMT), may be a viable method of facilitating skeletal muscle regeneration post-injury, given the importance of MRF in skeletal muscle regeneration. The aim of this systematic review was to collate current evidence, identifying key themes and changes in expression of MRF in in vivo models. Web of Science, PubMed, Scopus and Cochrane databases were systematically searched and identified 1459 studies, of which 10 met the inclusion criteria. Myogenic determination factor was most consistently regulated in response to PBMT treatment, and the expression of remaining MRFs was heterogenous. All studies exhibited a high risk of bias, primarily due to lack of blinding in PBMT application and MRF analysis. Our review suggests that the current evidence base for MRF expression from PBMT is highly variable. Future research should focus on developing a robust methodology for determining the effect of laser therapy on MRF expression, as well as long-term assessment of skeletal muscle regeneration., (© 2021 The Authors. Journal of Biophotonics published by Wiley-VCH GmbH.)

Evaluating consumption estimates for lipophilic drugs in wastewater has proven to be a challenge. A common feature for these compounds is that they are excreted in faeces and in conjugated form in urine. Limited research with no obvious experimental evidence has been conducted to investigate the degree to which faecal-bound chemical markers contribute towards mass loads in wastewater. Cannabis chemical markers, known as phytocannabinoids, have been suggested in literature to fall into this category. In this study, cannabis users (n = 9) and non-cannabis users (n = 5) were recruited and provided faecal and urine samples after using the substance. The common chemical markers of cannabis consumption, 11-nor-9-carboxy-Δ 9 -tetrahydrocannabinol (THC-COOH), 11-hydroxy-Δ 9 -tetrahydrocannabinol (THC-OH), Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), were investigated. An extraction method was developed for the cannabis chemical markers in faecal matter and urine and analysis was performed by liquid chromatography-mass spectrometry. Participant samples were used to establish adsorption and desorption dissolution kinetics models and to assess the equilibrium between faeces and water for these compounds. Equilibration between phases were found to be fast (<5 min). THC-COOH, which is the primary metabolite used in wastewater studies, partitioned ~40% in water while the less polar metabolite and CBD remained largely associated with the particulate fraction. Faecal loads of both cannabis users and non-users affected the total measured amounts of cannabinoids in the aqueous phase. The implications for wastewater monitoring of lipophilic substances are discussed., Competing Interests: Declaration of competing interest For the submission our manuscript entitled ‘Partitioning of phytocannabinoids between faeces and water – implications for wastewater-based epidemiology’ to the Journal of Science of the Total Environment. We here by acknowledge the following., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Multiparametric magnetic resonance imaging (mpMRI) has improved the triage of men with suspected prostate cancer, through precision prebiopsy identification of clinically significant disease. While multiple important characteristics, including tumour grade and size have been shown to affect conspicuity on mpMRI, tumour location and association with mpMRI visibility is an underexplored facet of this field. Therefore, the objective of this systematic review and meta-analysis is to collate the extant evidence comparing MRI performance between different locations within the prostate in men with existing or suspected prostate cancer. This review will help clarify mechanisms that underpin whether a tumour is visible, and the prognostic implications of our findings., Methods and Analysis: The databases MEDLINE, PubMed, Embase and Cochrane will be systematically searched for relevant studies. Eligible studies will be full-text English-language articles that examine the effect of zonal location on mpMRI conspicuity. Two reviewers will perform study selection, data extraction and quality assessment. A third reviewer will be involved if consensus is not achieved. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will inform the methodology and reporting of the review. Study bias will be assessed using a modified Newcastle-Ottawa scale. A thematic approach will be used to synthesise key location-based factors associated with mpMRI conspicuity. A meta-analysis will be conducted to form a pooled value of the sensitivity and specificity of mpMRI at different tumour locations., Ethics and Dissemination: Ethical approval is not required as it is a protocol for a systematic review. Findings will be disseminated through peer-reviewed publications and conference presentations., Prospero Registration Number: CRD42021228087., Competing Interests: Competing interests: JMN received funding from the MRC. BSSS received funding from the Rosetrees Trust. HCW received funding from PCUK, the Urology Foundation and the Rosetrees Trust. AK, AF and ME have stock interest in Nuada Medical. ME received funding from NIHR-i4i, MRC, Sonacare, Trod Medical, Cancer Vaccine Institute and Sophiris Biocorp for trials in prostate cancer. ME is a medical consultant to Sonacare, Sophiris Biocorp, Steba Biotech, GSK, Exact Imaging and Profound Medical. Travel allowance was previously provided from Sanofi Aventis, Astellas, GSK and Sonacare. ME is a proctor for HIFU with Sonacare Inc and paid for training other surgeons in this procedure., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Advanced glycation end products (AGEs) are formed via non-enzymatic reactions between amino groups of proteins and the carbonyl groups of reducing sugars. Previous studies have shown that highly glycated albumin prepared using a glucose-bovine serum albumin (Glu-BSA) model system incubated at 60°C for 6 weeks induces genotoxicity in WIL2-NS cells at 9 days of exposure measured by the cytokinesis-block micronucleus cytome (CBMNcyt) assay. However, this AGE model system is not physiologically relevant as normal body temperature is 37°C and the degree of glycation may exceed the extent of albumin modification in vivo. We hypothesised that the incubation temperature and purification method used in these studies may cause changes to the chemical profile of the glycated albumin and may influence the extent of genotoxicity observed at 3, 6 and 9 days of exposure. We prepared AGEs generated using Glu-BSA model systems incubated at 60°C or 37°C purified using trichloroacetic acid (TCA) precipitation or ultrafiltration (UF) and compared their chemical profile (glycation, oxidation, and aggregation) and genotoxicity in WIL2-NS cells using the CBMNcyt assay after 3, 6 and 9 days of exposure. The number of micronuclei (MNi) was significantly higher for cells treated with Glu-BSA incubated at 60°C and purified via TCA (12 ± 1 MNi/1000 binucleated cells) compared to Glu-BSA incubated at 37°C and purified using UF (6 ± 1 MNi/1000 binucleated cells) after 9 days (P < 0.0001). The increase in genotoxicity observed could be explained by a higher level of protein glycation, oxidation, and aggregation of the Glu-BSA model system incubated at 60°C relative to 37°C. This study highlighted that the incubation temperature, purification method and cell exposure time are important variables to consider when generating AGEs in vitro and will enable future studies to better reflect in vivo situations of albumin glycation., (© The Author(s) 2021. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Xenobiotic cannabinoids (phyto and synthetic) are highly lipophilic compounds and have been shown to accumulate within the particulate fraction of wastewater. Limited research has been conducted to investigate the occurrence of cannabinoids in sewage sludge and/or biosolids. The analysis of excreted cannabinoids from sewage sludge or biosolids can provide information about community health, as well as potentially long-term environmental impacts. In this study, a liquid-liquid extraction method was developed for the extraction and detection method for 50 cannabinoids by liquid chromatography-mass spectrometry, including the cannabis urinary biomarker 11-nor-9-carboxy-Δ 9 -tetrahydrocannabinol (THC-COOH), Δ 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), and a variety of different generation synthetic cannabinoids and their respective metabolites. Method validation assessed criteria including linearity, selectivity, recovery, and matrix effects. The method was applied to samples collected from a conventional activated sludge reactor treatment facility from various stages of the treatment process. Three cannabinoids were abundant in primary sludge including THC, THC-COOH, and CBD, where THC was the most ubiquitous with concentrations up to 3200 μg kg -1 . Only THC and THC-COOH were detectable in aged biosolids. The detection of some cannabinoids in biosolids demonstrated that these compounds are stable throughout the treatment process., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Immune checkpoint therapy (ICT) provides substantial clinical benefits to cancer patients, but a large proportion of cancers do not respond to ICT. To date, the genomic underpinnings of primary resistance to ICT remain elusive. Here, we performed immunogenomic analysis of data from TCGA and clinical trials of anti-PD-1/PD-L1 therapy, with a particular focus on homozygous deletion of 9p21.3 (9p21 loss), one of the most frequent genomic defects occurring in ~13% of all cancers. We demonstrate that 9p21 loss confers "cold" tumor-immune phenotypes, characterized by reduced abundance of tumor-infiltrating leukocytes (TILs), particularly, T/B/NK cells, altered spatial TILs patterns, diminished immune cell trafficking/activation, decreased rate of PD-L1 positivity, along with activation of immunosuppressive signaling. Notably, patients with 9p21 loss exhibited significantly lower response rates to ICT and worse outcomes, which were corroborated in eight ICT trials of >1,000 patients. Further, 9p21 loss synergizes with PD-L1/TMB for patient stratification. A "response score" was derived by incorporating 9p21 loss, PD-L1 expression and TMB levels in pre-treatment tumors, which outperforms PD-L1, TMB, and their combination in identifying patients with high likelihood of achieving sustained response from otherwise non-responders. Moreover, we describe potential druggable targets in 9p21-loss tumors, which could be exploited to design rational therapeutic interventions., (© 2021. The Author(s).)

Objective: This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways., Methods: We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed., Results: Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10 -17 , odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37-1.66) and rs4519530 (p = 6.98 × 10 -17 , OR = 1.47, 95% CI = 1.34-1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10 -8 , OR = 1.36, 95% CI = 1.22-1.52), and rs11153082 (p = 1.85 × 10 -8 , OR = 1.30, 95% CI = 1.19-1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache., Interpretation: We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193-202., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Aim: To assess the effects of social distancing and social isolation policies triggered by COVID-19 on alcohol consumption using wastewater analysis in Adelaide, South Australia., Design: Longitudinal quantitative analysis of influent wastewater data for alcohol concentration., Setting: Adelaide, South Australia., Participants: Wastewater catchment area representative of 1.1 million inhabitants., Measurements: Twenty-four hour composite influent wastewater samples were collected from four wastewater treatment plants in Adelaide, South Australia for 7 consecutive days (Wednesday-Tuesday) every 2 months from April 2016-April 2020. The alcohol metabolite ethyl sulfate was measured in samples using chromatography-tandem mass spectrometry. Data were population-weighted adjusted with consumption expressed as standard drinks/day/1000 people. Weekly consumption and weekend to mid-week consumption ratios were analysed to identify changes in weekday alcohol use pattern., Findings: Estimated weekend alcohol consumption was significantly lower (698 standard drinks/day/1000 people) after self-isolation measures were enforced in April 2020 compared with the preceding sampling period in February 2020 (1047 standard drinks/day/1000 people), P < 0.05. Weekend to midweek consumption ratio was 12% lower than the average ratio compared with all previous sampling periods. April 2020 recorded the lowest alcohol consumption relative to April in previous years, dating back to 2016., Conclusions: Wastewater analysis suggests that introduction of social distancing and isolation policies triggered by COVID-19 in Adelaide, South Australia, was associated with a decrease in population-level weekend alcohol consumption., (© 2020 Society for the Study of Addiction.)

Recent developments in sequencing the cancer genome have provided the first in-depth mapping of structural variants (SV) across 38 tumour types. Sixteen signatures of structural variants have been proposed which broadly characterise the variation seen across cancer types. One signature shows increased duplications and deletions at fragile sites, with little association with the typical DNA repair defects. We discuss how, for many of these fragile sites, the clinical impacts are yet to be explored. One example is NAALADL2, one of the most frequently altered fragile sites in the cancer genome. The copy-number variations (CNVs) which occur at fragile sites, such as NAALADL2, may span many genes without typical DNA repair defects and could have a large impact on cell signalling.

Introduction: There is an increasing body of evidence to suggest that visibility of prostate cancer on magnetic resonance (MRI) may be related to likelihood of adverse pathological outcomes. Biochemical recurrence (BCR) after radical prostatectomy remains a significant clinical challenge and a means of predicting likelihood of this prior to surgery could inform treatment choice. It appears that MRI could be a potential candidate strategy for BCR prediction, and as such, there is a need to review extant literature on the prognostic capability of MRI. Here, we describe a protocol for a systematic review and meta-analysis of the utility of biparametric MRI (bpMRI) and multiparametric MRI (mpMRI) in predicting BCR following radical prostatectomy for prostate cancer treatment., Methods and Analysis: PubMed, MEDLINE, Embase and Cochrane databases will be searched and screening will be guided by the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. In order to meet the inclusion criteria, papers must be English-language articles involving patients who have had bpMRI or mpMRI for suspected prostate cancer and have undergone radical prostatectomy as definitive therapy. Patients must have had prostate-specific antigen monitoring before and after surgery. All relevant papers published from July 1977 to October 2020 will be eligible for inclusion. The Newcastle-Ottawa score will be used to determine the quality and bias of the studies. This protocol is written in-line with the PRISMA protocol 2015 checklist., Ethics and Dissemination: There are no relevant ethical concerns. Dissemination of this protocol will be via peer-reviewed journals as well as national and international conferences., Prospero Registration Number: CRD42020206074., Competing Interests: Competing interests: Norris receives funding from the MRC. Simpson receives funding from the Rosetrees Trust. Whitaker receives funding from the PCUK, the Urology Foundation and Rosetrees Trust. Kirkham, Freeman and Emberton have stock interest in Nuada Medical Ltd. Emberton acts as a consultant, trainer and proctor to Sonatherm Inc; Angiodynamics Inc; Exact Imaging Inc., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Objectives : To assess the clinical outcomes of mpMRI before biopsy and evaluate the space remaining for novel biomarkers. Methods: The INNOVATE study was set up to evaluate the validity of novel fluidic biomarkers in men with suspected prostate cancer who undergo pre-biopsy mpMRI. We report the characteristics of this clinical cohort, the distribution of clinical serum biomarkers, PSA and PSA density (PSAD), and compare the mpMRI Likert scoring system to the Prostate Imaging-Reporting and Data System v2.1 (PI-RADS) in men undergoing biopsy. Results : 340 men underwent mpMRI to evaluate suspected prostate cancer. 193/340 (57%) men had subsequent MRI-targeted prostate biopsy. Clinically significant prostate cancer (csigPCa), i.e., overall Gleason ≥ 3 + 4 of any length OR maximum cancer core length (MCCL) ≥4 mm of any grade including any 3 + 3, was found in 96/195 (49%) of biopsied patients. Median PSA (and PSAD) was 4.7 (0.20), 8.0 (0.17), and 9.7 (0.31) ng/mL (ng/mL/mL) in mpMRI scored Likert 3,4,5 respectively for men with csigPCa on biopsy. The space for novel biomarkers was shown to be within the group of men with mpMRI scored Likert3 (178/340) and 4 (70/350), in whom an additional of 40% (70/178) men with mpMRI-scored Likert3, and 37% (26/70) Likert4 could have been spared biopsy. PSAD is already considered clinically in this cohort to risk stratify patients for biopsy, despite this 67% (55/82) of men with mpMRI-scored Likert3, and 55% (36/65) Likert4, who underwent prostate biopsy had a PSAD below a clinical threshold of 0.15 (or 0.12 for men aged <50 years). Different thresholds of PSA and PSAD were assessed in mpMRI-scored Likert4 to predict csigPCa on biopsy, to achieve false negative levels of ≤5% the proportion of patients whom who test as above the threshold were unsuitably high at 86 and 92% of patients for PSAD and PSA respectively. When PSA was re tested in a sub cohort of men repeated PSAD showed its poor reproducibility with 43% (41/95) of patients being reclassified. After PI-RADS rescoring of the biopsied lesions, 66% (54/82) of the Likert3 lesions received a different PI-RADS score. Conclusions : The addition of simple biochemical and radiological markers (Likert and PSAD) facilitate the streamlining of the mpMRI-diagnostic pathway for suspected prostate cancer but there remains scope for improvement, in the introduction of novel biomarkers for risk assessment in Likert3 and 4 patients, future application of novel biomarkers tested in a Likert cohort would also require re-optimization around Likert3/PI-RADS2, as well as reproducibility testing.

Wastewater-based epidemiology studies use catchment populations to normalise chemical marker mass loads in 24-h composite wastewater samples. However, one of the biggest uncertainties within the field is the accuracy of the population used. A population marker in wastewater may significantly reduce the uncertainty. This study evaluated the catecholamine metabolites - homovanillic acid (HVA) and vanillylmandelic acid (VMA) - as potential population biomarkers. Influent wastewater 24-h composite samples were collected from 38 wastewater catchments from around Australia (representing ~33% of Australia's population), extracted and analysed by liquid chromatography tandem mass spectrometry. Measured mass loads were compared to population sizes determined by mapping catchment maps against high-resolution census data. Both biomarkers correlated with coefficient of determinations (r 2 ) of 0.908 and 0.922 for HVA and VMA, respectively. From the regression analysis, a slope (i.e. the daily per-capita excretion) of 1.241 and 1.067 mg.day -1 .person -1 was obtained for HVA and VMA, respectively. The mass load ratio between VMA:HVA were very similar to that reported in literature for urinary analysis among all catchments. Overall, this study provided further evidence that catecholamine metabolites are suitable candidates as population biomarkers for future studies., Competing Interests: Declaration of competing interest The authorshave no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript, (Copyright © 2020 Elsevier B.V. All rights reserved.)