Web-Based Forums for People Experiencing Substance Use or Gambling Disorders: Scoping Review.

BACKGROUND: For people experiencing substance use or gambling disorders, web-based peer-supported forums are a space where they can share their experiences, gather around a collective goal, and find mutual support. Web-based peer support can help to overcome barriers to attending face-to-face meetings by enabling people experiencing addiction to seek support beyond their physical location and with the benefit of anonymity if desired. Understanding who participates in web-based peer-supported forums (and how), and the principles underpinning forums, can also assist those interested in designing or implementing similar platforms. OBJECTIVE: This study aims to review the literature on how people experiencing substance use or gambling disorders, and their family, friends, and supporters, use and participate in web-based peer-supported forums. Specifically, we asked the following research questions: (1) What are the characteristics of people who use web-based peer-supported substance use or gambling-focused forums? (2) How do people participate in web-based peer-supported forums? (3) What are the key principles reportedly underpinning the web-based peer-supported forums? (4) What are the reported outcomes of web-based peer-supported forums? METHODS: Inclusion criteria for our scoping review were peer-reviewed primary studies reporting on web-based addiction forums for adults and available in English. A primary search of 10 databases occurred in June 2021, with 2 subsequent citation searches of included studies in September 2022 and February 2024. RESULTS: Of the 14 included studies, the majority of web-based peer-supported forums reported were aimed specifically for, or largely used by, people experiencing alcohol problems. Results from the 9 studies that did report demographic data suggest forum users were typically women, aged between 40 years and early 50 years. Participation in web-based peer-supported forums was reported quantitatively and qualitatively. The forums reportedly were underpinned by a range of key principles, mostly mutual help approaches and recovery identity formation. Only 3 included studies reported on outcomes for forum users. CONCLUSIONS: Web-based peer-supported forums are used by people experiencing addiction in a number of ways, to share information and experiences, and give and receive support. Seeking web-based support offers an alternative approach to traditional face-to-face support options, and may reduce some barriers to engaging in peer support.

Rotation from methadone to buprenorphine using a micro-dosing regime in patients with opioid use disorder and serious mental illness: A case series.

INTRODUCTION: Inducting buprenorphine from methadone has traditionally involved initial opioid withdrawal, with risk of mental state deterioration in patients with serious mental illness (SMI). Micro-dosing of buprenorphine, with small incremental doses, is a novel off-label approach to transitioning from methadone and does not require a period of methadone abstinence. Given the limited literature about buprenorphine microdosing, we aimed to evaluate the feasibility and safety of inducting buprenorphine in a series of patients on methadone with SMI. METHODS: For this retrospective case series, we reviewed the records of 16 patients with SMI at a Melbourne addiction treatment centre, from January 2021 to July 2022, who transitioned via micro-dosing, from high-dose methadone (>30 mg) to buprenorphine and depot-buprenorphine. Psychiatric diagnoses, mental state, other substance withdrawal, transfer success, transition time, opioid withdrawal symptoms and overall patient experience were collected via objective and subjective reporting. RESULTS: Methadone to buprenorphine transfer was completed by 88% of patients. Mental health measures remained stable with the exception of mildly increased anxiety. Median transfer time was 6.5 days for inpatients, 9 days for mixed setting and 10 days for outpatients. Most patients (93%) rated their experience 'manageable' reporting mild withdrawal symptoms. One patient met study criteria for precipitated withdrawal. DISCUSSION AND CONCLUSIONS: This retrospective case series provides evidence that the use of a micro-dosing buprenorphine induction for methadone to buprenorphine transitions, including to depot-buprenorphine, has negligible risk, is tolerated by patients with SMI and is unlikely to precipitate an exacerbation of their mental illness.

Quantifying combined effects of colistin and ciprofloxacin against Escherichia coli in an in silico pharmacokinetic-pharmacodynamic model.

Co-administering a low dose of colistin (CST) with ciprofloxacin (CIP) may improve the antibacterial effect against resistant Escherichia coli, offering an acceptable benefit-risk balance. This study aimed to quantify the interaction between ciprofloxacin and colistin in an in silico pharmacokinetic-pharmacodynamic model from in vitro static time-kill experiments (using strains with minimum inhibitory concentrations, MICCIP 0.023-1 mg/L and MICCST 0.5-0.75 mg/L). It was also sought to demonstrate an approach of simulating concentrations at the site of infection with population pharmacokinetic and whole-body physiologically based pharmacokinetic models to explore the clinical value of the combination when facing more resistant strains (using extrapolated strains with lower susceptibility). The combined effect in the final model was described as the sum of individual drug effects with a change in drug potency: for ciprofloxacin, concentration at half maximum killing rate (EC50) in combination was 160% of the EC50 in monodrug experiments, while for colistin, the change in EC50 was strain-dependent from 54.1% to 119%. The benefit of co-administrating a lower-than-commonly-administrated colistin dose with ciprofloxacin in terms of drug effect in comparison to either monotherapy was predicted in simulated bloodstream infections and pyelonephritis. The study illustrates the value of pharmacokinetic-pharmacodynamic modelling and simulation in streamlining rational development of antibiotic combinations.

Three concurrent mechanisms generate gene copy number variation and transient antibiotic heteroresistance.

Heteroresistance is a medically relevant phenotype where small antibiotic-resistant subpopulations coexist within predominantly susceptible bacterial populations. Heteroresistance reduces treatment efficacy across diverse bacterial species and antibiotic classes, yet its genetic and physiological mechanisms remain poorly understood. Here, we investigated a multi-resistant Klebsiella pneumoniae isolate and identified three primary drivers of gene dosage-dependent heteroresistance for several antibiotic classes: tandem amplification, increased plasmid copy number, and transposition of resistance genes onto cryptic plasmids. All three mechanisms imposed fitness costs and were genetically unstable, leading to fast reversion to susceptibility in the absence of antibiotics. We used a mouse gut colonization model to show that heteroresistance due to elevated resistance-gene dosage can result in antibiotic treatment failures. Importantly, we observed that the three mechanisms are prevalent among Escherichia coli bloodstream isolates. Our findings underscore the necessity for treatment strategies that address the complex interplay between plasmids, resistance cassettes, and transposons in bacterial populations.

The impact of the COVID-19 pandemic on calls to an alcohol and drug helpline in Victoria, Australia, for alcohol, methamphetamine and cannabis use concerns.

INTRODUCTION: Helplines are often the first contact with the alcohol and other drug (AOD) treatment system. We examined call data from an AOD helpline in Victoria, Australia, to explore the association between COVID-19 lockdown measures and frequency of calls. METHODS: This was a retrospective analysis of AOD helpline data collected between January 2018 and September 2020, for alcohol, methamphetamine and cannabis use concerns. Linear and logistic regression analyses examined differences in pre-COVID-19 (January 2018 to March 2020) and during COVID-19 (March 2020 to September 2020) caller characteristics, and interrupted time-series analyses examined changes in frequency of calls relative to lockdown measures. RESULTS: There were 14,340 calls for alcohol (n = 10,196, 71.10%), methamphetamine (n = 2522, 17.59%) and cannabis (n = 1622, 11.31%). Relative to pre-COVID-19, during COVID-19 there was an increase in the rate of change over time in number of alcohol calls (b = 0.39), increase in first-time alcohol callers (OR = 1.29), and reduction in first-time methamphetamine callers (OR = 0.80). During COVID-19, alcohol callers had lower Socio-Economic Indicators for Areas scores (b = -3.06) and cannabis callers were younger (b = -2.07). During COVID-19, there were reductions in alcohol calls involving counselling/support (OR = 0.87) and information provision (OR = 0.87), cannabis calls involving information provision (OR = 0.71) and methamphetamine calls involving referral (OR = 0.80). DISCUSSION AND CONCLUSIONS: In the first 6 months of the pandemic, frequency of alcohol-related calls increased over time, and first-time alcohol-related callers increased. The number of calls for cannabis and methamphetamine remained stable. Results suggest the helpline was not used to its full capacity, suggesting a role for further promotion during times of crises.

Suppression of the Escherichia coli rnpA49 conditionally lethal phenotype by different compensatory mutations.

RNase P is an essential enzyme found across all domains of life that is responsible for the 5'-end maturation of precursor tRNAs. For decades, numerous studies have sought to elucidate the mechanisms and biochemistry governing RNase P function. However, much remains unknown about the regulation of RNase P expression, the turnover and degradation of the enzyme, and the mechanisms underlying the phenotypes and complementation of specific RNase P mutations, especially in the model bacterium, Escherichia coli In E. coli, the temperature-sensitive (ts) rnpA49 mutation in the protein subunit of RNase P has arguably been one of the most well-studied mutations for examining the enzyme's activity in vivo. Here, we report for the first time naturally occurring temperature-resistant suppressor mutations of E. coli strains carrying the rnpA49 allele. We find that rnpA49 strains can partially compensate the ts defect via gene amplifications of either RNase P subunit (rnpA49 or rnpB) or by the acquisition of loss-of-function mutations in Lon protease or RNase R. Our results agree with previous plasmid overexpression and gene deletion complementation studies, and importantly suggest the involvement of Lon protease in the degradation and/or regulatory pathway(s) of the mutant protein subunit of RNase P. This work offers novel insights into the behavior and complementation of the rnpA49 allele in vivo and provides direction for follow-up studies regarding RNase P regulation and turnover in E. coli.

The dynamics of more-than-human care in depot buprenorphine treatment: A new materialist analysis of Australian patients' experiences.

BACKGROUND: Long-acting injectable depot buprenorphine has become an important treatment option for the management of opioid dependence. However, little is known about patients' experiences of depot buprenorphine and its embodied effects. This qualitative study aims to explore patients' experiences of depot buprenorphine treatment, including how it feels within the body, experiences of dosing cycles across time, and how this form of treatment relies on wider ecologies of care beyond the clinical encounter. METHODS: Participants were recruited from sites in Sydney, regional New South Wales, and Melbourne, Victoria, Australia. Thirty participants (16 men, 14 women) participated in semi-structured interviews. Participants had histories of both heroin and prescription opioid consumption, and opioid agonist therapy including daily dosing of buprenorphine and methadone. RESULTS: Our analysis illuminates: (1) how patients' expectations and concerns about treatment are linked to past embodied experiences of withdrawal and uncertainty about the effectiveness of depot buprenorphine; (2) the diverse meanings patients attribute to the depot buprenorphine substrate 'under the skin'; and, (3) how depot buprenorphine is embedded within wider ecologies of care, such as counselling and social supports. CONCLUSION: Our analysis destabilises commonplace assumptions about a linear, causal relationship between the pharmacological action of depot buprenorphine and experiences of treatment. Instead, it highlights patients' variable experiences of depot buprenorphine, tracing the everyday practices, embodied feelings, expectations and wider networks of care that shape patient experiences. We conclude with some reflections on the implications of our analysis for alcohol and other drug treatment, specifically how they might inform the design of client education materials and care.

Theoretical considerations and empirical predictions of the pharmaco- and population dynamics of heteroresistance.

Antibiotics are considered one of the most important contributions to clinical medicine in the last century. Due to the use and overuse of these drugs, there have been increasing frequencies of infections with resistant pathogens. One form of resistance, heteroresistance, is particularly problematic; pathogens appear sensitive to a drug by common susceptibility tests. However, upon exposure to the antibiotic, resistance rapidly ascends, and treatment fails. To quantitatively explore the processes contributing to the emergence and ascent of resistance during treatment and the waning of resistance following cessation of treatment, we develop two distinct mathematical and computer-simulation models of heteroresistance. In our analysis of the properties of these models, we consider the factors that determine the response to antibiotic-mediated selection. In one model, heteroresistance is progressive, with each resistant state sequentially generating a higher resistance level. In the other model, heteroresistance is non-progressive, with a susceptible population directly generating populations with different resistance levels. The conditions where resistance will ascend in the progressive model are narrower than those of the non-progressive model. The rates of reversion from the resistant to the sensitive states are critically dependent on the transition rates and the fitness cost of resistance. Our results demonstrate that the standard test used to identify heteroresistance is insufficient. The predictions of our models are consistent with empirical results. Our results demand a reevaluation of the definition and criteria employed to identify heteroresistance. We recommend that the definition of heteroresistance should include a consideration of the rate of return to susceptibility.

Heteroresistance to piperacillin/tazobactam in Klebsiella pneumoniae is mediated by increased copy number of multiple ß-lactamase genes.

Background: Piperacillin/tazobactam is a ß-lactam/ß-lactamase inhibitor combination with a broad spectrum of activity that is often used as empirical and/or targeted therapy among hospitalized patients. Heteroresistance (HR) is a form of antibiotic resistance in which a minority population of resistant cells coexists with a majority susceptible population that has been found to be a cause of antibiotic treatment failure in murine models. Objectives: To determine the prevalence of HR and mechanisms of HR to piperacillin/tazobactam among Klebsiella pneumoniae bloodstream infection (BSI) isolates. Materials: From July 2018 to June 2021, K. pneumoniae piperacillin/tazobactam-susceptible BSI isolates were collected from two tertiary hospitals in Atlanta, GA, USA. Only first isolates from each patient per calendar year were included. Population analysis profiling (PAP) and WGS were performed to identify HR and its mechanisms. Results: Among 423 K. pneumoniae BSI isolates collected during the study period, 6% (25/423) were found to be HR with a subpopulation surviving above the breakpoint. WGS of HR isolates grown in the presence of piperacillin/tazobactam at concentrations 8-fold that of the MIC revealed copy number changes of plasmid-located ß-lactamase genes blaCTX-M-15, blaSHV33, blaOXA-1 and blaTEM-1 by tandem gene amplification or plasmid copy number increase. Conclusions: Prevalence of HR to piperacillin/tazobactam among bloodstream isolates was substantial. The HR phenotype appears to be caused by tandem amplification of ß-lactamase genes found on plasmids or plasmid copy number increase. This raises the possibility of dissemination of HR through horizontal gene transfer and requires further study.

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

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

Antibiotic resistance begets more resistance: chromosomal resistance mutations mitigate fitness costs conferred by multi-resistant clinical plasmids.

Plasmids are the primary vectors of horizontal transfer of antibiotic resistance genes among bacteria. Previous studies have shown that the spread and maintenance of plasmids among bacterial populations depend on the genetic makeup of both the plasmid and the host bacterium. Antibiotic resistance can also be acquired through mutations in the bacterial chromosome, which not only confer resistance but also result in changes in bacterial physiology and typically a reduction in fitness. However, it is unclear whether chromosomal resistance mutations affect the interaction between plasmids and the host bacteria. To address this question, we introduced 13 clinical plasmids into a susceptible Escherichia coli strain and three different congenic mutants that were resistant to nitrofurantoin (ΔnfsAB), ciprofloxacin (gyrA, S83L), and streptomycin (rpsL, K42N) and determined how the plasmids affected the exponential growth rates of the host in glucose minimal media. We find that though plasmids confer costs on the susceptible strains, those costs are fully mitigated in the three resistant mutants. In several cases, this results in a competitive advantage of the resistant strains over the susceptible strain when both carry the same plasmid and are grown in the absence of antibiotics. Our results suggest that bacteria carrying chromosomal mutations for antibiotic resistance could be a better reservoir for resistance plasmids, thereby driving the evolution of multi-drug resistance.IMPORTANCEPlasmids have led to the rampant spread of antibiotic resistance genes globally. Plasmids often carry antibiotic resistance genes and other genes needed for its maintenance and spread, which typically confer a fitness cost on the host cell observed as a reduced growth rate. Resistance is also acquired via chromosomal mutations, and similar to plasmids they also reduce bacterial fitness. However, we do not know whether resistance mutations affect the bacterial ability to carry plasmids. Here, we introduced 13 multi-resistant clinical plasmids into a susceptible and three different resistant E. coli strains and found that most of these plasmids do confer fitness cost on susceptible cells, but these costs disappear in the resistant strains which often lead to fitness advantage for the resistant strains in the absence of antibiotic selection. Our results imply that already resistant bacteria are a more favorable reservoir for multi-resistant plasmids, promoting the ascendance of multi-resistant bacteria.

Bacteria can compensate the fitness costs of amplified resistance genes via a bypass mechanism.

Antibiotic heteroresistance is a phenotype in which a susceptible bacterial population includes a small subpopulation of cells that are more resistant than the main population. Such resistance can arise by tandem amplification of DNA regions containing resistance genes that in single copy are not sufficient to confer resistance. However, tandem amplifications often carry fitness costs, manifested as reduced growth rates. Here, we investigated if and how these fitness costs can be genetically ameliorated. We evolved four clinical isolates of three bacterial species that show heteroresistance to tobramycin, gentamicin and tetracyclines at increasing antibiotic concentrations above the minimal inhibitory concentration (MIC) of the main susceptible population. This led to a rapid enrichment of resistant cells with up to an 80-fold increase in the resistance gene copy number, an increased MIC, and severely reduced growth rates. When further evolved in the presence of antibiotic, these strains acquired compensatory resistance mutations and showed a reduction in copy number while maintaining high-level resistance. A deterministic model indicated that the loss of amplified units was driven mainly by their fitness costs and that the compensatory mutations did not affect the loss rate of the gene amplifications. Our findings suggest that heteroresistance mediated by copy number changes can facilitate and precede the evolution towards stable resistance.

Using ambulance surveillance data to characterise blood-borne viral infection histories among patients presenting with acute alcohol and other drug-related harms.

OBJECTIVE: Preventable transmission of blood-borne viruses (BBV), including human immunodeficiency virus (HIV), hepatitis C virus (HCV) and hepatitis B virus (HBV), continue in at-risk populations, including people who use alcohol and drugs (AODs). To our knowledge, no studies have explored the use of ambulance data for surveillance of AOD harms in patients with BBV infections. METHODS: We used electronic patient care records from the National Ambulance Surveillance System for people who were attended by an ambulance in Victoria, Australia between July 2015 and July 2016 for AOD-related harms, and with identified history of a BBV infection. Descriptive and geospatial analyses explored the epidemiological and psychosocial characteristics of patients for these attendances. RESULTS: The present study included 1832 patients with a history of a BBV infection who required an ambulance for AOD-related harms. Amphetamines were reported in 24.7% of attendances where the patient identified HIV history, and heroin was reported more often for patients with viral hepatitis history (HCV: 19.2%; HBV: 12.7%). Higher proportions of attendances with a viral hepatitis history were observed in patients from the most socially disadvantaged areas. Geospatial analyses revealed higher concentrations of AOD attendances with a BBV history occurring in metropolitan Melbourne. CONCLUSIONS: Our study describes the utility of ambulance data to identify a sub-population of patients with a BBV history and complex medical and social characteristics. Repeat attendances of BBV history patients to paramedics could present an opportunity for ongoing surveillance using ambulance data and possible paramedic intervention, with potential linkage to appropriate BBV services.

Within-species variability of antibiotic interactions in Gram-negative bacteria.

Treatments with antibiotic combinations are becoming increasingly important even though the supposed clinical benefits of combinations are, in many cases, unclear. Here, we systematically examined how several clinically used antibiotics interact and affect the antimicrobial efficacy against five especially problematic Gram-negative pathogens. A total of 232 bacterial isolates were tested against different pairwise antibiotic combinations spanning five classes, and the ability of all combinations in inhibiting growth was quantified. Descriptive statistics, principal component analysis (PCA), and Spearman's rank correlation matrix were used to determine the correlations between the different combinations on interaction outcome. Several important conclusions can be drawn from the 696 examined interactions. Firstly, within a species, the interactions are in general conserved but can be isolate-specific for a given antibiotic combination and can range from antagonistic to synergistic. Secondly, additive and antagonistic interactions are the most common observed across species and antibiotics, with 87.1% of isolate-antibiotic combinations being additive, 11.6% antagonistic, and only 0.3% showing synergy. These findings suggest that to achieve the highest precision and efficacy of combination therapy, not only isolate-specific interaction profiling ought to be routinely performed, in particular to avoid using drug combinations that show antagonistic interaction and an expected associated reduction in efficacy, but also discovering rare and potentially valuable synergistic interactions.IMPORTANCEAntibiotic combinations are often used to treat bacterial infections, which aim to increase treatment efficacy and reduce resistance evolution. Typically, it is assumed that one specific antibiotic combination has the same effect on different isolates of the same species, i.e., the interaction is conserved. Here, we tested this idea by examining how several clinically used antibiotics interact and affect the antimicrobial efficacy against several bacterial pathogens. Our results show that, even though within a species the interactions are often conserved, there are also isolate-specific differences for a given antibiotic combination that can range from antagonistic to synergistic. These findings suggest that isolate-specific interaction profiling ought to be performed in clinical microbiology routine to avoid using antagonistic drug combinations that might reduce treatment efficacy.

Adolescent Suicidal Behaviors During the COVID-19 Pandemic in Australia: Analysis of Acute Harms Assessed via Ambulance Data.

PURPOSE: This study investigated changes in suicidal ideation, attempts, and nonsuicidal self-injury (NSSI)-related ambulance attendances among adolescents during the COVID-19 pandemic. METHODS: An interrupted time series analysis using data from the National Ambulance Surveillance System, a globally unique mental health and suicide surveillance system. Patients aged 12-17 years from the state of Victoria, Australia who were attended by ambulance for suicide attempts, suicide ideation, and NSSI between January 2016 and October 2021 were included. Monthly ambulance attendances during the pre-COVID period (January 2016-March 2020) were compared to those in the peak period of COVID-19 (April 2020-October 2021). RESULTS: There were 20,125 ambulance attendances for suicide ideation, suicide attempt, and NSSI in adolescents over the study period. During the pre-COVID period, the number of suicide ideation, attempts, and NSSI attendances was increasing by 1.1% per month (incidence rate ratio [IRR]:1.011; 95% confidence interval [1.009-1.013], p < .001). There was no change in the rate of all suicide ideation, attempt, and NSSI for all adolescents during the period of COVID-19. However, when disaggregated by gender, there was a 0.7% increase in the monthly rate of attendances for females (IRR: 1.007 [1.001-1.013], p = .029), and a 3.0% decrease for males (IRR: 0.970 [0.964-0.975], p < .001). DISCUSSION: Adolescent female suicide ideation, attempt, and NSSI attendances increased during the COVID-19 period, compared with males in the same time period. These findings suggest tailored intervention strategies may be needed to address the increasing trends of self-harm among young people.

Staphylococcus aureus mutants resistant to the feed-additive monensin show increased virulence and altered purine metabolism.

Ionophores are antibacterial compounds that affect bacterial growth by changing intracellular concentrations of the essential cations, sodium and potassium. They are extensively used in animal husbandry to increase productivity and reduce infectious diseases, but our understanding of the potential for and effects of resistance development to ionophores is poorly known. Thus, given their widespread global usage, it is important to determine the potential negative consequences of ionophore use on human and animal health. In this study, we demonstrate that exposure to the ionophore monensin can select for resistant mutants in the human and animal pathogen Staphylococcus aureus, with a majority of the resistant mutants showing increased growth rates in vitro and/or in mice. Whole-genome sequencing and proteomic analysis of the resistant mutants show that the resistance phenotype is associated with de-repression of de novo purine synthesis, which could be achieved through mutations in different transcriptional regulators including mutations in the gene purR, the repressor of the purine de novo synthesis pathway. This study shows that mutants with reduced susceptibility to the ionophore monensin can be readily selected and highlights an unexplored link between ionophore resistance, purine metabolism, and fitness in pathogenic bacteria.IMPORTANCEThis study demonstrates a novel link between ionophore resistance, purine metabolism, and virulence/fitness in the key human and animal pathogen Staphylococcus aureus. The results show that mutants with reduced susceptibility to the commonly used ionophore monensin can be readily selected and that the reduced susceptibility observed is associated with an increased expression of the de novo purine synthesis pathway. This study increases our understanding of the impact of the use of animal feed additives on both human and veterinary medicine.

High prevalence of heteroresistance in Staphylococcus aureus is caused by a multitude of mutations in core genes.

Heteroresistance (HR) is an enigmatic phenotype where, in a main population of susceptible cells, small subpopulations of resistant cells exist. This is a cause for concern, as this small subpopulation is difficult to detect by standard antibiotic susceptibility tests, and upon antibiotic exposure the resistant subpopulation may increase in frequency and potentially lead to treatment complications or failure. Here, we determined the prevalence and mechanisms of HR for 40 clinical Staphylococcus aureus isolates, against 6 clinically important antibiotics: daptomycin, gentamicin, linezolid, oxacillin, teicoplanin, and vancomycin. High frequencies of HR were observed for gentamicin (69.2%), oxacillin (27%), daptomycin (25.6%), and teicoplanin (15.4%) while none of the isolates showed HR toward linezolid or vancomycin. Point mutations in various chromosomal core genes, including those involved in membrane and peptidoglycan/teichoic acid biosynthesis and transport, tRNA charging, menaquinone and chorismite biosynthesis and cyclic-di-AMP biosynthesis, were the mechanisms responsible for generating the resistant subpopulations. This finding is in contrast to gram-negative bacteria, where increased copy number of bona fide resistance genes via tandem gene amplification is the most prevalent mechanism. This difference can be explained by the observation that S. aureus has a low content of resistance genes and absence of the repeat sequences that allow tandem gene amplification of these genes as compared to gram-negative species.

Opioid-related ambulance attendances during the first 2 years of the COVID-19 pandemic in Victoria, Australia.

BACKGROUND AND AIMS: Public health measures introduced to contain the spread of the SARS-CoV-2 virus likely affected opioid supply and demand, as well as the patterns and contexts of opioid use. We measured opioid-related harms during the first 2 years of COVID-19 restrictions in Victoria, Australia. DESIGN: We adopted an interrupted time series analysis design using interventional autoregressive integrated moving average (ARIMA) models. Opioid-related ambulance attendance data between January 2015 and March 2022 were extracted from the National Ambulance Surveillance System. SETTING: Victoria, Australia. PARTICIPANTS: Patients (≥15 years) attended to by an ambulance for opioid-related harms. MEASUREMENTS: Monthly opioid-related ambulance attendances for three drug types: heroin, prescription opioids and opioid agonist therapy (OAT) medications. FINDINGS: The monthly rate of heroin-related attendances fell by 26% immediately after the introduction of COVID-19 restrictions. A reduced rate of heroin-related attendances was observed during COVID-19 restrictions, resulting in 2578 averted heroin-related attendances. There was no change in the rate of attendances for extra-medical OAT medications or prescription opioids. CONCLUSIONS: Strict COVID-19 restrictions in Victoria, Australia appear to have resulted in a substantial reduction in heroin-related ambulance attendances, perhaps because of border closures and restrictions on movement affecting supply, changing patterns of drug consumption, and efforts to improve access to OAT. Despite policy changes allowing longer OAT prescriptions and an increased number of unsupervised doses, we found no evidence of increased harms related to the extra-medical use of these medications.

Experiences of telehealth among people receiving alcohol and other drug treatment during the COVID-19 pandemic: Implications for future telehealth delivery.

INTRODUCTION: The novel coronavirus (COVID-19) pandemic necessitated the rapid uptake of telehealth to deliver treatment for alcohol and other drug (AOD) concerns. However, little is known about how the move from in-person to telehealth delivery impacted clients' experience of care. This qualitative study aimed to explore experiences of telehealth among people receiving alcohol and other drug treatment during the COVID-19 pandemic, and their preferences regarding future telehealth care. METHODS: Participants were aged 34-66 years (M = 44 years, 60% male) and were recruited from Victorian AOD treatment services and consumer networks. A total of 20 semi-structured interviews were analysed using thematic analysis. RESULTS: Three themes were identified: (i) experiences of the practical impacts of telehealth; (ii) experiences of telehealth interactions; and (iii) preferences for future telehealth. Contextual factors, including location and socioeconomic status, were found to impact clients' ability to access reliable telehealth with sufficient privacy. While telehealth was generally associated with increased treatment engagement (for a typically stigmatised population), participants noted varying effects on the therapeutic alliance. Although in-person treatment was generally favoured, participants often valued telehealth as a modality to provide empathic care during the pandemic. Participants expressed a preference for a hybrid treatment model in the future, in which they could choose a combination of telehealth and in-person services. CONCLUSION: Client and clinician information and training are vital to improve the future delivery of telehealth for AOD treatment.