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Background Trace amine-associated receptor 1 (TAAR1) agonism shows promise for treating psychosis, prompting us to synthesise data from human and non-human studies. Methods We co-produced a living systematic review of controlled studies examining TAAR1 agonists in individuals (with or without psychosis/schizophrenia) and relevant animal models. Two independent reviewers identified studies in multiple electronic databases (until 17.11.2023), extracted data, and assessed risk of bias. Primary outcomes were standardised mean differences (SMD) for overall symptoms in human studies and hyperlocomotion in animal models. We also examined adverse events and neurotransmitter signalling. We synthesised data with random-effects meta-analyses. Results Nine randomised trials provided data for two TAAR1 agonists (ulotaront and ralmitaront), and 15 animal studies for 10 TAAR1 agonists. Ulotaront and ralmitaront demonstrated few differences compared to placebo in improving overall symptoms in adults with acute schizophrenia (N=4 studies, n=1291 participants; SMD=0.15, 95%CI: -0.05, 0.34), and ralmitaront was less efficacious than risperidone (N=1, n=156, SMD=-0.53, 95%CI: -0.86, -0.20). Large placebo response was observed in ulotaront phase-III trials. Limited evidence suggested a relatively benign side-effect profile for TAAR1 agonists, although nausea and sedation were common after a single dose of ulotaront. In animal studies, TAAR1 agonists improved hyperlocomotion compared to control (N=13 studies, k=41 experiments, SMD=1.01, 95%CI: 0.74, 1.27), but seemed less efficacious compared to dopamine D2 receptor antagonists (N=4, k=7, SMD=-0.62, 95%CI: -1.32, 0.08). Limited human and animal data indicated that TAAR1 agonists may regulate presynaptic dopaminergic signalling. Conclusions TAAR1 agonists may be less efficacious than dopamine D2 receptor antagonists already licensed for schizophrenia. The results are preliminary due to the limited number of drugs examined, lack of longer-term data, publication bias, and assay sensitivity concerns in trials associated with large placebo response. Considering their unique mechanism of action, relatively benign side-effect profile and ongoing drug development, further research is warranted. Registration PROSPERO-ID:CRD42023451628.

Background: There is an urgent need to develop more effective and safer antipsychotics beyond dopamine 2 receptor antagonists. An emerging and promising approach is TAAR1 agonism. Therefore, we will conduct a living systematic review and meta-analysis to synthesize and triangulate the evidence from preclinical animal experiments and clinical studies on the efficacy, safety, and underlying mechanism of action of TAAR1 agonism for psychosis. Methods: Independent searches will be conducted in multiple electronic databases to identify clinical and animal experimental studies comparing TAAR1 agonists with licensed antipsychotics or other control conditions in individuals with psychosis or animal models for psychosis, respectively. The primary outcomes will be overall psychotic symptoms and their behavioural proxies in animals. Secondary outcomes will include side effects and neurobiological measures. Two independent reviewers will conduct study selection, data extraction using predefined forms, and risk of bias assessment using suitable tools based on the study design. Ontologies will be developed to facilitate study identification and data extraction. Data from clinical and animal studies will be synthesized separately using random-effects meta-analysis if appropriate, or synthesis without meta-analysis. Study characteristics will be investigated as potential sources of heterogeneity. Confidence in the evidence for each outcome and source of evidence will be evaluated, considering the summary of the association, potential concerns regarding internal and external validity, and reporting biases. When multiple sources of evidence are available for an outcome, an overall conclusion will be drawn in a triangulation meeting involving a multidisciplinary team of experts. We plan trimonthly updates of the review, and any modifications in the protocol will be documented. The review will be co-produced by multiple stakeholders aiming to produce impactful and relevant results and bridge the gap between preclinical and clinical research on psychosis.

Background Since COVID-19 was first recognised, there has been ever-changing evidence and misinformation around effective use of medicines. Understanding how pandemics impact on medicine use can help policymakers act quickly to prevent harm. We quantified changes in dispensing of common medicines proposed for “re-purposing” due to their perceived benefits as therapeutic or preventive for COVID-19 in Australia. Methods We performed an interrupted time series analysis and cross-sectional study using nationwide dispensing claims data (January 2017-November 2020). We focused on six subsidized medicines proposed for re-purposing: hydroxychloroquine, azithromycin, ivermectin, colchicine, corticosteroids, and calcitriol (Vitamin D analog). We quantified changes in monthly dispensing and initiation trends during COVID-19 (March-November 2020) using autoregressive integrated moving average models and compared characteristics of initiators in 2020 and 2019. Results In March 2020, we observed a 99% (95%CI: 96%-103%) increase in hydroxychloroquine dispensing (approximately 22% attributable to new users), and a 199% increase (95%CI: 184%-213%) in initiation, with an increase in prescribing by general practitioners (42% in 2020 vs 25% in 2019) rather than specialists. These increases subsided following regulatory restrictions on prescribing. There was a small but sustained increase in ivermectin dispensing over multiple months, with an 80% (95%CI 42%-118%) increase in initiation in May 2020 following its first identification as potentially disease-modifying in April. Other than increases in March related to stockpiling, we observed no change in the initiation of calcitriol or colchicine during COVID-19. Dispensing of corticosteroids and azithromycin was lower than expected from April through November 2020. Conclusions While most increases in dispensing observed early on during COVID-19 were temporary and appear to be related to stockpiling among existing users, we observed increases in the initiation of hydroxychloroquine and ivermectin and a shift in prescribing patterns which may be related to the media hype around these medicines. A quick response by regulators can help limit inappropriate repurposing to lessen the impact on medicine supply and patient harm.

Abstract Background Despite persistent calls for HIV care to adopt a chronic care approach, few HIV treatment services have been able to establish service arrangements that prioritise self-management. To prevent cardiovascular and other chronic disease outcomes, the HealthMap program aims to enhance routine HIV care with opportunities for self-management support. This paper outlines the systematic process that was used to design and develop the HealthMap program, prior to its evaluation in a cluster-randomised trial. Methods Program development, planning and evaluation was informed by the PRECEDE-PROCOEDE Model and an Intervention Mapping approach and involved four steps: (1) a multifaceted needs assessment; (2) the identification of intervention priorities; (3) exploration and identification of the antecedents and reinforcing factors required to initiate and sustain desired change of risk behaviours; and finally (4) the development of intervention goals, strategies and methods and integrating them into a comprehensive description of the intervention components. Results The logic model incorporated the program’s guiding principles, program elements, hypothesised causal processes, and intended program outcomes. Grounding the development of HealthMap on a clear conceptual base, informed by the research literature and stakeholder’s perspectives, has ensured that the HealthMap program is targeted, relevant, provides transparency, and enables effective program evaluation. Conclusions The use of a systematic process for intervention development facilitated the development of an intervention that is patient centred, accessible, and focuses on the key determinants of health-related outcomes for people with HIV in Australia. The techniques used here may offer a useful methodology for those involved in the development and implementation of complex interventions.

Background: Many organisations in Australia undertake systematic reviews to inform development of evidence-based guidelines or would like to do so. However, the substantial resources required to produce systematic reviews limit the feasibility of evidence-based approaches to guideline development. We are working with Australian guideline developers to design, build and test systems that make creating evidence-based guidelines easier and more efficient. Methods: To understand the evidence needs of guideline developers and to inform the development of potential tools and services, we conducted 16 semi-structured interviews with Australian guideline developers. Developers were involved in different types of guidelines, represented both new and established guideline groups, and had access to widely different levels of resources. Results: All guideline developers recognised the importance of having access to timely evidence to support their processes, but were frequently overwhelmed by the scale of this task. Groups developing new guidelines often underestimated the time, expertise and work involved in completing searching and screening. Many were grappling with the challenge of updating and were keen to explore alternatives to the blanket updating of the full guideline. Horizon-scanning and evidence signalling were seen as providing more pragmatic approaches to updating, although some were wary of challenges posed by receiving evidence on a too-frequent basis. Respondents were aware that new technologies, such as machine learning, offered potentially large time and resource savings. Conclusions: As well as the constant challenge of managing financial constraints, Australian guideline developers seeking to develop clinical guidelines face several critical challenges. These include acquiring appropriate methodological expertise, investing in information technology, coping with the proliferation of research output, feasible publication and dissemination options, and keeping guidance up to date.

UnlabelledHuman immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells.Trial registrationClinicalTrials.gov NCT01365065.

OBJECTIVES: To identify associations between specific WHO stage 3 and 4 conditions diagnosed after ART initiation and all cause mortality for patients in resource-limited settings (RLS). DESIGN, SETTING: Analysis of routine program data collected prospectively from 25 programs in eight countries between 2002 and 2010. SUBJECTS, PARTICIPANTS: 36,664 study participants with median ART follow-up of 1.26 years (IQR 0.55-2.27). OUTCOME MEASURES: Using a proportional hazards model we identified factors associated with mortality, including the occurrence of specific WHO clinical stage 3 and 4 conditions during the 6-months following ART initiation. RESULTS: There were 2922 deaths during follow-up (8.0%). The crude mortality rate was 5.41 deaths per 100 person-years (95% CI: 5.21-5.61). The diagnosis of any WHO stage 3 or 4 condition during the first 6 months of ART was associated with increased mortality (HR: 2.21; 95% CI: 1.97-2.47). After adjustment for age, sex, region and pre-ART CD4 count, a diagnosis of extrapulmonary cryptococcosis (aHR: 3.54; 95% CI: 2.74-4.56), HIV wasting syndrome (aHR: 2.92; 95%CI: 2.21 -3.85), non-tuberculous mycobacterial infection (aHR: 2.43; 95% CI: 1.80-3.28) and Pneumocystis pneumonia (aHR: 2.17; 95% CI 1.80-3.28) were associated with the greatest increased mortality. Cerebral toxoplasmosis, pulmonary and extra-pulmonary tuberculosis, Kaposi's sarcoma and oral and oesophageal candidiasis were associated with increased mortality, though at lower rates. CONCLUSIONS: A diagnosis of certain WHO stage 3 and 4 conditions is associated with an increased risk of mortality in those initiating ART in RLS. This information will assist initiatives to reduce excess mortality, including prioritization of resources for diagnostics, therapeutic interventions and research.

AbstractIL-5 and interferon-γ responses were investigated in mitogen-stimulated whole-blood cultures from HIV patients with and without Mycobacterium tuberculosisdisease, to determine whether an imbalance of Th1/Th2 cytokines contributes to susceptibility to M. tuberculosisdisease or to immune restoration disease (IRD) associated with M. tuberculosisafter starting antiretroviral therapy (ART). Interferon-γ levels were constant on ART, whilst IL-5 levels generally rose over time. We suggest that increased IL-5 production reflects a recovery of CD4+T cell function and that a Th1/Th2 imbalance is not associated with increased susceptibility to M. tuberculosisdisease or IRD associated with M. tuberculosisupon starting ART. [ABSTRACT FROM AUTHOR]

In anxiety, depression and psychosis, there has been frustratingly slow progress in developing novel therapies that make a substantial difference in practice, as well as in predicting which treatments will work for whom and in what contexts. To intervene early in the process and deliver optimal care to patients, we need to understand the underlying mechanisms of mental health conditions, develop safe and effective interventions that target these mechanisms, and improve our capabilities in timely diagnosis and reliable prediction of symptom trajectories. Better synthesis of existing evidence is one way to reduce waste and improve efficiency in research towards these ends. Living systematic reviews produce rigorous, up-to-date and informative evidence summaries that are particularly important where research is emerging rapidly, current evidence is uncertain and new findings might change policy or practice. Global Alliance for Living Evidence on aNxiety, depressiOn and pSychosis (GALENOS) aims to tackle the challenges of mental health science research by cataloguing and evaluating the full spectrum of relevant scientific research including both human and preclinical studies. GALENOS will also allow the mental health community—including patients, carers, clinicians, researchers and funders—to better identify the research questions that most urgently need to be answered. By creating open-access datasets and outputs in a state-of-the-art online resource, GALENOS will help identify promising signals early in the research process. This will accelerate translation from discovery science into effective new interventions for anxiety, depression and psychosis, ready to be translated in clinical practice across the world.

The HIV care cascade is increasingly used to evaluate HIV treatment programs at the population level. However, the cascade indicators lack the ability to show changes over time, which reduces their utility to guide health policy. Alternatives have been proposed but are complex or result in a delay in results. We propose a new indicator of ART uptake, the time from HIV diagnosis to commencement of ART, and compare it to the existing cascade indicator of proportion of patients on treatment and the WHO proposed cohort cascade indicator of proportion of patients on treatment within one year of diagnosis.Records from patients from the two largest HIV treatment centres in the state of Victoria, Australia (Melbourne Sexual Health Centre and The Alfred Hospital Department of Infectious Diseases) from 2011 to 2015 were extracted. The intervals between date of diagnosis, entry into care and initiation of ART were compared.From 2011 to 2015 the proportion of in-care patients who were on ART rose from 87% to 93% (p

OBJECTIVE: To establish estimates of viral suppression in low- and middle-income countries (LMICs) in patients who received antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection. METHODS: Data on viral suppression after 12 months of ART in LMICs were collected from articles published in 2003 to 2011 and from abstracts of conferences held between 2009 and 2011. Pooled proportions for on-treatment and intention-to-treat populations were used as summary estimates. Random-effects models were used for heterogeneous groups of studies (I² > 75%). FINDINGS: Overall, 49 studies covering 48 cohorts and 30 016 individuals met the inclusion criteria. With thresholds for suppression between 300 and 500 copies of viral ribonucleic acid (RNA) per ml of plasma, 84.3% (95% confidence interval, CI: 80.4-87.9) of the pooled on-treatment population and 70.5% (95% CI: 65.2-75.6) of the intention-to-treat population showed suppression. Use of different viral RNA thresholds changed the proportions showing suppression: to 84% and 76% of the on-treatment population with thresholds set above 300 and at or below 200 RNA copies per ml, respectively, and to 78%, 71% and 63% of the intention-to-treat population at thresholds set at 1000, 300 to 500, and 200 or fewer copies per ml, respectively. CONCLUSION: The pooled estimates of viral suppression recorded after 12 months of ART in LMICs provide benchmarks that other ART programmes can use to set realistic goals and perform predictive modelling. Evidence from this review suggests that the current international target - i.e. viral suppression in > 70% of the intention-to-treat population, with a threshold of 1000 copies per ml - should be revised upwards.

HIV infection is characterised by persistent immune dysfunction of both the adaptive and innate immune responses. The aim of this study was to evaluate these responses using a novel high throughput assay in healthy controls and HIV-infected individuals prior to and following anti-retroviral treatment (ART).Cross-sectional study.Whole blood was assessed using the QuantiFERON Monitor® (QFM) assay containing adaptive and innate immunostimulants. Interferon (IFN)-γ levels (IU/mL) were measured by enzyme-linked immunosorbent assay (ELISA).We recruited HIV-infected participants (n = 20 off ART and viremic; n = 59 on suppressive ART) and HIV-uninfected controls (n = 229). Median IFN-γ production was significantly higher in HIV-infected participants compared to controls (IFN-γ 512 vs 223 IU/ml, p350 compared to

Recent efforts to cure human immunodeficiency virus type-1 (HIV-1) infection have focused on developing latency reversing agents as a first step to eradicate the latent reservoir. The histone deacetylase inhibitor, vorinostat, has been shown to activate HIV RNA transcription in CD4+ T-cells and alter host cell gene transcription in HIV-infected individuals on antiretroviral therapy. In order to understand how latently infected cells respond dynamically to vorinostat treatment and determine the impact of vorinostat on reservoir size in vivo, we have constructed viral dynamic models of latency that incorporate vorinostat treatment. We fitted these models to data collected from a recent clinical trial in which vorinostat was administered daily for 14 days to HIV-infected individuals on suppressive ART. The results show that HIV transcription is increased transiently during the first few hours or days of treatment and that there is a delay before a sustained increase of HIV transcription, whose duration varies among study participants and may depend on the long term impact of vorinostat on host gene expression. Parameter estimation suggests that in latently infected cells, HIV transcription induced by vorinostat occurs at lower levels than in productively infected cells. Furthermore, the estimated loss rate of transcriptionally induced cells remains close to baseline in most study participants, suggesting vorinostat treatment does not induce latently infected cell killing and thus reduce the latent reservoir in vivo.

The current difficulties in keeping systematic reviews up to date leads to considerable inaccuracy, hampering the translation of knowledge into action. Incremental advances in conventional review updating are unlikely to lead to substantial improvements in review currency. A new approach is needed. We propose living systematic review as a contribution to evidence synthesis that combines currency with rigour to enhance the accuracy and utility of health evidence. Living systematic reviews are high quality, up-to-date online summaries of health research, updated as new research becomes available, and enabled by improved production efficiency and adherence to the norms of scholarly communication. Together with innovations in primary research reporting and the creation and use of evidence in health systems, living systematic review contributes to an emerging evidence ecosystem.

A large proportion of patients receiving antiretroviral therapy (ART) in low and middle income countries (LMICs) have unknown treatment outcomes and are classified as lost to follow-up (LTFU). Physical tracing of patients classified as LTFU is common; however, effects of tracing on outcomes remains unclear. The objective of this systematic review is to compare estimates of LTFU, mortality and retention in LMIC in cohorts of patients with and without physical tracing.We systematically identified studies in LMIC programmatic settings using MEDLINE (2003-2011) and HIV conference abstracts (2009-2011). Studies reporting the proportion LTFU 12-months after ART initiation were included. Tracing activities were determined from manuscripts or by contacting study authors. Studies were classified as "tracing studies" if physical tracing was available for the majority of patients. Summary estimates from the 2 groups of studies (tracing and non-tracing) for LTFU, mortality, stop of ART, transfers out, and retention on ART were determined. 261 papers and 616 abstracts were identified of which 39 studies comprising 54 separate cohorts (n = 187,666) met inclusion criteria. Of those, physical tracing was available for 46% of cohorts. Treatment programs with physical tracing activities had lower estimated LTFU (7.6% vs. 15.1%; p