Declan Gm Murphy

Objectives: To synthesise evidence comparing the diagnostic performance of imaging modalities in differentiating malignant from benign small testicular masses. Patients and Methods: A Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA)‐compliant search of PubMed, Scopus, Cochrane and Web of Science databases up to 6 May 2026 identified 11 studies comprising 707 patients with small testicular masses (predominantly <2 cm) who underwent imaging prior to a histopathological or, where unavailable, a mixed clinical/radiological follow‐up reference standard. Diagnostic accuracy measures for six modalities (brightness‐mode [B‐Mode] ultrasonography [US], colour doppler US [CDUS], contrast‐enhanced US [CEUS], magnetic resonance imaging [MRI], strain elastography [SE] and strain ratio [SR]) were synthesised using a Bayesian bivariate hierarchical summary receiver operating characteristic model. Results: The CEUS demonstrated the most reliable discriminatory ability with a pooled sensitivity of 91% and pooled specificity of 81%, yielding the highest diagnostic odds ratio of 46. B‐Mode US remains a valid screening test with the highest sensitivity of 96% but a specificity of only 39%. CDUS showed a pooled sensitivity of 69% and a specificity of 81%. MRI had a pooled sensitivity of 91% and a specificity of 38%. SE demonstrated a pooled sensitivity of 87% and a specificity of 56%. Finally, SR reported the lowest sensitivity at 74% and a specificity of 50%. CEUS demonstrated significantly higher specificity than B‐Mode US (ratio 1.9, 95% posterior interval [PI] 1.2–4.4) and MRI (ratio 1.8, 95% PI 1.0–5.2). Conclusion: The CEUS demonstrates the highest combined sensitivity and specificity for differentiating benign from malignant testicular masses, significantly outperforming conventional B‐Mode US and MRI in specificity. CEUS represents a compelling decision‐making tool to support testis‐sparing strategies and reduce unnecessary orchidectomies for indeterminate small testicular masses.

Background: Autism clinical trials are hampered by the lack of treatment response biomarkers. We investigated N170 latency (N170L), an electrophysiological (EEG) index of face processing speed, as a candidate biomarker of treatment response to arbaclofen, a selective GABA-B agonist. We previously reported that N170L is, on average, slower in autism, and linked to genetic, neurobiological, and socialisation variability. Here, we explored whether: 1) arbaclofen modulates N170L over 16 weeks; 2) baseline N170L or change in N170L (ΔN170L) predicts change in social functioning over 16 weeks; 3) N170L improves estimation of treatment effects. Methods: In this phase II, randomised, double-blind, placebo-controlled trial, 122 autistic children and adolescents (aged 5–17) were administered arbaclofen ( N = 59) or placebo ( N = 63) for 16 weeks. N170L was extracted from EEG recorded during passive viewing of upright faces at week 0 (baseline; N = 96) and week 16 (endpoint; N = 87). Treatment efficacy on social functioning was assessed using the Socialization domain of the Vineland Adaptive Behavior Scales, 3rd edition, alongside parent/clinician-rated outcomes. Pre-registered hypotheses were tested using linear mixed-effects models. Results: N170L remained stable over 16 weeks, with no significant change overall ( p = 0.371), and arbaclofen did not modulate N170L relative to placebo ( p = 0.737). Baseline N170L did not predict change in any clinical outcome (all p > 0.472). However, individual differences in ΔN170L were associated with selected clinical outcomes. In the placebo group, slowing of N170L was associated with greater peer interaction difficulties ( p = 0.032) and improved global clinical status ( p = 0.002). For social cognition, the associations differed by treatment group ( p = 0.022), with N170L slowing linked to greater social-cognitive difficulties under placebo, but fewer social-cognitive difficulties under arbaclofen. Baseline N170L and ΔN170L minimally impacted treatment effects estimation as covariates. Limitations: Interpretation of N170L–clinical associations is limited by short trial duration and reliance on broad, informant-based social measures that, while clinically meaningful, indirectly index face-processing abilities. Conclusions: N170L showed limited utility as treatment response biomarker in this trial, although its relevance in other therapeutic contexts remains to be determined. We also demonstrated feasibility of integrating EEG into multi-site autism clinical trials, supporting future biomarker-enabled pharmacological research. Trial registration: ClinicalTrials.gov, NCT03682978. Registered September 25, 2018.

Many autistic people have challenges with adaptive function, impacting education, employment and independent-living goals. Adaptive function outcomes of autistic people vary considerably, which makes planning for future needs challenging. Here, using a developmentally sensitive approach, we investigated if cortico-cortical functional connectivity – a core neurobiological feature that differs in autism – could predict longitudinal changes in adaptive function in autistic people. Using electroencephalography in 150 autistic and 159 non-autistic participants aged 6–31 years, we investigated if mean degree and network organisation (small-world index) predict longitudinal changes in adaptive function over 19-months. We found that small-world index significantly predicted changes in adaptive function in autistic people across the entire age-range. Predictive performance was best for autistic youth (15–24-year-olds), where mean degree and small-world index explained 21 and 30% of additional variance in outcomes, respectively, outperforming measures of intelligence and autistic features. In categorising binary (improved versus not-improved) outcomes, the model containing mean degree had an AUC of 0.84 [95% CI: 0.71–0.97] in 15–24-year-olds, while that containing small-world index had an AUC of 0.76 [95% CI: 0.63–0.89] across the 6–31-year age-range. Both metrics demonstrated properties desired in prognostic biomarkers: high test-retest reliability and convergence with underlying biology (significant associations with genetic variation in brain volume-related genes). Thus, we demonstrate the first evidence that electroencephalography-derived functional connectivity metrics show promise as prognostic biomarkers of adaptive function in autistic people. Potential precision-medicine applications include stratifying participants in clinical trials and identifying those at risk of declining function in clinical settings.

Homologous recombination repair (HRR) gene alterations are key drivers of disease in prostate cancer. This has led to great interest in HRR targeted therapies, particularly polyadenosine diphosphate‐ribose inhibitors (PARPi), in the treatment of metastatic castrate resistant prostate cancer (mCRPC). HRR alterations are typically early events in prostate cancer tumorigenesis. As a result, clinical trials are investigating the efficacy of PARPi therapy in metastatic hormone sensitive prostate cancer (mHSPC). Recently, based on positive results from the phase III AMPLITUDE trial, niraparib was approved in the United States for the treatment of patients with BRCA2 ‐mutated mHSPC. Positive results have also recently been obtained from the phase III TALAPRO‐3 trial; talazoparib added to enzalutamide led to significantly better imaging‐based progression‐free survival than placebo plus enzalutamide among patients with mHSPC harboring HRR alterations. Furthermore, international guidelines now recommend HRR mutation testing for patients with mHSPC. However, in Australia there is currently no reimbursement for HRR mutation testing in the mHSPC setting. Here, we review the current knowledge of the clinical relevance of HRR alterations and highlight the benefits of genomic profiling of hormone‐sensitive disease prior to the development of castrate resistant disease.

The excitatory/inhibitory (E/I) imbalance theory suggests that excitatory and inhibitory alterations underlies autism characteristics. However, genetic underpinnings of this imbalance and its impact on brain function and behavior remains unclear. We explored causal links between glutamate and GABA gene-set polygenic scores (PGS) for autism and core autism characteristics, putting particular attention on the restricted- and repetitive behaviors (RRBs) domain by including functional activity (fMRI) during inhibitory control (in the anterior cingulate cortex (ACC) and striatum). Causal links between genes, brain and behavior was evaluated using Bayesian Constraint-based Causal Discovery (BCCD) algorithms, to build causal models of these relationships in a discovery sample (LEAP cohort: autistic = 343, neurotypical = 253) and two generalization cohorts with partially overlapping measures (TACTICS cohort: autistic = 60, neurotypical = 100, Simon Simplex Collection: autistic = 2756). In the discovery sample, we found a causal link between glutamate PGS and core clinical characteristics of autism, particularly the communication domain (Autism Diagnostic Interview-Revised) in autistic participants, with 95% reliability. We did not find links between functional activity during inhibitory control and other measures. For one generalization cohort, we further report on the impact of ¹ H-MRS measures of glutamate, identifying a causal link between GABA autism PGS on ACC glutamate concentrations. Not all links were identified in the generalization cohorts, which may be due to clinical and genetic differences between the cohorts. While our results reinforce the previously found association between glutamate genes and core clinical autism behaviors, task-based functional activity may not be causally related to RRBs.

Importance There is increasing interest in the potential of psilocybin to treat mental health and neurodevelopmental conditions. At high doses, the therapeutic benefit of psilocybin is linked to greater functional connectivity or integration between large-scale brain networks which underpin mood, emotion and cognition. However, it is unknown how the brain responds to psilocybin in autism - a condition characterised by both altered functional connectivity and differential response to drugs. Thus, a first step before clinical trials of psilocybin involving autistic people, is to evaluate the response of the autistic brain to psilocybin, initially at low dose. Objective Low doses of psilocybin were used to test the hypothesis that the functional connectivity of large-scale resting-state brain networks respond differently in autistic and non-autistic adults. Design The PSILAUT study had a pseudo-randomised, cross-over, double-blind, case-control design. There was no evaluation of clinical efficacy. PSILAUT was not a Clinical Trial according to UK regulations. Data collection was conducted from January 2023 to August 2024. Setting Single-centre, study conducted at the Institute of Psychiatry, Psychology & Neuroscience, Kings College London, London, United Kingdom. Participants Adult (> 18 years) participants with and without an autism spectrum disorder (ASD) diagnosis were recruited and matched for age, sex and IQ. Autistic participants were included if they had an existing diagnosis (DSM-IV, DSM-5 or ICD-10 criteria). Exposures A single oral dose of 2 or 5 mg psilocybin or (inactive) placebo administered on separate visits at least one week apart. Main Outcomes and Measures Resting-state fMRI was acquired to investigate the change in functional connectivity within and between brain networks, as measures of network integrity and integration, respectively. Results A total of 67 participants were recruited (18-58 years at first visit; 30 non-autistic participants, mean [SD] age, 30.0 [8.3] years, 15 males [50%] and 37 autistic participants, mean [SD] age, 28.6 [9.2] years, 19 males [51%]). We report for the first time that the autistic brain responds differently to low doses of psilocybin, despite no group differences in network connectivity in the baseline placebo condition. 5 mg psilocybin elicited the greatest shifts in functional connectivity in both groups, but in different directions. In non-autistic participants only, on average, after 5 mg psilocybin within-network connectivity of the frontoparietal (β = -0.053, T = -2.73, FDR-corrected P value = 0.027, Cohen d = -0.71) and limbic networks (β = -0.087, T = -2.59, FDR-corrected P value = 0.021, Cohen d = -0.61) decreased. In contrast, in autistic participants, 5 mg psilocybin increased between-network connectivity (i.e. integration) of higher-order and attentional networks, but decreased connectivity between the same networks in non-autistic participants (default mode and frontoparietal networks, dose x group interaction: β = 0.053, T = 2.91, FDR-corrected P value = 0.042; dorsal and ventral attention networks, dose x group interaction: β = 0.059, T = 2.31, FDR-corrected P value = 0.015). Across the whole sample, the extent to which psilocybin elicited an increase in connectivity between higher-order (β = 0.33, T = 2.16, FDR-corrected P value = 0.036) and attentional (β = 0.36, T = 2.43, FDR-corrected P value = 0.036) networks was positively correlated with core autistic traits quantified using the Autism Quotient. Conclusions and Relevance Functional brain networks that support mood, emotion and cognition are more responsive to low dose psilocybin in autistic adults compared to non-autistic adults. Given that increased network integration is associated with clinical utility, future applications of psilocybin in autistic people should include the evaluation of low doses.

Background/Objectives: On 1 November 2023, the Medicare Benefits Schedule (MBS) introduced major reforms to prostate-specific antigen (PSA) testing in Australia, extending the minimum re-test interval for average-risk men (item 66655) from 12 to 23 months and introducing a new annual high-risk item (66654). These changes were aimed at reducing overscreening, aligning practice with national guidelines, and improving cost efficiency; however, their real-world impact on PSA utilisation, downstream diagnostic activity, and health-system costs has not been evaluated. Methods: We performed a national, population-level analysis of all reimbursed PSA tests (items 66655 and 66654) and prostate magnetic resonance imaging (MRI) scans (item 63541) from November 2021 to October 2025 using MBS claims data. Monthly utilisation trends were examined descriptively and modelled using interrupted time-series segmented regression with Newey–West heteroscedasticity- and autocorrelation-consistent standard errors. Economic impacts were estimated using schedule fees. MRI trends were assessed to explore early signals of downstream diagnostic change. Results: Prior to the reform, average-risk PSA testing (item 66655) averaged 61,704 claims per month (median 62,526). After November 2023, utilisation fell immediately to 49,620 and stabilised at a lower mean of 44,702 claims per month (median 43,495), representing a sustained 27.6 percent reduction. High-risk PSA testing (item 66654) accounted for 130,739 claims post-reform (10.9 percent of monthly post-reform PSA activity), but the increase in high-risk testing did not offset the reduction in average-risk claims; total PSA claims fell from 61,704 to 50,149 per month (−18.7 percent). Interrupted time-series modelling confirmed a large, significant step decrease for item 66655 (−23,191 claims, 95% confidence interval (CI) −31,215 to −15,167; p < 0.001) and for total PSA testing (−16,876 claims, 95% CI −25,899 to −7853; p < 0.001). In contrast, prostate MRI utilisation increased from 3854 to 4454 monthly scans (+15.6 percent) with no significant step-change at the time of the reform (p = 0.74) but a significant acceleration in post-reform growth (+49 scans/month, p = 0.0095). The reform resulted in an estimated net saving of $2.8 million in annual PSA expenditure. Conclusions: The November 2023 MBS reforms led to a large, immediate, and durable reduction in reimbursed PSA screening among average-risk men, while high-risk testing increased modestly but remained proportionally small. Total PSA testing declined meaningfully, producing substantial cost savings for Medicare. Rising MRI utilisation indicates that downstream diagnostic activity did not fall in parallel with reimbursed PSA claims, though this trend may reflect independent drivers of MRI growth rather than preserved screening vigilance. Reductions varied by jurisdiction, with two smaller jurisdictions showing net increases over the study window, underscoring that the national pattern was not uniform.

Autism is characterized by social-communicative difficulties, with sex differences in symptom presentation. Social functioning is inherently dynamic, however, many neuroimaging studies rely on static, time-averaged approaches that obscure time-varying network interactions, potentially limiting our ability to capture the dynamic processes underlying social cognition. The fusiform gyrus (FFG), central to face and social perception, shows differences in functional connectivity in autism, yet is rarely examined dynamically or as a spatially heterogeneous structure. Here, we investigate the dynamic functional connectivity of FFG subregions in terms of their large-scale network configurations as a function of diagnosis and sex. We applied micro co-activation patterns analysis (µCAPs) to resting-state fMRI data from 286 autistic individuals (208:78 males:females) and 228 non-autistic individuals (146:82 males:females), aged 6–30 years, from the EU-AIMS LEAP dataset. µCAPs were identified using k-means clustering with FFG as the seed, and connectopic mapping positioned each µCAP along the principal connectivity gradient. We quantified µCAPs occurrence and further examined dwell time, transition probabilities, and spatial extent, along with associations with social functioning. Six µCAPs mapped onto distinct FFG subregions along a posterior-anterior axis. A significant sex-by-diagnosis interaction emerged for a default mode network (DMN)-related µCAP. Non-autistic females exhibited significantly more frequent occurrences, longer dwell times and distinct transition dynamics compared to males, while no sex difference was observed in autism. The spatial extent of this µCAP showed a reversal of typical sex effects. Autism is associated with an attenuation and reversal of typical sex differences in the functional configuration and spatial extent of FFG-DMN coupling, indicating that neural signatures of social-cognitive functions are sex-specific and dynamic. These findings suggest that sex is a neurobiologically meaningful dimension of heterogeneity in autism, expressed in dynamic network organization.