Psychological Science

Working memory is capacity-limited, but interactions with episodic memory may offset this constraint. We tested moment-by-moment contributions of episodic representations to working memory by combining the N-back and Mnemonic Similarity tasks. Thirty-one participants, undergoing eye-tracking, first encoded items in a one-back task, classifying them as "same" or "similar" to their predecessor. In a subsequent two-back task, mnemonic discrimination showed a graded, item-specific benefit of prior experience: performance was best for previously compared items, whereas recognition of identical repeats was unaffected. Successful discrimination of previously compared items was accompanied by greater pupil dilation, gradually emerging gaze patterns resembling those elicited by their similar pair-mate, and higher gaze-similarity between one-back and two-back target viewing. Diverging gaze patterns between pair-mates during one-back further predicted two-back discrimination. These findings challenge working memory's characterization as an isolated system, demonstrating how it recruits episodic computations - encoding distinct traces, predicting upcoming content, and reinstating it at retrieval.

BACKGROUND: An individual's adaptation to threatening environments under uncertainty is reflected in stress responses. Predictability (the ability to anticipate events) and controllability (the ability to control outcomes) are central to how one adapts, yet their joint influence on aversive learning remains unclear. METHODS: Thirty healthy adults completed a probabilistic aversive learning task in which cue-outcome contingencies varied across levels of predictability and controllability, i.e. whether shock intensity depended on prediction accuracy. Prediction accuracy, reaction time, subjective stress ratings, and skin conductance responses were recorded throughout. Trial-wise learning dynamics were estimated using the Volatile Kalman Filter. RESULTS: Prediction accuracy reduced as environments became less predictable and negatively associated with higher learning rates across predictability levels, with the strongest relationship observed in highly predictable blocks. Skin conductance responses showed that moderately predictable environments elicited responses like those in highly predictable environments when accurate predictions reduced shock intensity, but resembled responses in unpredictable environments when shock intensity was uncontrollable. Model comparison revealed a double dissociation between subjective stress ratings and skin conductance responses. Subjective ratings were best explained by model-derived volatility when prediction accuracy determined shock intensity and by belief uncertainty when it was independent of prediction accuracy, whereas skin conductance responses showed the reverse pattern. Reaction times were best explained by belief uncertainty when predictions influenced shock intensity. Higher anxiety was associated with elevated learning rates in highly and moderately predictable blocks when predictions did not control shock intensity.

Museum visits typically follow curator-defined routes that constrain how visitors shape their own experience, yet choice is widely held to heighten engagement, autonomy, and enjoyment. Virtual reality (VR) offers a setting in which to study these processes because it combines ecological immersion with precise, continuous behavioral measurement. We investigated (i) whether VR- derived behavioral signals are associated with self-reported enjoyment during a virtual museum tour, and (ii) whether the level of agency afforded to visitors influences enjoyment. Forty-eight adults completed a room-scale, life-size VR tour (8 * 4 m) of seven paintings from the Tel Aviv Museum of Art, each accompanied by a synchronized audio guide. Synchronized gaze and head- position streams were logged continuously (50 Hz) and segmented into painting-level viewing episodes using a trial-and-tile pipeline that intersects each painting's trial interval with an empirically defined spatial window in front of the canvas. Participants were randomly assigned to one of three agency conditions, Active (choice before every artwork), Semi-Active (choice for the first three), or Passive (fixed route),while the artwork sequence was held identical. Self- reported enjoyment at the tour and painting levels did not differ reliably across agency conditions. Among VR-derived measures, gaze engagement during the audio guide showed the clearest (though modest) association with painting-level liking, whereas locomotion and pacing measures were weak and inconsistent predictors. Agency nonetheless reliably modulated several gaze- and time-based viewing measures. The findings reveal a dissociation between subjective enjoyment and the micro-structure of viewing, and establish a reusable framework for full-tour, painting-level behavioral analysis in immersive settings.

Laboratory stress tasks are widely used to assess individual differences in acute stress reactivity, yet it remains unclear how these responses correspond to stress experienced in everyday life. Here, we combined the Montreal imaging stress task (MIST) with ecological momentary assessment (EMA) over three months to assess acute and everyday stress in 67 healthy women. Greater within-person variability in everyday stress, but not average stress levels, were associated with stronger overall stress-related brain responses (b = 0.73, p = .039), with a whole-brain association particularly evident in the bilateral caudate (rROI = .32, pcluster.FWE < .001). Greater everyday stress variability was also associated with stronger stress-related functional connectivity between the ventromedial prefrontal cortex (vmPFC) and parietal and posterior medial regions (pcluster.FWE < .001). We conclude that acute neural stress responses relate more closely to fluctuations in perceived stress than to how stressed an individual feels on average. This suggests that laboratory stress tasks capture acute stress responsivity that is distinct from average stress exposure, highlighting the importance of considering what these tasks measure when interpreting individual differences in acute stress responses.

Introduction: Decision making for selecting an object or a course of action from possible alternatives largely depends on our perceptual ability modulated by attention. When multiple stimuli appear close together in time, processing one stimulus can temporarily impair the processing of another due to temporal limitations of attention. Observers frequently fail to detect the second target (T2) presented within a few hundred milliseconds after the first target (T1) in a stream of stimuli, which is commonly known as attentional blink (AB). Existing theories attribute this perceptual lapse to T1 processing, distractor interference, or transient attentional gating; however, the computations underlying suppressive mechanism remains unresolved. We investigated whether pupil-size could reveal the underlying mechanisms of AB and predict conscious perception on a trial-by-trial basis. Methods: Pupil diameter and gaze locations were recorded using an infrared eye tracker. Machine learning techniques were used to classify trials when T2 was detected versus when it was not, after correct identification of T1, during an AB task from the pupil dynamics, which also yielded attentional episode (AE) associated with each element in the stream of visual stimuli when deconvolved. Results: Cross-validating classifiers achieved near-perfect accuracy not only in distinguishing but also predicting perceptual outcomes on a single-trial basis. AEs exhibited greater power when T2 was detected than when it was missed; the differential power in AEs on a logarithmic scale was highly synced with the differential pupil size. Conclusions: Collectively, these findings establish a framework for predicting attention-driven perceptual outcomes from pupil-dynamics at finer time-scale.

Anxiety-related traits (ARTs) have been linked to altered fear learning, but previous studies have typically examined different experimental phases and response systems, limiting the comparability of findings and the accumulation of consistent evidence. Here, we comprehensively examined associations between ARTs and fear conditioning across acquisition, extinction and renewal and across subjective, physiological and neural response systems in a well-powered sample (N = 267) using a two-day differential conditioning paradigm. ARTs were operationalized as a composite of trait anxiety, neuroticism, and intolerance of uncertainty and conditioned responding was assessed using skin conductance responses, fear-potentiated startle, US expectancy ratings, fear ratings, and functional magnetic resonance imaging. Higher ARTs were consistently associated with elevated subjective fear and US expectancy to both threat and safety cues during extinction and renewal, without corresponding elevations in physiological responding. At the same time, ARTs were not associated with threat-safety discrimination in subjective or physiological measures across phases, while neural associations were limited to reduced dorsal anterior cingulate cortex discrimination during early renewal. These findings suggest that ARTs are characterized by a CS unspecific cognitive bias toward heightened threat expectancy and evaluation rather than altered associative fear learning, highlighting the importance of distinguishing conditioned discrimination from general levels of responding across response systems.

Individuality is a defining feature of human biology. The functional network architecture of the human brain harbors person-specific qualities and forms individualized connectivity profiles that function as a neural fingerprint, both stable and unique across time. Here, using fMRI data from 431 Human Connectome Project participants, we examined whether neural individuality is more strongly exhibited in brain regions bearing signatures of recent human evolution. We calculated region-wise fingerprinting accuracy and associated it with four properties of evolutionary cortical organization: cortical expansion, myelin content estimate (T1w/T2w), human-specific gene-expression profiles, and functional homology to other primates. Across all four measures, neural individuality was strongest in cortical areas showing greater evolutionary novelty in humans, particularly frontoparietal control and default mode networks, and weaker in more conserved primary regions. Our findings connect evolutionary variation across species with stable functional variation among individuals.

Tactile imagery has attracted growing fundamental and clinical interest. Previous studies often investigated neural and functional similarities between imagined and actual touch. Several functional aspects of touch, such as differences between active and passive touch, between different haptic features during active touch or sensitivity of different body parts for passive touch, have also been explored in tactile imagery. Furthermore, considerable individual differences in the ability to engage in tactile imagery have been observed. However, several important aspects, involving different imagery components and a wide variety of touch qualities remain to be explored within a single comprehensive study. The current study therefore aims to provide a wide-ranging assessment of tactile imagery in terms of imagery processing components (vividness, maintenance, transformation), type of touch (active versus passive) and touch qualities (object properties for active touch, different tactile sensations across body sites for passive touch). We developed a comprehensive questionnaire containing 72 items to assess tactile imagery ability. 136 healthy participants were asked to imagine different touch types and rate imagery vividness and their ability to maintain and transform each sensation on 5-point Likert-scales. Active touch varied by object (plastic bottle, modeling clay, sponge) and property (temperature, weight, texture, resistance). Passive touch varied by body site (lip, shin, sole of the foot, lower back) and sensation (stroking, vibration, pinching). Overall, participants were able to perform tactile imagery: the vast majority reported at least some imagery across touch types. Individual variability was substantial: scores bridged both ends of the scale. Active tactile imagery differed significantly between objects, depending on tactile property. Object-property pairs with particularly strong imagery were bottle-temperature, bottle-weight and sponge-texture, whereas bottle-resistance elicited weaker imagery, as did temperature and weight for both sponge and clay. Passive tactile imagery was significantly stronger for body sites with higher receptor density (i.e. lip and foot). Imagery of stroking was significantly weaker than vibration and pinching. Active and passive imagery showed a strong, positive correlation, though some participants had relatively strong active imagery, but weaker passive imagery, or vice versa. Our findings confirm that tactile imagery ability varies across individuals and touch types, underlining the importance of a comprehensive imagery ability assessment tool specific to the tactile domain.

Generalization is a key cognitive process that allows humans to flexibly apply prior knowledge to guide new behaviors. Difficulties with generalization and flexibility are observed across neurodevelopmental disorders, especially autism, limiting adaptive function and quality of life. Cognitive-behavioral treatment benefits some but not all autistic individuals. As treatment requires application of learned skills to everyday life, variability in generalization ability may limit intervention success in autism. While cognitive substrates of learning and generalization are well established, their potential for explaining clinical outcomes is not known. Here, we combined a category learning task with computational modelling to distinguish two learning strategies underlying generalization -- prototype abstraction vs. exemplar memorization -- and tested whether individual differences in these learning strategies predicted real-world intervention outcomes in autistic youth. Fifty-four participants completed the category learning task at two pre-intervention timepoints, and then completed Unstuck and On Target:14-22 intervention targeting flexible problem solving, goal setting, and planning. We found that participants who consistently relied on prototype abstraction (N=26) were subsequently more likely to benefit from the intervention, showing improvement in parent- and self-reported flexibility. These findings identify prototype abstraction as a clinically relevant cognitive capacity that may help explain individual differences in intervention response and support the tailoring of interventions. More broadly, they demonstrate the value of linking basic cognitive mechanisms to clinical outcomes and may inform strategies to enhance the effectiveness of cognitive-behavioral interventions for youth with developmental disabilities.

Damage to the primary visual cortex causes loss of conscious vision, yet some patients retain the ability to respond to stimuli despite reporting no visual experience. Why similar lesions produce such different behavioral phenotypes remains unclear. While research to date has focused primarily on spared pathways that bypass V1, here we asked whether these divergent outcomes are also linked to the brain's intrinsic functional architecture. In the largest resting-state fMRI cohort of patients with unilateral V1 damage reported to date, we quantified information sharing between regions across cortical and subcortical parcels in blindsight-positive and blindsight-negative patients, as well as in age-matched healthy controls. Despite comparable lesions, the two patient groups displayed distinct hierarchical patterns on the cortex: B+ patients preserved a sensory-to-association organization as in healthy controls, whereas B- patients exhibited a marked flattening of this hierarchy. The effect was driven by abnormally low shared-information coupling within unimodal cortices and scaled continuously with single-subject behavioral blind-field detection performance. A thalamic region consistent with the pulvinar, linking the contralesional visual cortex and the frontal eye field, discriminated B+ from B- patients. These findings highlight the system-level consequences of V1 damage supporting blindsight, suggesting that the unimodal-transmodal axis might track not only global states of consciousness, but also whether sensory information can guide behavior without awareness.

Background/Objectives: Childhood appetitive traits are heritable behavioural phenotypes hypothesized to link genetic susceptibility to obesity risk. Yet their genetic architecture and role in mediating polygenic adiposity risk remain poorly understood. Methods: We conducted the largest survey of childhood eating behaviour to date, allowing us to perform genome-wide association studies of six appetitive domains derived from 18 items of the parent-reported Children's Eating Behaviour Questionnaire in up to 31,018 eight-year-old children from the Norwegian Mother, Father and Child Cohort Study (MoBa). A trio-based design enabled decomposition of direct and indirect genetic effects on appetite and BMI. Results: We identified ten independent genome-wide significant loci for childhood eating behaviour, primarily across Food Responsiveness, Satiety Responsiveness, and Food Fussiness, eight of which lie at established childhood or adult BMI loci. Food Responsiveness and Satiety Responsiveness showed both phenotypic and genetic correlations with BMI trajectories from early childhood through adolescence. Statistical mediation analyses indicated that 22.1% and 10.4% of the aggregated genetic association with BMI at age 8 could be decomposed through these traits, respectively. Locus-specific patterns further suggested mechanistic pathways, with the FTO locus acting predominantly via Food Responsiveness, and the ADCY3 locus via Satiety Responsiveness. Trio analyses demonstrated that both BMI and eating behaviour associations were predominantly explained by children's inherited alleles, with minimal contribution from indirect effect from parental adiposity, although parental genetic liability influenced reporting of Satiety Responsiveness. Conclusions: Childhood appetitive traits capture a substantial proportion of genetic susceptibility to adiposity through distinct eating behaviour pathways (under standard mediation assumptions). These effects are primarily driven by the child's own genotype rather than indirect parental influences, positioning appetite as a plausible, biologically grounded target for early obesity prevention.

Neighbourhood deprivation is one of the few potential policy-modifiable risk factors for psychiatric and neurological disorders, but the neurobiological pathways underlying these associations remain unclear. We investigated these relationships across three cohorts spanning the life span: the Healthy Brain and Child Development (HBCD) Study (n = 84, aged 0 to 4 weeks postnatal), the Adolescent Brain Cognitive Development (ABCD) Study (n = 4,792, aged 9 to 10 years), and the UK Biobank (UKB; approximately 500,000 adults, aged 44 to 87 years). Neighbourhood deprivation was associated with elevated disease risk, and individual lifestyle factors accounted for only a small fraction of this burden, indicating that the much larger residual effect reflects broader contextual characteristics of deprived environments rather than individual behaviours alone. Across all cohorts, greater deprivation consistently predicted lower cortical and subcortical brain volume, with effects detectable in early development and substantially stronger in adulthood. Across disorders, regional brain volume emerged as a consistent neuroanatomical mediator linking neighbourhood deprivation to neuropsychiatric disease. We further showed that deprivation preferentially affects brain regions intrinsically vulnerable to neuropsychiatric disorders. Spatial decoding analyses implicated dopaminergic and serotonergic neurotransmitter systems together with specific excitatory and inhibitory neuronal classes. Importantly, both the deprivation effects and their neuroanatomical mediation patterns were replicated across independent populations. Our study delivers a translational framework linking neighbourhood deprivation to brain health, which could inform public health policies and preventive interventions.

Genes encoding novel protein sequences are a ubiquitous feature of genomes. They fuel molecular and cellular evolutionary innovations and frequently contribute to species-specific characteristics. We are now unravelling the processes by which they originate, including de novo from noncoding sequences and through extreme divergence, yet how much and what types of novel proteins evolve through each process is still unclear Does the mechanism of origination shape the structural and functional potential of the resulting proteins? Here, we conducted a broad computational investigation of genetic and protein novelty at the scale of the entire subphylum of Saccharomycotina yeasts. We detected more than 5,000 robust de novo genes across 332 species and compared them to more than 10,000 novel genes resulting from extreme sequence divergence, revealing two distinct modes of evolution of novelty. A remarkable 40% of de novo proteins are predicted to localize to mitochondria compared to only 15% of divergent, with the latter also being substantially longer and more disordered. A detailed analysis of conservatively predicted tertiary structures of novel proteins shows that "invention" of novel folds can happen through both processes but is more likely to occur de novo. We also illustrate cases of evolutionary "re-invention" of existing protein folds from non-coding sequences. Our work deepens our understanding of the origins and importance of novel proteins opening new directions for further structural and functional characterization.

Pouring a drink feels deceptively trivial, yet it requires guiding a boundary-free fluid into a vessel without spilling, overflowing, or toppling it -- a task at which robots remain notoriously brittle. How humans achieve this so effortlessly is unknown, as motor control has predominantly been studied in brief, highly constrained laboratory tasks, leaving the control principles underlying ecological tasks largely unknown. Here we measured continuous sensorimotor control during liquid pouring across various containers, vessels, and speed demands. Despite substantial variation in movement trajectories and durations, individuals maintained a strikingly invariant preferred fill level. Counterintuitively, fill level variability decreased at higher fill levels, and precision was maintained even under time pressure. A stochastic optimal control model combining a data-driven nonlinear approximation of flow dynamics with a cost that balanced individualised fill level, energy expenditure and flow-rate reproduced the behaviour. Humans thus pour optimally, given their sensorimotor limits and idiosyncratic notion of "full".

Across different modalities, signals play a core role in attracting mates and influencing mating success. In several non-human primate species, females produce calls during mating that are thought to promote male competition over receptive females. The extent to which social system characteristics modulate the function of copulation calls remains less clear. We studied copulation calls in wild Guinea baboons (Papio papio), who live in a multilevel society structured around units in which females associate and mate almost exclusively with a single male. We hypothesised that females use copulation calls as an indirect form of mate competition, with competition increasing in larger units. In addition, we hypothesised that females are more likely to mate again after calling. We analysed 6116 copulations between 2014 and 2025, involving 99 reproductively active females and 78 subadult and adult males. Females produced copulation calls in 72.7% of copulations, with large inter-individual variation. Neither unit size nor its interaction with the female's swelling size or the presence of simultaneously receptive females affected the probability of calling. A survival analysis with a subset of the data (2353 copulations) revealed no effect of calling on the latency to the next mating. Our results render the hypothesis that female Guinea baboons use calls in indirect mate competition unlikely. Yet, the probability of calling varied with sexual swelling size, suggesting that calls signal female fertility. Possibly, Guinea baboon copulation calls represent an evolutionary remnant, no longer under selective pressure, and can be considered index signals of female fertility.

Background: Previous trauma research includes many limitations, such as the scarcity of pretraumatic health measurements and assessment of traumatic experiences with a broad scope across the lifespan. To respond to these gaps, we aimed to develop a new, prospective, population-based trauma dataset from childhood to middle age. Methods: We used the Young Finns Study that is a population-based, multi-generational, prospective study (n = 3596 for the main generation). It has started in 1980 (baseline assessment) and includes follow-ups in 1983, 1986, 1989, 1992, 1997, 2001, 2007, 2011/2012, and 2018-2020. From the 38-year follow-up and ten measurement points of the YFS, we collected all relevant trauma variables, including both free-format and structured questions that both the participants and their parents responded to. By a data-driven case-to-case analysis, we developed a scale to numerically capture variation in the quality of the experiences. Results: Our final dataset captured a total of 7769 traumatic experiences. We also developed the Traumatic Experience Severity Scale (TESS), including six subscales such as shamefulness, rarity, danger to life or health, effects on everyday life, human-made physical threat, and whether the target person was within or outside one's household. We also preprocessed the dataset to be later easily interleaved with other psychological, cardiovascular, and epigenetic variables of the YFS. Conclusions: We believe this new trauma dataset with thousands of experiences across the lifespan provides new opportunities to multidisciplinary, lifelong trauma research.

Purpose: To evaluate the safety, procedural performance, sample recovery, and surgeon preference of an ophthalmic needle designed specifically for anterior chamber (AC) paracentesis. Methods: In this multicenter study, AC paracentesis was performed in clinic and operating-room settings using a 32-gauge x 4-mm needle with low dead space. The procedure was evaluated using a standardized physician survey. Prespecified outcomes included procedure-related adverse events (primary outcome), needle entry and handling, aspiration and sample recovery, comparative performance versus a 30-gauge needle, and physician preference for future use. Results: A total of 110 needle uses by eight surgeons were included. No ocular complications occurred, including lens or iris injury, hyphema, AC collapse, wound leak, hypotony, infection, or retinal complication, and no procedure required needle exchange or conversion to another device. Two technical events without ocular sequelae were noted, in which needle entry was partial thickness and did not reach the AC (1.8%; exact 95% CI, 0.2%-6.4%). Physicians rated needle entry, handling and sample recovery as good or excellent. Compared with a 30-gauge needle, the study needle was rated as at least comparable across all assessed domains. All surgeons rated it better or much better for intra-procedural safety and preferred it for future AC taps. Conclusions and Relevance: This short, 32-gauge low-dead-space ophthalmic needle demonstrated a favorable safety profile and was preferred over a 30-gauge needle by all surgeons. As aqueous humor liquid biopsy expands in clinical diagnostics and trials, an ophthalmic-specific needle design may help improve the consistency and safety of aqueous humor collection for molecular analysis and broader clinical use. Keywords: Anterior chamber paracentesis; Aqueous humor; Liquid biopsy; Low dead space; Ophthalmic needle

Introduction: Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is a common endocrine disorder affecting women of reproductive age. Besides reproductive and metabolic disturbances, PMOS negatively impacts psychological well-being and quality of life. Despite available treatment options, there remains a need for safe and effective therapies that improve both clinical symptoms and fertility outcomes. Aim: To compare the efficacy of VAMHA and MYRHA tablet combination therapy with standard non-hormonal therapy in restoring regular menstruation. Secondary objectives included assessment of ovulation, menstrual symptoms, polycystic ovarian morphology, hormonal and metabolic parameters, anthropometric measures, and skin manifestations. Study Design: Open-label, randomized, multicentre, prospective comparative clinical study. Methods: Seventy-one women with PMOS were randomized to Group A (n=37) or Group B (n=34). Group A received VAMHA and MYRHA tablets (2 tablets each), while Group B received Metformin 500 mg plus Myoinositol 600 mg (1 tablet), twice daily for 180 days. Data were recorded in Case Report Forms. Statistical Analysis: Continuous variables were summarized using mean and standard deviation, while categorical variables were expressed as frequencies and percentages. Appropriate statistical tests, including Chi-square, were used. A p-value [&le;]0.05 was considered significant. Results: Significantly more participants in Group A achieved regular menstrual cycles than Group B (31 vs. 22; p<0.05). Ovulation occurred in 16 participants in Group A compared with 6 in Group B (p<0.05). Both groups showed significant improvement in menstrual irregularity and related symptoms. Significant reductions in Anti-Mullerian Hormone (AMH), fasting insulin, and body mass index (BMI) were observed in both groups (p<0.05). Resolution of polycystic ovarian morphology occurred in 13 participants (38.23%) in Group A and 10 (33.33%) in Group B. Both treatments were well tolerated with no major safety concerns. Conclusions: VAMHA and MYRHA combination therapy was superior to standard non-hormonal therapy in improving menstrual regularity and ovulation. It also produced favourable metabolic, hormonal, and ultrasonographic outcomes, suggesting its potential as a safe and effective option for comprehensive PMOS management and fertility enhancement.

Artificial intelligence applied to routine electrocardiograms (ECGs) has largely focused on detecting existing disease or predicting individual cardiovascular outcomes. Whether ECGs can support prediction of multiple future diseases across organ systems remains unclear. We developed ECG-RISK, a multitask survival model for 67 incident three-character ICD-10 endpoints using ECG waveforms, demographic characteristics and routinely collected laboratory data from 86,673 MIMIC-IV patients. Discrimination was highest for heart, brain, kidney and lung endpoints, with organ-level C-indices ranging from 0.796 to 0.825, whereas liver and pancreatic endpoints showed lower discrimination. The ECG-only model achieved strong discrimination across most endpoints, whereas the incremental improvement gained by incorporating ECG and laboratory inputs beyond demographic information varied substantially across endpoints. Across the nine exploratory aggregated outcomes, Kaplan Meier curves showed clear separation among model-score tertiles. Discrimination was highest for dementia (C-index, 0.891) and heart failure (C-index, 0.857). These findings support the feasibility of ECG-based longitudinal risk prediction across multiple diseases. External validation and competing-risk analyses are required to assess generalisability and clinical utility.

Objectives To evaluate whether access to a certified large language model (LLM)-based clinical decision support system improves physician diagnostic performance in rheumatology compared with conventional diagnostic resources alone. Methods In this multicentre, open-label, randomised controlled trial, 82 physicians from seven hospitals in two countries were randomised 1:1 to conventional diagnostic resources plus Prof. Valmed or conventional resources alone. Participants assessed three rheumatology vignettes before and after assistance. The primary outcome was top-1 diagnostic accuracy. Secondary outcomes included top-3 accuracy, diagnostic reasoning, confidence, case-processing time and perceived support quality. Results Top-1 accuracy increased from 22.2% to 33.3% in the intervention group and from 23.3% to 35.0% in the control group, with no between-group difference in improvement (adjusted OR 0.99, 95% CI 0.45 to 2.19; p=0.979). Differences in top-3 accuracy, diagnostic reasoning and confidence were also not significant. Assisted case-processing time was substantially shorter with LLM support (94 vs 206 s; adjusted mean difference -112 s, 95% CI -141 to -83; p<0.001). Information timeliness and perceived diagnostic support quality were rated significantly higher in the intervention group. Exploratory analyses showed persistent overconfidence and substantial AI over-reliance. Conclusions Certified LLM-based diagnostic support did not improve diagnostic accuracy compared with conventional resources, but substantially reduced case-processing time and improved perceived support quality. These findings suggest potential workflow benefits while highlighting overconfidence and over-reliance as important safety considerations.