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461 papers

The Human Dorsolateral Prefrontal Cortex in Pain and Pain Modulation: A Review and Activation-Likelihood Estimation Approach.

Crawford LS et al. · Jul 1, 2026

Background The dorsolateral prefrontal cortex (dlPFC) has become a cornerstone of pain neuroscience, believed critically involved in processing acute and chronic pain, as well as in pain modulation. The dlPFC is thought to balance sensory perception with the cognitive appraisal of noxious stimuli. In humans however, the dlPFC spans several cortical nodes, and little attention has been given to precisely which subareas are tethered to these delineable processes. The primary goal of this review and co-ordinate based meta-analysis was to precisely map dlPFC areas engaged under varied effects on overall pain perception. Methods Here, we combined a stringent meta-analytic approach of neuroimaging studies reporting dlPFC activation as a core finding (i.e., within title, abstract, or keywords of each manuscript), with activation likelihood estimation to determine dlPFC engagement across experimental acute pain (combined n = 814), chronic pain (combined n = 2467), and the pain modulatory phenomenon of placebo analgesia (combined n = 791), conditioned pain modulation (combined n = 184), and offset analgesia (combined n = 47). Through activation likelihood estimate and foci analysis, we produced schema of the similar and disparate locations of dlPFC activity within and between pain perceptual and modulatory effects. Results During both acute and chronic pain and in placebo analgesia, we identified remarkably similar activation patterns predominantly within Brodmann areas 8, 9, and 46-with no clear laterality effect and the left and right cortical hemispheres engaged regardless of the site of experimentally applied or conditionally-present pain. Offset analgesia and conditioned pain modulation appeared to preferentially engage Brodmann areas 8 and 45, and 9 and 46, respectively. Conclusions Despite the dlPFC large cortical surface area, these findings suggest that both the percept and inhibition of pain by placebo engage a similar focussed area of this region. Better understanding of exactly which cortical components of the extensive cortical pain system are involved in pain perception and modulation is critical for refining novel treatments such as non-invasive brain stimulation which seek to target and modulate specific sites of cortical processing to alleviate pain. Significance statement This meta-analysis precisely maps the dorsolateral prefrontal cortex (dlPFC) subregions engaged across acute pain, chronic pain and major endogenous pain-modulation paradigms. By integrating data from more than 4000 participants, it provides the most anatomically resolved evidence to date that dlPFC engagement is a shared feature of pain perception and modulation. These findings refine the cortical targets most relevant for therapeutic neuromodulation and strengthen the rationale for dlPFC-focused interventions in pain treatment.

Neuroscience

Nebivolol Protects the Thoracic and Abdominal Aorta and Their Perivascular Adipose Tissue From the Differential Detrimental Effects of Obesity.

Dourado TMH et al. · Jul 1, 2026

The effects of obesity on the vasculature and perivascular adipose tissue (PVAT) function vary according to the vascular territory. Nebivolol is a third-generation β-blocker that exerts vasculoprotective effects in obesity. The thoracic and abdominal aorta show different responses under physiological conditions, and their PVATs have a distinctive composition and secretory profile. We hypothesized that obesity would affect thoracic and abdominal aortic responsiveness, as well as their PVAT function, differently and that nebivolol would restore obesity-induced vascular and PVAT changes. To test this hypothesis, male Wistar Hannover rats were fed a hypercaloric diet for 14 weeks. Nebivolol (10 mg/kg/day) was administered via gavage during the last 4 weeks. Obesity increased superoxide (O 2 • - ) generation within the thoracic PVAT, but this response did not result in a loss of its anticontractile effect. Vascular hypercontractility was detected in thoracic aortas, which was mediated by the overproduction of NADPH oxidase-derived O 2 • - and reduced nitric oxide (NO) bioavailability. Conversely, obesity induced a pro-contractile phenotype in the PVAT of the abdominal aorta. This response occurred in an endothelium-dependent manner, was ameliorated by tiron, and was accompanied by increased O 2 • - levels. In all cases, nebivolol reversed the effects of obesity. In summary, obesity differentially affects the thoracic and abdominal aorta and their respective PVATs. Nebivolol exerts vasculoprotective effects through antioxidant mechanisms, leading to a reversal of obesity-induced vascular hypercontractility in both aortic segments. The beneficial effects of nebivolol described here could help mitigate cardiovascular complications associated with obesity. Obesity induces PVAT dysfunction. Extending this knowledge, we demonstrated that obesity differentially affects the thoracic and abdominal aorta along with their associated PVATs. This widespread impairment of PVAT function can drive various adverse vascular consequences, including arterial hypertension and aneurysm formation. Critically, peri-aortic PVAT is of particular clinical relevance due to its association with metabolic risk factors and vascular calcification. Nebivolol exerts vasculoprotective effects via antioxidant mechanisms within PVAT, ultimately reversing obesity-induced vascular hypercontractility in both aortic segments. Thus, investigating pharmacological agents that restore PVAT function, as demonstrated here with nebivolol, represents a promising therapeutic strategy to mitigate obesity-related cardiovascular complications.

Medicine

Blinded, bias-controlled multi-rater evaluation of human-versus-AI brain metastasis segmentation using a hybrid foundation-model framework.

Han Y et al. · Jul 1, 2026

Background Accurate segmentation of brain metastases (BM) is essential for diagnosis, stereotactic radiosurgery planning, and longitudinal assessment. However, manual contouring is time-intensive, limiting clinical scalability, and exhibits substantial inter-observer variability. This variability complicates objective assessment of automated segmentation methods and challenges interpretation of model performance. Purpose To address these limitations, we developed TUM-SAM, a hybrid foundation-model framework for fully automated BM segmentation, and introduced a bias-controlled, blinded multi-rater evaluation paradigm to determine whether AI-based BM segmentation has reached expert-level performance and whether AI-generated contours are preferred by human experts under unbiased assessment. Methods TUM-SAM integrates nnU-Net-based lesion detection with a tumor-adapted Med-SAM segmentation model to enable prompt-free, fully automated segmentation. Training used 301 patients (2548 lesions), and external evaluation used an independent cohort of 105 patients (397 lesions). Segmentation accuracy was benchmarked against DeepMedic and nnU-Net using Dice similarity coefficient (DSC) and 95th-percentile Hausdorff distance (HD95). Two physicians contoured all external cases, and a third physician contoured a 20-patient subset for a blinded, tumor-level, multi-rater preference study. Pairwise contour preferences were analyzed using a Bradley-Terry probabilistic model to obtain bias-adjusted estimates of relative contour quality while accounting for rater-specific tendencies and case difficulty. Results In the external cohort, TUM-SAM achieved a lesion-wise detection sensitivity of 0.94 and outperformed DeepMedic and nnU-Net across all tumor sizes, with a mean DSC of 0.84 and HD95 of 1.9 mm (nnU-Net/DeepMedic: DSC 3.3 mm). Across voxel-wise evaluation, TUM-SAM's geometric performance fell within the range of inter-observer variability among physicians and was sensitive to reference construction. In contrast, in the blinded rater study, experts preferred TUM-SAM-generated contours over individual physician contours in 81-87% of raw comparisons; Bradley-Terry analysis yielded conservative, bias-corrected win probabilities of 55-56%, indicating consistent preference after adjustment for rater and case difficulty. Conclusion Using a bias-controlled, blinded multi-rater evaluation framework, TUM-SAM demonstrates brain metastasis segmentation quality that is consistently preferred by expert physicians, highlighting the limitations of agreement-based voxel-wise metrics under inter-observer variability. These findings underscore the dependence of conventional evaluation on reference definition and support preference-based assessment as a complementary approach for evaluating AI segmentation quality in BM MRI.

Medicine

Clinical and research applications of fibroblast activation protein-α inhibitor tracers: a review.

Desaulniers M et al. · Jul 1, 2026

In the last decade, fibroblast activation protein-α inhibitors (FAPIs), which target the cancer-associated fibroblasts of the tumour microenvironment, have become a topic of great interest. In oncology, FAPI PET/CT imaging has repeatedly demonstrated a higher lesion detection rate than other conventional imaging modalities such as CT or 18F-FDG PET/CT for several tumours. In some cases, the initial staging and therapeutic management may even change. Some FAPI radioligands may also be labelled with therapeutic radionuclides for theranostic applications. It is thus possible to treat certain metastatic cancers with FAPI radioligand therapy (FAPI-RLT), which is generally well tolerated with little toxicity. Recently, new FAPIs have been developed with the particularity of having a higher binding affinity for the target, which further improves the lesion detection rate on PET/CT and clinical outcomes following FAPI-RLT. This review provides recent updates in the clinical use of FAPI PET/CT and FAPI-RLT and discusses potential emergent applications, including in inflammation imaging.

Medicine

Immediate Effects of Delayed Auditory Feedback on Stuttering: A Systematic Review and Meta-Analysis of Literature Published 2000-2024.

Iimura D et al. · Jul 1, 2026

Purpose This systematic review and meta-analysis evaluated the fluency- enhancing effect of DAF alone in individuals with developmental stuttering. Methods Following PRISMA 2020 guidelines, we searched multiple databases for studies published between 2000 and 2024. Eligible studies examined DAF conditions applied to speech tasks with stuttering-related outcomes. Meta-analyses were conducted using a random-effects model, with subgroup analyses by disfluency type, delay time, speech task, stuttering severity, and participant age. Results Of the 194 records screened, eight studies involving a total of 98 participants in total met the inclusion criteria, and five studies involving 61 participants were eligible for quantitative synthesis. Each study included 8-20 participants ranging from school-age children to adults. Most participants were male, and stuttering severity ranged from mild to severe. DAF conditions were evaluated using oral reading and spontaneous speech/monologue tasks. Meta-analysis revealed no significant overall benefit of DAF compared with normal auditory feedback (NAF; mean difference = -1.46, 95% CI [-4.83, 1.91]). Conclusion DAF alone does not consistently reduce disfluencies; however, specific populations and conditions may derive greater benefits from it. Larger, well-controlled studies are needed to clarify its therapeutic potential and clinical applications. What this paper adds What is already known on this subject Delayed auditory feedback (DAF) has been reported to improve fluency in people who stutter and is used in several assistive devices. However, its independent effect remains unclear because DAF is often combined with other altered auditory feedback conditions. What this study adds to existing knowledge This systematic review and meta-analysis evaluated the exclusive effect of DAF on stuttering. The results indicate that DAF alone does not consistently reduce disfluency compared with NAF, although certain conditions (e.g., shorter delays or reading tasks) may show greater benefits. What are the potential or actual clinical implications of this work? Clinicians should interpret the fluency-enhancing effects of DAF cautiously when used alone. Further well-controlled studies are needed to determine which individuals and speech contexts may benefit most from DAF-based interventions.

Psychology

Healthy Public Policy Must Build Capacity: Analysing the Implementation of 3.2.2A, Australia's New Food Safety Standard.

Barnes J et al. · Jul 1, 2026

Issue addressed The integration of a new standard for food safety in Australia signifies a notable step toward national unity in the adoption of Hazard Analysis and Critical Control Point (HACCP) principles and contemporary food safety management tools for the food service and retail sector. The standard introduces key measures, including certification of food safety supervisors, food safety training requirements for food handlers, and means for substantiating control of food safety hazards throughout key food handling processes. Methods This study explored the experiences and perspectives of local regulators regarding the implementation and feasibility of the new standard. Data were collected via an online survey and semi-structured interviews with Environmental Health Practitioners across two Australian states. Results Findings reveal that implementation of the standard varied between states, largely shaped by the degree of support provided by respective state authorities. Six key barriers to effective implementation emerged from participant accounts. Conclusions In response, five targeted recommendations are proposed, grounded in established health promotion principles. Until these challenges are adequately addressed, the standard risks remaining ineffectual, limiting its capacity to enhance public health outcomes. SO WHAT?: The key to effective implementation and realisation of Standard 3.2.2A as healthy public policy lies within the central tenets of public health theory and practice.

Agricultural and Biological Sciences

Diffusion-weighted Imaging Distortion in Prostate MRI: A Cross-sectional Study Comparing Supine and Prone Positioning.

Lee KL et al. · Jul 1, 2026

Objectives Diffusion weighted imaging (DWI) is a key component of multiparametric (mp) prostate MRI. DWI using echo-planar techniques is susceptible to distortion at the recto-prostatic air-tissue interface. This study was to determine whether prone patient positioning reduces adjacent rectal air and DW image distortion when compared with standard-of-care supine positioning. Materials and methods This prospective study included consecutive patients undergoing mpMRI for suspected PCa between 2023 and 2024. Prostate segmentation was performed on DW and contrast-enhanced images. DWI distortion was measured quantitatively. Qualitative image quality of DWI and T2-weighted imaging (T2WI) was evaluated using PI-QUAL version 2; a separate 5-point clinically based Likert scale was employed to evaluate the volume of rectal air adjacent to the prostate. Results Fifty-two patients were enrolled. In total, 58% of patients expressed a preference for supine imaging versus 20% for prone imaging. Qualitative DWI image quality improved significantly in the prone position [median: 4 (3 to 4)] versus supine [3 (1 to 4)]; P 4 cm 3 of supine rectal air (n = 19), distortion was significantly reduced by prone imaging [3.49 mm (2.84 to 4.03)] compared with supine [4.60 mm (3.17 to 5.95)]; P = 0.02. The mean additional scanning time for the necessary prone imaging was 8 minutes 18 seconds. Conclusions Prone positioning significantly reduces DWI distortion artefact when rectal air is present, but consistently results in degraded T2WI quality.

Medicine

Mex-3 RNA-binding family member A limits macrophage ferroptosis-associated injury linked to the SLC7A11/GPX4 pathway in diabetic atherosclerosis.

Ma Y et al. · Jul 1, 2026

Background Diabetes accelerates atherosclerotic plaque expansion and loss of stability, but the plaque-resident mechanisms through which the diabetic milieu promotes macrophage lipid-oxidative injury are not fully understood. Methods We used apolipoprotein E-deficient (ApoE -/- ) mice with Mex-3 RNA-binding family member A (MEX3A) deficiency and primary bone marrow-derived macrophage (BMDM) experiments under diabetic conditions to investigate the role of MEX3A in diabetic atherosclerosis and macrophage lipid-peroxidation injury. Results MEX3A loss worsened diabetic atherosclerosis while leaving body weight, glycaemia and lipid measurements largely unchanged relative to diabetes alone. MEX3A deficiency enlarged aortic lesions, enhanced lipid deposition, increased macrophage content, expanded necrotic cores and thinned fibrous caps, while reducing collagen content. In lesional macrophages, loss of MEX3A coincided with increased lipid reactive oxygen species, malondialdehyde, increased labile iron, 4-hydroxynonenal, a disturbed glutathione redox state, mitochondrial abnormalities compatible with ferroptotic stress, lower GPX4/SLC7A11 and higher ACSL4. CRISPR/Cas9-mediated Mex3a knockout in BMDMs recapitulated this phenotype, whereas restoring MEX3A blunted it. RNA immunoprecipitation-qPCR together with actinomycin D decay analyses demonstrated preferential recovery of Slc7a11 and Gpx4 transcripts with MEX3A and decreased stability of Slc7a11 and Gpx4 mRNAs after Mex3a knockout. GPX4 or SLC7A11 overexpression reduced lipid-peroxidation injury in Mex3a-knockout macrophages, whereas Gpx4 or Slc7a11 knockdown weakened the protection conferred by MEX3A re-expression. Ferrostatin-1 partially attenuated macrophage lipid peroxidation and plaque injury. Conclusions Together, these results place MEX3A among the protective regulators of diabetic plaque stability and support a MEX3ASLC7A11/GPX4-linked ferroptosis-associated mechanism in plaque macrophages. Key points MEX3A deficiency worsens diabetic atherosclerosis without further aggravating systemic metabolic indices. Loss of MEX3A promotes plaque lipid deposition, macrophage accumulation, necrotic core expansion and fibrous cap thinning. MEX3A limits macrophage lipid-peroxidation injury linked to the SLC7A11/GPX4 pathway. Ferrostatin-1 partially attenuates macrophage lipid peroxidation and plaque injury associated with MEX3A deficiency.

Medicine

Feasibility and Acceptability of a Breastfeeding Support Intervention Among Mothers of Infants Under Six Months Old Discharged From Malnutrition Treatment in Kilifi County.

Unda J et al. · Jul 1, 2026

Malnourished infants under 6 months experience poor growth and development. A pilot study applied the WHO guideline for treatment of acute malnutrition and found that it was possible to re-establish exclusive breastfeeding during inpatient treatment. However, weight gain could not be sustained 6 weeks after discharge suggesting that follow-up breastfeeding support may be required. Our study aimed to pilot the feasibility and acceptability of a follow-up intervention among infants discharged from malnutrition treatment. A home-based post-discharge breastfeeding support intervention was developed to be delivered by breastfeeding peer supporters in a series of three home visits and three intervention phone calls over a period of 7 weeks after discharge from the hospital. The intervention was piloted among 20 mother-infant pairs providing quantitative and qualitative data from a standardized questionnaire and in-depth interviews. Data was analyzed descriptively and using thematic analysis. The median infant birth weight was 2.07 kg and > 50% of the mothers had primary education or less. The intervention was feasible with 100% reach of the target participants with a geographic spread of 25% urban and 75% rural areas. All intervention components were applied consistently, resulting in 100% adherence over a 6-month period. The intervention was accepted by mothers, perceived to be beneficial, and reported to increase breastfeeding confidence. It was adaptable, adjusting to emerging challenges, and was successfully integrated into existing health services. The pilot demonstrated high feasibility and widespread acceptance of the intervention. Its effectiveness to improve weight gain among recovering infants is being determined in a trial.

Nursing

Dipolar Order Mapping Based on Spin-Lock Magnetic Resonance Imaging.

Gao Z et al. · Jul 1, 2026

Inhomogeneous magnetization transfer (ihMT) is sensitive to dipolar order associated with motion-restricted macromolecules and can be characterized by the dipolar relaxation time T1D$$ {T}_{1D} $$ . In this study, we propose a spin-lock MRI framework for T1D$$ {T}_{1D} $$ quantification. Specifically, we introduce a T1D$$ {T}_{1D} $$ -sensitive metric, RATIOdosl$$ RATI{O}_{dosl} $$ , derived from the distinct relaxation rate Rdosl$$ {R}_{dosl} $$ , defined as the difference between dual-frequency and single-frequency R1ρ$$ {R}_{1\rho } $$ measurements. To enable dual-frequency spin-lock acquisition, we developed a dedicated rotary-echo spin-lock sequence. Based on this framework, we further estimated T1D$$ {T}_{1D} $$ and the macromolecular proton fraction (MPF) within a unified acquisition. The proposed method was evaluated using numerical simulations, phantom experiments, and in vivo imaging in the healthy human brain. Simulations demonstrated high sensitivity of RATIOdosl$$ RATI{O}_{dosl} $$ to T1D$$ {T}_{1D} $$ and supported the robustness of the proposed approach under the investigated conditions. Phantom experiments showed measurable ihMT contrast and supported the feasibility of T1D$$ {T}_{1D} $$ estimation using RATIOdosl$$ RATI{O}_{dosl} $$ . In vivo experiments demonstrated simultaneous T1D$$ {T}_{1D} $$ and MPF mapping using only three spin-lock-prepared images. Across 10 healthy volunteers, mean white matter T1D$$ {T}_{1D} $$ values ranged from approximately 3.70 to 4.80 ms. By requiring only three contrast-prepared images, the proposed technique provides a rapid framework for simultaneous T1D$$ {T}_{1D} $$ and MPF mapping and may facilitate further investigation of dipolar-order-sensitive microstructural imaging in vivo.

Medicine