Fotou E et al. · Jul 1, 2026
Brain tumor therapy remains limited by the blood-brain barrier (BBB), which restricts drug access. BBB-penetrating peptides offer a promising strategy for delivering therapeutic and diagnostic payloads. Angiopep-2 is a well-established vector, yet novel radioconjugates based on this vector remain of interest. We report the synthesis and evaluation of DOTA-Angiopep-2 for radiolabeling with Lutetium-177 ( 177 Lu) and Terbium-161 ( 161 Tb). Notably, 177 Lu serves as a β- and γ-emitter, whereas 161 Tb is an Auger and β-emitter; both are utilized in therapy and SPECT imaging. Peptides were synthesized via solid-phase peptide synthesis. Cytotoxicity assays in T98 glioblastoma cells showed that Angiopep-2 is well-tolerated, maintaining ~100% viability at 20 μM and a moderate decline up to 100 μM. Radiolabeling achieved yields > 95% with excellent radiochemical stability at room temperature for up to 10 days and moderate stability in the presence of human serum. Biodistribution in healthy CFW mice showed a brain-associated radioactivity of 0.24% ± 0.05% IA/g at 5 min p.i. and a 12-fold increase in the brain-to-blood ratio (0.028-0.339) by 60 min p.i. These results support DOTA-Angiopep-2 as a versatile platform for radionuclide delivery and a potential candidate for future glioma-targeted studies. Further studies in tumor-bearing models are ongoing to evaluate therapeutic efficacy and translational potential.
Materials Science
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
Barakji JA et al. · Jul 1, 2026
Background Thrombocytopenia is frequent in adult intensive care unit (ICU) patients and may contribute to adverse outcomes, including bleeding, morbidity and mortality. To reduce the risk of bleeding, platelet transfusions are commonly used, yet transfusion thresholds vary, and the evidence base is very limited. Randomised clinical trials investigating platelet transfusion strategies in ICU patients are therefore a high research priority. With this survey, we aim to assess ICU doctors' willingness to randomise adult ICU patients to restrictive versus liberal platelet transfusion thresholds across clinically relevant scenarios in a future randomised trial. Methods We will conduct an international, web-based survey targeting ICU doctors within an established research network. The survey includes questions on respondent characteristics and willingness to enrol patients with an indication for platelet transfusion across a range of transfusion thresholds in different clinical scenarios, including non-bleeding patients, those undergoing invasive procedures, and those with bleeding. The survey has been pilot-tested and refined twice before distribution. We will summarise results using descriptive statistics and conduct stratified analyses by country and ICU type. Conclusions This international survey will assess ICU doctors' willingness to randomise adult ICU patients to restrictive versus liberal platelet transfusion strategies across multiple clinical scenarios.
Medicine
Nguyen HV. · Jul 1, 2026
Issue addressed Underage alcohol use has been linked to risks of physical, mental, and social harms to young people. Despite the known risks, research shows that parents may choose to supply alcohol to their children on occasions for various reasons. This has prompted several health promotional campaigns aimed at parents to discourage the practice of parental supply of alcohol, but there has been little evidence of how the messages are received by the target audiences, i.e., parents of adolescents. Methods Grounded in the existing literature on alcohol-related harms, social dimensions and communication of risks, the current paper conducted a qualitative analysis of interviews with parents of adolescents to understand their interpretation of risks in a series of Australian health promotion campaigns that addressed underage drinking. Result The study demonstrated how target audiences brought in their own lived experiences and social worldviews to interpret and internalise messaging about risks in ways that are nuanced and situational. Conclusions The findings demonstrated how parents' lived experiences and worldviews influenced their interpretation and alignment with the health promotion messages about parental supply of alcohol. While the ways the parents negotiated with the health promotion messages may not be scientifically-grounded, it was not always due to unawareness of risks but based upon strategies and assessment of risks in situational contexts. SO WHAT?: Understanding of how lived experiences inform interpretation of health promotion campaigns has implications for more effective alcohol-related risk communication aimed at behaviour change to reduce alcohol-related harms among young people.
Medicine
Chintolo E et al. · Jul 1, 2026
Background Little is known about myocardial perturbations in African children hospitalised with severe anaemia. Methods An observational study nested within a clinical trial of blood transfusion was conducted on the paediatric ward in Blantyre, Malawi. Children were ages 2 months-12 years hospitalized with uncomplicated severe anaemia (haemoglobin 4-6 g/dl). By randomisation, 13 children received 30 ml/kg whole blood, 13 received 20 ml/kg whole blood and 26 had no immediate transfusion (usual care). We measured standard parameters of cardiac function using ultrasonic cardiac output monitoring (USCOM) at enrolment, 8 and 24 hours and discharge. Results Fifty-two children, median age 39 months (interquartile range [IQR] 25-58) and median haemoglobin 5.1 g/dl (IQR 4.8-5.6) were studied. Severe tachycardia and tachypnoea over time corrected faster in the transfused arms than the controls. At enrolment, the stroke volume index was within the normal range and 26/52 (50%) had a cardiac output index (COI) >97.5% the standard centile. The COI decreased in all arms by discharge but was greatest in the transfusion arms (p=0.05 for 20 ml/kg and p=0.009 for 30 ml/kg). A higher volume or receipt of whole blood did not worsen cardiac function. No child required diuretics. Conclusions The data generated by this small but granular study of haemodynamic and cardiac function provide reassuring physiological evidence showing the safety of higher doses of blood transfusion than currently recommended. It also supports the findings of a secondary analysis of the Transfusion and Treatment of Severe Anaemia in African Children trial indicating that whole blood transfusions are safe. These data support the new evidence-based paediatric transfusion algorithm for anaemic African children and its recommendation for safe use.
Medicine
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
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
Zhong D et al. · Jul 1, 2026
Renal aging shortens healthspan and propagates organ dysfunction beyond the kidney, yet its molecular drivers remain incompletely defined. Here we identify microsomal prostaglandin E synthase-2 (mPGES-2) as a critical regulator of renal aging and its skeletal consequence. Genetic ablation of Ptges2 improved health indices in aged mice, prolonged median survival, and markedly alleviated glomerulosclerosis, podocyte injury, and renal senescence. Single-cell transcriptomic analysis, together with podocyte- and tubule-specific knockout models, showed that podocyte mPGES-2, rather than tubular mPGES-2, is the dominant intrarenal driver of aging-related kidney injury. Mechanistically, mPGES-2 promoted podocyte senescence through a PGE 2 /EP1 signaling axis. Podocyte-specific Ptges2 deletion also mitigated age-related osteoporosis and restored renal calcitriol and α-klotho, supporting a kidney-bone mechanism secondary to impaired renal endocrine function. Consistent with the genetic models, pharmacological inhibition of mPGES-2 with SZ0232 attenuated renal aging and improved bone microarchitecture in aged mice. Both genetic deficiency and pharmacological inhibition of mPGES-2 were well tolerated, with no overt adverse effects on major organs. These findings identify podocyte mPGES-2 as a druggable determinant of renal aging and a potential therapeutic target for aging-associated osteoporosis.
Medicine
Li PWC et al. · Jul 1, 2026
Background ICU survivors frequently develop post-intensive care syndrome (PICS), a cluster of persistent physical, cognitive and psychological impairments that substantially impair recovery and quality of life. Existing rehabilitation approaches are predominantly monomodal and exercise-focused, yielding inconsistent outcomes and failing to address the multidimensional burden of PICS adequately. Aim To evaluate the feasibility and preliminary efficacy of COMBAT-ICU, a home-based Combined Activity and Cognitive Intervention for ICU survivors at risk of PICS. Study design A parallel, three-arm, assessor-blinded pilot randomised controlled trial randomised 36 ICU survivors (1:1:1) to COMBAT-ICU-an 8-week blended program of progressive physical exercise and computerised cognitive training delivered via supervised home visits and online sessions-an exercise-only group or an attention control group. The primary outcomes were feasibility (recruitment, retention and intervention adherence) and safety; secondary exploratory outcomes encompassed PICS severity, physical capacity, cognition, mental health and health-related quality of life (HRQoL). Results COMBAT-ICU was feasible and safe (36 ICU survivors randomised), with no serious adverse events recorded, retention exceeding 82% at follow-up and session adherence exceeding 90%. COMBAT-ICU produced significantly greater reductions in PICS severity versus attention control at post-intervention (p = 0.014, d = -0.50) and follow-up (p = 0.043, d = -0.45). It also yielded clinically meaningful moderate-to-large effect sizes for walking endurance, global cognition, short-term memory and HRQoL index scores compared with attention control and consistently outperformed exercise-only across cognitive and HRQoL domains. Between-group differences in anxiety and depressive symptoms were small across all active groups. Conclusions COMBAT-ICU is feasible and shows promising preliminary efficacy in mitigating PICS. Integrating cognitive and physical training within a home-based blended delivery model may confer synergistic benefits beyond exercise alone, providing domain-specific effect size estimates and a compelling rationale for definitive multicentre trials. Relevance to clinical practice Multidomain home-based rehabilitation is a viable post-discharge strategy for ICU survivors. COMBAT-ICU offers an evidence-informed, scalable framework to enhance survivorship care, pending confirmation in larger, fully powered trials. Trial registration The trial was registered at ClinicalTrials.gov (NCT06117761).
Medicine
Hong J et al. · Jul 1, 2026
Accelerating global climate risks increasingly threaten renewable energy infrastructure (REI). However, little evidence on heterogeneous impacts of climate risks on REI across countries, the moderating role of REI resilience, and post-disaster recovery patterns is available, despite their critical importance for guiding resilient energy transitions and informing disaster risk governance. To address these issues, we employed dynamic panel models in 215 countries and regions from 2004 to 2022. We find that (1) climate risk significantly damages global REI, with disaster frequency and institutional resilience having mitigation effects. (2) The damage follows an inverted U-shape with increasing disaster frequency and an "N" shape with increasing disaster duration. As renewable energy generation share increases, the damage intensifies and progresses through four increasingly severe stages. (3) Economic resilience exhibits a "Creative destruction" effect in developed nations and a "Build back better" recovery in poor countries. (4) Although social resilience worsens climate disaster damage globally, high disaster frequency and institutional resilience can facilitate a "Recovery to trend" in socially advanced nations. (5) REI in South America is the most affected, followed by Asia and Africa, whereas Europe is the least impacted. Wind energy is the most vulnerable, followed by bioenergy, solar, and hydropower.
Engineering