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On the role of personality traits in shaping responses to physician payment systems
No full textWe study the interplay of extrinsic and intrinsic motivations regarding the quality of care physicians provide. In particular, we analyze the role of personality traits in explaining the heterogeneity in responses to common physician payment systems. We utilize data from several behavioral experiments (659 subjects) on physician payment systems and from post-experimental surveys on personality traits. The experiments use equivalent health framings and decision situations with either fee-for-service (FFS) or capitation (CAP) as baseline payments. Blended payment systems—performance pay and mixed systems—are introduced at a within-subject level to complement the baseline payments. We find that personality traits contribute to explaining some heterogeneity in behavioral responses to payment incentives. Under baseline systems, more agreeable individuals provide higher quality of care. Blended payment systems enhance the aggregate treatment quality. Nevertheless, we observe a moderation effect in CAP-based blended systems: by Conscientiousness in mixed schemes, and by Conscientiousness and Agreeableness under performance pay. Quality increases are smaller for individuals higher in these traits. The moderation can be mainly explained by a ceiling effect, though we also observe a quality reduction/crowding-out effect. Our findings emphasize the importance of the interplay between financial incentives, physician provision behavior, and personality traits and inform the discussion on the design of tailored physician payment systems.</p
Temporal Changes in Fetal and Maternal Parameters in Early-Onset Fetal Growth Restriction:A Multicenter, Retrospective Cohort Study
No full textObjective(s): Timing of birth is complex in early-onset fetal growth restriction (FGR) and the literature is limited regarding the exact sequence of changes in antenatal parameters. This study aimed to examine this sequence in a large early-onset FGR cohort. Design: Multicenter, retrospective cohort study. Setting: Six tertiary care hospitals in the Netherlands. Population: A post hoc analysis of the OPtimal TIming of antenatal COrticosteroids in early-onset fetal growth REstriction (OPTICORE) study was performed. Methods: Repeated measures of antenatal parameters were assessed routinely from diagnosis to birth. Mixed-effects models were used to determine the probability of abnormality (binary) and the trend (Z-score, continuous) over time for each parameter (< 32 and ≥ 32 weeks). Main Outcome Measures: The time sequence of changes in fetal and maternal health parameters from diagnosis to birth in early-onset FGR pregnancies. Results: A total of 1453 patients were included, of whom 1025 patients gave birth < 32 weeks and 428 ≥ 32 weeks, with median gestational ages of 29 + 3 weeks (IQR 27 + 6, 30 + 5) and 34 + 4 weeks (IQR 33 + 0, 37 + 0), respectively. The most apparent changes in fetal parameters in the last days preceding birth comprised: absent/reversed end-diastolic velocity of the umbilical artery and cardiotocography abnormalities. Regarding maternal parameters, an increased probability of antihypertensive agent(s) use was seen shortly preceding birth < 32 weeks. Conclusion(s): This large cohort of early-onset FGR pregnancies provides a time sequence of fetal and maternal health parameters from diagnosis to birth, which could inform clinical management.</p
Thyroid Arterial Embolization for the Management of Benign and Malignant Thyroid Disease:A Systematic Review
No full textObjective: Thyroid arterial embolization (TAE) is a minimally invasive procedure that reduces blood flow to the thyroid gland by injecting particles into the superior and/or inferior thyroid artery. It has been sporadically used for goiter, Graves’ disease, thyrotoxicosis, and thyroid cancers, but no reviews have assessed its safety and efficacy.Methods: Databases were searched until January 2024. English-language studies on TAE were included. Studies using TAE for arterial aneurysms or lacking full text were excluded. No meta-analyses were performed. Results: Among 1203 retrieved articles, 24 studies met inclusion criteria: TAE was used for goiter (8 studies), Graves’ disease (8), thyroid malignancy (5), and thyrotoxicosis (4). The primary outcome was safety and efficacy. Limited evidence suggested benefits, including goiter size reduction and symptom relief with minimal complications like neck pain and hematoma. In Graves’ disease, TAE induced hormonal and immunologic changes, normalizing thyroid function in some patients. In thyroid cancer, it alleviated symptoms and facilitated safer surgery. However, serious risks, including nontarget embolization and mortality, require caution. Conclusion: This review presents an overview of the literature regarding safety and efficacy of TAE. The lack of robust data, significant risk of serious complications (including nontarget embolization and mortality), and absence of a standardized, safe protocol preclude recommending TAE as a routine treatment option. Given the high efficacy and lower complication rates of current established therapies, TAE should only be considered in exceptional circumstances, when standard treatments have failed or are contraindicated, and then only at specialized centers with extensive embolization expertise.</p
Association of anesthesia strategies with outcomes in endovascular treatment for distal and medium vessel occlusions:A propensity score-matched analysis of the MR CLEAN registry and meta-analysis
No full textBACKGROUND:Recent trials did not demonstrate the benefit of endovascular therapy (EVT) for distal or medium vessel occlusions (DMVOs), raising questions about factors influencing outcomes. Anesthesia choice may play a role, yet its impact remains unclear. This study assessed general anesthesia (GA) versus non-GA in EVT for DMVOs, evaluating procedural, functional, and safety outcomes. PATIENTS AND METHODS: Patients undergoing EVT for AIS due to anterior DMVOs in the middle cerebral artery (MCA-M2, M3, M4) and anterior cerebral artery (ACA-A1, A2, A3) from the MR CLEAN registry between March 2014 and December 2018 were included. They were stratified into GA and non-GA groups, with propensity score matching employed to adjust for differences in baseline risk. Primary outcomes included functional outcomes at 90 days, assessed by ordinal regression analysis of modified Rankin Scale (mRS) scores at 90 days, and recanalization rates measured by Thrombolysis in Cerebral Infarction (TICI) scores. Secondary outcomes included dichotomized mRS scores, death at 90 days, and symptomatic intracranial hemorrhage (sICH). A systematic review and meta-analysis of relevant DMVO studies with a random effects model was performed. This study was registered with PROSPERO (CRD42024607294). RESULTS: Among 5193 patients in the registry, 657 were eligible for our study, with 506 in the non-GA group, and 151 in the GA group. The median age was 73 years (IQR 64-81) in the non-GA group and 73 years (IQR 61-80) in the GA group (p = 0.35). The proportion of male patients was 50.2% in the non-GA group and 57.0% in the GA group (p = 0.15). In the matched cohort (n = 170), recanalization rates were higher in the GA group compared to the non-GA group (excellent recanalization rates (TICI2c/3): 61.0% vs 32.1%; OR 3.31, 95% CI (1.74-6.29), p < 0.001). There were no significant differences in the overall distribution of functional outcomes at 90 days (common OR 0.93, 95% CI (0.54-1.56), p = 0.77). Mortality was comparable between groups (34.1% vs 31.8%; OR 1.11, 95% CI (0.59-2.11), p = 0.74), and there was no significant difference in sICH (12.9% vs 5.9%; OR 0.42, 95% CI (0.14-1.27), p = 0.12). The systematic review and meta-analysis included six studies with a total of 3521 patients. The pooled analysis indicated that GA was associated with significantly lower rates of excellent functional outcomes (mRS 0-1: OR 0.74, 95% CI (0.58-0.94), p = 0.01) and higher mortality (OR 1.36, 95% CI (1.07-1.74), p = 0.01) compared to the non-GA at 90 days. DISCUSSION AND CONCLUSION: In the MR CLEAN Registry, GA was associated with higher recanalization rates during EVT, but this technical advantage did not translate into improved 90-day functional outcomes. Our meta-analysis further indicated that non-GA strategies were associated with better functional recovery and lower mortality. These associations, however, warrant cautious interpretation given potential unmeasured confounders, including blood pressure management and conversion from non-GA to GA. Broad categorization of anesthesia as GA versus non-GA overlooks critical factors such as agent selection, physiological targets, and intraoperative monitoring, which may substantially impact cerebral perfusion and outcomes. Further prospective randomized studies with detailed anesthetic data and expert input are needed to refine these findings and guide clinical practice.</p
Development of a Complex Human In Vitro Model of Endochondral Ossification.
No full textDuring development and regeneration, bone is formed by endochondral ossification (EO) through the remodeling of a cartilage template. This complex process involves multiple cell types and interactions that cannot currently be modeled in vitro. This study aimed to develop a novel tissue-engineered human in vitro model of certain aspects of the early stages of EO by integrating cartilage which undergoes mineralization, self-assembled vascular networks, and osteoclasts into a single system. We first studied the dynamics of osteoclastogenesis and vascularization in an in vivo model of stromal cell-mediated EO, to inform our in vitro system. Next, we aimed to develop a fully human cell-based three-dimensional model of EO by combining pediatric bone marrow stromal cells differentiating into chondrocytes, osteoclasts derived from human CD14+ monocytes, and human umbilical vein endothelial cells and adipose-derived stromal cells as vessel-forming cells. We investigated how mineralizing cartilage affects osteoclast and vessel formation in vitro through separate cartilage-osteoclasts and cartilage-vessels cocultures. Finally, we combined these elements and established a complex in vitro model that supports the functionality of all these cell types and recapitulates chondrogenesis, cartilage mineralization, vessel formation and osteoclastogenesis. This integrated approach reaches unprecedented complexity and will enable new tissue engineering strategies to model skeletal diseases or cancer metastasis to the bone.</p
A T-cell receptor targeting <i>RUNX1 </i>frameshift mutations in acute myeloid leukemia
No full textRunt-related transcription factor 1 (RUNX1) is a key regulator of hematopoietic differentiation. RUNX1 mutations in acute myeloid leukemia (AML) are associated with poor prognosis. One-third are frameshift mutations encoding an oncogenic protein with an elongated C-terminus translated in an alternative reading frame. Here, we investigated whether the alternative reading frame of oncogenic RUNX1 can be targeted by immunotherapy. We introduced a construct with a RUNX1 frameshift mutation into B-cell lines with common HLA class I alleles and identified 13 neopeptides by immunopeptidomics. To investigate whether these peptides are neoantigens, peptide-MHC tetramers were used to screen healthy individuals for RUNX1 neoantigen-specific CD8 T cells. T-cell clones were isolated against 5 neoantigens in 4 HLA alleles. Two neoantigens were recognized on an HLA-B*07:02-positive AML cell line with an endogenous RUNX1 frameshift mutation. The T-cell receptors (TCRs) of these clones were sequenced, and analyzed after transfer into CD8 T cells. One TCR induced effective killing of RUNX1-mutated AML cells in vitro and in immunodeficient mice. TCR-engineered T cells also killed patient-derived AML cells, including leukemic stem cells. In conclusion, we showed that RUNX1 frameshift mutations can be effectively targeted, demonstrating the potential relevance of TCR-based immunotherapy to treat patients with RUNX1-mutated AML.</p
Artificial intelligence and animal farming:a scenario of drivers, barriers, and impacts in 2032
No full textIn animal farming, there is the hope that artificial intelligence (AI) will improve efficiency and increase profits while providing solutions to reduce pollution and pesticide use and improve environmental sustainability, animal health and welfare. However, many are also concerned about AI’s ethical, legal, social, and economic impacts. These include the instrumentalisation of animals, bias caused by AI in how animals are portrayed, allowing the continuation of a harmful farming industry, and concerns around power asymmetries, data ownership, and copyright infringements. Therefore, there is a tension between the potential benefits and drawbacks of AI use in animal farming. This paper takes a forward-looking view of the benefits and challenges that AI may create in animal farming by the year 2032. Through several iterative rounds with stakeholders, this paper maps out a future scenario of AI in animal farming, identifying technological developments alongside potential drivers, barriers, and impacts. The scenario concludes with five recommendations for policymakers: 1. Initiate education programmes on AI in the sector; 2. Create ethical guidelines for AI in animal farming; 3. Science policy should be realistic and not only rely on technical solutions like AI; 4. Ensure public safety from harm caused by AI; 5. Implement better guidance on data-sharing in the sector.</p
Drivers of clinical resistance to venetoclax and hypomethylating agents in acute myeloid leukemia and strategies for improving efficacy
No full textThe B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (VEN) in combination with hypomethylating agents (HMAs) has improved treatment outcomes for acute myeloid leukemia (AML) patients unfit for intensive chemotherapy and is increasingly used in the relapsed/refractory setting. However, primary resistance remains a significant challenge, affecting 20%–35% of treatment-naïve and around 50% of previously treated AML patients. To investigate the mechanisms driving primary resistance to VEN–HMA therapy, we analyzed genetic, transcriptomic, BCL-2 family protein expression, and ex vivo drug sensitivity data from 101 AML patients and correlated these profiles with clinical outcomes to VEN–HMA. Our study found that blasts from refractory patients exhibit an elevated BCL-XL/BCL-2 protein expression ratio, an immature CD34+CD38− phenotype, and frequent TP53 mutations. Consistent with the high ratio of BCL-XL/BCL-2, resistant samples showed increased ex vivo sensitivity to the dual BCL-2/BCL-XL inhibitor navitoclax. In addition, SMAC mimetics were effective in refractory blasts, which correlated with high TNF gene expression in these cells. Ex vivo treatment with the combination of navitoclax and SMAC mimetics further enhanced the eradication of VEN–HMA refractory blasts, although toxicity was also observed in healthy CD34+ cells. In conclusion, our integrative analysis identifies molecular signatures associated with primary VEN–HMA resistance and highlights BCL-2/BCL-XL inhibition and SMAC mimetics as therapeutic strategies to target resistance.</p
Risk factors for breast fibrosis and unfavorable cosmetic outcomes after breast conserving therapy in the contemporary treatment era:a systematic review
No full textBackground: This systematic review aimed to identify risk factors for fibrosis and unfavorable cosmetic outcomes after breast conserving therapy (BCT) for breast cancer in the light of contemporary oncoplastic surgery and 3D-radiotherapy techniques. Methods: The systematic literature search was carried out in Embase, Ovid Medline, Cochrane Central Register of Controlled Trials, and CINAHL. Studies published after 2005, reporting two or more risk factors for fibrosis or unfavorable cosmetic outcomes as primary outcomes were eligible for inclusion. Only prospective studies with 100 or more patients analyzed were included. The Quality In Prognosis Studies tool and Cochrane risk-of-bias tool were used to assess risk of bias. Patient, tumor, and treatment-related predictors were identified. Results: Twelve papers investigating 12.118 patients were identified. Risk factors for both the development of fibrosis and unfavorable cosmetic outcomes were increasing age, larger tumor size, re-resection, poor early cosmetic outcomes before the start of radiotherapy, high boost dose, boost volume per 10 cc, homogeneity-index, dose whole breast irradiation, and adjuvant chemotherapy. No specific risk factors in the setting of BCT with complex oncoplastic surgery techniques or ultra-hypo fractionated radiotherapy were identified in this review. Conclusion: The risk factors identified in this review are largely similar to those found in 2D-radiotherapy studies; dose homogeneity was additionally identified. Administering chemotherapy before radiotherapy should be considered for patients requiring both treatments. However, the lack of sufficient high-quality data regarding BCT with (complex) oncoplastic surgery techniques and ultra-hypo fractionated radiotherapy schedules address the need for large, multidisciplinary prospective studies with long-term follow-up.</p
Clinical and Liquid Biomarkers of 20-Year Prostate Cancer Risk in Men Aged 45 to 70 Years
No full textImportance:Prostate cancer incidence is projected to double by 2040, yet optimal risk stratification approaches for screening remain unclear despite recent international endorsements of organized programs that call for risk-adapted algorithms using readily available biomarkers. Objective:To identify biomarkers for risk-adapted prostate cancer screening in men without prostate cancer. Design, Setting, and Participants:This cohort study used data from the Study of Health in Pomerania (SHIP), a prospective population-based research initiative in Germany that randomly invited participants aged 20 to 79 years who underwent comprehensive examinations with structured 20-year follow-up. Data were collected from October 17, 1997, through September 14, 2021, with final analysis completed November 16, 2025. Exposures:Baseline clinical and liquid biomarkers, including body mass index, waist-to-hip ratio, and glycated hemoglobin, together with prostate cancer–specific biomarkers of serum prostate-specific antigen (PSA) and magnetic resonance imaging–derived prostate volume and PSA density. Main Outcomes and Measures:The primary outcome was long-term prostate cancer incidence. Cumulative incidence functions for prostate cancer and death were treated as competing risks. Cause-specific Cox models were used to estimate risk and assess the association between baseline biomarkers and long-term incidence. Results:Among 2651 men included in the study (median [IQR] age, 54.0 [48.0-62.0] years), 1482 (55.9%) had low baseline PSA levels (<1.00 ng/mL), with a cumulative prostate cancer incidence of 0.1% (95% CI, 0.0%-0.4%), 0.6% (95% CI, 0.3%-1.2%), and 3.3% (95% CI, 2.1%-4.8%) at 5, 10, and 20 years, respectively. In 958 men (36.1%) with intermediate PSA levels (1.00-3.00 ng/mL), prostate cancer incidence was 1.4% (95% CI, 0.7%-2.3%), 5.0% (95% CI, 3.6%-6.6%), and 11.8% (95% CI, 9.2%-14.8%) at 5, 10, and 20 years, respectively. In 211 men (8.0%) with high PSA levels (>3.00 ng/mL), prostate cancer incidence was 14.5% (95% CI, 10.1%-19.7%), 28.3% (95% CI, 22.2%-34.8%), and 34.8% (95% CI, 27.5%-42.2%) at 5, 10, and 20 years, respectively. Cumulative prostate cancer incidence differed significantly among the PSA groups (P <.001). In univariable and multivariable Cox regression, age (hazard ratio [HR], 1.04; 95% CI, 1.02-1.07), PSA (HR, 1.06; 95% CI, 1.04-1.07), and PSA density (HR, 1.41; 95% CI, 1.30-1.52) remained consistently associated with prostate cancer risk, whereas other variables showed either no association or inconsistent results across models. Conclusions and Relevance:This cohort study found that a low baseline PSA level was associated with low long-term prostate cancer risk among men aged 45 to 70 years, supporting risk-adapted screening with extended intervals for men with low PSA levels.</p