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Low Target Attainment of Intravenous Cefuroxime in Critically Ill Term Neonates and Children:A Pooled Population Pharmacokinetics Study
No full textBackground and Objective: Cefuroxime is a widely prescribed beta-lactam antibiotic, particularly in pediatric cardiac and medical–surgical intensive care units. The aim of this study was to describe intravenous cefuroxime disposition in critically ill pediatric patients. Moreover, target attainment of currently applied dosing regimens was evaluated, and suggestions for improving these dosing regimens were provided. Methods: Two datasets were pooled for population pharmacokinetic (popPK) analysis, using NONMEM version 7.5. To assess the optimal target attainment (> 90% of patients with 100% time [T] > [4×] minimal inhibitory concentration [MIC]8mg/L), pharmacokinetic (PK) profiles of different dosage regimens (intermittent/continuous) were simulated using the estimated popPK parameters. Results: The cohort consisted of 45 pediatric patients with a median (interquartile range [IQR]) age of 391 days [31–3505] and body weight of 9.0 kg [5.0–29.8]. A two-compartment popPK model with first-order elimination and allometric scaling best described cefuroxime disposition. Intravenous cefuroxime clearance was estimated at 5.29 L/h/70 kg. Postnatal age and creatinine clearance (mL/min/1.73 m2) were the best descriptive covariates for the maturation of cefuroxime clearance. Simulations evaluating the current cefuroxime dosing regimens stratified for estimated glomerular filtration rate (eGFR) levels illustrated moderate (< 90%) (eGFR < 30 and 30–80 mL/min/1.73 m2) and poor (< 20%) (eGFR 80–120 and > 120 mL/min/1.73 m2) cefuroxime target attainment across the entire age range. Alternative dosing regimens, including four times daily schedules and continuous infusion, improved target attainment, particularly in older children and those with augmented renal clearance.Conclusions: These findings indicate that underexposure due to augmented renal function is possible when applying the current cefuroxime dosing regimens. Future research should focus on individualized dosing strategies to optimize cefuroxime exposure and efficacy in pediatric populations.</p
Social attunement and alcohol use:The role of age and gender
No full textBACKGROUND: Alcohol use typically peaks during adolescence and early adulthood, when its social reinforcement value is high, and then decreases as individuals take on more adult-like responsibilities. The present study investigates whether social attunement (SA) plays a role in higher alcohol use in adolescence as well as a lower alcohol use when aging.METHODS: This online study included an international sample of 683 alcohol users (16 - 81yrs). Participants completed a SA Questionnaire, an Implicit SA task (ISAT), and measures of alcohol use. The ISAT measured SA as the change in willingness to drink in response to peer feedback between two blocks of images representing social alcohol, social non-alcohol, and social non-drinking settings. Linear regressions were conducted to assess the association between SA and alcohol use, and the role of age and gender in these associations.RESULTS: Unlike expected, interactions between age and SA did not predict alcohol use across social situations regardless of feedback condition. However, exploratory post-hoc analyses using the total SA score per social condition showed significant interactions between age and SA in predicting alcohol use in social situations involving non-alcoholic or no drinks. In social non-alcohol drinking settings, SA was positively associated with alcohol use among younger participants, but this association became negative in older individuals. Contrastingly, in the social non-drinking condition, SA was negatively associated with alcohol use among younger participants, but this association became positive in older individuals.DISCUSSION: Depending on age and social setting, SA can both be a risk- or protective factor for alcohol use.</p
Balancing privacy and platform power in the mobile ecosystem:The case of Apple’s App Tracking Transparency
No full textIn 2021, Apple shook up the AdTech industry by introducing the iOS 14.5 update, which not only changed the default access to an app's advertising identifier but also restructured the process of user consent within mobile apps through the App Tracking Transparency (ATT) framework. Given that Apple dominates one of the main mobile operating systems (iOS), and one of the major mobile app store (Apple App Store) in the European Union (EU), the question arises to what extent such a powerful private party is able to govern privacy standards at this scale. While the introduction of the ATT has already raised competition concerns, its impact on privacy and data protection within the EU legal order remains largely unexplored. Therefore, this article investigates how the ATT affects EU privacy and data protection compliance and explores the extent of the General Data Protection Regulation (GDPR) in restricting the privacy regulator role of app stores and mobile operating systems. While the ATT limits certain privacy risks by limiting disclosures to third-parties, Apple is redefining core privacy concepts such as tracking. This may lead to the emergence of “walled gardens”, closed ecosystems which are managed and curated by their owners, which may alter the structure of the mobile ecosystem in general. The paper contributes to the overall discussion about the impact of private sector-led initiatives and powerful private actors in setting privacy standards
Outcomes for ER-positive CHEK2 c.1100delC breast cancer patients compared with breast cancer patients without the variant
No full textPurpose: Germline CHEK2 c.1100delC-associated breast cancer (BC) patients have been reported with worse prognosis than patients without the variant. However, results are based on older cohorts and treatment regimens. As part of the Hebon-CHEK2 study, we aim to study prognosis in a Dutch cohort of genetically tested ER-positive BC patients diagnosed from 2006 onwards. Methods: All patients underwent genetic testing based on personal and family history risk, and data on BC outcomes were collected. Hazard ratios (HRs) and 95 % confidence intervals (CI) for the association of CHEK2-status with prognosis were estimated via delayed entry Cox regression models, adjusted for age and year of diagnosis, tumor size, nodal status, and primary treatment regimens. Furthermore, we meta-analyzed our results with previous studies. Results: We included 480 CHEK2 BC patients and 944 BC patients without the variant. Median follow-up was 6.0 years. Heterozygotes were more often diagnosed with small tumors, and lymph node positive disease. No significant difference was found for recurrent disease and distant disease-free survival, neither before 5 years (HR = 0.73; 95 %CI = 0.35–1.53 and HR = 0.99; 95 %CI = 0.44–2.21, respectively), nor after 5 years follow-up (HR = 0.29; 95 %CI = 0.06–1.28 and HR = 0.39; 95 %CI = 0.10–1.39, respectively). Also no significant difference in BC-specific survival (HR = 0.77; 95 %CI = 0.42–1.39) or overall survival (HR = 0.69; 95 %CI = 0.43–1.08) was found. Meta-analysis of our results with previous studies showed a worse BC-specific survival for heterozygotes. Conclusion: In our study, with more recent years of diagnosis and treatment, we found no difference in prognosis, as opposed to previous studies. Further research is needed to validate our findings.</p
The Genitourinary Pathology Society and International Society of Urological Pathology Joint Expert Consultation Recommendations on intraductal carcinoma of the prostate
No full textConflicting practice recommendations regarding the grading of intraductal carcinoma of the prostate (IDCP) from two leading uropathology societies, the Genitourinary Pathology Society (GUPS) and the International Society of Urological Pathology (ISUP), are confusing for both pathologists and treating clinicians. The objectives of this consultation were to clarify unresolved issues regarding IDCP and atypical intraductal proliferation (AIP) terminology, diagnostic criteria, grading, and management implications, as well as to develop uniform reporting guidelines for IDCP and AIP, endorsed by both societies. A 32-member expert panel, composed of five core members, 25 expert urological pathologists, and two expert urologists, employed a modified Delphi process consisting of multiple rounds of consultation and voting. These were supplemented by discussions at the 2025 United States and Canadian Academy of Pathologists Annual Meeting to achieve expert consensus (defined as at least 67% agreement). Consensus was reached on several key issues. IDCP was regarded most commonly as reflecting the retrograde spread of invasive prostate cancer (PCa). IDCP diagnosis should be based on the Guo and Epstein criteria, supported by basal cell immunohistochemistry in cases that are difficult to distinguish from invasive PCa. The term AIP should be used only in equivocal proliferations where IDCP is favoured but the criteria are not fully met, and these should be reported as ‘AIP, suspicious for IDCP’. In the presence of invasive PCa, IDCP should generally be incorporated into Gleason grading irrespective of Grade Group (GG). However, a significant minority (30%) favoured excluding IDCP from the Gleason score if the invasive component was solely Gleason pattern (GP) 3. Pure IDCP (not associated with invasive PCa) and AIP, suspicious for IDCP, should not be graded. IDCP should not be incorporated in the grading of invasive PCa when it is spatially distinct from invasive PCa. A second opinion from a senior or dedicated GU pathologist and discussion within a multidisciplinary management setting should be considered, in the rare settings of pure IDCP or GP3 + IDCP (formerly GG1 + IDCP scenario). This joint GUPS–ISUP consultation provides unified recommendations for the diagnosis, terminology, grading, and reporting of IDCP and AIP, and will pave the way for the development of future IDCP/AIP WHO guidelines. Their adoption should reduce interobserver variation, facilitate consistent communication with clinicians, and improve patient management.</p
Red blood cell–derived transglutaminase 2 influences thrombus formation
No full textBackground: Red blood cells (RBCs) are important constituents of venous clots and contribute to thrombus size and stability. However, it remains unclear whether and how RBCs affect the thrombus. Transglutaminase (TG)2), a protein with similar activity to factor XIIIa, may influence thrombus characteristics. Objectives: We explored whether RBC-derived TG2 influences thrombus characteristics using a novel approach involving TG2 knockout (KO) RBCs. Methods:Inhibitors and TG2 KO RBCs were used in clotting assays. In vitro–generated clots were analyzed using advanced microscopy techniques to quantify the fibrin network. Whole blood clotting kinetics were assessed by thrombin generation assay and thromboelastography. Vesiculation was assessed using microparticle flow cytometry.Results: Our study showed clots formed with TG2 KO RBCs or upon TG2 inhibition displayed fewer and thinner fibrin fibers at the clot surface. Inhibition of TG2 further revealed a redistribution of fibrin away from the clot surface toward deeper regions. Functionally, TG2 inhibition accelerated thrombin generation and clot formation, as shown by shortened lag time in thrombin generation assay and faster kinetics in thromboelastography. A normal fibrin density was observed in clots treated with the TG2 inhibitor after addition of RBC-derived extracellular vesicles (EVs). Moreover, TG2 inhibition increased EV formation, associated with more phosphatidylserine exposure on RBC membranes. Conclusion:TG2 activity within RBCs plays a specific role in modulating EV formation, which in turn influences the fibrin structure and spatial distribution within blood clots. Absence of TG2 activity leads to more EV formation, promoting faster thrombin generation and clot formation, suggesting a regulatory role for TG2 in coagulation kinetics.</p
Participating in decision-making at the end of life:The self-reported ability of people with cancer across 11 countries
No full textObjectives: Uncertainty among healthcare providers about patients’ ability to make care decisions is a barrier to shared decision-making. We aimed to assess the self-reported decision-making ability of patients with cancer at the end of life. Methods: Data from 11 countries of adults with a limited life expectancy and cancer as the primary diagnosis were used. Participants completed a questionnaire, including one item on decision-making ability and two on decision-making preferences. Correlations between self-reported ability and preferences were tested using Kendall's tau. Associations between decision-making ability and patient characteristics were determined using mixed-effects ordinal regression models. Results: The sample (n = 1076, 53 % identified as men) had a mean age of 69 years (SD: 11.5). Among them, 80 % reported being able to make decisions about their life and care most of the time, 14 % some of the time, 5 % only a little of the time, and 2 % never. Regarding preferences, 95 % preferred to be involved in decision-making and 44 % preferred the doctors to make the decisions. These preferences were weakly correlated with decision-making ability (Kendall's tau: 0.13 and −0.11, respectively). Feeling able to make decisions was less likely for those institutionalized (versus living with relatives, OR: 0.26, 95 % CI: 0.12;0.55), those with tertiary education (versus primary/no education, OR: 0.43, 95 % CI: 0.22;0.85) and those without clear understanding of their health (versus those with understanding, OR: 0.29, 95 % CI: 0.16;0.52). Conclusions: Although most patients felt able to make decisions about their care, two out of every ten did not. About five out of ten preferred their doctors to make decisions. Practice implications: As almost all patients want to be involved in decisions, we suggest that providers discuss with patients how decisions will be made. This may enable providers to identify patients’ needs and adapt the decision-making process to their abilities and preferences.</p
Aggregate and disaggregate natural resources impacts on environmental sustainability:An Asymmetric NARDL analysis
No full textWhile many studies have explored the relationship between aggregate natural resource rents and environmental sustainability, understanding the broader impact of TNRR on the ecological footprint remains critical. However, focusing solely on the aggregate measure may obscure the distinct effects of different types of natural resources on environmental outcomes. This study bridges that gap by analyzing not only the aggregate effect of TNRR on EF but also the disaggregated impacts of different types of natural resource rents —oil, gas, minerals, coal, and forests—on EF in Algeria between 1970/Q1 and 2022/Q4, Applying nonlinear autoregressive distributed lag (NARDL) models. Our results reveal a non-symmetric impact of aggregate TNRR in Algeria's ecological footprint, with positive shocks significantly increasing EF and negative shocks decreasing it. The disaggregated analysis uncovers nuanced sector-specific dynamics: oil rents mirror the asymmetric pattern of aggregate TNRR, while gas and mineral rents increase EF regardless of shock direction. Coal rents show no significant impact, and forest rents demonstrate a sharp increase in EF with positive shocks and a reduction with negative shocks. These results underscore the need for a differentiated approach to resource management in Algeria, emphasizing economic diversification, promotion of cleaner energy alternatives, and sustainable forest management practices.</p
Developing an integrated evaluation indicator system for non-communicable disease management in China’s primary care:a modified Delphi-analytic hierarchy process study based on the structure-process-outcome framework
No full textBackground: The aging population and increasing prevalence of chronic conditions have led to higher healthcare costs and greater resource utilization globally, exerting considerable pressure on healthcare system sustainability. Integrating services in primary healthcare can improve access and effectiveness for chronic disease management. However, China’s primary healthcare institutions have not achieved full integration of essential clinical services and public health services, hindering the continuity of care and chronic disease management. Guided by the Structure- Process- Outcome framework, this study aimed to develop core indicators to evaluate the capacity of integrated noncommunicable disease services within China’s public healthcare system. Methods: A modified Delphi method was employed with 22 experts over two rounds between January and May 2025. The panel reached a consensus on key indicators for integrating clinical and preventive services in primary healthcare institutions. The Analytic Hierarchy Process was employed to determine the weight values of the indicators. Results: A total of 78 indicators were identified, comprising 34 structural, 15 process, and 29 outcome indicators, with weight values of 0.2807, 0.2708, and 0.4485, respectively. The authority coefficient (Cr) was 0.7795. The coordination of experts’ opinions, measured by the Kendall coordination coefficient W, ranged from 0.219 to 0.246 (P < 0.01). Additionally, the consistency ratio (CR) values for each level were < 0.1. Conclusions: This study established a core set of indicators to evaluate the integration of clinical care and preventive services within China’s primary healthcare institutions. These indicators reflect the global health priorities of people-centered and inter-sectorally coordinated care. They support policy implementation and offer valuable insights for other countries seeking to develop or strengthen integrated primary healthcare systems in response to the growing chronic disease burden.</p