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Background Sepsis and septic shock are significant global healthcare challenges with high mortality rates. Effective management requires timely and adequate antimicrobial therapy. Beta-lactam antibiotics, commonly used in patients with sepsis, are crucial for treating these infections. However, standard dosing often leads to insufficient plasma levels due to dynamic physiological changes in critically ill patients. Previous randomized controlled trials highlighted the need for timely dose adjustments to improve clinical outcomes. This is the study protocol for the BULLSEYE trial in which we aim to optimize antibiotic treatment during the initial 48 h of sepsis by comparing standard to double dosing of beta-lactam antibiotics. Methods This open-label, multicenter, randomized controlled trial will compare standard to double dosing of beta-lactam antibiotics (cefuroxime, ceftazidime, ceftriaxone, cefotaxime, amoxicillin, amoxicillin/clavulanic acid, flucloxacillin, meropenem, and piperacillin/clavulanic acid) in critically ill patients with septic shock. Participants will be randomized into two arms: the control arm receiving standard care, and the intervention arm receiving double antibiotic doses for 48 h, irrespective of renal function. Following this period, all patients will receive standard doses as per local protocol. The primary outcome is all cause 28-day mortality, with secondary outcomes including 90-day, 365-day, hospital and ICU mortality, hospital and ICU length of stay, SOFA scores, time to shock reversal, microbiological eradication, clinical cure, pharmacodynamic target attainment, safety, quality of life, and medical consumption. Discussion The BULLSEYE trial aims to improve sepsis treatment in critically ill patients. Despite anticipated recruitment challenges, its large sample size ensures robust comparability. This pivotal trial could significantly impact sepsis treatment, leading to better clinical outcomes. Trial registration EU_CT 2024–512950-13–00. Protocol version 2.3, protocol date 09–12-2024. Prospectively registered on 09–01-2025 at Clinicaltrails.gov nr. NCT06766461.

Purpose Fentanyl is an analgesic that is frequently prescribed, which resulted in non-intentional as well as intentional misuse and deaths. Here, we present a postmortem case of a patient who clearly died of a fentanyl overdose due to an extensive number of fentanyl patches combined with oral intake of fentanyl and cocaine. We aimed to show how postmortem analysis can be used to interpret postmortem fentanyl concentrations in unique cases like the one we present. Case description A 23-year-old male was found dead in his bedroom with 67 non-prescribed patches of fentanyl on his body. In the room, there also were fentanyl tablets of 100 µg and cocaine powder, which had possibly also been taken by the deceased. To confirm the cause of death, urine and subclavian blood were retrieved to perform a standard postmortem toxicology screening. The toxicological screening revealed the presence of several drugs, including cocaine, fentanyl, lidocaine and paracetamol. Further analysis of the quantitative postmortem values of fentanyl with ultra-performance liquid chromatography-tandem mass spectrometry revealed a fentanyl concentration of 57.9 µg/L. Considering several issues around postmortem drug analyses, this value seemed to be in line with concentrations found in previously reported postmortem cases. Conclusion We were able to confirm the expected cause of death with an extensive toxicological screening in combination with the circumstantial evidence. We identified fentanyl as most important cause for the fatal outcome in this specific case and simultaneously contributed to the limited availability of knowledge on postmortem fentanyl concentrations.

PurposeFormative assessments can help motivate students and ease students’ learning through feedback. There is a pressing need for improvement of clinical pharmacotherapy (CPT) education since junior doctors make many prescribing errors. The aim of this study was to determine whether a formative assessment with personalized narrative feedback helps medical students to increase their prescribing skills.MethodsThis retrospective cohort study was conducted among masters’ medical students at Erasmus Medical Centre, The Netherlands. Students made a formative and a summative skill-based prescription assessment, both during clerkships as part of their regular curriculum. Errors in both assessments were categorized by type and possible consequence and compared with each other.ResultsA total of 388 students made 1964 errors in the formative assessment and 1016 in the summative assessment. Most improvements after the formative assessment were seen for mentioning the weight of a child on the prescription (n = 242, 19%). Most new and repeated errors in the summative assessment were missing usage instructions (n = 82, 16% and n = 121, 41%).ConclusionsThis formative assessment with personalized and individual narrative feedback has helped students to increase the technical correctness of their prescriptions. However, errors repeated after the feedback were predominantly errors showing that only one formative assessment has not yet enhanced the clinical prescribing enough.

Issue Title: ESICM LIVES 2015

While the role of cortical microstructure in organising neural function is well established, it remains unclear how structural constraints can give rise to more flexible elements of cognition. While nonhuman primate research has demonstrated a close structure-function correspondence, the relationship between microstructure and function remains poorly understood in humans, in part because of the reliance on post mortem analyses, which cannot be directly related to functional data. To overcome this barrier, we developed a novel approach to model the similarity of microstructural profiles sampled in the direction of cortical columns. Our approach was initially formulated based on an ultra-high-resolution 3D histological reconstruction of an entire human brain and then translated to myelin-sensitive magnetic resonance imaging (MRI) data in a large cohort of healthy adults. This novel method identified a system-level gradient of microstructural differentiation traversing from primary sensory to limbic regions that followed shifts in laminar differentiation and cytoarchitectural complexity. Importantly, while microstructural and functional gradients described a similar hierarchy, they became increasingly dissociated in transmodal default mode and fronto-parietal networks. Meta-analytic decoding of these topographic dissociations highlighted involvement in higher-level aspects of cognition, such as cognitive control and social cognition. Our findings demonstrate a relative decoupling of macroscale functional from microstructural gradients in transmodal regions, which likely contributes to the flexible role these regions play in human cognition.

The vast net of fibres within and underneath the cortex is optimised to support the convergence of different levels of brain organisation. Here, we propose a novel coordinate system of the human cortex based on an advanced model of its connectivity. Our approach is inspired by seminal, but so far largely neglected models of cortico–cortical wiring established by postmortem anatomical studies and capitalises on cutting-edge in vivo neuroimaging and machine learning. The new model expands the currently prevailing diffusion magnetic resonance imaging (MRI) tractography approach by incorporation of additional features of cortical microstructure and cortico–cortical proximity. Studying several datasets and different parcellation schemes, we could show that our coordinate system robustly recapitulates established sensory-limbic and anterior–posterior dimensions of brain organisation. A series of validation experiments showed that the new wiring space reflects cortical microcircuit features (including pyramidal neuron depth and glial expression) and allowed for competitive simulations of functional connectivity and dynamics based on resting-state functional magnetic resonance imaging (rs-fMRI) and human intracranial electroencephalography (EEG) coherence. Our results advance our understanding of how cell-specific neurobiological gradients produce a hierarchical cortical wiring scheme that is concordant with increasing functional sophistication of human brain organisation. Our evaluations demonstrate the cortical wiring space bridges across scales of neural organisation and can be easily translated to single individuals.

One paradox of autism is the co-occurrence of deficits in sensory and higher-order socio-cognitive processing. Here, we examined whether these phenotypical patterns may relate to an overarching system-level imbalance—specifically a disruption in macroscale hierarchy affecting integration and segregation of unimodal and transmodal networks. Combining connectome gradient and stepwise connectivity analysis based on task-free functional magnetic resonance imaging (fMRI), we demonstrated atypical connectivity transitions between sensory and higher-order default mode regions in a large cohort of individuals with autism relative to typically-developing controls. Further analyses indicated that reduced differentiation related to perturbed stepwise connectivity from sensory towards transmodal areas, as well as atypical long-range rich-club connectivity. Supervised pattern learning revealed that hierarchical features predicted deficits in social cognition and low-level behavioral symptoms, but not communication-related symptoms. Our findings provide new evidence for imbalances in network hierarchy in autism, which offers a parsimonious reference frame to consolidate its diverse features. Autism spectrum disorder (ASD) is associated with symptoms ranging from sensory hypersensitivity to social difficulties. Here, the authors provide evidence of atypical connectivity transitions between sensory and higher-order cortical areas in people with ASD, which could underlie the diverse symptoms.

Brain structure scaffolds intrinsic function, supporting cognition and ultimately behavioral flexibility. However, it remains unclear how a static, genetically controlled architecture supports flexible cognition and behavior. Here, we synthesize genetic, phylogenetic and cognitive analyses to understand how the macroscale organization of structure-function coupling across the cortex can inform its role in cognition. In humans, structure-function coupling was highest in regions of unimodal cortex and lowest in transmodal cortex, a pattern that was mirrored by a reduced alignment with heritable connectivity profiles. Structure-function uncoupling in macaques had a similar spatial distribution, but we observed an increased coupling between structure and function in association cortices relative to humans. Meta-analysis suggested regions with the least genetic control (low heritable correspondence and different across primates) are linked to social-cognition and autobiographical memory. Our findings suggest that genetic and evolutionary uncoupling of structure and function in different transmodal systems may support the emergence of complex forms of cognition. Brain structure scaffolds intrinsic function, supporting cognition and behavioral flexibility. Here, the authors show how macroscale organization of cortical microstructure and resting-state function uncouple in transmodal cortex of humans and macaques.

Neurodevelopmental disorders have a heritable component and are associated with region specific alterations in brain anatomy. However, it is unclear how genetic risks for neurodevelopmental disorders are translated into spatially patterned brain vulnerabilities. Here, we integrated cortical neuroimaging data from patients with neurodevelopmental disorders caused by genomic copy number variations (CNVs) and gene expression data from healthy subjects. For each of the six investigated disorders, we show that spatial patterns of cortical anatomy changes in youth are correlated with cortical spatial expression of CNV genes in neurotypical adults. By transforming normative bulk-tissue cortical expression data into cell-type expression maps, we link anatomical change maps in each analysed disorder to specific cell classes as well as the CNV-region genes they express. Our findings reveal organizing principles that regulate the mapping of genetic risks onto regional brain changes in neurogenetic disorders. Our findings will enable screening for candidate molecular mechanisms from readily available neuroimaging data. How neurodevelopmental disorder-associated risk genes are translated into spatially patterned brain vulnerabilities is unclear. Here, the authors show that disorder-specific patterns of neuroanatomical changes are aligned to brain expression maps of disease risk genes in healthy subjects.