University Hospital of Zurich

Aiming for personalization of elective clinical target volumes (CTV), we are reporting on regional lymphatic spread patterns in laryngeal squamous cell carcinoma (SCC), considering not only subsite, T-stage, and lateralization of the primary tumor, but also involvement of adjacent lymph node levels (LNLs). LNL involvement in 1005 patients with laryngeal SCC treated at University Hospital Zurich between 2013 and 2021 and UMCG Groningen between 2006 and 2023 was analyzed. LNL involvement was assessed based on imaging and, if available, pathology. Patterns of LNL involvement can be visualized on https://lyprox.org/. For T2-glottic tumors (N=193), involvement was <4% in all LNLs, supporting the hypothesis that ENI could potentially be omitted. In T3/T4-glottic patients without ipsilateral LNL II involvement (N=198), involvement of LNLs III and IV was 5% and 1%, suggesting that ENI of LNL IV could be omitted in cN0 patients. For T3/T4-glottic tumors (N=239) almost no contralateral involvement was observed for lateralized tumors (N=37), suggesting contralateral treatment could potentially be omitted or limited to LNL II in patients with clinically negative contralateral neck. For supraglottic SCC without midline extension of the primary tumor (N=75), contralateral LNL involvement was below 3%. In patients with midline extension but without contralateral LNL II involvement (N=193), involvement of downstream levels was rare (LNL III 5%, LNL IV 3%). We provided detailed information about lymphatic spread patterns of laryngeal SCC, depending on subsite, T-stage, lateralization, and upstream involvement. Subgroups of patients can be identified in whom the elective CTV or surgical approach may be reduced compared to current guidelines.

Hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome is a rare pediatric epilepsy syndrome characterized by prolonged focal febrile seizures, postictal hemiparesis, and progressive unilateral brain injury, often followed by chronic epilepsy. We report a previously healthy 10-month-old girl who presented with a prolonged left-sided focal fever-associated seizure. She tested positive for SARS-CoV-2 but did not meet criteria for multisystem inflammatory syndrome in children. On admission, she had left-sided flaccid hemiparesis. Brain MRI showed mild diffusion restriction and marked hyperperfusion of the right hemispheric gray matter, most prominently in the frontal, temporo-occipital, and hippocampal regions. EEG showed high-amplitude slowing over the right hemisphere without epileptiform discharges. No further seizures occurred, and long-term antiseizure treatment was not required. At 9-month follow-up, the patient was seizure-free and developmentally age-appropriate, but the hemiparesis persisted. Serial MRI showed progressive right hemispheric cortical and subcortical atrophy and hippocampal sclerosis. Extensive diagnostic workup found no other structural, infectious, or metabolic cause. This case illustrates the classical biphasic course of HHE syndrome and highlights the diagnostic value of early MRI, EEG, and genetic testing. The patient carried a paternally inherited heterozygous IRF3 variant, a gene essential for innate antiviral immunity. Although causality cannot be established, the temporal association with SARS-CoV-2 infection and an IRF3 variant suggests a possible genetic predisposition to infection-triggered injury. Continued clinical vigilance and long-term follow-up are essential, as epilepsy develops in most children with HHE. Greater awareness of this syndrome may support earlier recognition and timely rehabilitation to optimize functional outcomes.

4D flow MRI facilitates quantification of cardiac phase-resolved blood velocity vector fields and has successfully been deployed to study cerebrovascular flow. Besides cardiac-induced flow pulsation, respiration is known to modulate arterial and venous blood flow in the brain. Quantification of the respiratory flow modulation (RFM) holds potential to further our insights into vascular coupling and improve our understanding of cerebral circulation in general. A 5D phase-contrast flow MRI framework was developed to volumetrically quantify RFM by resolving velocity vector fields over the cardiac and respiratory cycle, with high spatial (0.82 mm isotropic) and cardiac (55 ms) resolutions, using two respiratory states whilst accounting for variable physiological RFM delays, with a reasonable acquisition time (20 min at 60 bpm). Recent advances in deep learning-based image reconstruction and analysis methods are incorporated to facilitate the approach. The 5D flow MRI framework was validated in 10 healthy volunteers with reference to fully sampled respiratory-resolved 2D flow MRI orthogonal to the internal carotid artery (ICA), yielding Pearson correlation coefficients of 0.97 and 0.90 and biases of and 0.09 % and 1.77 % for RFM of mean velocity magnitude and amplitude, respectively. The value of cerebrovascular 5D flow MRI is demonstrated using full-field spatially resolved RFM quantification of mean velocity and velocity amplitude, revealing a high physiological intra-subject variability. Cerebrovascular 5D flow MRI enables the study of full-field respiratory flow modulation holding potential of furthering our understanding of cerebral circulation.

Noninvasive neuromonitoring provides valuable insights into cerebral physiology and function, with the potential to support individualized care for patients who are critically ill. As precision medicine continues to advance within the intensive care unit, the integration of multiple noninvasive monitoring techniques may offer a more comprehensive, real-time understanding of dynamic cerebral pathophysiology while avoiding the risks of invasive procedures. This study aimed to identify the implementation challenges of combining multiple noninvasive neuromonitoring modalities. Six modalities were selected: blind transcranial Doppler ultrasonography, optic nerve sheath diameter measurement, multichannel continuous electroencephalography (cEEG), automated pupillometry, near-infrared spectroscopy (NIRS), and skull extensometer (Brain4Care). To assess the readiness of each modality for integration into a multimodal noninvasive monitoring setup, a group of experts propose the Noninvasive Neuromonitoring Multimodal Readiness (nnMR) score. This scoring system aims to provide a structured evaluation of each modality's multimodal suitability based on criteria such as data continuity and processing, physiological signal representation, spatial and temporal resolution, and software integration in the intensive care unit setting. nnMR scores showed that cEEG and NIRS enable continuous monitoring without manual processing. Blind transcranial Doppler and NIRS offer a good temporal resolution; optic nerve sheath diameter provides good spatial resolution; cEEG and skull extensometer combine both. Only cEEG demonstrates anatomical clarity. Software integration remains limited across all modalities. Key challenges to multimodal implementation include the need for skilled personnel, artifact susceptibility, mismatched temporal and spatial resolutions, and limited long-term signal stability. Integration into unified analytical platforms is further constrained by a lack of standardization, requiring separate manual data input, processing, and quantification. The nnMR score was developed to assess the current readiness of each modality for multimodal, continuous, and long-term clinical application. To validate the proposed nnMR score, engagement with the broader neurocritical care community is essential. Realizing the full potential of multimodal neuromonitoring will require advances in signal validation, software integration, resolution alignment, artifact detection, fixation techniques, and standardization, necessitating close collaboration among researchers, engineers, manufacturers, and clinicians.

Lymphatic vessels play an important role in pathologies, such as cardiovascular diseases or metastasizing cancers. However, mechanisms involved in cancer metastasis through lymphatic vessels remain largely unknown. In this study, we engineer 3D lymphatic microvessels by co-culturing human lymphatic endothelial cells (hLECs) with human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) in synthetic and fully defined enzymatically crosslinked poly(ethylene glycol) (TG-PEG) hydrogels. By tuning the stiffness of the TG-PEG scaffolds, varying seeding densities of hLECs and hBM-MSCs, and stimulation with lymphangiogenic factors, we identify suitable culture conditions for lymphatic network formation. Immunocytochemistry-based evaluations reveal the formation of lymphatic structures consisting of hLECs that are ensheathed with basement membrane extracellular matrix components and hBM-MSCs, which express perivascular-specific markers. Finally, the addition of non-invasive MCF-7 and invasive MDA-MB-231 breast cancer cells to the forming lymphatic structures shows a clear negative influence of cancer cells on the length of lymphatic networks. Moreover, we observe a closer association of invasive than of non-invasive cancer cells with the lymphatic networks, which can be inhibited by blocking of CCL21. Our findings present a promising approach to investigate the cancer microenvironment, as our model can serve as a tool to study physiological lymphangiogenesis and pathological phenomena in vitro.

Liver transplantation outcomes have improved. However, immunosuppression also raises infection susceptibility. Potential differences in infections between donation after circulatory death (DCD) and donation after brain death (DBD) recipients remain unclear. This study analyzed postoperative infections and compared their incidence between DCD and DBD recipients. Patients undergoing liver transplantation from January 1, 2016, to December 31, 2022, were included. DCD and marginal DBD liver grafts underwent hypothermic oxygenated machine perfusion (HOPE). Bacterial, viral, and fungal infections were identified using standardized definitions. Infections were categorized into periods: 0-2 weeks (period 1), 3-4 weeks (period 2), 1-6 months (period 3), and beyond 6 months (period 4). The primary outcome was the occurrence of infection within the first post-transplant year, including pathogen spectrum, timing, and infection site. The secondary outcome was the assessment of infection risk factors investigated with Poisson regression. A total of 300 liver transplants were included. In all, 42.8% of DBD recipients and 44.3% of DCD recipients suffered from at least 1 infection. In total, 298 relevant infections occurred, with bacteria accounting for 73.2% in DBD and 86.4% in DCD recipients. Bacterial infections predominated in all periods. In periods 1 and 2, bloodstream infections, abdominal and surgical site infections were most frequent, while liver-related infections, especially in DCD, and bloodstream infections dominated in periods 3 and 4. Viral and fungal infections were less frequent. One-year survival was 87.1% for DBD and 87.7% for DCD recipients. Poisson regression identified DCD recipients (IRR 1.99, 95% CI 1.37-2.92, p <0.001) and younger age (IRR 0.98, 95% CI 0.97-0.99, p <0.001) as more likely to develop infections. DCD liver recipients experienced more infections in the first post-transplant year. While mortality was not different, the increased infection rates in DCD recipients highlight the need for infection prevention and surveillance.

The implementation of evidence-based practices such as kangaroo care (KC), a practice provided in clinical neonatal care, is subject to a complex and dynamic interplay of factors. Using traditional methods to capture and assess this complexity and underlying mechanisms related to implementation, has often proven difficult. This study applied system dynamics and network diffusion modeling to map implementation determinants of KC implementation and to examine underlying implementation mechanisms through which these factors influence the average duration of KC within the complex adaptive implementation system of neonatal intensive care units. A causal loop diagram (CLD) was developed through a systems mapping exercise with 32 multiprofessional KC experts and validated through interviews with participants with lived KC experience. The CLD was subsequently converted into a network graph to derive a network diffusion model. The model estimated the influence of cascades initiated by selected variables ('seeds') on the outcome variable of Average hours of KC provided. The CLD comprised 73 variables and 155 connections across three interconnected domains: parental engagement, workforce capacity and service delivery context. In the network diffusion model,Nurses per ShiftandAvailability of KC Education & Counselinginitiated the strongest influential cascades onaverage time of KC provided. This study demonstrates the utility of integrating system dynamics and network science to investigate complex mechanisms underlying implementation processes. Further applications are needed to validate and refine these methods and to strengthen their contribution to research surrounding implementation mechanisms.

Existing studies on the economic impact of schizophrenia are fragmented and vary in methodology, hindering an ample understanding of the total economic burden. To quantify the global economic burden of schizophrenia by synthesizing findings from systematic reviews and meta-analyses, and to assess variations by cost category, world region and income level. We conducted a protocol-driven umbrella review registered on PROSPERO (CRD42024504092). A systematic search of MEDLINE, EMBASE, Cochrane Library, and APA PsycINFO identified reviews reporting annual per-patient monetary cost estimates for schizophrenia. Monetary values were adjusted for inflation and converted to 2024 US dollars. Twenty-six systematic reviews involving 152 primary studies were included. The median annual per-patient total cost of schizophrenia across included primary studies was $33,236 (mean $47,872), with direct costs accounting for $23,126 (medical: $19,543; ancillary: $1,152) and indirect costs for $21,333. Costs were varied by income level: in high-income countries, the median total cost was $34,175, compared to $3,345 in upper-middle-income and $3,452 in lower-middle-income countries. Regional disparities were substantial, with Europe & Central Asia reporting the highest median costs among high-income settings. Data from low- and middle-income regions were limited or absent. Methodological heterogeneity, lack of standardization in cost reporting, and underrepresentation of low-resource settings limit generalizability. The included cost-of-illness estimates indicate that schizophrenia is associated with substantial annual per-patient costs, with hospitalization, long-term care, and productivity losses frequently among the largest reported components. However, the evidence base is heavily weighted toward high-income countries, and limited data from lower-resource settings constrain cross-country comparability. Future research should adopt standardized costing frameworks and expand data collection in underrepresented regions to improve the consistency, transparency, and geographic coverage of economic burden estimates.