University Hospitals Geneva Medical Center

Abstract Daptomycin is a last resort antibiotic used to treat vancomycin-resistant enterococcal infections, but daptomycin resistance (DAP R ) arises quickly during treatment. Resistance is due to sequential acquisition of point mutations in the two-component system LiaFSR and in cardiolipin synthases and is associated with alteration of phospholipid and glycolipid membrane composition. The molecular mechanisms underlying these lipid changes are currently unknown. Similarly, it is unclear why mutations in liaFSR occur prior to mutations in cls . We discovered that Enterococcus faecalis remodels membrane composition as a phenotypic response to daptomycin that parallels the membrane composition of DAP R strains. The enrichment in glycolipids that follows antibiotic exposure is due to LtaS1, the main LTA synthase of E. faecalis . Moreover, LtaS1 activity is governed by a network of two-component systems formed by LiaFSR, SapRS, and BsrRS that couple antibiotic sensing with membrane lipid remodeling. Together, our results provide a unifying mechanism that drives phenotypic membrane fortification in a Gram-positive pathogen which simultaneously predisposes the cell to acquire genetic high-level daptomycin resistance. Significance Statement Daptomycin is the preferred alternative to treat vancomycin-resistant Enterococcus infections. However, the efficacy of daptomycin is limited by the acquisition of daptomycin resistance. Alterations in lipid membrane composition represent a conserved strategy to fortify the Gram-positive membrane. We discovered that E. faecalis phenotypically remodels membrane composition in response to daptomycin and that the enrichment in glycolipids is dependent on LTA synthesis. We expand our limited knowledge of enterococcal LTA synthases, confirming LtaS1 as the main LTA synthase and placing LTA biogenesis under control of a network of antibiotic-responsive two-component systems. Our work provides a molecular explanation for the sequential evolution of daptomycin resistance and may support the use of existing LtaS inhibitors to prevent acquisition of daptomycin resistance.

The use of intra-aortic balloon pump (IABP) alongside venoarterial extracorporeal membrane oxygenation (VA-ECMO) in critically ill patients presenting refractory cardiogenic shock raises questions regarding its impact on organs perfusion. This in vitro study aimed to examine the combined effects of IABP and VA-ECMO on coronary, cerebral, and renal perfusion, particularly considering the choice of arterial cannulation site. A mock circuit with a pulsatile pump was used to simulate different scenarios with increasing severities of low cardiac output syndromes treated by concomitant IABP and VA-ECMO support. Flow rates were measured using ultrasonic flowmeters. Each scenario was tested with two different VA-ECMO outflow access sites: femoral and axillary arteries, at heart rates of 60 and 100 bpm. Results showed that concomitant use of IABP with VA-ECMO in the axillary artery increases more significantly cerebral and coronary flow rates compared to femoral access in intermediate and severe shock. Nevertheless, renal perfusion appeared to be more negatively affected in this configuration. In summary, employing IABP alongside axillary VA-ECMO enhances cerebral and coronary flow but may compromise renal perfusion. Shock severity, heart rate, and cannulation site should be considered for a tailored approach. Future investigations using sophisticated autoregulated systems are needed to confirm these observations.

Breast cancer is the most common cancer worldwide, and magnetic resonance imaging (MRI) constitutes a very sensitive technique for invasive cancer detection. When reviewing breast MRI examination, clinical radiologists rely on multimodal information, composed of imaging data but also information not present in the images such as clinical information. Most machine learning (ML) approaches are not well suited for multimodal data. However, attention-based architectures, such as Transformers, are flexible and therefore good candidates for integrating multimodal data. The aim of this study was to develop and evaluate a novel multimodal deep learning (DL) model combining ultrafast dynamic contrast-enhanced (UF-DCE) MRI images, lesion characteristics and clinical information for breast lesion classification. From 2019 to 2023, UF-DCE breast images and radiology reports of 240 patients were retrospectively collected from a single clinical center and annotated. Imaging data were constituted of volumes of interest (VOI) extracted around segmented lesions. Non-imaging data were constituted of both clinical (categorical) and geometrical (scalar) data. Clinical data were extracted from annotated reports and were associated to their corresponding lesions. We compared the diagnostic performances of traditional ML methods for non-imaging data, an image model based on the DL architecture, and a novel Transformer-based architecture, the Multimodal Sieve Transformer with Vision Transformer encoder (MMST-V). The final dataset included 987 lesions (280 benign, 121 malignant lesions, and 586 benign lymph nodes) and 1081 reports. For classification with non-imaging data, scalar data had a greater influence on performances of lesion classification (Area under the receiver operating characteristic curve (AUROC)=0.875±0.042) than categorical data (AUROC=0.680±0.060). MMST-V achieved better performances (AUROC=0.928±0.027) than classification based on non-imaging data (AUROC=0.900±0.045), and imaging data only (AUROC=0.863±0.025). The proposed MMST-V is an adaptative approach that can consider redundant information provided by multimodal information. It demonstrated better performances than unimodal methods. Results highlight that the combination of clinical patient data and detailed lesion information as additional clinical knowledge enhances the diagnostic performances of UF-DCE breast MRI.

Abstract Anxiety disorders are accompanied by changes in brain plasticity, stress vulnerability and heightened risk of depression. Here, we found that serum LPA16:0 abundance increased with trait anxiety in both human and mice and was sufficient to reduce the proliferation of adult hippocampal neural stem/progenitor cells. In humans, the main LPA receptor, LPA1, bears single nucleotide polymorphism variants associated with anxiety. In mice, LPA16:0 decreased hippocampal neurogenesis and stress resilience, whereas LPA1antagonism or the reduction of platelets, the main source of circulating LPA16:0, increased adult neurogenesis and resilience to acute stress. Finally, the inhibition of adult neurogenesis abolished the beneficial effect of LPA1antagonism on resilience against both acute and chronic stress.Together, these findings identify LPA16:0-LPA1signaling as a regulation mechanism of adult neurogenesis and a potential therapeutic target for mood disorders.

BackgroundPersistent symptoms of SARS‐CoV‐2 are prevalent weeks to months following the infection. To date, it is difficult to disentangle the direct from the indirect effects of SARS‐CoV‐2, including lockdown, social, and economic factors.ObjectiveThe study aims to characterize the prevalence of symptoms, functional capacity, and quality of life at 12 months in outpatient symptomatic individuals tested positive for SARS‐CoV‐2 compared to individuals tested negative.MethodsFrom 23 April to 27 July 2021, outpatient symptomatic individuals tested for SARS‐CoV‐2 at the Geneva University Hospitals were followed up 12 months after their test date.ResultsAt 12 months, out of the 1447 participants (mean age 45.2 years, 61.2% women), 33.4% reported residual mild to moderate symptoms following SARS‐CoV‐2 infection compared to 6.5% in the control group. Symptoms included fatigue (16% vs. 3.1%), dyspnea (8.9% vs. 1.1%), headache (9.8% vs. 1.7%), insomnia (8.9% vs. 2.7%), and difficulty concentrating (7.4% vs. 2.5%). When compared to the control group, 30.5% of SARS‐CoV‐2 positive individuals reported functional impairment at 12 months versus 6.6%. SARS‐CoV‐2 infection was associated with the persistence of symptoms (adjusted odds ratio [aOR] 4.1; 2.60–6.83) and functional impairment (aOR 3.54; 2.16–5.80) overall, and in subgroups of women, men, individuals younger than 40 years, those between 40–59 years, and in individuals with no past medical or psychiatric history.ConclusionSARS‐CoV‐2 infection leads to persistent symptoms over several months, including in young healthy individuals, in addition to the pandemic effects, and potentially more than other common respiratory infections. Symptoms impact functional capacity up to 12 months post infection.

Abstract Background: In 10-15% of cases of vestibular schwannoma (VS) age at diagnosis is 40 years or less. Little is known about the differences in natural history, surgical findings and postoperative outcomes of such younger patients as compared to those of greater age. Objectives : To analyze clinical and surgical and imaging data of a consecutive series of n=50 patients with unilateral sporadic VS, aged 40 years or younger – separated in a very young group (15-30 years) and a moderately young group (31-40 years). Study design: Retrospective case series Methods: 50 consecutive patients under 40 years of age underwent microsurgical resection of unilateral sporadic VS via the retrosigmoid approach. The study cohort was subdivided into two groups according to the age range: Group A, age range 15-30 years (n=23 patients) and Group B, age range 31-40 years (n=27 patients). The adherence of VS capsule to surrounding nervous structures and the tendency of the tumors to bleed were evaluated by reviewing video records; the course of the FN in relation to the tumor’s surface was assessed in each case. Microsurgical removal of tumor was classified as total (T), near total (residual tumor volume <5%), subtotal (residual tumor volume 5-10%) or partial (residual tumor volume >10%). Results: Mean tumor size of entire cohort was 2,53 (range: 0,6-5,8) cm: 2,84 cm in Group A and 2,36 cm in Group B (p=NS). Facial nerve course and position within the cerebellopontine angle did not differ significantly between the two groups. At 6-month follow-up, FN functional outcome was: HBI-II in 69,5% in Group A, versus 96,3% in Group B (p<,001). Hearing preservation was achieved in 60,0% of patients of Group A and in 58,3% of Group B (p=NS). Total and near-total resection was feasible in 95,6% of cases of Group A and in 88,9% of Group B (p=NS). Tumor capsule was tightly adherent to nervous structures in 69,6% patients of Group A and in 22,2% of Group B (p<,05). Significant bleeding was encountered in 56,5% of Group A tumors, and in 29,6% of Group B tumors (p<,01).Conclusions: Microsurgery of VS in patients aged 40 or less is associated with good functional results, and with high rates of total and near total tumor removal. Patients <30 years of age have more adherent tumor capsules. Furthermore, their tumors exhibit a tendency to larger sizes, to hypervascularization, to profuse intraoperative bleeding and they present worse long-term functional FN results when compared to patients in their fourth decade of life. Our limited experience seems to suggest that a near total resection in very young VS patients with large tumors should be preferred in adherent and hypervascularized cases, in order to maximize resection and preserve function.

Intrauterine growth restriction (IUGR) is associated with reduced kidney size at birth, accelerated renal function decline, and increased risk for chronic kidney and cardiovascular diseases in adults. Precise mechanisms underlying fetal programming of adult diseases remain largely elusive and warrant extensive investigation. Setting up a mouse model of hypoxia-induced IUGR, fetal adaptations at mRNA, protein and cellular levels, and their long-term functional consequences are characterized, using the kidney as a readout. Here, we identify fetuin-A as an evolutionary conserved HIF target gene, and further investigate its role using fetuin-A KO animals and an adult model of ischemia-reperfusion injury. Beyond its role as systemic calcification inhibitor, fetuin-A emerges as a multifaceted protective factor that locally counteracts calcification, modulates macrophage polarization, and attenuates inflammation and fibrosis, thus preserving kidney function. Our study paves the way to therapeutic approaches mitigating mineral stress-induced inflammation and damage, principally applicable to all soft tissues.

To investigate brain perfusion patterns in systemic lupus erythematosus (SLE) patients with and without neuropsychiatric systemic lupus erythematosus (NPSLE and non‐NPSLE, respectively) and to identify biomarkers for the diagnosis of NPSLE using noninvasive three‐dimensional (3D) arterial spin labeling (ASL). Thirty‐one NPSLE and 24 non‐NPSLE patients and 32 age‐ and sex‐matched normal controls (NCs) were recruited. Three‐dimensional ASL‐MRI was applied to quantify cerebral perfusion. Whole brain, gray (GM) and white matter (WM), and voxel‐based analysis (VBA) were performed to explore perfusion characteristics. Correlation analysis was performed to find the relationship between the perfusion measures, lesion volumes, and clinical variables. Receiver operating characteristic (ROC) analysis and support vector machine (SVM) classification were applied to differentiate NPSLE patients from non‐NPSLE patients and healthy controls. Compared to NCs, NPSLE patients showed increased cerebral blood flow (CBF) within WM but decreased CBF within GM, while non‐NPSLE patients showed increased CBF within both GM and WM. Compared to non‐NPSLE patients, NPSLE patients showed significantly reduced CBF in the frontal gyrus, cerebellum, and corpus callosum. CBF within several brain regions such as cingulate and corpus callosum showed significant correlations with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborating Clinics (SLICC) damage index scores. ROC analysis showed moderate performance in distinguishing NPSLE from non‐NPSLE patients with AUCs > 0.7, while SVM analysis demonstrated that CBF within the corpus callosum achieved an accuracy of 83.6% in distinguishing NPSLE from non‐NPSLE patients. Different brain perfusion patterns were observed between NPSLE and non‐NPSLE patients. CBF measured by noninvasive 3D ASL could be a useful biomarker for the diagnosis and disease monitoring of NPSLE and non‐NPSLE patients.

The dorsal anterior cingulate cortex (dACC) and the anterior insula (AI) constitute the salience network and form as well the major cortical components of the central autonomic nervous system. These two cortical regions have the highest density in α4β2 nicotinic acetylcholine receptors (nAChRs) within the whole cortex.The aim of the study was to test the association between nAChRs density/availability in the salience network and the heart rate variability in humans. We selected subjects from a previous positron emission tomography (PET) imaging study in epilepsy with 18F-FA-85380, a specific marker for α4β2 nAChRs, including 10 healthy controls, 10 patients with nonlesional focal epilepsy and 8 patients with idiopathic generalized epilepsy. Participants underwent a 10 min-resting electrocardiogram as they were lying still in a semi-supine position while watching an emotionally neutral video. We tested the association between parasympathetic tone and the regional brain nAChR availability, as measured by 18F-F-A-85380 binding potential (BP), using linear regression. We observed an association between higher nAChRs availability in the bilateral dACC and the right dorsal AI/frontal operculum and a lower parasympathetic tone, without significant effect of the clinical group on this relation. Our study is the first one to show a neurochemical correlate to the parasympathetic role of the anterior cingulate cortex and the AI. The nicotinic system, which plays a major role in the peripheral autonomic nervous system intervening both in the parasympathetic and sympathetic chains, seems also to play a role in the central autonomic nervous system.

In the context of deceased organ donation, donors are routinely tested for HIV, to check for suitability for organ donation. This article examines whether a donor's HIV status should be disclosed to the donor's next of kin. On the one hand, confidentiality requires that sensitive information not be disclosed, and a duty to respect confidentiality may persist after death. On the other hand, breaching confidentiality may benefit third parties at risk of having been infected by the organ donor, as it may permit them to be tested for HIV and seek treatment in case of positive results. We conclude that the duty to warn third parties surpasses the duty to respect confidentiality. However, in order to minimize risks linked to the breach of confidentiality, information should be restrained to only concerned third parties, that is, those susceptible to having been infected by the donor.