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Abstract In this phase I dose-escalation trial, we assess the maximum tolerated dose (MTD) of Bermekimab in combination with Nanoliposomal Irinotecan (Nal-Iri) and 5-Fluorouracil/Folinic Acid (5-FU/FA). Secondarily, we investigate effects on weight, lean body mass, quality-of-life, the gut microbiome composition, inflammatory biomarkers, progression-free survival, and overall survival. This was a single-arm, open-label adaptive Bayesian dose-escalation study of Bermekimab combined with Nal-Iri and 5FU/FA in patients with advanced or locally advanced PDAC who failed gemcitabine-based chemotherapy. 22 patients enrolled between 2017 and 2019. 3 of 21 patients experienced dose-limiting toxicities attributable to the chemotherapy backbone. 58% (10/17) of patients exhibited weight stability. Physical performance status was preserved among all subjects. Patients reported improvements in quality-of-life metrics via QLQ-PAN26 questioner (−3.6, p = 0.18) and functional well-being (1.78, p = 0.02). Subjects exhibited a decrease in inflammatory cytokines, notably, vascular endothelial growth factor (−0.86, p = 0.017) with Bermekimab. Bermekimab treatment was associated with an increased abundance of gut health-promoting bacterial genera Akkermansia, with 3.82 Log2-fold change from baseline. In sum, Bermekimab is safe to be used in conjunction with Nal-Iri and 5-FU/FA chemotherapy. This benign toxicological profile warrants further Phase I/II investigation of Bermekimab in combinatorial strategies, and the impact of anti-IL-1α antibodies on the gut microbiome. Clinical trials registration: NCT03207724 05/07/2017.

Background and aimsAccurate differentiation of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) is an area of unmet clinical need. In this study, a novel Multitasking dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) technique was used to quantitatively evaluate the microcirculation properties of pancreas in CP and PDAC and differentiate between them.MethodsThe Multitasking DCE technique was able to acquire one 3D image per second during the passage of MRI contrast agent, allowing the quantitative estimation of microcirculation properties of tissue, including blood flow Fp, plasma volume fraction vp, transfer constant Ktrans, and extravascular extracellular volume fraction ve. Receiver operating characteristic (ROC) analysis was performed to differentiate the CP pancreas, PDAC pancreas, normal control pancreas, PDAC tumor, PDAC upstream, and PDAC downstream. ROCs from quantitative analysis and conventional analysis were compared.ResultsFourteen PDAC patients, 8 CP patients and 20 healthy subjects were prospectively recruited. The combination of Fp, vp, Ktrans, and ve can differentiate CP versus PDAC pancreas with good AUC (AUC [95% CI] = 0.821 [0.654 – 0.988]), CP versus normal pancreas with excellent AUC (1.000 [1.000 – 1.000]), PDAC pancreas versus normal pancreas with excellent AUC (1.000 [1.000 – 1.000]), CP versus PDAC tumor with excellent AUC (1.000 [1.000 – 1.000]), CP versus PDAC downstream with excellent AUC (0.917 [0.795 – 1.000]), and CP versus PDAC upstream with fair AUC (0.722 [0.465 – 0.980]). This quantitative analysis outperformed conventional analysis in differentiation of each pair.ConclusionMultitasking DCE MRI is a promising clinical tool that is capable of unbiased quantitative differentiation between CP from PDAC.

Introduction: Leukocytoclastic vasculitis (LCV) is a small vessel vasculitis typically affecting dermal capillaries and venules. The condition is often idiopathic but can be associated with infections, neoplasms, autoimmune disorders, and certain drugs. Case Report: A 91-year-old female with past medical history of Alzheimer dementia and hypertension, being treated for lower extremity cellulitis, presented to the emergency department for an allergic reaction. Trimethoprim/sulfamethoxazole (TMP/SMX) had been initiated six days earlier. The patient was noted to have normal vital signs. Palpable purpura was discovered on the lower back, buttocks, lower extremities, ankles, and feet. Laboratory studies were within normal limits. Given the clinical presentation, physical exam findings, and normal eosinophil count, the diagnosis of LCV secondary to TMP/SMX was made. Conclusion: Most cases of LCV are limited to cutaneous symptoms and self-resolve with supportive care.

Abstract The COVID-19 pandemic has emphasised the importance of vaccines and preparedness against viral threats crossing species barriers. In response, a worldwide vaccination campaign targeting SARS-CoV-2 was implemented, which provides some cross-protective immunological memory to other coronavirus species with zoonotic potential. Following a vaccination regimen against SARS-CoV-2 spike in a preclinical mouse model, we were able to demonstrate the induction of neutralizing antibodies towards multiple human ACE2 (hACE2)-binding Sarbecovirus spikes. Importantly, compared to vaccines based on the SARS-CoV-2 Reference strain, vaccines based on Omicron spike sequences induced drastically less broadly cross-protective neutralizing antibodies against other hACE2-binding sarbecoviruses. This observation remained true whether the vaccination regimens were based on protein subunit or mRNA / LNP vaccines. Overall, while it may be necessary to update vaccine antigens to combat the evolving SARS-CoV-2 virus for enhanced protection from COVID-19, Reference-based vaccines may be a more valuable tool to protect against novel coronavirus zoonoses.

Abstract Background Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer’s disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relation between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans. Methods We used an APP knock-in mouse model, APPNL-G-F, exhibiting amyloid pathology, to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF using liquid chromatography mass spectrometry. Mouse proteomes were investigated at the age of 7 weeks (n = 5) and 40 weeks (n = 5). Results were compared with previously published human AD CSF proteomic data (n = 496) to identify key proteins and pathways associated with ChP changes in AD. Results ChP tissue proteome was dysregulated in APPNL-G-F mice relative to wild-type mice at both 7 and 40 weeks. At both ages, ChP tissue proteomic changes were associated with epithelial cells, mitochondria, protein modification, extracellular matrix and lipids. Nonetheless, some ChP tissue proteomic changes were different across the disease trajectory; pathways related to lysosomal function, endocytosis, protein formation, actin and complement were uniquely dysregulated at 7 weeks, while pathways associated with nervous system, immune system, protein degradation and vascular system were uniquely dysregulated at 40 weeks. CSF proteomics in both mice and humans showed similar ChP-related dysregulated pathways. Conclusions Together, our findings support the hypothesis of ChP dysfunction in AD. These ChP changes were related to amyloid pathology. Therefore, the ChP could become a novel promising therapeutic target for AD.

Abstract Background Functional somatic symptoms (FFS) and bodily distress disorders are highly prevalent across all medical settings. Services for these patients are dispersed across the health care system with minimal conceptual and operational integration, and patients do not currently access therapeutic offers in significant numbers due to a mismatch between their and professionals’ understanding of the nature of the symptoms. New service models are urgently needed to address patients’ needs and to align with advances in aetiological evidence and diagnostic classification systems to overcome the body–mind dichotomy. Method A panel of clinical experts from different clinical services involved in providing aspects of health care for patients with functional symptoms reviewed the current care provision. This review and the results from a focus group exploration of patients with lived experience of functional symptoms were explored by the multidisciplinary expert group, and the conclusions are summarised as recommendations for best practice. Results The mapping exercise and multidisciplinary expert consultation revealed five themes for service improvement and pathway development: time/access, communication, barrier-free care, choice and governance. Service users identified four meta-themes for best practice recommendations: focus on healthcare professional communication and listening skills as well as professional attributes and knowledge base to help patients being both believed and understood in order to accept their condition; systemic and care pathway issues such as stronger emphasis on primary care as the first point of contact for patients, resources to reduce the length of the patient journey from initial assessment to diagnosis and treatment. Conclusion We propose a novel, integrated care pathway for patients with ‘functional somatic disorder’, which delivers care according to and working with patients’ explanatory beliefs. The therapeutic model should operate based upon an understanding of the embodied nature of patient’s complaints and provide flexible access points to the care pathway.

Abstract Purpose 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU. Patients and methods NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity. Results Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in

IntroductionSoil organic carbon (SOC) content can vary significantly across a given plot. Therefore, a representative sampling is a prerequisite to obtain meaningful results from analysis and of utter importance when SOC quantification is used to quantify (temporary) carbon dioxide removal (CDR). However, certain management practices aiming to increase SOC further increase the level of heterogeneity and may challenge representative sampling schemes. This includes concentrated root-zone application of biochar, which immediately increases SOC with the input of biochar-C and may promote the local enrichment of non-biochar SOC over time.MethodsHere, we used numerical modelling to quantify the number of single sampling points (soil cores) needed to achieve a representative sample of biochar-C and total SOC on a plot after application of biochar in rows, e.g., for growing vegetables, or in the circumference of trees in agroforestry systems.ResultsAfter row application of 5 t ha−1 biochar in soil with rather low SOC content (26 t ha−1), 140 soil cores (per 0.25 ha plot) where necessary to achieve representative sampling of C-stocks (±5% error) in 90% of the repeated sampling simulation cases. Compared to realistic and cost-effective soil sampling scenarios in agronomic practice, we conclude that concentrated root zone application of biochar makes representative sampling for quantification of SOC in soils with low baseline C-stocks virtually impossible.DiscussionThis finding calls into question the soil-sampling and SOC-analysis-based (“result-based”) monitoring of SOC as a (temporary) CDR when biochar might have been applied. Considering the rapid scaling of biochar production and use in agriculture, this is a considerable challenge for SOC certification. Instead, action-based incentives, rewarding farmers for carrying out specific practices, could be applied to promote carbon farming practices.

Abstract Colonoscopy and endoscopic ultrasound play pivotal roles in the assessment of rectal diseases, especially rectal cancer and inflammatory bowel diseases. Optical coherence tomography (OCT) offers a superior depth resolution, which is a critical factor for individualizing the therapeutic concept and evaluating the therapy response. We developed two distinct rectoscope prototypes, which were integrated into a 1300 nm MHz-OCT system constructed at our facility. The rapid rotation of the distal scanning probe at 40,000 revolutions per minute facilitates a 667 Hz OCT frame rate, enabling real-time endoscopic imaging of large areas. The performance of these OCT-rectoscopes was assessed in an ex vivo porcine colon and a post mortem human in-situ colon. The OCT-rectoscope consistently distinguished various layers of the intestinal wall, identified gut-associated lymphatic tissue, and visualized a rectal polyp during the imaging procedure with 3D-reconstruction in real time. Subsequent histological examination confirmed these findings. The body donor was preserved using an ethanol-glycerol-lysoformin-based technique for true-to-life tissue consistency. We could demonstrate that the novel MHZ-OCT-rectoscope effectively discriminates rectal wall layers and crucial tissue characteristics in a post mortem human colon in-situ. This real-time-3D-OCT holds promise as a valuable future diagnostic tool for assessing disease state and therapy response on-site in rectal diseases.

Abstract Background Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease caused by inherited or de novo germline pathogenic variants in TP53. Individuals with LFS have a 70–100% lifetime risk of developing cancer. The current standard of care involves annual surveillance with whole-body and brain MRI (WB-MRI) and clinical review; however, there are no chemoprevention agents licensed for individuals with LFS. Preclinical studies in LFS murine models show that the anti-diabetic drug metformin is chemopreventive and, in a pilot intervention trial, short-term use of metformin was well-tolerated in adults with LFS. However, metformin’s mechanism of anticancer activity in this context is unclear. Methods Metformin in adults with Li-Fraumeni syndrome (MILI) is a Precision-Prevention phase II open-labelled unblinded randomised clinical trial in which 224 adults aged ≥ 16 years with LFS are randomised 1:1 to oral metformin (up to 2 mg daily) plus annual MRI surveillance or annual MRI surveillance alone for up to 5 years. The primary endpoint is to compare cumulative cancer-free survival up to 5 years (60 months) from randomisation between the intervention (metformin) and control (no metformin) arms. Secondary endpoints include a comparison of cumulative tumour-free survival at 5 years, overall survival at 5 years and clinical characteristics of emerging cancers between trial arms. Safety, toxicity and acceptability of metformin; impact of metformin on quality of life; and impact of baseline lifestyle risk factors on cancer incidence will be assessed. Exploratory end-points will evaluate the mechanism of action of metformin as a cancer preventative, identify biomarkers of response or carcinogenesis and assess WB-MRI performance as a diagnostic tool for detecting cancers in participants with LFS by assessing yield and diagnostic accuracy of WB-MRI. Discussion Alongside a parallel MILI study being conducted by collaborators at the National Cancer Institute (NCI), MILI is the first prevention trial to be conducted in this high-risk group. The MILI study provides a unique opportunity to evaluate the efficacy of metformin as a chemopreventive alongside exploring its mechanism of anticancer action and the biological process of mutated P53-driven tumourigenesis. Trial registration ISRCTN16699730. Registered on 28 November 2022. URL: https://www.isrctn.com/ EudraCT/CTIS number 2022-000165-41.

Abstract Biofilms are resistant to many traditional antibiotics, which has led to search for new antimicrobials from different and unique sources. To harness the potential of aquatic microbial resources, we analyzed the meta-omics datasets of microalgae-bacteria communities and mined them for potential antimicrobial and quorum quenching enzymes. One of the most interesting candidates (Dlh3), a dienelactone hydrolase, is a α/β-protein with predicted eight α-helices and eight β-sheets. When it was applied to one of the major fish pathogens, Edwardsiella anguillarum, the biofilm development was reproducibly inhibited by up to 54.5%. The transcriptome dataset in presence of Dlh3 showed an upregulation in functions related to self-defense like active genes for export mechanisms and transport systems. The most interesting point regarding the biotechnological potential for aquaculture applications of Dlh3 are clear evidence of biofilm inhibition and that health and division of a relevant fish cell model (CHSE-214) was not impaired by the enzyme.

The COVID-19 pandemic has been the scene of several epistemic battles at the science-society interface, creating deadlocks that have been hard to overcome. To cut through the paralysing elements of these discussions, we present an analysis of three epistemic battles, concerning empirical evidence, expertise, and model projections. Our analysis singles out a crucial factor that drives unhelpful disputes like these: the contested prioritisation of specific types of scientific knowledge, which are considered adequate for policy only if they meet predetermined standards. To move beyond these deadlocks, we introduce the conceptual tools of epistemic pluralism and contextualism, which give concrete indications in the three controversies we discuss and show us the way forward in debates on science-based policy.

The transport of deformable particles (TDPs) through porous media has been of considerable interest due to the multiple applications found in industrial and medical processes. The adequate design of these applications has been mainly achieved through experimental efforts, since TDPs through porous media are challenging to model because of the mechanical blockage of the pore throat due to size exclusion, deformation in order to pass through the pore throat under the driven pressure, and breakage under strong extrusion. In this work, based on the diffusivity equation and considering the TDP as a complex fluid whose viscosity and density depend on the local pressure, a simple but accurate theoretical model is proposed to describe the pressure behavior under steady- and unsteady-state flow conditions. Assuming a linear pressure dependence of the viscosity and density of the TDPs, valid for moderate pressure changes, the solution of the mathematical model yields a quantitative correlation between the pressure evolution and the parameters compressibility, viscosity coefficient, elastic modulus, particle size, and friction factor. The predictions of the model agree with experiments and allow the understanding of transport of deformable particles through a porous media.

Abstract SARS-CoV-2 subunit vaccines continue to be the focus of intense clinical development worldwide. Protein antigens in these vaccines most commonly consist of the spike ectodomain fused to a heterologous trimerization sequence, designed to mimic the compact, prefusion conformation of the spike on the virus surface. Since 2020, we have produced dozens of such constructs in CHO cells, consisting of spike variants with different mutations fused to different trimerization sequences. This set of constructs displayed notable conformational heterogeneity, with two distinct trimer species consistently detected by analytical size exclusion chromatography. A recent report showed that spike ectodomain fusion constructs can adopt an alternative trimer conformation consisting of loosely associated ectodomain protomers. Here, we applied multiple biophysical and immunological techniques to demonstrate that this alternative conformation is formed to a significant extent by several SARS-CoV-2 variant spike proteins. We have also examined the influence of temperature and pH, which can induce inter-conversion of the two forms. The substantial structural differences between these trimer types may impact their performance as vaccine antigens.

Abstract Background Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences. Methods We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD and ADNI). In total, 973 participants (n = 205 controls, n = 546 mild cognitive impairment, n = 222 AD) were analyzed for 7,433,949 common SNPs and 19,511 protein-coding genes. Structural equation models tested whether biomarker PCs mediate genetic risk effects on AD, and stratified and interaction models probed for sex-specific effects. Results Five loci showed genome-wide significant association with CSF profiles, two were novel (rs145791381 [inflammation] and GRIN2D [synaptic functioning]) and three were previously described (APOE, TMEM106B, and CHI3L1). Follow-up analyses of the two novel signals in independent datasets only supported the GRIN2D locus, which contains several functionally interesting candidate genes. Mediation tests indicated that variants in APOE are associated with AD status via processes related to amyloid and tau pathology, while markers in TMEM106B and CHI3L1 are associated with AD only via neuronal injury/inflammation. Additionally, seven loci showed sex-specific associations with AD biomarkers. Conclusions These results suggest that pathway and sex-specific analyses can improve our understanding of AD genetics and may contribute to precision medicine.

Background: The use of diuretics is extremely common in infants cared for in neonatal wards, despite the lack of proven efficacy for many conditions. The main objective of this study was to assess the rate of diuretics exposure in a multicenter French cohort. The secondary objectives were to describe the evolution of this exposure over time, the indications, the prescription practices, and the exposure rates among centers.Methods: An observational study was conducted in 40 Level 3 French neonatal intensive care units using the same computerized order-entry system. Neonates hospitalized between January 2017 to December 2021 with a corrected age between 24 and 44 weeks of gestation at admission were eligible.Results: A total of 86,032 patients were included. The exposure rate was 8.5%, more specifically 29.4% for children born at < 32 weeks of gestation and 3.7% for neonates born at term. There was no significant variation over the study period, but the exposure ranged from 2.4% to 26.5% depending on the center. The main drugs prescribed were furosemide, spironolactone and dopamine with a diuretic purpose. The main indications were “fluid retention,” and to a lesser extent “bronchopulmonary dysplasia” and “post-transfusion.” For furosemide, the first exposure occurred in mean at 16.5 (±17.8) days of life, mean duration of exposure was 6.2 (±9.5) days, and the cumulative dose was in mean 10.7 (23.9) mg/kg.Conclusion: Diuretic prescription practices vary between centers. The administration of these drugs is often non-evidence based, doses and duration of treatment easily exceed toxic thresholds.

Microfluidics is an important technology for the biomedical industry and is often utilised in our daily lives. Recent advances in micro-milling technology have allowed for rapid fabrication of smaller and more complex structures, at lower costs, making it a viable alternative to other fabrication methods. The microfluidic chip fabrication developed in this research is a step-by-step process with a self-contained wet milling chamber. Additionally, ethanol solvent bonding is used to allow microfluidic chips to be fully fabricated within approximately an hour. The effect of using this process is tested with quantitative contact profileometery data to determine the expected surface roughness in the microchannels. The effect of surface roughness on the controllability of microparticles is tested in functional microfluidic chips using image processing to calculate particle velocity. This process can produce high-quality channels when compared with similar studies in the literature and surface roughness affects the control of microparticles. Lastly, we discuss how the outcomes of this research can produce rapid and higher-quality microfluidic devices, leading to improvement in the research and development process within the fields of science that utilise microfluidic technology. Such as medicine, biology, chemistry, ecology, and aerospace.

Las poblaciones de la Amazonía surinamesa, sean ellas de origen indígena o africano, han implementado durante siglos diversos sistemas de rotación de cultivos. La presencia de hormigas en sus parcelas era vista como un indicador del agotamiento de la fertilidad. Se consideraba que las hormigas señalaban la necesidad de abrir una nueva parcela en otro lugar, desempeñando así un papel importante para las comunidades. El poder colonial en Surinam, incluso aunque fuera una colonia neerlandesa hacía siglos, era muy poco presente en el espacio amazónico hasta bien entrado el siglo XX. Los biólogos que participaban en las primeras expediciones científicas en el espacio amazónico de la colonia interpretaron la interacción de humanos y hormigas como señal de la naturaleza «parasítica» de ambos. Este ensayo muestra cómo las campañas de erradicación de hormigas, financiadas por el poder colonial desde los años 50, abrieron el camino para grandes proyectos infraestructurales, con poder destructivo muchas veces más significativo que los métodos de cultivo tradicionales.

Background: For patients with acute myocardial infarction (AMI), direct coronary angiography (CA) is recommended, while for non-AMI patients, the diagnostic work-up depends on clinical criteria. This analysis provides initial prospective German data for the degree of guideline-adherence (GL) in the use of CA on non-AMI patients presenting at the emergency department (ED) with suspected acute coronary syndrome (ACS) according to the 2015 ESC-ACS-GL. Furthermore the implications of the application of the 2020 ESC-ACS-GL recommendations were evaluated. Methods: Patient symptoms were identified using a standardized questionnaire; medical history and diagnostic work-up were acquired from health records. In accordance with the 2015 ESC-ACS-GL, CA was considered GL-adherent if intermediate risk criteria (IRC) were present or non-invasive, image-guided testing (NIGT) was pathological. Results: Between January 2019 and August 2021, 229 patients were recruited across seven centers. Patients presented with chest pain, dyspnea, and other symptoms in 66.7%, 16.2% and 17.1%, respectively, were in mean 66.3 ± 10.5 years old, and 36.3% were female. In accordance with the 2015 ESC-ACS-GL, the use of CA was GL-adherent for 64.0% of the patients. GL-adherent compared to non-adherent use of CA resulted in revascularization more often (44.5% vs. 17.1%, p

Abstract Water infiltration into fractures is ubiquitous in crustal rocks. However, little is known about how such a progressive wetting process affects fracture stiffness and seismic wave propagation, which are highly relevant for characterizing fracture systems in situ. We study the acousto‐mechanical behavior of a free‐standing fractured granite subjected to gradual water infiltration with a downward‐moving wetting front over 12 days. We observe significant differences (i.e., by an order of magnitude) in wave amplitudes across the fractured granite compared to an intact granite, with both cases showing a strong correlation between wave amplitudes and wetting front movement. Effects of water infiltration into the fracture and surrounding matrix on seismic attenuation are captured by a numerical model with parameters constrained by experimental data. Back‐calculated fracture stiffness decreases exponentially with the wetting front migration along the fracture. We propose that moisture‐induced matrix expansion around the fracture increases asperity mismatch, leading to reduced fracture stiffness.

Abstract Neuroinflammation is an important component of many neurodegenerative diseases, whether as a primary cause or a secondary outcome. For that reason, either as diagnostic tools or to monitor progression and/or pharmacological interventions, there is a need for robust biomarkers of neuroinflammation in the brain. Mitochondrial TSPO (18 kDa Translocator protein) is one of few available biomarkers of neuroinflammation for which there are clinically available PET imaging agents. In this study, we further characterised neuroinflammation in a mouse model of prion-induced chronic neurodegeneration (ME7) including a pharmacological intervention via a CSF1R inhibitor. This was achieved by autoradiographic binding of the second-generation TSPO tracer, [3H]PBR28, along with a more comprehensive examination of the cellular contributors to the TSPO signal changes by immunohistochemistry. We observed regional increases of TSPO in the ME7 mouse brains, particularly in the hippocampus, cortex and thalamus. This increased TSPO signal was detected in the cells of microglia/macrophage lineage as well as in astrocytes, endothelial cells and neurons. Importantly, we show that the selective CSF1R inhibitor, JNJ-40346527 (JNJ527), attenuated the disease-dependent increase in TSPO signal, particularly in the dentate gyrus of the hippocampus, where JNJ527 attenuated the number of Iba1+ microglia and neurons, but not GFAP+ astrocytes or endothelial cells. These findings suggest that [3H]PBR28 quantitative autoradiography in combination with immunohistochemistry are important translational tools for detecting and quantifying neuroinflammation, and its treatments, in neurodegenerative disease. Furthermore, we demonstrate that although TSPO overexpression in the ME7 brains was driven by various cell types, the therapeutic effect of the CSF1R inhibitor was primarily to modulate TSPO expression in microglia and neurons, which identifies an important route of biological action of this particular CSF1R inhibitor and provides an example of a cell-specific effect of this type of therapeutic agent on the neuroinflammatory process.

Abstract Development of beamforming methods for towed sonar multiplet line arrays is stimulated by their increased use in undersea surveillance. Such methods employ various forms of narrowband optimal beamforming to resolve port/starboard ambiguity present when the array is conventionally beamformed. In this paper, we depart from the purely narrowband approach and discuss methods for port/starboard ambiguity rejection (PSAR) using a broadband formulation. The proposed methodology relies on subband beamforming for which we use non-adaptive variants of beamspace Minimum Variance Distortionless Response (MVDR) and the Linear Constraint Minimum Variance (LCMV) beamformers. We provide detailed description and comparison of both subband methods and establish a connection between them. The paper provides assessment of PSAR properties of the developed broadband beamformers using outputs of signal processing of both simulated and experimental sonar data. Experimental data for this work were obtained through the participation in the Littoral Continuous Active Sonar (LCAS) trials.

Abstract The present study aimed at investigating the influence of personality on both anticipatory stress vulnerability and the effectiveness of coping strategies in an occupational stressful context. Following assessment of individual personality traits (Big Five Inventory), 147 volunteers were exposed to the anticipation of a stressful event. Anxiety and cardiac reactivity were assessed as markers of vulnerability to anticipatory stress. Participants were then randomly assigned to three groups and subjected to a 5-min intervention: relaxation breathing, relaxation breathing combined with cardiac biofeedback, and control. The effectiveness of coping interventions was determined through the cardiac coherence score achieved during the intervention. Higher neuroticism was associated with higher anticipatory stress vulnerability, whereas higher conscientiousness and extraversion were related to lower anticipatory stress vulnerability. Relaxation breathing and biofeedback coping interventions contributed to improve the cardiac coherence in all participants, albeit with greater effectiveness in individuals presenting higher score of openness to experience. The present findings demonstrated that personality traits are related to both anticipatory stress vulnerability and effectiveness of coping interventions. These results bring new insights into practical guidelines for stress prevention by considering personality traits. Specific practical applications for health professionals, who are likely to manage stressful situations daily, are discussed.

Summary: Background: Identifying female individuals at highest risk of developing life-threatening breast cancers could inform novel stratified early detection and prevention strategies to reduce breast cancer mortality, rather than only considering cancer incidence. We aimed to develop a prognostic model that accurately predicts the 10-year risk of breast cancer mortality in female individuals without breast cancer at baseline. Methods: In this model development and validation study, we used an open cohort study from the QResearch primary care database, which was linked to secondary care and national cancer and mortality registers in England, UK. The data extracted were from female individuals aged 20–90 years without previous breast cancer or ductal carcinoma in situ who entered the cohort between Jan 1, 2000, and Dec 31, 2020. The primary outcome was breast cancer-related death, which was assessed in the full dataset. Cox proportional hazards, competing risks regression, XGBoost, and neural network modelling approaches were used to predict the risk of breast cancer death within 10 years using routinely collected health-care data. Death due to causes other than breast cancer was the competing risk. Internal–external validation was used to evaluate prognostic model performance (using Harrell's C, calibration slope, and calibration in the large), performance heterogeneity, and transportability. Internal–external validation involved dataset partitioning by time period and geographical region. Decision curve analysis was used to assess clinical utility. Findings: We identified data for 11 626 969 female individuals, with 70 095 574 person-years of follow-up. There were 142 712 (1·2%) diagnoses of breast cancer, 24 043 (0·2%) breast cancer-related deaths, and 696 106 (6·0%) deaths from other causes. Meta-analysis pooled estimates of Harrell's C were highest for the competing risks model (0·932, 95% CI 0·917–0·946). The competing risks model was well calibrated overall (slope 1·011, 95% CI 0·978–1·044), and across different ethnic groups. Decision curve analysis suggested favourable clinical utility across all age groups. The XGBoost and neural network models had variable performance across age and ethnic groups. Interpretation: A model that predicts the combined risk of developing and then dying from breast cancer at the population level could inform stratified screening or chemoprevention strategies. Further evaluation of the competing risks model should comprise effect and health economic assessment of model-informed strategies. Funding: Cancer Research UK.

Abstract Clusterin (CLU) is one of the most significant genetic risk factors for late onset Alzheimer’s disease (AD). However, the mechanisms by which CLU contributes to AD development and pathogenesis remain unclear. Studies have demonstrated that the trafficking and localisation of glycosylated CLU proteins is altered by CLU-AD mutations and amyloid-β (Aβ), which may contribute to AD pathogenesis. However, the roles of non-glycosylated and glycosylated CLU proteins in mediating Aβ toxicity have not been studied in human neurons. iPSCs with altered CLU trafficking were generated following the removal of CLU exon 2 by CRISPR/Cas9 gene editing. Neurons were generated from control (CTR) and exon 2 −/− edited iPSCs and were incubated with aggregated Aβ peptides. Aβ induced changes in cell death and neurite length were quantified to determine if altered CLU protein trafficking influenced neuronal sensitivity to Aβ. Finally, RNA-Seq analysis was performed to identify key transcriptomic differences between CLU exon 2 −/− and CTR neurons. The removal of CLU exon 2, and the endoplasmic reticulum (ER)-signal peptide located within, abolished the presence of glycosylated CLU and increased the abundance of intracellular, non-glycosylated CLU. While non-glycosylated CLU levels were unaltered by Aβ25–35 treatment, the trafficking of glycosylated CLU was altered in control but not exon 2 −/− neurons. The latter also displayed partial protection against Aβ-induced cell death and neurite retraction. Transcriptome analysis identified downregulation of multiple extracellular matrix (ECM) related genes in exon 2 −/− neurons, potentially contributing to their reduced sensitivity to Aβ toxicity. This study identifies a crucial role of glycosylated CLU in facilitating Aβ toxicity in human neurons. The loss of these proteins reduced both, cell death and neurite damage, two key consequences of Aβ toxicity identified in the AD brain. Strikingly, transcriptomic differences between exon 2 −/− and control neurons were small, but a significant and consistent downregulation of ECM genes and pathways was identified in exon 2 −/− neurons. This may contribute to the reduced sensitivity of these neurons to Aβ, providing new mechanistic insights into Aβ pathologies and therapeutic targets for AD.

Suriname was one of the first countries in the global South to produce aluminium. The establishment of this industry, including the hydroelectric dam that was meant to power it, was the key idea upon which Suriname’s entire dream of modernity and independence was constructed. Negotiations with the Aluminum Company of America (Alcoa) resulted in Suriname accepting a treaty under which hardly any benefits accumulated in the country itself, while the establishment of the industry caused loss of land, environmental damage and the deculturation of the Surinamese Maroon communities. After these revolted against the state, Alcoa left the country, leaving behind an ‘aluminium landscape’ where aluminium is no longer produced, but where the original population, insofar as its members have not moved to the cities, is still heavily affected by the changes caused by the Surinamese aluminium boom.

Background: With 900′000 coronary angiographies (CA) per year, Germany has the highest annual per capita volume in Europe. Until now there are no prospective clinical data on the degree of guideline-adherence in the use of CA in patients with suspected chronic coronary syndrome (CCS) in Germany. Methods: Between January 2019 and August 2021, 458 patients with suspected CCS were recruited in nine German centres. Guideline-adherence was evaluated according to the current European Society of Cardiology and German guidelines. Pre-test probability (PTP) for CAD was determined using age, gender, and a standardized patient questionnaire to identify symptoms. Data on the diagnostic work-up were obtained from health records. Results: Patients were in mean 66.6 years old, male in 57.3 %, had known CAD in 48.4 % and presented with typical, atypical, non-anginal chest pain or dyspnoea in 35.7 %, 41.3 %, 23.0 % and 25.4 %, respectively. PTP according to the European guidelines was in mean 24.2 % (11.9 %-36.5 % 95 % CI). 20.9 % of the patients received guideline-recommended preceding non-invasive image guided testing. The use of CA was adherent to the European and German guideline recommendations in 20.4 % and 25.4 %, respectively. In multivariate-analysis, arterial hypertension and prior revascularization were predictors of guideline non-adherence. Conclusion: These are the first prospective clinical data which demonstrated an overall low degree of guideline-adherence in the use of CA in patients with suspected CCS in the German health care setting. To improve adherence rates, the availability of and access to non-invasive image guided testing needs to be strengthened. (German Clinical Trials Registry DRKS00015638 – Registration Date: 19.02.2019)

Background and objectives: Environmental factors influence the development of very preterm infants (VPIs, born at less than 32 weeks of gestation). It is important to identify all potential sources of paraben exposure in these vulnerable infants. We aimed to quantify paraben exposure via drug administration in a cohort of VPI cared for in neonatal intensive care units (NICUs).Methods: A prospective, observational study was carried out over a five-year period in a regional setting (two NICUs using the same computerized order-entry system). The main outcome was exposure to paraben-containing drugs. The secondary outcomes were: time of the first exposure, daily intake, number of infants exceeding paraben acceptable daily intake (ADI: 0–10 mg/kg/d), duration of exposure, and cumulative dose.Results: The cohort consisted of 1,315 VPIs [BW 1129.9 (±360.4) g]. Among them, 85.5% were exposed to paraben-containing drugs. In 40.4% of infants, the first exposure occurred during the second week of life. Mean paraben intake and duration of exposure were, respectively, 2.2 (±1.4) mg/kg/d and 33.1 (±22.3) days. The cumulative paraben intake was 80.3 (±84.6) mg/kg. The ADI was exceeded in 3.5% of exposed infants. Lower GA was associated with higher intake and longer exposure (p < 0.0001). The main molecules involved in paraben exposure were: sodium iron feredetate, paracetamol, furosemide, and sodium bicarbonate + sodium alginate.Conclusion: Commonly used drugs are potential source of parabens, and ADI can be easily exceeded in VPIs cared for in NICUs. Efforts are needed to identify paraben-free alternative formulations for these vulnerable infants.

Human metapneumovirus (HMPV) is a pneumovirus that may cause severe respiratory disease in humans. HMPV infection has been found to increase susceptibility to bacterial superinfections leading to increased morbidity and mortality. The molecular mechanisms underlying HMPV-mediated increase in bacterial susceptibility are poorly understood and largely understudied. Type I interferons (IFNs), while critical for antiviral defenses, may often have detrimental effects by skewing the host immune response and cytokine output of immune cells. It is currently unknown if HMPV skews the inflammatory response in human macrophages triggered by bacterial stimuli. Here we report that HMPV pre-infection impacts production of specific cytokines. HMPV strongly suppresses IL-1β transcription in response to LPS or heat-killed Pseudomonas aeruginosa and Streptococcus pneumonia, while enhancing mRNA levels of IL-6, TNF-α and IFN-β. We demonstrate that in human macrophages the HMPV-mediated suppression of IL-1β transcription requires TANK-binding kinase 1 (TBK1) and signaling via the IFN-β-IFNAR axis. Interestingly, our results show that HMPV pre-infection did not impair the LPS-stimulated activation of NF-κB and HIF-1α, transcription factors that stimulate IL-1β mRNA synthesis in human cells. Furthermore, we determined that sequential HMPV-LPS treatment resulted in accumulation of the repressive epigenetic mark H3K27me3 at the IL1B promoter. Thus, for the first time we present data revealing the molecular mechanisms by which HMPV shapes the cytokine output of human macrophages exposed to bacterial pathogens/LPS, which appears to be dependent on epigenetic reprogramming at the IL1B promoter leading to reduced synthesis of IL-1β. These results may improve current understanding of the role of type I IFNs in respiratory disease mediated not only by HMPV, but also by other respiratory viruses that are associated with superinfections.

The prevalence of asymptomatic leishmaniasis in dogs and their owners in the main endemic areas of France has not been studied to date. The objective of this study was to quantify asymptomatic Leishmania infantum infection in southeast France in healthy people and their dogs using molecular and serological screening techniques. We examined the presence of parasitic DNA using specific PCR targeting kinetoplast DNA (kDNA) and specific antibodies by serology (ELISA for dogs and Western blot for humans) among immunocompetent residents and their dogs in the Alpes-Maritimes. Results from 343 humans and 607 dogs were included. 46.9% (n = 161/343) of humans and 18.3% (n = 111/607) of dogs were PCR positive; 40.2% of humans (n = 138/343) and 9.9% of dogs (n = 60/607) were serology positive. Altogether, 66.2% of humans (n = 227) and 25.7% of dogs (n = 156) had positive serologies and/or positive PCR test results. Short-haired dogs were more frequently infected (71.8%, n = 112) than long-haired dogs (12.2%, n = 19) (p = 0.043). Dogs seemed to be more susceptible to asymptomatic infection according to their breed types (higher infection rates in scenthounds, gun dogs and herding dogs) (p = 0.04). The highest proportion of dogs and human asymptomatic infections was found in the Vence Region, corresponding to 28.2% (n = 20/71) of dogs and 70.5% (n = 31/44) of humans (4.5/100,000 people). In conclusion, the percentage of infections in asymptomatic humans is higher than in asymptomatic dogs in the studied endemic area. It is questionable whether asymptomatic infection in humans constitutes a risk factor for dogs.

We present a hardware data structure specifically designed for FPGAs that enables the execution of the hard real-time database CRUD operations using a hybrid data structure that combines trees and rings. While the number of rows and columns has to be limited for hard real-time execution, the actual content can be of any size. Our structure restricts full navigational freedom to every but the leaf layer, thus keeping the memory overhead for the data stored in the leaves low. Although its nodes differ in function, all have exactly the same size and structure, reducing the number of cascaded decisions required in the database operations. This enables fast and efficient hardware implementation on FPGAs. In addition to the usual comparison with known data structures, we also analyze the tradeoff between the memory consumption of our approach and a simplified version that is doubly linked in all layers.

The majority of breast cancers express the estrogen receptor (ER) and for this group of patients, endocrine therapy is the cornerstone of systemic treatment. However, drug resistance is common and a focus for breast cancer preclinical and clinical research. Over the past 2 decades, the PI3K/Akt/mTOR axis has emerged as an important driver of treatment failure, and inhibitors of mTOR and PI3K are now licensed for the treatment of women with advanced ER-positive breast cancer who have relapsed on first-line hormonal therapy. This review presents the preclinical and clinical data that led to this new treatment paradigm and discusses future directions.

Abstract Background Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer’s disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels. Methods We performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer’s Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study. Results We found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood–brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC, associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins. Conclusions CSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood–brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles.

Summary: TSPEAR variants cause autosomal recessive ectodermal dysplasia (ARED) 14. The function of TSPEAR is unknown. The clinical features, the mutation spectrum, and the underlying mechanisms of ARED14 are poorly understood. Combining data from new and previously published individuals established that ARED14 is primarily characterized by dental anomalies such as conical tooth cusps and hypodontia, like those seen in individuals with WNT10A-related odontoonychodermal dysplasia. AlphaFold-predicted structure-based analysis showed that most of the pathogenic TSPEAR missense variants likely destabilize the β-propeller of the protein. Analysis of 100000 Genomes Project (100KGP) data revealed multiple founder TSPEAR variants across different populations. Mutational and recombination clock analyses demonstrated that non-Finnish European founder variants likely originated around the end of the last ice age, a period of major climatic transition. Analysis of gnomAD data showed that the non-Finnish European population TSPEAR gene-carrier rate is ∼1/140, making it one of the commonest AREDs. Phylogenetic and AlphaFold structural analyses showed that TSPEAR is an ortholog of drosophila Closca, an extracellular matrix-dependent signaling regulator. We, therefore, hypothesized that TSPEAR could have a role in enamel knot, a structure that coordinates patterning of developing tooth cusps. Analysis of mouse single-cell RNA sequencing (scRNA-seq) data revealed highly restricted expression of Tspear in clusters representing enamel knots. A tspeara−/−;tspearb−/− double-knockout zebrafish model recapitulated the clinical features of ARED14 and fin regeneration abnormalities of wnt10a knockout fish, thus suggesting interaction between tspear and wnt10a. In summary, we provide insights into the role of TSPEAR in ectodermal development and the evolutionary history, epidemiology, mechanisms, and consequences of its loss of function variants.

Background: Postnatal corticosteroids (PC) are widely used in very preterm infants. International reports and national multicenter trials describe a marked variability across countries and inter-sites, in the use of PC. Few information is available on therapeutic indications and prescription characteristics of PC.Aim: The main objective of this study was to describe the exposure to PC in a large cohort of preterm infants born at less than 32 weeks of gestation, according to the prescription data of 41 tertiary-care NICUs in France. Secondary objectives were to describe therapeutic indications, day of life (DOL) of the first exposure, route of administration, duration, cumulative dose for each drug, and differences in exposure rates across centers.Methods: We conducted a prospective observational cohort analysis from January 2017 to December 2021, in 41 French tertiary-care NICUs using the same computerized order-entry system.Results: In total, 13,913 infants [birth weight 1144.8 (±365.6) g] were included. Among them, 3633 (26.1%) were exposed to PC, 21.8% by systemic and 10.1% by inhaled route. Within the study population, 1,992 infants (14.3%) received the first corticosteroid treatment in the first week of life and 1641 (11.8%) after DOL 7. The more frequent indications were prevention and/or treatment of bronchopulmonary dysplasia, and arterial hypotension. Hydrocortisone was the more often prescribed molecule. For systemic PC the first exposure occurred in mean at DOL 9.4 (±13.5), mean duration of treatment was 10.3 (±14.3) days, and the cumulative dose (expressed as the equivalent dose of hydrocortisone) was in median [IQR] 9.0 [5.5–28.8] mg/kg. For inhaled PC, the first exposure occurred in mean at DOL 34.1 (±19.7), and mean duration of treatment 28.5 (±24.4) days. The exposure rate ranged from a minimum of 5% to a maximum of 56% among centers, and significantly increased over the study period (p < 0.0001).Conclusion: In this French cohort of very preterm infants, around one patient out to five was exposed to PC during hospital stay in the NICU. The exposure occurred early, starting from the first week of life. Exposure rate widely varied among centers. Pharmacoepidemiology studies are useful to increase knowledge on corticosteroid utilization patterns in preterm infants.