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In this work, we simulate barchan swarms using the Two-Flank Agent-Based Model and investigate how changes to model parameters and environmental drivers lead to different swarm dynamics. In particular, we explore how the parameter qshift, which controls the rate of equilibration between the flanks of an asymmetric dune and thereby the stability of an asymmetric morphology, influences the frequencies of different collision types in the swarm and can be adjusted to produce swarms with dune sizes that are longitudinally homogeneous. Such size stability has been observed in real-world swarms but has not been obtained by previous agent-based models. We also find that, for certain densities of newly added barchans, the dune number density remains constant with downwind distance, something which has also been reported in nature but not in previous agent-based models. We also investigated how boundary condition changes propagate through swarms, something which will become increasingly important in the face of human infrastructure expansion and anthropogenic climate change. Finally, we are able to investigate how asymmetry and spatially patterning in the swarms are influenced by bimodal wind regimes. Since these simulations produce many more realistic phenomena than previous models, this work represents a significant step forward in the our understanding of the interplay between environmental conditions and dune interactions in shaping the dynamics of barchan swarms.

Giulia Zago,1,2,* Mirte Muller,1,* Michel van den Heuvel,1 Paul Baas1 1Department of Thoracic Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek (NKI-AvL), Amsterdam, the Netherlands; 2Medical Oncology 2, Istituto Oncologico Veneto (IOV), Padova, Italy *These authors contributed equally to this work Abstract: Non-small-cell lung cancer (NSCLC) is often diagnosed at an advanced stage of disease, where it is no longer amenable to curative treatment. During the last decades, the survival has only improved significantly for lung cancer patients who have tumors harboring a driver mutation. Therefore, there is a clear unmet need for effective therapies for patients with no mutation. Immunotherapy has emerged as an effective treatment for different cancer types. Nivolumab, a monoclonal inhibitory antibody against PD-1 receptor, can prolong survival of NSCLC patients, with a manageable toxicity profile. In two Phase III trials, nivolumab was compared to docetaxel in patients with, respectively, squamous (CheckMate 017) and non-squamous NSCLC (CheckMate 057). In both trials, nivolumab significantly reduced the risk of death compared to docetaxel (41% and 27% lower risk of death for squamous and non-squamous NSCLC, respectively). Therefore, nivolumab has been approved in the US and in Europe as second-line treatment for advanced NSCLC. Unfortunately, accurate predictive factors for patient selection are lacking, making it difficult to decide who will benefit and who will not. Currently, there are many ongoing trials that evaluate the efficacy of nivolumab in different settings and in combination with other agents. This paper reviews the present literature about the role of nivolumab in the treatment of NSCLC. Particular attention has been given to efficacy studies, toxicity profile, and current and emerging predictive factors. Keywords: nivolumab, advanced non-small-cell lung cancer, immunotherapy, anti-PD-1

Abstract Striated grooves in tool marks are common at the base of sandstones, especially in deep‐marine successions, but their use in physical‐process and environmental reconstruction is underdeveloped. To fill this gap in knowledge, striations in the central groove of chevron marks and in chevron‐less groove marks were formed in the laboratory by dragging tools armoured with silt, sand or gravel across muddy substrates. These experiments simulated the formation of striated grooves by armoured mud clasts carried at the base of quasi‐laminar and fully laminar debris flows, aiming to: (1) delineate the bed shear strengths for the formation of striated grooves at different armour sediment sizes; (2) examine how the preservation potential of striated grooves depends on clay bed rheology and size of armour sediment and (3) discuss how the pre‐lithification clay bed consolidation state and size of armour sediment can be reconstructed from striated grooves in the geological record. The experimental results revealed that tools with small‐diameter silt and sand armours dragged along soft beds lack striations or, at best, leave poorly defined striations, whereas firm beds and gravel armours exhibit well‐defined striations. The spacing of striations formed by gravel clasts corresponds well with the clast diameter, implying that striation spacing is a good proxy for the diameter of armoured gravel under natural conditions. In contrast, the spacing of striae formed by sand armours is greater than the grain diameter, suggesting that the spacing of fine striations can only be used to predict a maximum armour sand size. A comparison of different processes of formation of armoured mud clasts demonstrated that the armouring of mud clasts most probably happens after incorporation of the clasts by erosion into the head of the debris flow and subsequent movement across a loose sandy or gravelly bed surface.

Abstract A precise quantification of mitral regurgitation (MR) severity is essential for treatment and outcome of patients with MR. 3D echocardiography facilitates estimation of MR but selection of patients with necessity of invasive treatment remains challenging. We investigate effective regurgitation orifice area (EROA) quantification by 3D compared to 2D echocardiography in patients with MR and highlight the improved discrimination of MR severity. We consecutively enrolled fifty patients with primary or secondary and at least moderate MR undergoing 2D and 3D colour Doppler echocardiography prior to transcatheter edge-to-edge repair (TEER). Improved accuracy of MR grading using 3D vena contracta area (VCA) as an estimate of EROA was compared to 2D proximal isovelocity surface area (PISA) quantification method and a multiparameter reference standard. Quantification of EROA remarkably varies between 2D and 3D echocardiography and the discrimination between moderate and severe MR was significantly (p = 0.001) different using 2D PISA or 3D VCA, respectively. 3D VCA correlated significantly (r = 0.501, p

(Series Information) European Papers - A Journal on Law and Integration, 2024 9(1), 209-228 | Article | (Table of Contents) I. Introduction. – II. The two-step accession to Schengen. – II.1. Schengen accession under primary law. – II.2. Schengen accession under secondary law. – III. Application of the Schengen acquis in Schengen candidate states. – III.1. Binding but not applicable. – III.2. Defining Schengen’s external borders. – III.3. The legal regime at the Schengen state’s border with Schengen candidate countries. – IV. Participation without full membership. – V. Conclusion. | (Abstract) This Article looks at the practical and legal implications of the Schengen “waiting room”. It examines the rules that apply to the verification of readiness in preparation of a Council decision on full accession and the extent to which the rules of the Schengen acquis apply to Schengen Candidate Countries prior to the lifting of internal border controls. It pays particular attention to the legal regime that applies at the borders between “old” and “new” Member States, more specifically Schengen members and Schengen Candidate Countries, and the borders between the Schengen Candidate Countries and third countries. It is argued that the prolonged exclusion from the Schengen area has resulted in a de facto duplication of the EU’s external border, accompanied with an incremental, near full application of the Schengen acquis, short of lifting internal border controls. As a result, for already well over fifteen years, Romania and Bulgaria have been part of the accompanying measures that should allow for free travel, yet its nationals have not been able to enjoy the benefits of their EU citizenship in full.

Background: Glycoprotein (GP)VI is a platelet-specific collagen receptor required for platelet activation during hemostasis. Platelet reactivity toward collagen is routinely assessed during diagnostic workup of platelet disorders. GPVI can be activated by inducing receptor clustering with suspensions of fibrillar collagen or synthetic cross-linked collagen-related peptide (CRP-XL). However, these suspensions are poorly standardized or difficult to produce. Nanobodies are small recombinant camelid-derived heavy-chain antibody variable regions. They are highly stable, specific, and ideal candidates for developing a stable GPVI agonist for diagnostic assays. Objectives: Develop a stable nanobody-based GPVI agonist. Methods: Nanobody D2 (NbD2) was produced as dimers and purified. Tetramers were generated via C-terminal fusion of dimers with click chemistry. Nanobody constructs were functionally characterized with light transmission aggregometry (LTA) in platelet-rich plasma and whole blood flow cytometry. Diagnostic performance was assessed in patients with inherited platelet function disorders with LTA and flow cytometry. Results: NbD2 was specific for human platelet GPVI. Dimers did not result in platelet activation in LTA or flow cytometry settings and fully inhibited CRP-XL-induced P-selectin expression and fibrinogen binding in whole blood and attenuated collagen-induced platelet aggregation in platelet-rich plasma. However, NbD2 tetramers caused full platelet aggregation, as well as P-selectin expression and fibrinogen binding. NbD2 tetramers were able to discriminate between inherited platelet function disorder patients and healthy controls based on fibrinogen binding, similar to CRP-XL. Conclusion: Nanobody tetramers to GPVI induce platelet activation and can be used to assess the GPVI pathway in diagnostic assays.

Background During military deployment, stress regulation is vital to protect against the development of anxiety and trauma-related symptoms. Brain endocannabinoids play an important role in stress regulation and previous research has shown that genetic variations in the FAAH rs324420 polymorphism demonstrate protective effects during stress. In addition, this polymorphism shows interactions with the CRHR1 and CNR1 polymorphisms on anxiety. The present study examines whether genetic variations of the FAAH, CRHR1 and CNR1 polymorphisms interact with the development of anxiety and trauma related symptoms in military veterans. Methods Veterans (N = 949) who went on military deployment and experienced a stressful event were genotyped for FAAH rs324420, CRHR1 rs110402 and CNR1 rs2180619. Anxiety and trauma symptoms were measured pre-deployment and 6 months after deployment. Anxiety was measured with the anxiety subscale of the Symptom Checklist-90 (SCL-90) and trauma with the Self-Rating Inventory for PTSD (SRIP). Results Covariance Pattern Models demonstrated no significant relation of genetic variations in FAAH rs324420 on anxiety and PTSD symptoms from pre-deployment to 6 months after military deployment. Additionally, we investigated interactions between the FAAH s324420, CRHR1 rs110402 and CNR1 rs2180619 polymorphisms. This also demonstrated no significant effects on anxiety and PTSD symptoms pre- to post deployment. However, the covariate of childhood trauma that was included in the models was significant in all these models. Conclusion Genetic variations in FAAH rs324420 and its interactions with CRHR1 rs110402 and CNR1 rs2180619 are not related to the development of anxiety and trauma-related symptoms. The study however, indicates the importance of considering childhood trauma in the investigation of the effects of polymorphisms that are related to the endocannabinoid system on the development of anxiety and PTSD symptoms.

In an acute contact test with bees the compound of interest is dissolved in a carrier solvent (frequently acetone) and then a droplet of the solution is placed on the dorsal thorax of the bee. The volume of the droplet is standardised to 1 µL for honeybees and to 2 µL for bumblebees. In practice the same droplet volume is used for bees with very different sizes. In this research the effect of the droplet volume was evaluated with acute contact tests with dimethoate for the alfalfa leafcutter bee, the red mason bee, the honeybee and the bumblebee. The results were analysed with a ToxicoKinetic ToxicoDynamic (TKTD) model to separate kinetic from dynamic effects. This allows to compare the sensitivity of the bee based on the effect threshold and not on the time, species and test dependent LD50s. The analysis of the test results indicates that the magnitude of the response of the bees increased with increasing droplet size. The results also showed that the manifestation of effects over time is slower for the red mason bee and the bumblebee compared to the honeybee and the alfalfa leafcutter bee. This implies that the result of a 2 day test with a fixed dosing volume results in different response for a bumblebee compared to the alfalfa leafcutter bee, not because of different sensitivities of the bees involved but due to the difference of relative dosed surface ratio. So comparing the sensitivity of bee species, based on standardised tests is biased and amplifies the sensitivity for the smaller bee species.

Abstract Background Obstetrician-Gynaecologists (ObGyns) frequently face work-related adverse events such as severe obstetric complications and maternal or neonatal deaths. In 2014, the WATER-1 study showed that ObGyns are at risk of developing work-related posttraumatic stress disorder (PTSD), while many hospitals lacked a professional support system. The aim of the present study is to evaluate the current prevalence of work-related traumatic events and mental health problems among Dutch ObGyns, as well as to examine the current and desired support. Methods In 2022, an online questionnaire was sent to all members of the Dutch Society of Obstetrics and Gynaecology (NVOG), including resident and attending ObGyns. The survey included questions about experienced work-related events, current and desired coping strategies, and three validated screening questionnaires for anxiety, depression, and PTSD (HADS, TSQ, and PCL-5). Results The response rate was 18.8% and 343 questionnaires were included in the analysis. Of the respondents, 93.9% had experienced at least one work-related adverse event, 20.1% had faced a complaint from the national disciplinary board, and 49.4% had considered leaving the profession at any moment in their career. The prevalence rates of clinically relevant anxiety, depression, and psychological distress were 14.3, 4.4, and 15.7%, respectively. The prevalence of work-related PTSD was 0.9% according to DSM-IV and 1.2% according to DSM-5. More than half of the respondents (61.3%) reported the presence of a structured support protocol or approach in their department or hospital, and almost all respondents (92.6%) rated it as sufficient. Conclusions The percentages of anxiety, depression, psychological distress and PTSD are comparable to the similar study performed in 2014. Most Dutch ObGyns experience adverse events at work, which can be perceived as traumatic and, in certain cases, may lead to the development of PTSD. Structured support after adverse work-related events is now available in almost two-thirds of workplaces, and was mostly experienced as good. Despite substantial improvements in the availability and satisfaction of professional support after work-related adverse events, the prevalence rates of mental problems remain considerable, and it is imperative to sustain conversation about the mental well-being of ObGyns.

Besides being an essential structural component of plasma membranes and the precursor of many functional compounds and signaling molecules, cholesterol was also proposed to play a role in the etiology and/or manifestation of Parkinson’s disease (PD). However, so far systematic investigations on the role of cholesterol and its metabolites present in the brain for the etiology of PD are missing. Here, we investigate for the first time the association of PD with SNPs in the genes of four cytochromes P450 (P450), CYP46A1, CYP39A1, CYP27A1 and CYP7B1, which are critical for the degradation of cholesterol in the brain. Analyzing 1,349 individuals from the PPMI data base, we found 24 SNPs in these four genes, which are significantly over- or under-represented in patients suffering from idiopathic PD (IPD). Studying each of the 362 IPD patients individually, we found that most patients (45%) showed only one associated SNP in one of the four P450 genes, while 31% displayed two associated SNPs and 18% three associated SNPs. The occurrence of some associated SNPs is in the same order of magnitude as SNPs in the GBA (beta-glucocerebrosidase) and thus might reflect a genetic predisposition for PD. As all 24 SNPs were located in introns and 3′ untranslated regions, we evaluated the prospective regulatory impact of the surrounding genomic regions by using transcriptome and epigenome data from the Foundational Data Initiative for Parkinson Disease (FOUNDIN-PD). FOUNDIN-PD provides gene expression, open chromatin and DNA methylation data in a cohort of 89 induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons derived from people in the PPMI study. Indeed, two of the 24 SNPs, one in CYP7B1 (rs118111353) and the other one in CYP27A1 (rs74446825), were localized within a region of open chromatin in differentiated neurons. Interestingly, all iPSC lines with open chromatin in rs118111353 showed the reference allele. As all four P450, CYP46A1, CYP39A1, CYP27A1 and CYP7B1, are expressed in dopaminergic neurons, we discuss further functional studies to connect SNPs in regulatory regions with gene expression levels. Finally, potential possibilities for personalized therapeutic treatment of patients with SNPs in the four investigated P450 are discussed.

Chicán es una pequeña comunidad rural de origen maya ubicada en la península de Yucatán, conocida como “el pueblo de los sordos” por la alta prevalencia de sordera profunda. El objetivo de este estudio fue determinar el coeficiente de consanguinidad en la comunidad de Chicán utilizando el método de isonimia marital como estrategia para explicar la estructura poblacional y la alta prevalencia de sordera congénita profunda. El registro de los datos se realizó mediante encuestas a 219 individuos residentes de Chicán. Se registraron 40 apellidos diferentes, de ellos 30 son de origen maya. El 23,3% de la muestra presentó apellidos isonímicos, siendo Collí (94,1%) el más frecuente. La consanguinidad total observada fue de 0,0585, mientras que el componente aleatorio (Fr = 0,0571) fue 38 veces mayor que el componente no aleatorio (Fn = 0,0015). Se registraron 18 personas con sordera congénita profunda, de las cuales 11 fueron isonímicas para el apellido Collí. Los resultados indican que las uniones consanguíneas en Chicán se deben principalmente al pequeño tamaño de la población y a su relativo aislamiento. La alta prevalencia de sordera profunda en Chicán puede ser consecuencia de la consanguinidad, la cual predispone a la aparición de trastornos hereditarios recesivos.

Background and purpose: Chronic postsurgical pain after total knee arthroplasty (TKA) is frequent and may be reduced by pain neuroscience education (PNE), teaching people about pain from a neurobiological perspective. This study investigated primarily the effectiveness of 2 individual sessions of PNE versus usual care on pain levels 3 months postoperatively in patients undergoing TKA. Secondary outcomes were physical functioning, stiffness, health-related quality of life, pain catastrophizing, attention to pain, and levels of anxiety and depression. Methods: A prospective single-center, parallel-group randomized controlled trial was undertaken including patients aged 18 years or older scheduled for primary TKA. 68 patients were randomly assigned to PNE or usual care. The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score 3 months postoperatively. Outcomes were measured preoperatively, at 2 weeks (acute phase), and at 3 and 12 months postoperatively. Results: We found no statistically significant difference (0.4 points; 95% confidence interval [CI] –1.7 to 2.4) in WOMAC pain scores 3 months after TKA between the PNE and control group. We found a statistically significant difference between the 2 groups for attention to pain at 3 months in favor of PNE (P = 0.02). Conclusion: This RCT showed that PNE was not superior to usual care in terms of reducing pain at 3 months after TKA. Attention to pain, as a secondary outcome, was significantly lower in the PNE group compared with usual care. Other secondary outcome measures showed no significant differences.

Background: Malignant pleural mesothelioma (MPM) is a rare thoracic malignancy with poor prognosis and limited treatment options. Immunotherapy shows potential for improved outcomes; however, real-world evidence on its use will take time to accumulate. This study examined patient characteristics, treatment patterns, overall survival (OS), and predictors of mortality among patients diagnosed with MPM in Denmark prior to the introduction of newer treatments. Methods: This historical cohort study based on routinely collected Danish National Registry data included adults newly diagnosed with MPM between 01 January 2011 and 31 May 2018. Summary statistics were used to describe patient characteristics and initial treatment. OS was estimated using Kaplan-Meier methods; Cox regression was used to compare patient mortality against the (age/sex-matched) general population and to investigate mortality predictors. Results: Overall, 880 patients were included; 44% had advanced MPM, 37% had non-advanced MPM, and 19% had unknown MPM stage. Median age at diagnosis was 71.9 years, and 82% of the patients were male. Within 180 days of diagnosis, no treatment was recorded for 215 patients (54%) with advanced MPM and 150 (46%) with non-advanced MPM. Median time-to-initial treatment (interquartile range) was 47 days (31–111) overall, 40 days (28–77) in patients with advanced MPM, and 53 days (35–121) with non-advanced MPM. Median OS was 13.7 months overall (non-advanced MPM: 18.0 months vs. advanced MPM: 10.0 months). Predictors of higher mortality were older age at diagnosis, histology, and advanced MPM stage. Interpretation: These findings provide a baseline upon which to evaluate MPM epidemiology as newer treatments are adopted in routine practice.

Abstract Jade and greenstone objects have been held in high regard by many cultures stemming from their limited geological availability and their unique optical and mechanical properties. Jade and greenstone objects symbolized life, fertility, and eternity to early Mesoamerican people. In recent years, scientific studies on jade and greenstone objects have been performed to establish provenance and usage, identify composition, and verify the presence of a particular material. These studies of jade and greenstone objects are generally divided geographically, with considerable interest in China and Central America. Most studies are focused on objects from one particular archaeological site; however, a few studies have focused on collections from a range of sites. The use of multiple complimentary analytical techniques has been shown to be the most effective method for characterizing and understanding the technical information obtained from cultural heritage objects. In our study, we examine a set of Mesoamerican jade and greenstone objects from the collection at the Dallas Museum of Art using multiple non-destructive techniques, including scanning electron microscopy with energy dispersive spectroscopy, Raman spectroscopy, X-ray diffraction, and handheld X-ray fluorescence spectroscopy. We briefly discuss the advantages and disadvantages of each technique. Lastly, we present the results from our study and discuss them in their archaeological and historical context.

Wave–current ripples that develop on seabeds of mixed non-cohesive sand and cohesive clay are commonplace in coastal and estuarine environments. While laboratory research on ripples forming in these types of mixed-bed environments is relatively limited, it has identified deep cleaning, the removal of clay below the ripple troughs, as an important factor controlling ripple development. New large-scale flume experiments seek to address this sparsity in data by considering two wave–current conditions with initial clay content, C0, ranging from 0 % to 18.3 %. The experiments record ripple development and pre- and post-experiment bed clay contents to quantify clay winnowing. The present experiments are combined with previous wave-only, wave–current, and current-only experiments to produce a consistent picture of larger and smaller flatter ripples over a range of wave–current conditions and C0. Specifically, the results reveal a sudden decrease in the ripple steepness for C0 > 10.6 %, likely associated with a decrease in hydraulic conductivity of 3 orders of magnitude. Accompanying the sudden change in steepness is a gradual linear decrease in wavelength with C0 for C0 > 7.4 %. Ultimately, for the highest values of C0, the bed remains flat, but clay winnowing still takes place, albeit at a rate 2 orders of magnitude lower than for rippled beds. For a given flow, the initiation time, when ripples first appear on a flat bed, increases with increasing C0. This, together with the fact that the bed remains flat for the highest values of C0, demonstrates that the threshold of motion increases with C0. The inferred threshold enhancement, and the occurrence of large and small ripples, is used to construct a new three-dimensional phase diagram of bed characteristics involving the wave and current Shields parameters and C0, which has important implications for morphodynamic modelling.

This paper analyzes spatial gestures and cognition in a new, or so-called “emerging”, visual language, the Yucatec Maya Sign Language (YSML). This sign language was created by deaf and hearing signers in various Yucatec Maya villages on the Yucatec Peninsula (Mexico). Although the sign language is not a signed version of spoken Yucatec Maya, both languages evolve in a similar cultural setting. Studies have shown that cultures around the world seem to rely on one preferred spatial Frame of Reference (FoR), shaping in many ways how people orient themselves and think about the world around them. Prior research indicated that Yucatec Maya speakers rely on the use of the geocentric FoR. However, contrary to other cultures, it is mainly observable through the production of gestures and not speech only. In the case of space, gestures in spoken Yucatec Maya exhibit linguistic features, having the status of a lexicon. Our research question is the following: if the preferred spatial FoR among the Yucatec Mayas is based on co-expressivity and spatial linguistic content visually transmitted via multimodal interactions, will deaf signers of an emerging language created in the same cultural setting share the same cognitive preference? In order to answer this question, we conducted three experimental tasks in three different villages where YMSL is in use: a non-verbal rotation task, a Director-Matcher task and a localization task. Results indicate that YMSL signers share the same preference for the geocentric FoR.

Abstract Spermiogenesis is a radical process of differentiation whereby sperm cells acquire a compact and specialized morphology to cope with the constraints of sexual reproduction while preserving their main cargo, an intact copy of the paternal genome. In animals, this often involves the replacement of most histones by sperm-specific nuclear basic proteins (SNBPs). Yet, how the SNBP-structured genome achieves compaction and accommodates shaping remain largely unknown. Here, we exploit confocal, electron and super-resolution microscopy, coupled with polymer modeling to identify the higher-order architecture of sperm chromatin in the needle-shaped nucleus of the emerging model cricket Gryllus bimaculatus. Accompanying spermatid differentiation, the SNBP-based genome is strikingly reorganized as ~25nm-thick fibers orderly coiled along the elongated nucleus axis. This chromatin spool is further found to achieve large-scale helical twisting in the final stages of spermiogenesis, favoring its ultracompaction. We reveal that these dramatic transitions may be recapitulated by a surprisingly simple biophysical principle based on a nucleated rigidification of chromatin linked to the histone-to-SNBP transition within a confined nuclear space. Our work highlights a unique, liquid crystal-like mode of higher-order genome organization in ultracompact cricket sperm, and establishes a multidisciplinary methodological framework to explore the diversity of non-canonical modes of DNA organization.

Penetrating posterior urethral trauma from gunshot wounds (GSW) is rare and requires prompt treatment to minimize complications. Data regarding the management of such cases is scarce in the literature and poorly addressed in the guidelines. Different management approaches exist, including urinary diversion with immediate versus delayed urethroplasty/fistula repair. We present our case series to add to our experience to the literature. Three patients aged 18–44 presented with ballistic posterior urethra injuries from GSW. Initial management involved urethral catheter placement, with one patient requiring operative placement of urethral and suprapubic catheters (SPTs). Complications included recurrent membranous stricture, urinary retention, rectourethral fistula, and erectile dysfunction (ED). Posterior urethral injuries from GSW are complex as they can be either isolated or affect adjacent organs. Bladder, ureteral, and urethral injuries must be ruled out. Unlike bladder neck injuries, immediate urethroplasty/fistula repair would be very challenging and not advised for standard prostatic or membranous injuries. Urethral catheter or suprapubic tube is recommended and can result in fistula closure and urethral patency. It is critical to maintain close follow-up with the patient due to the possibility of stricture recurrence. Urethroplasty in a delayed fashion can be very successful.

Abstract Background After primary treatment for breast cancer, patients are recommended to use hospital follow-up care routinely. Long-term data on the utilization of this follow-up care are relatively rare. Methods Information regarding the utilization of routine hospital follow-up care was retrieved from hospital documents of 662 patients treated for breast cancer. Utilization of hospital follow-up care was defined as the use of follow-up care according to the guidelines in that period of time. Determinants of hospital follow up care were evaluated with multivariate analysis by generalized estimating equations (GEE). Results The median follow-up time was 9.0 (0.3-18.1) years. At fifth and tenth year after diagnosis, 16.1% and 33.5% of the patients had less follow-up visits than recommended in the national guideline, and 33.1% and 40.4% had less frequent mammography than recommended. Less frequent mammography was found in older patients (age > 70; OR: 2.10; 95%CI: 1.62-2.74), patients with comorbidity (OR: 1.26; 95%CI: 1.05-1.52) and patients using hormonal therapy (OR: 1.51; 95%CI: 1.01-2.25). Conclusions Most patients with a history of breast cancer use hospital follow-up care according to the guidelines. In older patients, patients with comorbidity and patients receiving hormonal therapy yearly mammography is performed much less than recommended.

Abstract Nuclear Magnetic Resonance (NMR) spectroscopy is a most powerful molecular characterization and quantification technique, yet two major persistent factors limit its more wide-spread applications: poor sensitivity, and intricate complex and expensive hardware required for sophisticated experiments. Here we show NMR with a single planar-spiral microcoil in an untuned circuit with hyperpolarization option and capability to execute complex experiments addressing simultaneously up to three different nuclides. A microfluidic NMR-chip in which the 25 nL detection volume can be efficiently illuminated with laser-diode light enhances the sensitivity by orders of magnitude via photochemically induced dynamic nuclear polarization (photo-CIDNP), allowing rapid detection of samples in the lower picomole range (normalized limit of detection at 600 MHz, nLODf,600, of 0.01 nmol Hz1/2). The chip is equipped with a single planar microcoil operating in an untuned circuit that allows different Larmor frequencies to be addressed simultaneously, permitting advanced hetero-, di- and trinuclear, 1D and 2D NMR experiments. Here we show NMR chips with photo-CIDNP and broadband capabilities addressing two of the major limiting factors of NMR, by enhancing sensitivity as well as reducing cost and hardware complexity; the performance is compared to state-of-the-art instruments.

Abstract Background Cerebral amyloid angiopathy (CAA) is a disease caused by the accumulation of the amyloid-beta protein and is a major cause of intracerebral hemorrhage (ICH) and vascular dementia in the elderly. The presence of the amyloid-beta protein in the vessel wall may induce a chronic state of cerebral inflammation by activating astrocytes, microglia, and pro-inflammatory substances. Minocycline, an antibiotic of the tetracycline family, is known to modulate inflammation, gelatinase activity, and angiogenesis. These processes are suggested to be key mechanisms in CAA pathology. Our aim is to show the target engagement of minocycline and investigate in a double-blind placebo-controlled randomized clinical trial whether treatment with minocycline for 3 months can decrease markers of neuroinflammation and of the gelatinase pathway in cerebrospinal fluid (CSF) in CAA patients. Methods The BATMAN study population consists of 60 persons: 30 persons with hereditary Dutch type CAA (D-CAA) and 30 persons with sporadic CAA. They will be randomized for either placebo or minocycline (15 sporadic CAA/15 D-CAA minocycline, 15 sporadic CAA/15 D-CAA placebo). At t = 0 and t = 3 months, we will collect CSF and blood samples, perform a 7-T MRI, and collect demographic characteristics. Discussion The results of this proof-of-principle study will be used to assess the potential of target engagement of minocycline for CAA. Therefore, our primary outcome measures are markers of neuroinflammation (IL-6, MCP-1, and IBA-1) and of the gelatinase pathway (MMP2/9 and VEGF) in CSF. Secondly, we will look at the progression of hemorrhagic markers on 7-T MRI before and after treatment and investigate serum biomarkers. Trial registration ClinicalTrials.gov NCT05680389. Registered on January 11, 2023

Presenting systems of differential equations in the form of diagrams has become common in certain parts of physics, especially electromagnetism and computational physics. In this work, we aim to put such use of diagrams on a firm mathematical footing, while also systematizing a broadly applicable framework to reason formally about systems of equations and their solutions. Our main mathematical tools are category-theoretic diagrams, which are well known, and morphisms between diagrams, which have been less appreciated. As an application of the diagrammatic framework, we show how complex, multiphysical systems can be modularly constructed from basic physical principles. A wealth of examples, drawn from electromagnetism, transport phenomena, fluid mechanics, and other fields, is included.

As a consequence of the rapid growth of the globally installed offshore wind energy capacity, the size of individual wind farms is increasing. This poses a challenge to models that predict energy production. For instance, the current generation of wake models has mostly been calibrated on existing wind farms of much smaller size. This work analyzes annual energy production and wake losses for future, multi-gigawatt wind farms with atmospheric large-eddy simulation. To that end, 1 year of actual weather has been simulated for a suite of hypothetical 4 GW offshore wind farm scenarios. The scenarios differ in terms of applied turbine type, installed capacity density, and layout. The results suggest that production numbers increase significantly when the rated power of the individual turbines is larger while keeping the total installed capacity the same. Even for turbine types with similar rated power but slightly different power curves, significant differences in production were found. Although wind speed was identified as the most dominant factor determining the aerodynamic losses, a clear impact of atmospheric stability and boundary layer height has been identified. By analyzing losses of the first-row turbines, the yearly average global-blockage effect is estimated to between 2 and 3 %, but it can reach levels over 10 % for stably stratified conditions and wind speeds around 8 m s−1. Using a high-fidelity modeling technique, the present work provides insights into the performance of future, multi-gigawatt wind farms for a full year of realistic weather conditions.

ABSTRACTThe analysis of peripheral blood mononuclear cells (PBMCs) by flow cytometry holds promise as a platform for immune checkpoint inhibition (ICI) biomarker identification. Our aim was to characterize the systemic immune compartment in resectable esophageal adenocarcinoma patients treated with neoadjuvant ICI therapy. In total, 24 patients treated with neoadjuvant chemoradiotherapy (nCRT) and anti-PD-L1 (atezolizumab) from the PERFECT study (NCT03087864) were included and 26 patients from a previously published nCRT cohort. Blood samples were collected at baseline, on-treatment, before and after surgery. Response groups for comparison were defined as pathological complete responders (pCR) or patients with pathological residual disease (non-pCR). Based on multicolor flow cytometry of PBMCs, an immunosuppressive phenotype was observed in the non-pCR group of the PERFECT cohort, characterized by a higher percentage of regulatory T cells (Tregs), intermediate monocytes, and a lower percentage of type-2 conventional dendritic cells. A further increase in activated Tregs was observed in non-pCR patients on-treatment. These findings were not associated with a poor response in the nCRT cohort. At baseline, immunosuppressive cytokines were elevated in the non-pCR group of the PERFECT study. The suppressive subsets correlated at baseline with a Wnt/β-Catenin gene expression signature and on-treatment with epithelial–mesenchymal transition and angiogenesis signatures from tumor biopsies. After surgery monocyte activation (CD40), low CD8+Ki67+ T cell rates, and the enrichment of CD206+ monocytes were related to early recurrence. These findings highlight systemic barriers to effective ICI and the need for optimized treatment regimens.

We evaluated how the gender composition of top-cited authors within different subfields of research has evolved over time. We considered 9,071,122 authors with at least 5 full papers in Scopus as of September 1, 2022. Using a previously validated composite citation indicator, we identified the 2% top-cited authors for each of 174 science subfields (Science-Metrix classification) in 4 separate publication age cohorts (first publication pre-1992, 1992 to 2001, 2002 to 2011, and post-2011). Using NamSor, we assigned 3,784,507 authors as men and 2,011,616 as women (for 36.1% gender assignment uncertain). Men outnumbered women 1.88-fold among all authors, decreasing from 3.93-fold to 1.36-fold over time. Men outnumbered women 3.21-fold among top-cited authors, decreasing from 6.41-fold to 2.28-fold over time. In the youngest (post-2011) cohort, 32/174 (18%) subfields had > = 50% women, 97/174 (56%) subfields had > = 30% women, and 3 subfields had =

Abstract We introduce a novel agent‐based model for simulating interactions between migrating barchan dunes. A new two‐flank representation of barchans allows modeling of bedform asymmetries that are intrinsic to collision dynamics but have not been explored before. Although simple compared with real‐world barchans or those in continuum and cellular automata simulations, all known barchan behaviors emerge from the rules of our model. In particular, the two mechanisms for asymmetry growth in bimodal winds are observed and qualitatively agree with existing theories. We also reproduce the emergence of calving and all types of collisions that have been reported in reductionist models, water‐tank experiments, and field observations. The computational efficiency of the new model, compared with continuum simulations, enables the simulation of large swarms of dunes while maintaining the complex phenomenology of these bedforms, some of which has been lacking in previous agent‐based models.

Introducción: El trasplante renal es el tratamiento de elección de la enfermedad renal en etapa terminal (ERT). Desde marzo de 2020, la actividad de trasplantes en México se ha visto afectada debido a la pandemia de COVID-19. Objetivo: Determinar el impacto en la mortalidad de pacientes en lista de espera (LE) para trasplante renal de donante cadavérico en un hospital de referencia en Yucatán, por suspensión de actividades debido a la pandemia. Material y métodos: Pacientes > 18 años en LE para trasplante renal en este hospital. En caso de muerte de un paciente, se investigó la causa, especialmente si estaba asociada a COVID-19. Un valor de p de dos colas ≤ 0.05 se consideró significativo en todos los análisis. Resultados: La razón de probabilidad de muerte por COVID-19 en un paciente con ERT en la LE en 2020 fue OR = 5.04 (IC 95%: 1.65-7.14, p = 0.023). La razón de probabilidad de morir con ERT en la LE con retraso en las consultas de seguimiento fue de OR = 6.59 (IC 95%: 2.7-16.28, p = 0.008). Conclusión: La probabilidad de muerte de un paciente con ERT en la LE con retraso en las consultas de seguimiento y retención del trasplante es estadísticamente más alta que la probabilidad de muerte por COVID-19.

IntroductionAtypical hemolytic uremic syndrome (aHUS) is a rare kidney disease caused by dysregulation of the complement alternative pathway. The complement dysregulation specifically leads to damage to the glomerular endothelium. To further understand aHUS pathophysiology, we validated an ex vivo model for measuring complement deposition on both control and patient human glomerular microvascular endothelial cells (GMVECs).MethodsEndothelial cells were incubated with human test sera and stained with an anti-C5b-9 antibody to visualize and quantify complement depositions on the cells with immunofluorescence microscopy.ResultsFirst, we showed that zymosan-activated sera resulted in increased endothelial C5b-9 depositions compared to normal human serum (NHS). The levels of C5b-9 depositions were similar between conditionally immortalized (ci)GMVECs and primary control GMVECs. The protocol with ciGMVECs was further validated and we additionally generated ciGMVECs from an aHUS patient. The increased C5b-9 deposition on control ciGMVECs by zymosan-activated serum could be dose-dependently inhibited by adding the C5 inhibitor eculizumab. Next, sera from five aHUS patients were tested on control ciGMVECs. Sera from acute disease phases of all patients showed increased endothelial C5b-9 deposition levels compared to NHS. The remission samples showed normalized C5b-9 depositions, whether remission was reached with or without complement blockage by eculizumab. We also monitored the glomerular endothelial complement deposition of an aHUS patient with a hybrid complement factor H (CFH)/CFH-related 1 gene during follow-up. This patient had already chronic kidney failure and an ongoing deterioration of kidney function despite absence of markers indicating an aHUS flare. Increased C5b-9 depositions on ciGMVECs were observed in all samples obtained throughout different diseases phases, except for the samples with eculizumab levels above target. We then tested the samples on the patient’s own ciGMVECs. The C5b-9 deposition pattern was comparable and these aHUS patient ciGMVECs also responded similar to NHS as control ciGMVECs.DiscussionIn conclusion, we demonstrate a robust and reliable model to adequately measure C5b-9-based complement deposition on human control and patient ciGMVECs. This model can be used to study the pathophysiological mechanisms of aHUS or other diseases associated with endothelial complement activation ex vivo.

Factor I (FI) is an essential regulator of the complement system. Together with co-factors, FI degrades C3b, which inhibits further complement activation. Genetic mutations in FI are associated with pathological conditions like age-related macular degeneration and atypical hemolytic uremic syndome. Here, we evaluated eight recombinant FI genetic variants found in patients. We assessed FI’s co-factor activity in the presence of two co-factors; Factor H and soluble CR1. Different analytical assays were employed; SDS-PAGE to evaluate the degradation of C3b, ELISA to measure the generation of fluid phase iC3b and the degradation of surface-bound C3b using a novel Luminex bead-based assay. We demonstrate that mutations in the FIMAC and SP domains of FI led to significantly reduced protease activity, whereas the two analyzed mutations in the LDLRA2 domain did not result in any profound changes in FI’s function. The different assays employed displayed a strong positive correlation, but differences in the activity of the genetic variants Ile55Phe and Gly261Asp could only be observed by combining different methods and co-factors for evaluating FI activity. In conclusion, our results provide a new perspective regarding available diagnostic tools for assessing the impact of mutations in FI.

Abstract Background It is helpful in planning treatment for patients with ductal carcinoma in situ (DCIS) if the size and grade could be reliably predicted from the mammography. The aims of this study were to determine if the type of calcification can be best used to predict histopathological grade from the mammograms, to examine the association of mammographic appearance of DCIS with grade and to assess the correlation between mammographic size and pathological size. Methods Mammographic films and pathological slides of 115 patients treated for DCIS between 1986 and 2000 were reviewed and reclassified by a single radiologist and a single pathologist respectively. Prediction models for the European Pathologist Working Group (EPWG) and Van Nuys classifications were generated by ordinal regression. The association between mammographic appearance and grade was tested with the χ2-test. Relation of mammographic size with pathological size was established using linear regression. The relation was expressed by the correlation coefficient (r). Results The EPWG classification was correctly predicted in 68%, and the Van Nuys classification in 70% if DCIS was presented as microcalcifications. High grade was associated with presence of linear calcifications (p < 0.001). Association between mammograhic- and pathological size was better for DCIS presented as microcalcifications (r = 0.89, p < 0.001) than for DCIS presented as a density (r = 0.77, p < 0.001). Conclusions Prediction of histopathological grade of DCIS presenting as microcalcifications is comparable using the Van Nuys and EPWG classification. There is no strict association of mammographic appearance with histopathological grade. There is a better linear relation between mammographic- and pathological size of DCIS presented as microcalcifications than as a density, although both relations are statistically significant.

Abstract Background Little is known about the association between juvenile idiopathic arthritis (JIA) and autoimmune thyroid disease (AITD) and therefore there are no indications for AITD screening in this population, which is possible using standard blood tests. The objective of this study is to determine the prevalence and predictors of symptomatic AITD in JIA patients from the international Pharmachild registry. Methods Occurrence of AITD was determined from adverse event forms and comorbidity reports. Associated factors and independent predictors for AITD were determined using univariable and multivariable logistic regression analyses. Results The prevalence of AITD after a median observation period of 5.5 years was 1.1% (96/8965 patients). Patients who developed AITD were more often female (83.3% vs. 68.0%), RF positive (10.0% vs. 4.3%) and ANA positive (55.7% vs. 41.5%) than patients who did not. AITD patients were furthermore older at JIA onset (median 7.8 years vs. 5.3 years) and had more often polyarthritis (40.6% vs. 30.4%) and a family history of AITD (27.5% vs. 4.8%) compared to non-AITD patients. A family history of AITD (OR = 6.8, 95% CI: 4.1 – 11.1), female sex (OR = 2.2, 95% CI: 1.3 – 4.3), ANA positivity (OR = 2.0, 95% CI: 1.3 – 3.2) and older age at JIA onset (OR = 1.1, 95% CI: 1.1 – 1.2) were independent predictors of AITD on multivariable analysis. Based on our data, 16 female ANA positive JIA patients with a family history of AITD would have to be screened during ±5.5 years using standard blood tests to detect one case of AITD. Conclusions This is the first study to report independent predictor variables for symptomatic AITD in JIA. Female ANA positive JIA patients with positive family history are at increased risk of developing AITD and thus might benefit from yearly serological screening.

The growing complexity and interdisciplinary nature of Materials Science research demand efficient data management and exchange through structured knowledge representation. Domain-Level Ontologies (DLOs) for Materials Science have emerged as a valuable tool for describing materials properties, processes, and structures, enabling effective data integration, interoperability, and knowledge discovery. However, the harmonization of DLOs, and, more generally, the establishment of fully interoperable multi-level ecosystems, remains a challenge due to various factors, including the diverse landscape of existing ontologies. This work provides, for the first time in literature, a comprehensive overview of the state-of-the-art of DLOs for Materials Science, reviewing more than 40 DLOs and highlighting their main features and purposes. Furthermore, an alignment methodology including both manual and automated steps, making use of Top-Level Ontologies’ (TLO) capability of promoting interoperability, and revolving around the engineering of FAIR standalone entities acting as minimal data pipelines (“bridge concepts”), is presented. A proof of concept is also provided. The primary aspiration of this undertaking is to make a meaningful contribution towards the establishment of a unified ontology framework for Materials Science, facilitating more effective data integration and fostering interoperability across Materials Science subdomains.

Individuals with an upper motor neuron syndrome, e.g., stroke survivors, may have a pathological increase of passive ankle stiffness due to spasticity, that impairs ankle function and activities such as walking. To improve mobility, walking aids such as ankle-foot orthoses and orthopaedic shoes are prescribed. However, these walking aids generally limit the range of motion (ROM) of the foot and may therewith negatively influence activities that require a larger ROM. Here we present a new ankle-foot orthosis “Hermes”, and its first experimental results from four hemiparetic chronic stroke patients. Hermes was designed to facilitate active ankle dorsiflexion by mechanically compensating the passive ankle stiffness using a negative-stiffness mechanism. Four levels of the Hermes’ stiffness compensation (0%, 35%, 70% and 100%) were applied to evaluate active ROM in a robotic ankle manipulator and to test walking feasibility on an instrumented treadmill, in a single session. The robotic tests showed that Hermes successfully compensated the ankle joint stiffness in all four patients and improved the active dorsiflexion ROM in three patients. Three patients were able to walk with Hermes at one or more Hermes’ stiffness compensation levels and without reducing their preferred walking speeds compared to those with their own walking aids. Despite a small sample size, the results show that Hermes holds great promise to support voluntary ankle function and to benefit walking and daily activities.

Abstract Background Health inequities lead to low rates of cancer screening in certain populations, such as low-income and ethnic minority groups. Different interventions to address this have been developed with mixed results. However, interventions are not always developed in collaboration with the people they target. The aim of our article is to present the viewpoint of patients, survivors, advocates, and lay persons on interventions to increase cancer screening from a health inequity perspective. Methods We prepared talking points to guide discussions between coauthors, who included representatives from nine patient and survivor advocacy groups, organizations working for citizen/patient empowerment, and health equity experts. Perspectives and opinions were first collected through video conferencing meetings and a first draft of the paper was prepared. All authors, read through, revised, and discussed the contents to reach an agreement on the final perspectives to be presented. Results Several themes were identified: it is important to not view screening as a discrete event; barriers underlying an individual’s access and willingness to undergo screening span across a continuum; individually tailored interventions are likely to be more effective than a one-size fits-all approach because they may better accommodate the person’s personal beliefs, knowledge, behaviors, and preferences; targeting people who are unknown to medical services and largely unreachable is a major challenge; including professional patient advocacy groups and relevant lay persons in the cocreation of interventions at all stages of design, implementation, and evaluation is essential along with relevant stakeholders (healthcare professionals, researchers, local government and community organizations etc). Conclusions Interventions to address cancer screening inequity currently do not adequately solve the issue, especially from the viewpoint of patients, survivors, and lay persons. Several core pathways should be focused on when designing and implementing interventions: advancing individually tailored interventions; digital tools and social media; peer-based approaches; empowerment; addressing policy and system barriers; better design of interventions; and collaboration, including the involvement of patients and patient advocacy organizations.

Introduction: Burnout syndrome is defined as that condition characterized by emotional exhaustion, depersonalization and low personal fulfillment at work. Objective: To identify if the mean scores of emotional fatigue, depersonalization and self-realization were different based on the sociodemographic variables of the nursing staff of the Elvia Carrillo Puerto Regional Hospital during the COVID-19 pandemic in 2020. Methodology: Observational and cross-sectional study. The Maslach Burnout In-ventory questionnaire was applied to 229 nurses from Mérida, Yucatán, México selected by quotas. Results: The means of emotional fatigue, depersonalization and self-realization were 15.27 (SD: 11.4), 4.85 (SD: 4.8) and 37.4 (SD: 7.7); depersonalization showed significant differences by level of education and type of contract; self-realization and emotional fatigue showed significant differences due to the number of jobs; fatigue, depersonalization and self-realization had differences when grouped based on marital status. Conclusion: Separated people, with three or more jobs, temporary contract and with a high level of educational training showed higher scores in the burnout syndrome indicators

Summary: Background: The PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice. Methods: Febrile children and controls were recruited on presentation to hospital in 9 European countries 2016–2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed. Findings: Of 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92–5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07–7.59), Group A streptococcus (OR 2.73, 95% CI 1.13–6.09) and E. coli (OR 2.7, 95% CI 1.02–6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11–0.46), influenza B (OR 0.12, 95% CI 0.02–0.37) and RSV (OR 0.16, 95% CI: 0.06–0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23–0.72) and EBV (OR 0.71, 95% CI 0.56–0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively. Interpretation: Most febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics. Funding: EU Horizon 2020 grant 668303.

Parkinson’s disease (PD) is one of the most frequent neurological diseases affecting millions of people worldwide. While the majority of PD cases are of unknown origin (idiopathic), about 5%–10% are familial and linked to mutations in different known genes. However, there are also people with a genetic predisposition to PD who do not develop the disease. To elucidate factors leading to the manifestation of PD we compared the occurrence of single nucleotide polymorphisms (SNPs) in various cytochrome P450 (P450) genes in people with a genetic predisposition and suffering from PD (GPD) to that of people, who are genetically predisposed, but show no symptoms of the disease (GUN). We used the PPMI (Parkinson’s Progression Markers Initiative) database and the gene sequences of all 57 P450s as well as their three redox partners. Corresponding odds ratios (OR) and confidence intervals (CI) were calculated to assess the incidence of the various SNPs in the two groups of individuals and consequently their relation to PD. We identified for the first time SNPs that are significantly (up to 10fold!) over- or under-represented in GPD patients compared to GUN. SNPs with OR > 5 were found in 10 P450s being involved in eicosanoid, vitamin A and D metabolism as well as cholesterol degradation pointing to an important role of endogenous factors for the manifestation of PD clinical symptoms. Moreover, 12 P450s belonging to all P450 substrate classes as well as POR have SNPs that are significantly under-represented (OR < 0.2) in GPD compared to GUN, indicating a protective role of those SNPs and the corresponding P450s regarding disease advancement. To the best of our knowledge our data for the first time demonstrate an association between known PD predisposition genes and SNPs in other genes, shown here for different P450 genes and for their redox partner POR, which promote the manifestation of the disease in familial PD. Our results thus shed light onto the pathogenesis of PD, especially the switch from GUN to GPD and might further help to advance novel strategies for preventing the development or progression of the disease.

Summary: Mechanisms of infection and pathogenesis have predominantly been studied based on differential gene or protein expression. Less is known about posttranslational modifications, which are essential for protein functional diversity. We applied an innovative glycoproteomics method to study the systemic proteome-wide glycosylation in response to infection. The protein site-specific glycosylation was characterized in plasma derived from well-defined controls and patients. We found 3862 unique features, of which we identified 463 distinct intact glycopeptides, that could be mapped to more than 30 different proteins. Statistical analyses were used to derive a glycopeptide signature that enabled significant differentiation between patients with a bacterial or viral infection. Furthermore, supported by a machine learning algorithm, we demonstrated the ability to identify the causative pathogens based on the distinctive host blood plasma glycopeptide signatures. These results illustrate that glycoproteomics holds enormous potential as an innovative approach to improve the interpretation of relevant biological changes in response to infection.

Introducción: La neoplasia vulvar intraepitelial es poco frecuente; sin embargo, es necesario destacar que en los últimos años su incidencia ha aumentado de manera significativa en las pacientes más jóvenes, debido al aumento de la infección genital por el virus de papiloma humano. Objetivo: Describir la intervención quirúrgica de vulvectomía parcial en una paciente con cáncer de vulva, haciendo una valoración fundamentada en la teoría de Déficit de Autocuidado de Dorothea Orem, con un enfoque en el Proceso de Atención de Enfermería, durante el perioperatorio. Material y métodos: Estudio de caso observacional, transversal y descriptivo, enfocado en una paciente que se seleccionó en una institución de salud pública de segundo nivel de atención de la ciudad de Mérida, Yucatán, México. Resultados: Las intervenciones de enfermería fueron realizadas satisfactoriamente, por lo cual, la paciente tuvo un perioperatorio y una estadía hospitalaria sin complicaciones. Discusión: La modificación en el estilo de vida tras el diagnóstico de la patología vulvar en la paciente de estudio, nos demuestra que puede ser prevenida aplicando los métodos de autocuidado descritos por Dorothea Orem. Conclusión: La enfermera quirúrgica tiene un rol importante; en el preoperatorio, ayudando a la paciente a manejar sus sentimientos y brindándole información de su padecimiento y futura cirugía, en el transoperatorio evitando daños y vigilando que se realice una cirugía segura, en el posoperatorio, realizando una valoración para evitar riesgos que puedan prolongar su estadía hospitalaria.

IntroductionObesity has been linked to vascular dysfunction, cognitive impairment and neurodegenerative diseases. However, experimental models that recapitulate brain pathology in relation to obesity and vascular dysfunction are still lacking.MethodsIn this study we performed the histological and histochemical characterization of brains from Ldlr-/-.Leiden mice, an established model for obesity and associated vascular disease. First, HFD-fed 18 week-old and 50 week-old Ldlr-/-.Leiden male mice were compared with age-matched C57BL/6J mice. We then assessed the effect of high-fat diet (HFD)-induced obesity on brain pathology in Ldlr-/-.Leiden mice and tested whether a treatment with an anti-complement component 5 antibody, a terminal complement pathway inhibitor recently shown to reduce vascular disease, can attenuate neurodegeneration and neuroinflammation. Histological analyses were complemented with Next Generation Sequencing (NGS) analyses of the hippocampus to unravel molecular pathways underlying brain histopathology.ResultsWe show that chow-fed Ldlr-/-.Leiden mice have more severe neurodegeneration and show an age-dependent astrogliosis that is not observed in age-matched C57BL/6J controls. This was substantiated by pathway enrichment analysis using the NGS data which showed that oxidative phosphorylation, EIF2 signaling and mitochondrial dysfunction pathways, all associated with neurodegeneration, were significantly altered in the hippocampus of Ldlr-/-.Leiden mice compared with C57BL/6J controls. Obesity-inducing HFD-feeding did not aggravate neurodegeneration and astrogliosis in Ldlr-/-.Leiden mice. However, brains from HFD-fed Ldlr-/-.Leiden mice showed reduced IBA-1 immunoreactivity and increased CD68 immunoreactivity compared with chow-fed Ldlr-/-.Leiden mice, indicating alteration of microglial immunophenotype by HFD feeding. The systemic administration of an anti-C5 treatment partially restored the HFD effect on microglial immunophenotype. In addition, NGS data of hippocampi from Ldlr-/-.Leiden mice showed that HFD feeding affected multiple molecular pathways relative to chow-fed controls: HFD notably inactivated synaptogenesis and activated neuroinflammation pathways. The anti-C5 treatment restored the HFD-induced effect on molecular pathways to a large extent.ConclusionThis study shows that the Ldlr-/-.Leiden mouse model is suitable to study brain histopathology and associated biological processes in a context of obesity and provides evidence of the potential therapeutic value of anti-complement therapy against obesity-induced neuroinflammation.

Background Immune checkpoint inhibitors (ICIs) are now a first-line treatment option for patients with pleural mesothelioma with the recent approval of ipilimumab and nivolumab. Mesothelioma has a low tumor mutation burden and no robust predictors of survival with ICI. Since ICIs enable adaptive antitumor immune responses, we investigated T-cell receptor (TCR) associations with survival in participants from two clinical trials treated with ICI.Methods We included patients with pleural mesothelioma who were treated with nivolumab (NivoMes, NCT02497508) or nivolumab and ipilimumab (INITIATE, NCT03048474) after first-line therapy. TCR sequencing was performed with the ImmunoSEQ assay in 49 and 39 pretreatment and post-treatment patient peripheral blood mononuclear cell (PBMC) samples. These data were integrated with TCR sequences found in bulk RNAseq data by TRUST4 program in 45 and 35 pretreatment and post-treatment tumor biopsy samples and TCR sequences from over 600 healthy controls. The TCR sequences were clustered into groups of shared antigen specificity using GIANA. Associations of TCR clusters with overall survival were determined by cox proportional hazard analysis.Results We identified 4.2 million and 12 thousand complementarity-determining region 3 (CDR3) sequences from PBMCs and tumors, respectively, in patients treated with ICI. These CDR3 sequences were integrated with 2.1 million publically available CDR3 sequences from healthy controls and clustered. ICI-enhanced T-cell infiltration and expanded T cell diversity in tumors. Cases with TCR clones in the top tertile in the pretreatment tissue or in circulation had significantly better survival than the bottom two tertiles (p