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Abstract Seroma or lymphocele remains the most common complication after mastectomy and lymphadenectomy for breast cancer. Many different techniques are available to prevent this complication: wound drainage, reduction of the dead space by flap fixation, use of various types of energy, external compression dressings, shoulder immobilization or physical activity, as well as numerous drugs and glues. We searched MEDLINE, clinicaltrials.gov, Cochrane Library, and Web of Science databases for publications addressing the issue of prevention of lymphocele or seroma after mastectomy and axillary lymphadenectomy. Quality was assessed using Hawker’s quality assessment tool. Incidence of seroma or lymphocele were collected. Fifteen randomized controlled trials including a total of 1766 patients undergoing radical mastectomy and axillary lymphadenectomy for breast cancer were retrieved. The incidence of lymphocele or seroma in the study population was 24.2% (411/1698): 25.2% (232/920) in the test groups and 23.0% (179/778) in the control groups. Neither modification of surgical technique (RR 0.86; 95% CI [0.72, 1.03]) nor application of a medical treatment (RR 0.96; 95% CI [0.72, 1.29]) was effective in preventing lymphocele. On the contrary, decreasing the drainage time increased the risk of lymphocele (RR 1.88; 95% CI [1.43, 2.48). There was no publication bias but the studies were of medium to low quality. To conclude, despite the heterogeneity of study designs, drainage appears to be the most effective technique, although the overall quality of the data is low.

Objectives To describe healthcare providers’ symptoms evoked by patient safety incidents (PSIs), the duration of these symptoms and the association with the degree of patient harm caused by the incident.Design Cross-sectional survey.Setting 32 Dutch hospitals that participate in the ‘Peer Support Collaborative’.Participants 4369 healthcare providers (1619 doctors and 2750 nurses) involved in a PSI at any time during their career.Interventions All doctors and nurses working in direct patient care in the 32 participating hospitals were invited via email to participate in an online survey.Primary and secondary outcome measures Prevalence of symptoms, symptom duration and its relationship with the degree of patient harm.Results In total 4369 respondents were involved in a PSI and completely filled in the questionnaire. Of these, 462 reported having been involved in a PSI with permanent harm or death during the last 6 months. This had a personal, professional impact as well as impact on effective teamwork requirements. The impact of a PSI increased when the degree of patient harm was more severe. The most common symptom was hypervigilance (53.0%). The three most common symptoms related to teamwork were having doubts about knowledge and skill (27.0%), feeling unable to provide quality care (15.6%) and feeling uncomfortable within the team (15.5%). PSI with permanent harm or death was related to eightfold higher likelihood of provider-related symptoms lasting for more than 1 month and ninefold lasting longer than 6 months compared with symptoms reported when the PSI caused no harm.Conclusion The impact of PSI remains an underestimated problem. The higher the degree of harm, the longer the symptoms last. Future studies should evaluate how these data can be integrated in evidence-based support systems.

Abstract Background To develop and validate a novel administration device for holmium-166 transarterial radioembolisation (TARE) with the purpose of facilitating controlled fractional microsphere administration for a more flexible and image-guided TARE procedure. Methods A Controlled Administration Device (CAD) was developed using MR-conditional materials. The CAD contains a rotating syringe to keep the microspheres in suspension during administration. Different rotational speeds were tested ex vivo to optimise the homogeneity of microsphere fractions administered from the device. The technical performance, accuracy, and safety was validated in three patients in a clinical TARE setting by administering a standard clinical dose in 5 fractions (identifier: NCT05183776). MRI-based dosimetry was used to validate the homogeneity of the given fractions in vivo, and serious adverse device event ((S)A(D)E) reporting was performed to assess safety of the CAD. Results A rotational speed of 30 rpm resulted in the most homogeneous microsphere fractions with a relative mean deviation of 1.1% (range: -9.1-8.0%). The first and last fraction showed the largest deviation with a mean of -26% (std. 16%) and 7% (std. 13%). respectively. In the three patient cases the homogeneity of the microsphere fractions was confirmed given that MRI-based dosimetry showed near linear increase of mean absorbed target liver dose over the given fractions with R2 values of 0.98, 0.97 and 0.99. No (S)A(D)E’s could be contributed to the use of the CAD. Conclusions The newly developed CAD facilitates safe and accurate fractional microsphere administration during TARE, and can be used for multiple applications in the current and future workflows of TARE.

Abstract Background Quantitative imaging is a crucial step for dosimetry in radionuclide therapies. Traditionally, SPECT/CT imaging is quantified based on scanner-specific conversion factors or self-calibration, but recently absolute quantification methods have been introduced in commercial SPECT reconstruction software (Broad Quantification, Siemens Healthineers). In this phantom study we investigate the accuracy of three quantification methods for holmium-166 SPECT/CT imaging, and provide recommendations for clinical dosimetry. Methods One cylindrical phantom, filled with a homogeneous holmium-166-chloride activity concentration solution, was imaged at one time point to determine a scanner-specific conversion factor, and to characterize the spatial dependency of the activity concentration recovery. One Jaszczak phantom with six fillable spheres, 10:1 sphere-to-background ratio, was imaged over a large range of holmium-166 activities (61-3130 MBq). The images were reconstructed with either an ordered subset expectation maximization (OSEM, Flash3D-reconstruction; scanner-specific quantification or self-calibration quantification) or an ordered subset conjugate gradient (OSCG, xSPECT-reconstruction; Broad Quantification) algorithm. These three quantification methods were compared for the data of the Jaszczak phantom and evaluated based on whole phantom recovered activity, activity concentration recovery coefficients (ACRC), and recovery curves. Results The activity recovery in the Jaszczak phantom was 28–115% for the scanner-specific, and 57–97% for the Broad Quantification quantification methods, respectively. The self-calibration-based activity recovery is inherently always 100%. The ACRC for the largest sphere (Ø60 mm, ~ 113 mL) ranged over (depending on the activity level) 0.22–0.89, 0.76–0.86, 0.39–0.72 for scanner-specific, self-calibration and Broad Quantification, respectively. Conclusion Of the three investigated quantification methods, the self-calibration technique produces quantitative SPECT images with the highest accuracy in the investigated holmium-166 activity range.

Abstract The H1 Collaboration reports the first measurement of the 1-jettiness event shape observable $$\tau _1^b$$ τ 1 b in neutral-current deep-inelastic electron-proton scattering (DIS). The observable $$\tau _1^b$$ τ 1 b is equivalent to a thrust observable defined in the Breit frame. The data sample was collected at the HERA ep collider in the years 2003–2007 with center-of-mass energy of $$\sqrt{s}=319\,\textrm{GeV} $$ s = 319 GeV , corresponding to an integrated luminosity of 351.1 $$\textrm{pb}^{-1}$$ pb - 1 . Triple differential cross sections are provided as a function of $$\tau _1^b$$ τ 1 b , event virtuality $$Q^{2}$$ Q 2 , and inelasticity y, in the kinematic region $$Q^{2} >150\,\textrm{GeV}^2 $$ Q 2 > 150 GeV 2 . Single differential cross sections are provided as a function of $$\tau _1^b$$ τ 1 b in a limited kinematic range. Double differential cross sections are measured, in contrast, integrated over $$\tau _1^b$$ τ 1 b and represent the inclusive neutral-current DIS cross section measured as a function of $$Q^{2}$$ Q 2 and y. The data are compared to a variety of predictions and include long-standing and more recent Monte Carlo event generators, predictions in fixed-order perturbative QCD where calculations up to $$\mathcal {O}(\alpha _\textrm{s} ^3)$$ O ( α s 3 ) are available for $$\tau _1^b$$ τ 1 b or inclusive DIS, and resummed predictions at next-to-leading logarithmic accuracy matched to fixed order predictions at $$\mathcal {O}(\alpha _\textrm{s} ^2)$$ O ( α s 2 ) . These comparisons reveal sensitivity of the 1-jettiness observable to QCD parton shower and resummation effects, as well as the modeling of hadronization and fragmentation. Within their range of validity, the fixed-order predictions provide a good description of the data. Monte Carlo event generators are predictive over the full measured range and hence their underlying models and parameters can be constrained by comparing to the presented data.

Abstract The Breit frame provides a natural frame to analyze lepton–proton scattering events. In this reference frame, the parton model hard interactions between a quark and an exchanged boson defines the coordinate system such that the struck quark is back-scattered along the virtual photon momentum direction. In Quantum Chromodynamics (QCD), higher order perturbative or non-perturbative effects can change this picture drastically. As Bjorken-x decreases below one half, a rather peculiar event signature is predicted with increasing probability, where no radiation is present in one of the two Breit-frame hemispheres and all emissions are to be found in the other hemisphere. At higher orders in $$\alpha _{s}$$ α s or in the presence of soft QCD effects, predictions of the rate of these events are far from trivial, and that motivates measurements with real data. We report on the first observation of the empty current hemisphere events in electron–proton collisions at the HERA collider using data recorded with the H1 detector at a center-of-mass energy of 319 GeV. The fraction of inclusive neutral-current DIS events with an empty hemisphere is found to be $$0.0112 \pm 3.9\%_\text {stat} \pm 4.5\%_{\text {syst}} \pm 1.6\%_{\text {mod}}$$ 0.0112 ± 3.9 % stat ± 4.5 % syst ± 1.6 % mod in the selected kinematic region of $$150

Abstract Many countries have implemented policies to reduce the use of chemical inputs in agriculture. However, these policies face many obstacles that limit their effectiveness. The purpose of this paper is to review the main challenges associated with reducing chemical inputs in agriculture and to propose potential solutions. Our analysis, based on a literature review linking agronomy and economics, shows that several agronomic options have proven effective in reducing chemical inputs or mitigating their negative impacts. We argue that the organization of the agri-food system itself is a major barrier to their implementation. Involving all stakeholders, from the chemical input industry to consumers, and designing appropriate policy frameworks are key to address this issue. We recommend combining different policy instruments, such as standards, taxes and subsidies, in a simplified and coherent way to increase effectiveness and ensure better coordination in the adoption of sustainable practices.

Abstract Background Promoting healthy and sustainable diets is increasingly important and the Mediterranean Diet (MD) has been recognized as an appropriate example that can be adapted to different countries. Considering that the college years are the time when US young adults are most likely to adopt unhealthy eating habits, the present study assessed adherence to the MD and the sustainability of dietary behaviors in a nationally representative sample of US university students, aiming to identify crucial levers for improving their eating behaviors. Methods MD adherence and the adoption of healthy and sustainable dietary patterns were assessed through the KIDMED and the Sustainable-HEalthy-Diet (SHED Index questionnaires, respectively, administered through an online survey that also included sociodemographic and behavioral questions. Non-parametric and logistic regression analyses were performed. Results A sample of 1485 participants (median (IQR) age 21.0 (19.0–22.0); 59% women) correctly completed the survey. A medium adherence to the MD was the most prevalent (47%). According to multivariate logistic regression analysis, the likelihood of being more compliant with the MD increased when meeting physical activity recommendations, having a high SHED Index score, having the willingness to purchase and eat healthy and sustainable dishes, eating ultra-processed plant-based meat alternatives foods daily, and regularly attending the university canteen. Conclusions Encouraging dietary patterns rich in plant-based foods and with a moderate intake of animal products is crucial to increasing the adoption of healthy and sustainable diets, and university dining services represent a suitable setting to build a supportive environment that educates students on human and planetary health.

The evolution of a successful strategy for the synthesis of the strained, cage-like antiviral diterpenoids wickerols A and B is described. Initial attempts to access the carbocyclic core were surprisingly challenging and in retrospect, presaged the many detours needed to ultimately arrive at the fully adorned wickerol architecture. In most cases, conditions to trigger desired outcomes with respect to both reactivity and stereochemistry were hard-won. The successful synthesis ultimately leveraged alkenes in virtually all productive bond-forming events. A series of conjugate addition reactions generated the fused tricyclic core, a Claisen rearrangement was used to install an otherwise unmanageable methyl-bearing stereogenic center, and a Prins cyclization closed the strained bridging ring. This final reaction proved enormously interesting because the strain of the ring system permitted diversion of the presumed initial Prins product into several different scaffolds.

Crowding effects significantly influence the phase behavior and the structural and dynamic properties of the concentrated protein mixtures present in the cytoplasm of cells or in the blood serum. This poses enormous difficulties for our theoretical understanding and our ability to predict the behavior of these systems. While the use of course grained colloid-inspired models allows us to reproduce the key physical solution properties of concentrated monodisperse solutions of individual proteins, we lack corresponding theories for complex polydisperse mixtures. Here, we test the applicability of simple mixing rules in order to predict solution properties of protein mixtures. We use binary mixtures of the well-characterized bovine eye lens proteins α and γB crystallin as model systems. Combining microrheology with static and dynamic scattering techniques and observations of the phase diagram for liquid–liquid phase separation, we show that reasonably accurate descriptions are possible for macroscopic and mesoscopic signatures, while information on the length scale of the individual protein size requires more information on cross-component interaction.

A full account of the development of a concise and highly stereoselective synthesis of (+)-7,20-diisocyanoadociane (DICA)─a structurally complex isocyanoditerpene with potent antiplasmodial activity─is described. The strategy that evolved relies on the rapid construction of unsaturated tricyclic precursors designed to undergo stereocontrolled Birch reductions and a subsequent "bay ring" formation to generate the isocycloamphilectane core. This report is divided into three sections: (1) a description of the initial strategy and the results that focused our efforts on a single route to the DICA core, (2) a discussion of the precise choreography needed to enable a first-generation formal synthesis of (±)-DICA, and (3) the execution of a 13-step second-generation synthesis of (+)-DICA that builds on important lessons learned from the first-generation effort.

The controversially discussed taxonomy of the Cryptococcus neoformans/Cryptococcus gattii species complex encompasses at least eight major molecular types. Cerebral cryptococcomas are a common manifestation of cryptococcal neurological disease. In this study, we compared neurotypical symptoms and differential neurovirulence induced by one representative isolate for each of the eight molecular types studied. We compared single focal lesions caused by the different isolates and evaluated the potential relationships between the fungal burden and properties obtained with quantitative magnetic resonance imaging (qMRI) techniques such as diffusion MRI, T2 relaxometry and magnetic resonance spectroscopy (MRS). We observed an inverse correlation between parametric data and lesion density, and we were able to monitor longitudinally biophysical properties of cryptococcomas induced by different molecular types. Because the MRI/MRS techniques are also clinically available, the same approach could be used to assess image-based biophysical properties that correlate with fungal cell density in lesions in patients to determine personalized treatments.

While elucidating the evolutionary trajectory of green anacondas, we previously documented the existence of two distinct species, Eunectes akayima sp. nov. and Eunectes murinus (Linnaeus, 1758), that separated approximately 10 million years ago. Our research integrates a novel molecular clock approach, focuses on tectonic plate movements with fossil records as minimal chronological markers, and offers a refined understanding of speciation events in relation to major biogeographical occurrences in South America. Mitochondrial DNA analysis demonstrates a significant genetic divergence between the species, which is supported by a notable difference in sexual size dimorphism (SSD) intensity between the two species, along with other morphological differences. This paper also rectifies earlier oversights in the description of the new species and clarifies taxonomic ambiguities in compliance with the International Code of Zoological Nomenclature (henceforth ICZN). In addition, we designate a neotype for E. murinus to stabilize the group. In an effort to honor Indigenous nations, E. akayima sp. nov. derives its name from the Carib language, advocating for the inclusion of traditional names in scientific discourse. Our paper not only contributes to the taxonomic stability of anacondas but also advocates for the usage of Indigenous names in zoological nomenclature by adopting a more inclusive and flexible approach to the ICZN and eliminating unintended exclusionary practices that we have inherited in science as in other disciplines.

Reproducibility of expression patterns in iPSC-derived cells from different labs is an important first step in ensuring replication of biochemical or functional assays that are performed in different labs. Here we show that reproducible gene expression patterns from iPSCs and iPSC-derived neurons matured and collected at two separate laboratory locations can be achieved by closely matching protocols and reagents. While there are significant differences in gene expression between iPSCs and differentiated neurons, as well as between different donor lines of the same cell type, transcriptional changes that vary with laboratory sites are relatively small. These results suggest that making great efforts to match protocols, reagents and technical methods between labs may improve the reproducibility of iPSC-derived cell models.

Participatory Design (PD) is increasingly interested in the repair process, motivated by the curiosity to articulate a more caring and relational attitude toward our socioecological environment. However, placing ‘repair’ centrally in PD is difficult, since the latter has been traditionally focused on ‘making together’ and less on repairing what was once made, or even ‘unmake’. While repair is part of our continuous activities (repairing clothes, bikes, marriages, and relationships), it is often a painful and challenging endeavor. Repair entails hope but also grief. This article discusses how we used a Live Lab to explore more intimate design approaches, opening pathways to explore plural relations and access embodied and emotional knowledge. Finally, based on our research experience in a garden city, we reflect upon how acting within an intimacy framework contributes to PD’s repair process, by bringing socioecological entanglements to the agenda of citizens.

Abstract Background Sarcomatoid renal cell cancer (RCC) is a distinct histological variant of RCC that is associated with rapid progression and a poor prognosis. The optimal treatment for patients with sarcomatoid RCC remains to be defined. Gemcitabine plus doxorubicine (GD) has shown some efficacy, however durability of response is limited. We carried out a prospective, open-label study to investigate the efficacy and safety of sorafenib in patients after GD failure in sarcomatoid RCC. Methods Fifteen patients with pure sarcomatoid RCC and objective progressive disease were treated with GD (gemcitabine 1500 mg/m2, doxorubicine 50 mg/m2 administered by weekly intravenous infusion) until progression of disease. Subsequently 9 patients were switched to sorafenib (400 mg twice daily). Tumor response was measured by physical examination and computerized tomography scans and evaluated according to Response Evaluation Criteria in Solid Tumors criteria. Results Median time to progression (TTP) under GD was 6.6 months (range 0.8 - 8 months). During GD treatment there were no remissions and 6 patients died from progressive disease. Median TTP for the 9 patients switched to sorafenib was 10.9 months (range 0.6 - 25.5 months). During sorafenib therapy one patient had a partial remission lasting for 3 months and 4 patients experienced stable disease with a duration of 3 to 9 months. Four patients immediately progressed on sorafenib treatment but had a slower dynamic of tumor progression than under GD. Dosing in both treatment phases was generally well tolerated with manageable toxicities and no requirement for dose reduction. Conclusions Chemotherapy with GD was ineffective in our patients with pure sarcomatoid RCC. Subsequent anti-angiogenic treatment using the multi-tyrosine kinase inhibitor sorafenib resulted in additional progression-free survival in 5 of 9 patients. Further evaluation of targeted anti-angiogenic agents for the treatment of sarcomatoid RCC is warranted.

Apolipoprotein E (ApoE), an important mediator of lipid transportation in plasma and the nervous system, plays a large role in diseases such as atherosclerosis and Alzheimer's. The major allele variants ApoE3 and ApoE4 differ only by one amino acid. However, this difference has major consequences for the physiological behaviour of each variant. In this paper, we follow (i) the initial interaction of lipid-free ApoE variants with model membranes as a function of lipid saturation, (ii) the formation of reconstituted High-Density Lipoprotein-like particles (rHDL) and their structural characterisation, and (iii) the rHDL ability to exchange lipids with model membranes made of saturated lipids in the presence and absence of cholesterol [1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) or 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) with and without 20 mol% cholesterol]. Our neutron reflection results demonstrate that the protein variants interact differently with the model membranes, adopting different protein conformations. Moreover, the ApoE3 structure at the model membrane is sensitive to the level of lipid unsaturation. Small-angle neutron scattering shows that the ApoE containing lipid particles form elliptical disc-like structures, similar in shape but larger than nascent or discoidal HDL based on Apolipoprotein A1 (ApoA1). Neutron reflection shows that ApoE-rHDL do not remove cholesterol but rather exchange saturated lipids, as occurs in the brain. In contrast, ApoA1-containing particles remove and exchange lipids to a greater extent as occurs elsewhere in the body.

Ad26.COV2.S vaccination can lead to vaccine-induced immune thrombotic thrombocytopenia (VITT), a rare but severe adverse effect, characterized by thrombocytopenia and thrombosis. The mechanism of VITT induction is unclear and likely multifactorial, potentially including the activation of platelets and endothelial cells mediated by the vaccine-encoded spike protein (S protein). Here, we investigated the biodistribution of the S protein after Ad26.COV2.S dosing in three animal models and in human serum samples. The S protein was transiently present in draining lymph nodes of rabbits after Ad26.COV2.S dosing. The S protein was detected in the serum in all species from 1 day to 21 days after vaccination with Ad26.COV2.S, but it was not detected in platelets, the endothelium lining the blood vessels, or other organs. The S protein S1 and S2 subunits were detected at different ratios and magnitudes after Ad26.COV2.S or COVID-19 mRNA vaccine immunization. However, the S1/S2 ratio did not depend on the Ad26 platform, but on mutation of the furin cleavage site, suggesting that the S1/S2 ratio is not VITT related. Overall, our data suggest that the S-protein biodistribution and kinetics after Ad26.COV2.S dosing are likely not main contributors to the development of VITT, but other S-protein-specific parameters require further investigation.

Abstract Protein dynamics have been investigated on a wide range of time scales. Nano‐ and picosecond dynamics have been assigned to local fluctuations, while slower dynamics have been attributed to larger conformational changes. However, it is largely unknown how fast (local) fluctuations can lead to slow global (allosteric) changes. Here, fast molecule‐spanning dynamics on the 100 to 200 ns time scale in the heat shock protein 90 (Hsp90) are shown. Global real‐space movements are assigned to dynamic modes on this time scale, which is possible by a combination of single‐molecule fluorescence, quasi‐elastic neutron scattering and all‐atom molecular dynamics (MD) simulations. The time scale of these dynamic modes depends on the conformational state of the Hsp90 dimer. In addition, the dynamic modes are affected to various degrees by Sba1, a co‐chaperone of Hsp90, depending on the location within Hsp90, which is in very good agreement with MD simulations. Altogether, this data is best described by fast molecule‐spanning dynamics, which precede larger conformational changes in Hsp90 and might be the molecular basis for allostery. This integrative approach provides comprehensive insights into molecule‐spanning dynamics on the nanosecond time scale for a multi‐domain protein.

Abstract[Purpose] Transarterial radioembolization (TARE) is an established treatment modality for patients with unresectable liver cancer. However, a better understanding of treatment parameters that influence microsphere distribution could further improve the therapy. This systematic review examines and summarizes the available evidence on intraprocedural parameters that influence the microsphere distribution during TARE as investigated by in vivo, ex vivo, in vitro and in silico studies. [Methods] A standardized search was performed in Medline, Embase and Web of Science to identify all published articles investigating microsphere distribution or dynamics during TARE. Studies presenting original research on parameters influencing the microsphere distribution during TARE were included. [Results] A total of 42 studies reporting a total of 11 different parameters were included for narrative analysis. The investigated studies suggest that flow distribution is not a perfect predictor of microsphere distribution. Increasing the injection velocity may help increase the similarity between flow and microsphere distributions. Furthermore, the microsphere distributions are very sensitive to the radial and axial catheter position. [Conclusion] The most promising parameters for future research which can be controlled in the clinic appear to be microsphere injection velocity as well as the axial catheter position. Up to now, many of the included studies do not take clinical feasibility into account, limiting the translation of results to clinical settings. Future research should therefore focus on the applicability of in vivo, in vitro, or in silico research to patient specific scenarios to improve the efficacy of radioembolization as treatment for liver cancer.

Objectives To evaluate the relationship among dysnatraemia at hospital presentation and duration of admission, risk of intensive care unit (ICU) admission and all-cause mortality and to assess the underlying pathophysiological mechanism of hyponatraemia in patients with COVID-19. Our hypothesis is that both hyponatraemia and hypernatraemia at presentation are associated with adverse outcomes.Design Observational study.Setting Secondary care; 11 Dutch hospitals (2 university and 9 general hospitals).Participants An analysis was performed within the retrospective multicentre cohort study COVIDPredict. 7811 patients were included (60% men, 40% women) between 24 February 2020 and 9 August 2022. Patients who were ≥18 years with PCR-confirmed COVID-19 or CT with COVID-19 reporting and data system score≥4 and alternative diagnosis were included. Patients were excluded when serum sodium levels at presentation were not registered in the database or when they had been transferred from another participating hospital.Outcome measures We studied demographics, medical history, symptoms and outcomes. Patients were stratified according to serum sodium concentration and urinary sodium excretion.Results Hyponatraemia was present in 2677 (34.2%) patients and hypernatraemia in 126 (1.6%) patients. Patients with hyponatraemia presented more frequently with diarrhoea, lower blood pressure and tachycardia. Hyponatraemia was, despite a higher risk for ICU admission (OR 1.27 (1.11–1.46; p

An anionic oxy-Cope/transannular Michael addition cascade converts a spirocyclic architecture-readily available by Diels-Alder cycloaddition-into the hydrophenalene carbon skeleton of the pseudopterosin aglycones. Oxidation of the resulting cyclohexenone ring to the phenol that is characteristic of the targets completes a short formal synthesis.

Abstract Diffusion of water through membranes presents a considerable challenge, as the diffusivity often depends on the local concentration of water. One particular example with strong biological relevance is the stratum corneum (SC) as the primary permeability barrier for the skin. A simple alternative for the constant diffusivity model is provided by the Fujita’s two-parameter rational approximation, which captures the experimentally observed fact that the SC diffusion constant for water increases with increasing the water concentration. Based on Fick’s law of diffusion, a one-dimensional concentration-dependent diffusion model is developed and applied for the analysis of both the steady-state transepidermal water loss (TEWL) and the non-steady-state so-called skin surface water loss (SSWL) occurred after removal of an occlusion patch from the SC surface. It is shown that some of the age-related changes in the SSWL can be qualitatively explained by the variation of the dimensionless Fujita concentration-dependence parameter.