Showing papers by "University of Basel published in 2022"

TADF: Enabling luminescent copper(<scp>i</scp>) coordination compounds for light-emitting electrochemical cells

Abstract: The last decade has seen a surge of interest in the emissive behaviour of copper(i) coordination compounds, both neutral compounds that may have applications in organic light-emitting doides (OLEDs) and copper-based ionic transition metal complexes (Cu-iTMCs) with potential use in light-emitting electrochemical cells (LECs). One of the most exciting features of copper(i) coordination compounds is their possibility to exhibit thermally activated delayed fluorescence (TADF) in which the energy separation of the excited singlet (S1) and excited triplet (T1) states is very small, permitting intersystem crossing (ISC) and reverse intersystem crossing (RISC) to occur at room temperature without the requirement for the large spin-orbit coupling inferred by the presence of a heavy metal such as iridium. In this review, we focus mainly in Cu-iTMCs, and illustrate how the field of luminescent compounds and those exhibiting TADF has developed. Copper(i) coordination compounds that class as Cu-iTMCs include those containing four-coordinate [Cu(P^P)(N^N)]+ (P^P = large-bite angle bisphosphane, and N^N is typically a diimine), [Cu(P)2(N^N)]+ (P = monodentate phosphane ligand), [Cu(P)(tripodal-N3)]+, [Cu(P)(N^N)(N)]+ (N = monodentate N-donor ligand), [Cu(P^P)(N^S)]+ (N^S = chelating N,S-donor ligand), [Cu(P^P)(P^S)]+ (P^S = chelating P,S-donor ligand), [Cu(P^P)(NHC)]+ (NHC = N-heterocyclic carbene) coordination domains, dinuclear complexes with P^P and N^N ligands, three-coordinate [Cu(N^N)(NHC)]+ and two-coordinate [Cu(N)(NHC)]+ complexes. We pay particular attention to solid-state structural features, e.g. π-stacking interactions and other inter-ligand interactions, which may impact on photoluminescence quantum yields. Where emissive Cu-iTMCs have been tested in LECs, we detail the device architectures, and this emphasizes differences which make it difficult to compare LEC performances from different investigations.

Effect of preventive chemotherapy with praziquantel on schistosomiasis among school-aged children in sub-Saharan Africa: a spatiotemporal modelling study

Abstract: Over the past 20 years, schistosomiasis control has been scaled up. Preventive chemotherapy with praziquantel is the main intervention. We aimed to assess the effect of preventive chemotherapy on schistosomiasis prevalence in sub-Saharan Africa, comparing 2000-10 with 2011-14 and 2015-19.In this spatiotemporal modelling study, we analysed survey data from school-aged children (aged 5-14 years) in 44 countries across sub-Saharan Africa. The data were extracted from the Global Neglected Tropical Diseases database and augmented by 2018 and 2019 survey data obtained from disease control programmes. Bayesian geostatistical models were fitted to Schistosoma haematobium and Schistosoma mansoni survey data. The models included data on climatic predictors obtained from satellites and other open-source environmental databases and socioeconomic predictors obtained from various household surveys. Temporal changes in Schistosoma species prevalence were estimated by a categorical variable with values corresponding to the three time periods (2000-10, 2011-14, and 2015-19) during which preventive chemotherapy interventions were scaled up.We identified 781 references with relevant geolocated schistosomiasis survey data for 2000-19. There were 19 166 unique survey locations for S haematobium and 23 861 for S mansoni, of which 77% (14 757 locations for S haematobium and 18 372 locations for S mansoni) corresponded to 2011-19. Schistosomiasis prevalence among school-aged children in sub-Saharan Africa decreased from 23·0% (95% Bayesian credible interval 22·1-24·1) in 2000-10 to 9·6% (9·1-10·2) in 2015-19, an overall reduction of 58·3%. The reduction of S haematobium was 67·9% (64·6-71·1) and that of S mansoni 53·6% (45·2-58·3) when comparing 2000-10 with 2015-19.Our model-based estimates suggest that schistosomiasis prevalence in sub-Saharan Africa has decreased considerably, most likely explained by the scale-up of preventive chemotherapy. There is a need to consolidate gains in the control of schistosomiasis by means of preventive chemotherapy, coupled with other interventions to interrupt disease transmission.European Research Council and WHO.

Association of Regional Wall Shear Stress and Progressive Ascending Aorta Dilation in Bicuspid Aortic Valve

Abstract: The aim of this study was to evaluate the role of wall shear stress (WSS) as a predictor of ascending aorta (AAo) growth at 5 years or greater follow-up. Aortic 4-dimensional flow cardiac magnetic resonance (CMR) can quantify regions exposed to high WSS, a known stimulus for arterial wall dysfunction. However, its association with longitudinal changes in aortic dilation in patients with bicuspid aortic valve (BAV) is unknown. This retrospective study identified 72 patients with BAV (age 45 ± 12 years) who underwent CMR for surveillance of aortic dilation at baseline and ≥5 years of follow-up. Four-dimensional flow CMR analysis included the calculation of WSS heat maps to compare regional WSS in individual patients with population averages of healthy age- and sex-matched subjects (database of 136 controls). The relative areas of the AAo and aorta (in %) exposed to elevated WSS (outside the 95% CI of healthy population averages) were quantified. At a median follow-up duration of 6.0 years, the mean AAo growth rate was 0.24 ± 0.20 mm/y. The fraction of the AAo exposed to elevated WSS at baseline was increased for patients with higher growth rates (>0.24 mm/y, n = 32) compared with those with growth rates <0.24 mm/y (19.9% [IQR: 10.2%-25.5%] vs 5.7% [IQR: 1.5%-21.3%]; P = 0.008). Larger areas of elevated WSS in the AAo and entire aorta were associated with higher rates of AAo dilation >0.24 mm/y (odds ratio: 1.51; 95% CI: 1.05-2.17; P = 0.026 and odds ratio: 1.70; 95% CI: 1.01-3.15; P = 0.046, respectively). The area of elevated AAo WSS as assessed by 4-dimensional flow CMR identified BAV patients with higher rates of aortic dilation and thus might determine which patients require closer follow-up.

Quantum interference of identical photons from remote GaAs quantum dots

Abstract: Photonic quantum technology provides a viable route to quantum communication, quantum simulation, and quantum information processing. Recent progress has seen the realisation of boson sampling using 20 single-photons and quantum key distribution over hundreds of kilometres. Scaling the complexity requires architectures containing multiple photon-sources, photon-counters, and a large number of indistinguishable single photons. Semiconductor quantum dots are bright and fast sources of coherent single-photons. For applications, a significant roadblock is the poor quantum coherence upon interfering single photons created by independent quantum dots. Here, we demonstrate two-photon interference with near-unity visibility ($93.0\pm0.8$)\% using photons from two completely separate GaAs quantum dots. The experiment retains all the emission into the zero-phonon-line -- only the weak phonon-sideband is rejected -- and temporal post-selection is not employed. Exploiting the quantum interference, we demonstrate a photonic controlled-not circuit and an entanglement with fidelity ($85.0\pm 1.0$)\% between photons of different origins. The two-photon interference visibility is high enough that the entanglement fidelity is well above the classical threshold. The high mutual-coherence of the photons stems from high-quality materials, a diode-structure, and the relatively large quantum dot size. Our results establish a platform, GaAs QDs, for creating coherent single photons in a scalable way.

Luminescent chromium(0) and manganese(<scp>i</scp>) complexes

Abstract: In this Frontier article, recently discovered chromium(0) and manganese(I) complexes emitting from metal-to-ligand charge transfer (MLCT) excited states are highlighted. Chelating isocyanide ligands give access to this new class of 3d6 emitters with MLCT lifetimes in (or close to) the nanosecond regime in solution at room temperature. Although the so far achievable luminescence quantum yields in these open-shell complexes are yet comparatively low, the photophysical properties of the new chromium(0) and manganese(I) isocyanides are reminiscent of those of well-known ruthenium(II) polypyridines. Our findings provide insight into how undesired nonradiative MLCT deactivation in 3d6 complexes can be counteracted, and they seem therefore relevant for the further development of new luminescent first-row transition metal complexes based on iron(II) and cobalt(III) in addition to chromium(0) and manganese(I).

Are reactive oxygen species (ROS) a suitable metric to predict toxicity of carbonaceous aerosol particles?

Abstract: Abstract. It is being suggested that particle-bound or particle-induced reactive oxygen species (ROS), which significantly contribute to the oxidative potential (OP) of aerosol particles, are a promising metric linking aerosol compositions to toxicity and adverse health effects. However, accurate ROS quantification remains challenging due to the reactive and short-lived nature of many ROS components and the lack of appropriate analytical methods for a reliable quantification. Consequently, it remains difficult to gauge their impact on human health, especially to identify how aerosol particle sources and atmospheric processes drive particle-bound ROS formation in a real-world urban environment. In this study, using a novel online particle-bound ROS instrument (OPROSI), we comprehensively characterized and compared the formation of ROS in secondary organic aerosols (SOAs) generated from organic compounds that represent anthropogenic (naphthalene, SOANAP) and biogenic (β-pinene, SOAβPIN) precursors. The SOA mass was condensed onto soot particles (SP) under varied atmospherically relevant conditions (photochemical aging and humidity) to mimic the SOA formation from a mixing of traffic-related carbonaceous primary aerosols and volatile organic compounds (VOCs). We systematically analyzed the ability of the aqueous extracts of the two aerosol types (SOANAP-SP and SOAβPIN-SP) to induce ROS production and OP. We further investigated cytotoxicity and cellular ROS production after exposing human lung epithelial cell cultures (A549) to extracts of the two aerosols. A significant finding of this study is that more than 90 % of all ROS components in both SOA types have a short lifetime, highlighting the need to develop online instruments for a meaningful quantification of ROS. Our results also show that photochemical aging promotes particle-bound ROS production and enhances the OP of the aerosols. Compared to SOAβPIN-SP, SOANAP-SP elicited a higher acellular and cellular ROS production, a higher OP, and a lower cell viability. These consistent results between chemical-based and biological-based analyses indicate that particle-bound ROS quantification could be a feasible metric to predict aerosol particle toxicity and adverse human effects. Moreover, the cellular ROS production caused by SOA exposure not only depends on aerosol type but is also affected by exposure dose, highlighting a need to mimic the process of particle deposition onto lung cells and their interactions as realistically as possible to avoid unknown biases.

Transfer learned potential energy surfaces: accurate anharmonic vibrational dynamics and dissociation energies for the formic acid monomer and dimer

Abstract: The vibrational dynamics of the formic acid monomer (FAM) and dimer (FAD) is investigated from machine-learned potential energy surfaces at the MP2 (PESMP2) and transfer-learned (PESTL) to the CCSD(T) levels of theory. The normal mode (MAEs of 17.6 and 25.1 cm-1) and second order vibrational perturbation theory (VPT2, MAEs of 6.7 and 17.1 cm-1) frequencies from PESTL for all modes below 2000 cm-1 for FAM and FAD agree favourably with experiment. For the OH stretch mode the experimental frequencies are overestimated by more than 150 cm-1 for both FAM and FAD from normal mode calculations. Conversely, VPT2 calculations on PESTL for FAM reproduce the experimental OH frequency to within 22 cm-1. For FAD the VPT2 calculations find the high-frequency OH stretch at 3011 cm-1, compared with an experimentally reported, broad (∼100 cm-1) absorption band with center frequency estimated at ∼3050 cm-1. In agreement with earlier reports, MD simulations at higher temperature shift the position of the OH-stretch in FAM to the red, consistent with improved sampling of the anharmonic regions of the PES. However, for FAD the OH-stretch shifts to the blue and for temperatures higher than 1000 K the dimer partly or fully dissociates using PESTL. Including zero-point energy corrections from diffusion Monte Carlo simulations for FAM and FAD and corrections due to basis set superposition and completeness errors yields a dissociation energy of D0 = -14.23 ± 0.08 kcal mol-1 compared with an experimentally determined value of -14.22 ± 0.12 kcal mol-1.

Rapid antigen test to identify COVID-19 infected patients with and without symptoms admitted to the Emergency Department.

Abstract: PURPOSE: Early detection of SARS-CoV-2 patients is essential to contain the pandemic and keep the hospital secure. The rapid antigen test seems to be a quick and easy diagnostic test to identify patients infected with SARS-CoV-2. To assess the possible role of the antigen test in the Emergency Department (ED) assessment of potential SARS-CoV-2 infection in both symptomatic and asymptomatic patients. METHODS: Between 1 July 2020 and 10 December 2020, all patients consecutively assessed in the ED for suspected COVID-19 symptoms or who required hospitalisation for a condition not associated with COVID-19 were subjected to a rapid antigen test and RT-PCR swab. The diagnostic accuracy of the antigen test was determined in comparison to the SARS-CoV-2 PCR test using contingency tables. The possible clinical benefit of the antigen test was globally evaluated through decision curve analysis (DCA). RESULTS: A total of 3899 patients were subjected to antigen tests and PCR swabs. The sensitivity, specificity and accuracy of the antigen test were 82.9%, 99.1% and 97.4% (Cohen's K = 0.854, 95% CI 0.826-0.882, p < 0.001), respectively. In symptomatic patients, sensitivity was found to be 89.8%, while in asymptomatic patients, sensitivity was 63.1%. DCA appears to confirm a net clinical benefit for the preliminary use of antigen tests. CONCLUSIONS: The antigen test performed in the ED, though not ideal, can improve the overall identification of infected patients. While it appears to perform well in symptomatic patients, in asymptomatic patients, although it improves their management, it seems not to be definitive.

Manifolds of quasi-constant SOAP and ACSF fingerprints and the resulting failure to machine learn four-body interactions

Abstract: Atomic fingerprints are commonly used for the characterization of local environments of atoms in machine learning and other contexts. In this work, we study the behavior of two widely used fingerprints, namely, the smooth overlap of atomic positions (SOAP) and the atom-centered symmetry functions (ACSFs), under finite changes of atomic positions and demonstrate the existence of manifolds of quasi-constant fingerprints. These manifolds are found numerically by following eigenvectors of the sensitivity matrix with quasi-zero eigenvalues. The existence of such manifolds in ACSF and SOAP causes a failure to machine learn four-body interactions, such as torsional energies that are part of standard force fields. No such manifolds can be found for the overlap matrix (OM) fingerprint due to its intrinsic many-body character.

Shared and specific functions of Arfs 1-5 at the Golgi revealed by systematic knockouts.

Abstract: ADP-ribosylation factors (Arfs) are small GTPases regulating membrane traffic in the secretory pathway. They are closely related and appear to have overlapping functions, regulators, and effectors. The functional specificity of individual Arfs and the extent of redundancy are still largely unknown. We addressed these questions by CRISPR/Cas9-mediated genomic deletion of the human class I (Arf1/3) and class II (Arf4/5) Arfs, either individually or in combination. Most knockout cell lines were viable with slight growth defects only when lacking Arf1 or Arf4. However, Arf1+4 and Arf4+5 could not be deleted simultaneously. Class I Arfs are nonessential, and Arf4 alone is sufficient for viability. Upon Arf1 deletion, the Golgi was enlarged, and recruitment of vesicle coats decreased, confirming a major role of Arf1 in vesicle formation at the Golgi. Knockout of Arf4 caused secretion of ER-resident proteins, indicating specific defects in coatomer-dependent ER protein retrieval by KDEL receptors. The knockout cell lines will be useful tools to study other Arf-dependent processes.

Prereferral rectal artesunate and referral completion among children with suspected severe malaria in the Democratic Republic of the Congo, Nigeria and Uganda

Abstract: Children who receive prereferral rectal artesunate (RAS) require urgent referral to a health facility where appropriate treatment for severe malaria can be provided. However, the rapid improvement of a child's condition after RAS administration may influence a caregiver's decision to follow this recommendation. Currently, the evidence on the effect of RAS on referral completion is limited.An observational study accompanied the roll-out of RAS in three malaria endemic settings in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Community health workers and primary health centres enrolled children under 5 years with suspected severe malaria before and after the roll-out of RAS. All children were followed up 28 days after enrolment to assess their treatment-seeking pathways.Referral completion was 67% (1408/2104) in DRC, 48% (287/600) in Nigeria and 58% (2170/3745) in Uganda. In DRC and Uganda, RAS users were less likely to complete referral than RAS non-users in the pre-roll-out phase (adjusted OR (aOR)=0.48, 95% CI 0.30 to 0.77 and aOR=0.72, 95% CI 0.58 to 0.88, respectively). Among children seeking care from a primary health centre in Nigeria, RAS users were less likely to complete referral compared with RAS non-users in the post-roll-out phase (aOR=0.18, 95% CI 0.05 to 0.71). In Uganda, among children who completed referral, RAS users were significantly more likely to complete referral on time than RAS non-users enrolled in the pre-roll-out phase (aOR=1.81, 95% CI 1.17 to 2.79).The findings of this study raise legitimate concerns that the roll-out of RAS may lead to lower referral completion in children who were administered prereferral RAS. To ensure that community-based programmes are effectively implemented, barriers to referral completion need to be addressed at all levels. Alternative effective treatment options should be provided to children unable to complete referral.NCT03568344; ClinicalTrials.gov.

monaLisa: an R/Bioconductor package for identifying regulatory motifs

Abstract: Proteins binding to specific nucleotide sequences, such as transcription factors, play key roles in the regulation of gene expression. Their binding can be indirectly observed via associated changes in transcription, chromatin accessibility, DNA methylation and histone modifications. Identifying candidate factors that are responsible for these observed experimental changes is critical to understand the underlying biological processes. Here, we present monaLisa, an R/Bioconductor package that implements approaches to identify relevant transcription factors from experimental data. The package can be easily integrated with other Bioconductor packages and enables seamless motif analyses without any software dependencies outside of R.monaLisa is implemented in R and available on Bioconductor at https://bioconductor.org/packages/monaLisa with the development version hosted on GitHub at https://github.com/fmicompbio/monaLisa.Supplementary data are available at Bioinformatics online.

Multiscale light-sheet organoid imaging framework

Abstract: Abstract Organoids provide an accessible in vitro system to mimic the dynamics of tissue regeneration and development. However, long-term live-imaging of organoids remains challenging. Here we present an experimental and image-processing framework capable of turning long-term light-sheet imaging of intestinal organoids into digital organoids. The framework combines specific imaging optimization combined with data processing via deep learning techniques to segment single organoids, their lumen, cells and nuclei in 3D over long periods of time. By linking lineage trees with corresponding 3D segmentation meshes for each organoid, the extracted information is visualized using a web-based “Digital Organoid Viewer” tool allowing combined understanding of the multivariate and multiscale data. We also show backtracking of cells of interest, providing detailed information about their history within entire organoid contexts. Furthermore, we show cytokinesis failure of regenerative cells and that these cells never reside in the intestinal crypt, hinting at a tissue scale control on cellular fidelity.

Physiological and climate controls on foliar mercury uptake by European tree species

Abstract: Abstract. Despite the importance of vegetation uptake of atmospheric gaseous elemental mercury (Hg(0)) within the global Hg cycle, little knowledge exists on the physiological, climatic, and geographic factors controlling stomatal uptake of atmospheric Hg(0) by tree foliage. We investigate controls on foliar stomatal Hg(0) uptake by combining Hg measurements of 3569 foliage samples across Europe with data on tree species' traits and environmental conditions. To account for foliar Hg accumulation over time, we normalized foliar Hg concentration over the foliar life period from the simulated start of the growing season to sample harvest. The most relevant parameter impacting daily foliar stomatal Hg uptake was tree functional group (deciduous versus coniferous trees). On average, we measured 3.2 times higher daily foliar stomatal Hg uptake rates in deciduous leaves than in coniferous needles of the same age. Across tree species, for foliage of beech and fir, and at two out of three forest plots with more than 20 samples, we found a significant (p<0.001) increase in foliar Hg values with respective leaf nitrogen concentrations. We therefore suggest that foliar stomatal Hg uptake is controlled by tree functional traits with uptake rates increasing from low to high nutrient content representing low to high physiological activity. For pine and spruce needles, we detected a significant linear decrease in daily foliar stomatal Hg uptake with the proportion of time during which water vapor pressure deficit (VPD) exceeded the species-specific threshold values of 1.2 and 3 kPa, respectively. The proportion of time within the growing season during which surface soil water content (ERA5-Land) in the region of forest plots was low correlated negatively with foliar Hg uptake rates of beech and pine. These findings suggest that stomatal uptake of atmospheric Hg(0) is inhibited under high VPD conditions and/or low soil water content due to the regulation of stomatal conductance to reduce water loss under dry conditions. Other parameters associated with forest sampling sites (latitude and altitude), sampled trees (average age and diameter at breast height), or regional satellite-observation-based transpiration product (Global Land Evaporation Amsterdam Model: GLEAM) did not significantly correlate with daily foliar Hg uptake rates. We conclude that tree physiological activity and stomatal response to VPD and soil water content should be implemented in a stomatal Hg model to assess future Hg cycling under different anthropogenic emission scenarios and global warming.

Mapping out the Aqueous Surface Chemistry of Metal Oxide Nanocrystals: Carboxylate, Phosphonate, and Catecholate Ligands

Abstract: Iron oxide and hafnium oxide nanocrystals are two of the few successful examples of inorganic nanocrystals used in a clinical setting. Although crucial to their application, their aqueous surface chemistry is not fully understood. The literature contains conflicting reports regarding the optimum binding group. To alleviate these inconsistencies, we set out to systematically investigate the interaction of carboxylic acids, phosphonic acids, and catechols to metal oxide nanocrystals in polar media. Using nuclear magnetic resonance spectroscopy and dynamic light scattering, we map out the pH-dependent binding affinity of the ligands toward hafnium oxide nanocrystals (an NMR-compatible model system). Carboxylic acids easily desorb in water from the surface and only provide limited colloidal stability from pH 2 to pH 6. Phosphonic acids, on the other hand, provide colloidal stability over a broader pH range but also feature a pH-dependent desorption from the surface. They are most suited for acidic to neutral environments (pH <8). Finally, nitrocatechol derivatives provide a tightly bound ligand shell and colloidal stability at physiological and basic pH (6-10). Whereas dynamically bound ligands (carboxylates and phosphonates) do not provide colloidal stability in phosphate-buffered saline, the tightly bound nitrocatechols provide long-term stability. We thus shed light on the complex ligand binding dynamics on metal oxide nanocrystals in aqueous environments. Finally, we provide a practical colloidal stability map, guiding researchers to rationally design ligands for their desired application.

Contributions of adaptation and purifying selection to SARS-CoV-2 evolution

Abstract: Abstract Continued evolution and adaptation of SARS-CoV-2 has led to more transmissible and immune-evasive variants with profound impacts on the course of the pandemic. Here I analyze the evolution of the virus over 2.5 years since its emergence and estimate the rates of evolution for synonymous and non-synonymous changes separately for evolution within clades—well-defined monophyletic groups with gradual evolution—and for the pandemic overall. The rate of synonymous mutation is found to be around 6 changes per year. Synonymous rates within variants vary little from variant to variant and are compatible with the overall rate of 7 changes per year (or $7.5 \times 10^{-4}$ per year and codon). In contrast, the rate at which variants accumulate amino acid changes (non-synonymous mutations) was initially around 12-16 changes per year, but in 2021 and 2022 it dropped to 6-9 changes per year. The overall rate of non-synonymous evolution, that is across variants, is estimated to be about 26 amino acid changes per year (or $2.7 \times 10^{-3}$ per year and codon). This strong acceleration of the overall rate compared to within clade evolution indicates that the evolutionary process that gave rise to the different variants is qualitatively different from that in typical transmission chains and likely dominated by adaptive evolution. I further quantify the spectrum of mutations and purifying selection in different SARS-CoV-2 proteins and show that the massive global sampling of SARS-CoV-2 is sufficient to estimate site-specific fitness costs across the entire genome. Many accessory proteins evolve under limited evolutionary constraints with little short-term purifying selection. About half of the mutations in other proteins are strongly deleterious.

Treatment Effect of the SGLT2 Inhibitor Empagliflozin on Chronic Syndrome of Inappropriate Antidiuresis: Results of a Randomized, Double-Blind, Placebo-Controlled, Crossover Trial

Abstract: Significance Statement The syndrome of inappropriate antidiuresis (SIAD) is a major cause of hypotonic hyponatremia. Despite its prevalence, treatment options are sparse, and data on their effect on hyponatremia-associated morbidity such as neurocognitive impairment are largely lacking. New treatment options are needed. The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin promotes osmotic diuresis via urinary glucose excretion and could be used as a treatment for chronic SIAD. This randomized, double-blind, placebo-controlled, crossover trial with 14 participants revealed that empagliflozin is well tolerated and effective compared with placebo. In addition, treatment with empagliflozin possibly led to an improvement in neurocognitive function. The results set the stage for further studies evaluating empagliflozin as a treatment option in patients with SIAD-induced hyponatremia. Background The syndrome of inappropriate antidiuresis (SIAD) is characterized by a reduction of free water excretion with consecutive hypotonic hyponatremia and is therefore challenging to treat. The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin promotes osmotic diuresis via urinary glucose excretion, likely leading to increased electrolyte free water clearance. Methods In this randomized, double-blind, placebo-controlled, crossover trial, we compared 4-week treatment with empagliflozin 25 mg/d to placebo in outpatients with chronic SIAD-induced hyponatremia. At baseline and after both treatment cycles, patients underwent different assessments including neurocognitive testing (Montreal Cognitive Assessment [MoCA]). The primary end point was the difference in serum sodium levels between treatments. Results Fourteen patients, 50% female, with a median age of 72 years (interquartile range [IQR], 65–77), completed the trial. Median serum sodium level at baseline was 131 mmol/L (IQR, 130–132). After treatment with empagliflozin, median serum sodium level rose to 134 mmol/L (IQR, 132–136), whereas no increase was seen with placebo (130 mmol/L; IQR, 128–132), corresponding to a serum sodium increase of 4.1 mmol/L (95% confidence interval [CI], 1.7 to 6.5; P=0.004). Exploratory analyses showed that treatment with empagliflozin led to improved neurocognitive function with an increase of 1.16 (95% CI, 0.05 to 2.26) in the MoCA score. Treatment was well tolerated; no serious adverse events were reported. Conclusion The SGLT2 inhibitor empagliflozin is a promising new treatment option for chronic SIAD-induced hyponatremia, possibly improving neurocognitive function. Larger studies are needed to confirm the observed treatment effects. Clinical Trial registration number: ClinicalTrials.gov NCT03202667. Export