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This article focuses on elements of successful sociocultural inclusion and linguistic participation in a bilingual dual-language preschool for Latinx children. It presents a subset of findings from a three-year qualitative research project in which Latinx critical race theory and a translanguaging framework were used to illuminate critical intersections between children's funds of knowledge, their translanguaging talents, and their interests in play and social interaction. Learning Stories served as both the focus for documentation and the unit of analysis for understanding children's translanguaging experiences, as well as for promoting new forms of authentic assessment for family engagement.

Abstract Multiple linear regression models were trained to predict the degree of substitution (DS) of cellulose acetate based on raw infrared (IR) spectroscopic data. A repeated k-fold cross validation ensured unbiased assessment of model accuracy. Using the DS obtained from 1H NMR data as reference, the machine learning model achieved a mean absolute error (MAE) of 0.069 in DS on test data, demonstrating higher accuracy compared to the manual evaluation based on peak integration. Limiting the model to physically relevant areas unexpectedly showed the $${\hbox {C}{-}\hbox {H}}$$ peak to be the strongest predictor of DS. By applying a n-best feature selection algorithm based on the F-statistic of the Pearson correlation coefficient, several relevant areas were identified and the optimized model achieved an improved MAE of 0.052. Predicting the DS of other cellulose acetate data sets yielded similar accuracy, demonstrating that the developed models are robust and suitable for efficient and accurate routine evaluations. The model solely trained on cellulose acetate was further able to predict the DS of other cellulose esters with an accuracy of $$\approx 0.1-0.2$$ in DS and model architectures for a more general analysis of cellulose esters were proposed.

Abstract Alloying in metal castings is one of the principal methods of strengthening an alloy for various structural and functional applications, but very rarely does it modify an alloy’s elastic modulus. We report a methodology of combining isostructural Laves phases to form a multi-component, high symmetry, isotropic phase that was discovered to enhance the elastic modulus of a cast aluminum alloy to 91.5 ± 7.4 GPa. Flux grown single crystals of the rhombicuboctahedron phase (RCO), so named for the observed morphology, were used to enhance understanding of the structure and mechanical properties of the phase. The pure RCO phase’s structure and site occupancies were co-refined using x-ray and neutron diffraction. Dynamic nanomechanical testing of the cast alloy shows the primary RCO phase has a high, relatively isotropic, elastic modulus. This RCO containing aluminum alloy is found to have a specific modulus that exceeds that of the leading Al, Mg, Steel, and Ti alloys.

ABSTRACT: TNG908 is a clinical stage PRMT5 inhibitor with an MTA-cooperative binding mechanism designed to leverage the synthetic lethal interaction between PRMT5 inhibition and MTAP deletion. MTAP deletion occurs in 10–15 % of all human cancer representing multiple histologies. MTA is a negative regulator of PRMT5 that accumulates as a result of MTAP deletion. In this study, we demonstrate that TNG908 selectively binds the PRMT5·MTA complex driving selective inhibition of PRMT5 in MTAP-null cancers, a mechanism that creates a large therapeutic index relative to first generation PRMT5 inhibitors that have alternative binding mechanisms that are not tumor-selective. Strong preclinical activity in multiple MTAP-deleted xenograft models, as well as demonstrated brain penetrance in preclinical models, support the potential for histology-agnostic clinical development of TNG908 in MTAP-deleted solid tumors, including CNS malignancies. TNG908 is being tested clinically in patients with MTAP-deleted tumors, including glioblastoma, in a Phase I/II clinical trial (NCT05275478).

Abstract Terpenes represent a promising renewable feedstock for the substitution of fossil resources in the synthesis of renewable platform chemicals, like diamines. This work describes the synthesis and full characterization of 1,4-p-menthane diamine (1,4-PMD) obtained from α-terpinene (1). A two-step procedure using dibenzyl azodicarboxylate (DBAD) and H2 as rather benign reagents was employed under comparatively mild conditions. Both C–N bonds were formed simultaneously during a visible-light mediated Diels–Alder reaction, which was investigated in batch or flow, avoiding regioselectivity issues during the amination steps that are otherwise typical for terpene chemistry. Heterogeneously catalyzed quadruple hydrogenation of the cycloadduct (2a) yielded 1,4‑PMD (3). While the intermediate cycloadduct was shown to be distillable, the target diamine can be sublimed, offering sustainable purification methods.

AIM OF THE STUDY: We aimed to evaluate the utilisation of all prescribed drugs during pregnancy dispensed in outpatient care in Switzerland between 2015 and 2021. METHODS: We conducted a descriptive study using the Swiss Helsana claims database (2015-2021). We established a cohort of pregnancies by identifying deliveries and estimating the date of the last menstrual period. We analysed the drug burden during a 270-day pre-pregnancy period, during pregnancy (overall and by trimester), and during a 270-day postpartum period. Subsequently, we quantified 1) the median number of drug dispensations (total vs. unique drug claims); and 2) the prevalence of exposure to at least one dispensed drug and the number of dispensed drugs (0, 1, 2, 3, 4, and ≥5); and 3) the 15 most frequently dispensed drugs were identified during each period, overall and stratified by maternal age. RESULTS: Among 34,584 pregnant women (5.6% of all successful pregnancies in Switzerland), 87.5% claimed at least one drug (not including vitamins, supplements, and vaccines), and 33.3% claimed at least five drugs during pregnancy. During trimester 1 alone, 8.2% of women claimed at least five distinct drugs. The proportion of women who claimed prescribed drugs was lower pre-pregnancy (69.1%) and similar postpartum (85.6%) when compared to during pregnancy (87.5%). The most frequently claimed drugs during pregnancy were meaningfully different during pregnancy than before and after. CONCLUSIONS: This study suggests that 8 of 10 women in Switzerland are exposed to prescribed drugs during pregnancy. Most drugs dispensed during pregnancy are comparatively well investigated and are considered safe. However, the high drug burden in this vulnerable patient population underlines the importance of evidence on the benefit-risk profile of individual drugs taken during pregnancy.

Abstract Deposition of amyloid beta (Aβ) into plaques is a major hallmark of Alzheimer’s disease (AD). Different amyloid precursor protein (APP) mutations cause early-onset AD by altering the production or aggregation properties of Aβ. We recently identified the Uppsala APP mutation (APPUpp), which causes Aβ pathology by a triple mechanism: increased β-secretase and altered α-secretase APP cleavage, leading to increased formation of a unique Aβ conformer that rapidly aggregates and deposits in the brain. The aim of this study was to further explore the effects of APPUpp in a transgenic mouse model (tg-UppSwe), expressing human APP with the APPUpp mutation together with the APPSwe mutation. Aβ pathology was studied in tg-UppSwe brains at different ages, using ELISA and immunohistochemistry. In vivo PET imaging with three different PET radioligands was conducted in aged tg-UppSwe mice and two other mouse models; tg-ArcSwe and tg-Swe. Finally, glial responses to Aβ pathology were studied in cell culture models and mouse brain tissue, using ELISA and immunohistochemistry. Tg-UppSwe mice displayed increased β-secretase cleavage and suppressed α-secretase cleavage, resulting in AβUpp42 dominated diffuse plaque pathology appearing from the age of 5–6 months. The γ-secretase cleavage was not affected. Contrary to tg-ArcSwe and tg-Swe mice, tg-UppSwe mice were [11C]PiB-PET negative. Antibody-based PET with the 3D6 ligand visualized Aβ pathology in all models, whereas the Aβ protofibril selective mAb158 ligand did not give any signals in tg-UppSwe mice. Moreover, unlike the other two models, tg-UppSwe mice displayed a very faint glial response to the Aβ pathology. The tg-UppSwe mouse model thus recapitulates several pathological features of the Uppsala APP mutation carriers. The presumed unique structural features of AβUpp42 aggregates were found to affect their interaction with anti-Aβ antibodies and profoundly modify the Aβ-mediated glial response, which may be important aspects to consider for further development of AD therapies.

Abstract The depletion of fossil resources as well as environmental concerns contribute to an increasing focus on finding more sustainable approaches for the synthesis of polymeric materials. In this work, a synthesis route towards non-isocyanate polyurethanes (NIPUs) using renewable starting materials is presented. Based on the terpenes limonene and carvone as renewable resources, five-membered cyclic carbonates are synthesized and ring-opened with allylamine, using thiourea compounds as benign and efficient organocatalysts. Thus, five renewable AA monomers are obtained, bearing one or two urethane units. Taking advantage of the terminal double bonds of these AA monomers, step-growth thiol-ene polymerization is performed using different dithiols, to yield NIPUs with molecular weights of above 10 kDa under mild conditions. Variation of the dithiol and amine leads to polymers with different properties, with M n of up to 31 kDa and T g’s ranging from 1 to 29 °C.

Abstract Tetraphenylethylenes (TPEs) are well-known for their aggregation-induced emission properties. The synthesis of TPE derivatives, as well as other highly substituted olefins, generally requires the use of hazardous reagents, such as metalorganic compounds, to overcome the high activation energies caused by the sterically congested double bond. Herein, we present an efficient and metal-free procedure for the synthesis of tetraarylethylenes via alkylidene-homocoupling of N-tosylhydrazones, derived from readily available benzophenones, in excellent yields. The method relies only on cheap and benign additives, i.e. elemental sulfur and potassium carbonate, and easily competes with other established procedures in terms of scope, yield and practicability. A mechanistic study revealed a diazo compound, a thioketone and a thiirane as key intermediates in the pathway of the reaction. Based on this, a modified method, which allows for selective alkylidene-cross-coupling, generating a broader scope of tri- and tetrasubstituted olefins in good yields, is showcased as well.

Abstract Kagomé metals are widely recognized, versatile platforms for exploring topological properties, unconventional electronic correlations, magnetic frustration, and superconductivity. In the RV6Sn6 family of materials (R = Sc, Y, Lu), ScV6Sn6 hosts an unusual charge density wave ground state as well as structural similarities with the AV3Sb5 system (A = K, Cs, Rb). In this work, we combine Raman scattering spectroscopy with first-principles lattice dynamics calculations to reveal phonon mixing processes in the charge density wave state of ScV6Sn6. In the low temperature phase, we find at least four new peaks in the vicinity of the V-containing totally symmetric mode near 240 cm−1 suggesting that the density wave acts to mix modes of P6/m m m and $$R\bar{3}m$$ R 3 ¯ m symmetry - a result that we quantify by projecting phonons of the high symmetry state onto those of the lower symmetry structure. We also test the stability of the short-range ordered density wave state under compression and propose that both physical and chemical pressure quench the effect. We discuss these findings in terms of symmetry and the structure-property trends that can be unraveled in this system.

Abstract Purpose There are only limited data on drug utilization patterns in pediatric inpatients, especially on general wards. The aim of the study was to describe prescribing patterns and their associations with prescribing errors in a university children’s hospital in the German-speaking part of Switzerland. Method This was a subanalysis of a retrospective single-center observational study. Patient characteristics and drug use of 489 patients with 2693 drug prescriptions were associated with prescribing errors. Drugs were categorized by the Anatomic Therapeutic Chemical Classification System (ATC), patients were categorized by age group according to European Medicines Agency guidelines, and prescribing errors were analyzed by type [Pharmaceutical Care Network Europe (PCNE) classification] and severity of error [adapted National Coordinating Council for Medication Error Reporting (NCC MERP) index]. Results The most frequently prescribed ATC classes were nervous system (N) (42.6%), alimentary system (A) (15.6%), and anti-infective drugs (J) (10.7%). Eighty-two percent of patients were prescribed an analgesic. Most drugs were prescribed for oral (47%) or intravenous (32%) administration, but the rectal route was also frequent (10%). The most frequently prescribed drugs were paracetamol, metamizole, and ibuprofen. The high number of metamizole prescriptions (37% of patients were prescribed metamizole) is typical for German-speaking countries. Older pediatric patients were prescribed more drugs than younger patients. A statistically significant difference was found in the rate of potentially harmful errors across age groups and for gender; children between 2 and 11 years had a higher rate of potentially harmful errors than infants under 2 years (p = 0.029) and female patients had a higher rate of potentially harmful errors than male patients (p = 0.023). Recurring errors were encountered with certain drugs (nalbuphine, cefazolin). Conclusions Our study provides insight into prescribing patterns on pediatric general wards in a university children’s hospital in Switzerland and highlights some areas for future research. Especially, the higher risk for prescribing errors among female pediatric patients needs further investigation.

AIMS OF THE STUDY: Unlicensed drugs are frequently used in paediatric care. To what extent they are prescribed in hospital care in Switzerland is unclear. Because prescribing errors seem to occur more frequently with unlicensed drugs, we aimed to assess the prevalence of unlicensed drug prescriptions in two study periods (2018 and 2019) at the University Children’s Hospital Zurich, compare these periods and investigate whether unlicensed drugs were more prone to prescribing errors than licensed drugs. METHODS: We conducted a sub-analysis of a retrospective single-centre observational study and analysed 5,022 prescriptions for a total of 1,000 patients from 2018 and 2019 in paediatric general wards. The rate of unlicensed drugs, consisting of imported or formula drugs, was investigated. The prescriptions from 2019 were further analysed on prescribing errors to see whether errors occurred more often in unlicensed or licensed drug use. RESULTS: Of all prescriptions, 10.8% were unlicensed drugs, with around half each being imported and formula drugs. Among all patients, 34% were prescribed at least one unlicensed drug. Younger paediatric patients were prescribed more unlicensed drugs than older paediatric patients (newborns: 15.8% of prescriptions, infants: 13.4%, children: 10.6%, adolescents: 7.1%). Ibuprofen suppositories, midazolam oral solution and gentamicin i.v. solution were the most frequently prescribed imported drugs. Macrogol powder, lisinopril oral suspension and potassium chloride i.v. solution were the most frequently prescribed formula drugs. The most common drug forms in unlicensed use were oral liquid forms and i.v. solutions. Unlicensed drugs had a significantly higher rate of prescribing errors than licensed drugs (31.6 errors per 100 prescriptions [95% CI: 26.1–37.0] versus 24.3 errors per 100 prescriptions [95% CI: 22.3–26.2], p = 0.024). In particular, formula drugs carried a higher risk (36.4 errors per 100 prescriptions, p = 0.012). CONCLUSIONS: Unlicensed drugs are frequently prescribed in this paediatric hospital setting in Switzerland. Around every tenth prescription is an unlicensed drug. Because unlicensed drugs showed a significantly higher rate of prescribing errors, licensed drugs are favourable in terms of medication safety and should be prescribed whenever possible. If no licensed drug is available, imported drugs should be favoured over formula drugs due to lower prescribing error rates. To increase medication safety in paediatrics in Switzerland, efforts are necessary to increase the number of suitable licensed drug formulations for paediatric patients, including developing new innovative drug formulations for children.

OBJECTIVE: To investigate claims patterns for metamizole and other non-opioid analgesics in Switzerland. To characterise users of these non-opioid analgesics regarding sex, age, comedications and canton of residence. METHODS: We conducted a retrospective descriptive study using administrative claims data of outpatient prescribed non-opioid analgesics of the Swiss health insurance company Helsana between January 2014 and December 2019. First, we evaluated the number of claims and defined daily doses per year of metamizole, ibuprofen, diclofenac and paracetamol in adults aged 18 years or over. Second, we characterised new users of these non-opioid analgesics in terms of sex, age, claimed comedications and canton of residence. RESULTS: From 2014 to 2019, among the investigated non-opioid analgesics, metamizole showed the highest increase in claims (+9545 claims, +50%) and defined daily doses (+86,869 defined daily doses, +84%) per 100,000 adults. Metamizole users had the highest median age (62 years [IQR: 44–77]) compared to ibuprofen (47 years [IQR: 33–62]), diclofenac (57 years [IQR: 43–71]) and paracetamol (58 years [IQR: 39–75]) users. Metamizole users also more frequently claimed proton pump inhibitors, anticoagulants, platelet aggregation inhibitors and antihypertensive drugs than users of other non-opioid analgesics. While metamizole was most frequently claimed in German-speaking regions of Switzerland, ibuprofen and paracetamol were most frequently claimed in the French-speaking regions and diclofenac in German- and Italian-speaking regions. CONCLUSION: In Switzerland, metamizole was increasingly claimed between 2014 and 2019. Metamizole was most frequently claimed by older adults and patients with comedications suggestive of underlying conditions, which can be worsened or caused by use of nonsteroidal anti-inflammatory drugs. The lack of studies regarding the effectiveness and safety of metamizole in this population warrants further investigation.

Direct imaging and tuning of flat band localization in kagome materials remains a challenge. Here, scanning tunneling microscopy and photoemission spectroscopy are used to study FeSn, revealing real-space localization and magnetic tuning of the flat band state within the Fe3Sn kagome lattice layer.

The asymmetric distribution of chiral objects with opposite chirality is of great fundamental interest ranging from molecular biology to particle physics. In quantum materials, chiral states can build on inversion-symmetry-breaking lattice structures or emerge from spontaneous magnetic ordering induced by competing interactions. Although the handedness of a chiral state can be changed through external fields, a spontaneous chirality flipping has yet to be discovered. We present experimental evidence of chirality flipping via changing temperature in a topological magnet EuAl_{4}, which features orthogonal spin density waves (SDW) and charge density waves (CDW). Using circular dichroism of Bragg peaks in the resonant magnetic x-ray scattering, we find that the chirality of the helical SDW flips through a first-order phase transition with modified SDW wavelength. Intriguingly, we observe that the CDW couples strongly with the SDW and displays a rare commensurate-to-incommensurate transition at the chirality flipping temperature. Combining with first-principles calculations and angle-resolved photoemission spectroscopy, our results support a Fermi surface origin of the helical SDW with intertwined spin, charge, and lattice degrees of freedom in EuAl_{4}. Our results reveal an unprecedented spontaneous chirality flipping and lay the groundwork for a new functional manipulation of chirality through momentum-dependent spin-charge-lattice interactions.

Abstract Compound mixtures represent an alternative, additional approach to DNA and synthetic sequence-defined macromolecules in the field of non-conventional molecular data storage, which may be useful depending on the target application. Here, we report a fast and efficient method for information storage in molecular mixtures by the direct use of commercially available chemicals and thus, zero synthetic steps need to be performed. As a proof of principle, a binary coding language is used for encoding words in ASCII or black and white pixels of a bitmap. This way, we stored a 25 × 25-pixel QR code (625 bits) and a picture of the same size. Decoding of the written information is achieved via spectroscopic (1H NMR) or chromatographic (gas chromatography) analysis. In addition, for a faster and automated read-out of the data, we developed a decoding software, which also orders the data sets according to an internal “ordering” standard. Molecular keys or anticounterfeiting are possible areas of application for information-containing compound mixtures.

Seasonal snow cover plays a major role in the climate system of the Northern Hemisphere via its effect on land surface albedo and fluxes. In climate models the parameterization of interactions between snow and atmosphere remains a source of uncertainty and biases in the representation of local and global climate. Here, we evaluate the ability of an ensemble of regional climate models (RCMs) coupled with different land surface models to simulate snow–atmosphere interactions over Europe in winter and spring. We use a previously defined index, the snow-albedo sensitivity index (SASI), to quantify the radiative forcing associated with snow cover anomalies. By comparing RCM-derived SASI values with SASI calculated from reanalyses and satellite retrievals, we show that an accurate simulation of snow cover is essential for correctly reproducing the observed forcing over middle and high latitudes in Europe. The choice of parameterizations, and primarily the choice of the land surface model, strongly influences the representation of SASI as it affects the ability of climate models to simulate snow cover accurately. The degree of agreement between the datasets differs between the accumulation and ablation periods, with the latter one presenting the greatest challenge for the RCMs. Given the dominant role of land surface processes in the simulation of snow cover during the ablation period, the results suggest that, during this time period, the choice of the land surface model is more critical for the representation of SASI than the atmospheric model.

RhPb was initially recognized as one of CoSn-like compounds with P6/mmm symmetry, containing an ideal kagome lattice of d-block atoms. However, theoretical calculations predict the realization of the phonon soft mode, which leads to the kagome lattice distortion and stabilization of the structure with P6[over ¯]2m symmetry [A. Ptok et al., Phys. Rev. B 104, 054305 (2021)2469-995010.1103/PhysRevB.104.054305]. Here, we present the single crystal x-ray diffraction results supporting this prediction. Furthermore, we discuss the main dynamical properties of RhPb with P6[over ¯]2m symmetry, i.e. phonon dispersions and surface Green's functions using the modern theoretical methods based on density functional theory. The bulk phononic dispersion curves contain several flattened bands, Dirac nodal lines, and triple degenerate Dirac points. As a consequence, the phononic drumhead surface state is realized for the (100) surface, terminated by the zigzaglike edge of Pb honeycomb sublattice.

Land cover in sub-polar and alpine regions of northern and eastern Europe have already begun changing due to natural and anthropogenic changes such as afforestation. This will impact the regional climate and hydrology upon which societies in these regions are highly reliant. This study aims to identify the impacts of afforestation/reforestation (hereafter afforestation) on snow and the snow-albedo effect and highlight potential improvements for future model development. The study uses an ensemble of nine regional climate models for two different idealised experiments covering a 30-year period; one experiment replaces most land cover in Europe with forest, while the other experiment replaces all forested areas with grass. The ensemble consists of nine regional climate models composed of different combinations of five regional atmospheric models and six land surface models. Results show that afforestation reduces the snow-albedo sensitivity index and enhances snowmelt. While the direction of change is robustly modelled, there is still uncertainty in the magnitude of change. The greatest differences between models emerge in the snowmelt season. One regional climate model uses different land surface models which shows consistent changes between the three simulations during the accumulation period but differs in the snowmelt season. Together these results point to the need for further model development in representing both grass–snow and forest–snow interactions during the snowmelt season. Pathways to accomplishing this include (1) a more sophisticated representation of forest structure, (2) kilometre-scale simulations, and (3) more observational studies on vegetation–snow interactions in northern Europe.

The roughness of the land surface (z0) is a key property, exerting significant influence on the amount of near-surface turbulent activity and consequently the turbulent exchange of energy, water, momentum, and chemical species between the land and the atmosphere. Variations in z0 are substantial across different types of land cover, ranging from typically less than 1 mm over fresh snow or sand deserts up to more than 1 m over urban areas or forests. In this study, we revise the parameterizations and parameter choices related to z0 in the Community Land Model 5.1 (CLM), the land component of the Community Earth System Model (CESM). We propose a number modifications for z0 in CLM, guided by observational data. Most importantly, we find that the observations support an increase in z0 for all types of forests and a decrease in the momentum z0 for bare soil, snow, glaciers, and crops. We then assess the effect of those modifications in land-only and land–atmosphere coupled simulations. With the revised parameterizations, diurnal variations of the land surface temperature (LST) are dampened in forested regions and are amplified over warm deserts. These changes mitigate model biases compared to MODerate resolution Imaging Spectroradiometer (MODIS) remote sensing observations. The changes in LST are generally stronger during the day than at night. For example, the LST increases by 5.1 K at 13:30 local solar time but only by 0.6 K at 01:30 during boreal summer across the entire Sahara. The induced changes in the diurnal variability of near-surface air temperatures are generally of the opposite sign and of smaller magnitude. Near-surface winds accelerate in areas where the momentum z0 was lowered, such as the Sahara, the Middle East, and Antarctica, and decelerate in regions with forests. Overall, this study finds that the current representation of z0 in CLM is not in agreement with observational constraints for several types of land cover. The proposed model modifications are shown to considerably alter the simulated climate in terms of temperatures and wind speed at the land surface.

In the context of the first phase of the Coordinated Regional Climate Downscaling Experiment in the European domain (EURO-CORDEX) flagship plot study on Land Use and Climate Across Scales (LUCAS), we investigate the biophysical impact of afforestation on the seasonal cycle of soil temperature over the European continent with an ensemble of 10 regional climate models. For this purpose, each ensemble member performed two idealized land cover experiments in which Europe is covered either by forests or grasslands. The multi-model mean exhibits a reduction of the annual amplitude of soil temperature (AAST) due to afforestation over all European regions, although this is not a robust feature among the models. In the Mediterranean, the spread of simulated AAST response to afforestation is between −4 and +2 ∘C at 1 m below the ground, while in Scandinavia the inter-model spread ranges from −7 to +1 ∘C. We show that the large range in the simulated AAST response is due to the representation of the summertime climate processes and is largely explained by inter-model differences in leaf area index (LAI), surface albedo, cloud fraction and soil moisture, when all combined into a multiple linear regression. The changes in these drivers essentially determine the ratio between the increased radiative energy at surface (due to lower albedo in forests) and the increased sum of turbulent heat fluxes (due to mixing-facilitating characteristics of forests), and consequently decide the changes in soil heating with afforestation in each model. Finally, we pair FLUXNET sites to compare the simulated results with observation-based evidence of the impact of forest on soil temperature. In line with models, observations indicate a summer ground cooling in forested areas compared to open lands. The vast majority of models agree with the sign of the observed reduction in AAST, although with a large variation in the magnitude of changes. Overall, we aspire to emphasize the biophysical effects of afforestation on soil temperature profile with this study, given that changes in the seasonal cycle of soil temperature potentially perturb crucial biochemical processes. Robust knowledge on biophysical impacts of afforestation on soil conditions and its feedbacks on local and regional climate is needed in support of effective land-based climate mitigation and adaption policies.

Abstract Background Previous studies suggested an elevated risk of venous thromboembolism (VTE) among patients with type 2 diabetes mellitus (T2DM), with a possible sex difference. The impact of glycemic control on the risk of VTE is unclear. Our objective was to analyze the association between glycemic control and the risk of unprovoked (idiopathic) VTE in men and women with T2DM. Methods We conducted a nested case–control analysis (1:4 matching) within a cohort of patients with incident T2DM between 1995 and 2019 using data from the CPRD GOLD. We excluded patients with known risk factors for VTE prior to onset of DM. Cases were T2DM patients with an unprovoked treated VTE. The exposure of interest was glycemic control measured as HbA1c levels. We conducted conditional logistic regression analyses adjusted for several confounders. Results We identified 2′653 VTE cases and 10′612 controls (53.1% females). We found no association between the HbA1c level and the risk of VTE in our analyses. However, when the most recent HbA1c value was recorded within 90 days before the index date, women with HbA1c levels > 7.0% had a 36–55% increased relative risk of VTE when compared to women with HbA1c > 6.5–7.0%. Conclusions Our study raises the possibility that female T2DM patients with HbA1c levels > 7% may have a slightly higher risk for unprovoked VTE compared to women with HbA1c levels > 6.5–7.0%. This increase may not be causal and may reflect differences in life style or other characteristics. We observed no effect of glycemic control on the risk of VTE in men.

Background: Delirium is a brain condition associated with poor outcomes in rehabilitation. It is therefore important to assess delirium incidence in rehabilitation. Purpose: To develop and validate a chart-based method to identify incident delirium episodes within the electronic database of a Swiss rehabilitation clinic, and to identify a study population of validated incident delirium episodes for further research purposes. Design: Retrospective validation study. Settings: Routinely collected inpatient clinical data from ZURZACH Care. Participants: All patients undergoing rehabilitation at ZURZACH Care, Rehaklinik Bad Zurzach between 2015 and 2018 were included. Methods: Within the study population, we identified all rehabilitation stays for which ≥2 delirium-predictive key words (common terms used to describe delirious patients) were recorded in the medical charts. We excluded all prevalent delirium episodes and defined the remaining episodes to be potentially incident. At least two physicians independently confirmed or refuted each potential incident delirium episode by reviewing the patient charts. We calculated the positive predictive value (PPV) with 95% confidence interval (95% CI) for all potential incident delirium episodes and for specific subgroups. Results: Within 10,515 rehabilitation stays we identified 554 potential incident delirium episodes. Overall, 125 potential incident delirium episodes were confirmed by expert review. The PPV of the chart-based method varied from 0.23 (95% CI 0.19–0.26) overall to 0.69 (95% CI 0.56–0.79) in specific subgroups. Conclusions: Our chart-based method was able to capture incident delirium episodes with low to moderate accuracy. By conducting an additional expert review of the medical charts, we identified a study population of validated incident delirium episodes. Our chart-based method contributes towards an automated detection of potential incident delirium episodes that, supplemented with expert review, efficiently yields a validated population of incident delirium episodes for research purposes.

Abstract Background Low back pain (LBP) is one of the most common musculoskeletal disorders, causing significant personal and social burden. Current research is focused on the processes of the central nervous system (particularly the sensorimotor system) and body perception, with a view to developing new and more efficient ways to treat chronic low back pain (CLBP). Several clinical tests have been suggested that might have the ability to detect alterations in the sensorimotor system. These include back-photo assessment (BPA), two-point discrimination (TPD), and the movement control tests (MCT). The aim of this study was to determine whether the simple clinical tests of BPA, TPD or MCT are able to discriminate between nonspecific CLBP subjects with altered body perception and healthy controls. Methods A cross-sectional study was conducted. At one point in time, 30 subjects with CLBP and 30 healthy controls were investigated through using BPA, TPD and MCT on the lower back. Correlations among the main covariates and odds ratios for group differences were calculated. Results MCT showed an odds ratio for the presence of CLBP of 1.92, with a statistically significant p-value (0.049) and 95%CI. The TPD and BPA tests were unable to determine significant differences between the groups. Conclusions Of the three tests investigated, MCT was found to be the only suitable assessment to discriminate between nonspecific CLBP subjects and healthy controls. The MCT can be recommended as a simple clinical tool to detect alterations in the sensorimotor system of nonspecific CLBP subjects. This could facilitate the development of tailored management strategies for this challenging LBP subgroup. However, further research is necessary to elucidate the potential of all the tests to detect alterations in the sensorimotor system of CLBP subjects. Trial registration No trial registration was needed as the study contains no intervention. The study was approved by the Swiss Ethics Commission of Northwest and Central Switzerland (EKNZ) reference number 2015–243.

Climate model biases in the representation of albedo variations between land cover classes contribute to uncertainties on the climate impact of land cover changes since pre-industrial times, especially on the associated radiative forcing. Recent publications of new observation-based datasets offer opportunities to investigate these biases and their impact on historical surface albedo changes in simulations from the fifth phase of the Coupled Model Intercomparison Project (CMIP5). Conducting such an assessment is, however, complicated by the non-availability of albedo values for specific land cover classes in CMIP and the limited number of simulations isolating the land use forcing. In this study, we demonstrate the suitability of a new methodology to extract the albedo of trees and crops–grasses in standard climate model simulations. We then apply it to historical runs from 17 CMIP5 models and compare the obtained results to satellite-derived reference data. This allows us to identify substantial biases in the representation of the albedo of trees and crops–grasses as well as the surface albedo change due to the transition between these two land cover classes in the analysed models. Additionally, we reconstruct the local surface albedo changes induced by historical conversions between trees and crops–grasses for 15 CMIP5 models. This allows us to derive estimates of the albedo-induced radiative forcing from land cover changes since pre-industrial times. We find a multi-model range from 0 to −0.17 W m−2, with a mean value of −0.07 W m−2. Constraining the surface albedo response to transitions between trees and crops–grasses from the models with satellite-derived data leads to a revised multi-model mean estimate of −0.09 W m−2 but an increase in the multi-model range. However, after excluding one model with unrealistic conversion rates from trees to crops–grasses the remaining individual model results vary between −0.03 and −0.11 W m−2. These numbers are at the lower end of the range provided by the IPCC AR5 (-0.15±0.10 W m−2). The approach described in this study can be applied to other model simulations, such as those from CMIP6, especially as the evaluation diagnostic described here has been included in the ESMValTool v2.0.

Abstract Changing climate and land‐use practices have the potential to bring previously isolated populations of pest insects into new sympatry. This heightens the need to better understand how differing patterns of host–plant association, and unique endosymbionts, serve to promote genetic isolation or integration. We addressed these factors in populations of potato psyllid, Bactericera cockerelli (Šulc), a generalist herbivore that vectors a bacterial pathogen (Candidatus Liberibacter solanacearum, causal pathogen of zebra chip disease) of potato (Solanum tuberosum L.). Genome‐wide SNP data revealed two major genetic clusters—psyllids collected from potato crops were genetically similar to psyllids found on a common weed, Lycium spp., but dissimilar from those found on another common non‐crop host, Solanum dulcamara L. Most psyllids found on Lycium spp. and potato represented a single mitochondrial cytochrome oxidase I (COI) haplotype that has been suggested to not be native to the region, and whose arrival may have been concurrent with zebra chip disease first emerging. The putatively introduced COI haplotype usually co‐occurred with endosymbiotic Wolbachia, while the putatively resident COI haplotype generally did not. Genetic intermediates between the two genetic populations of insects were rare, consistent with recent sympatry or reproductive isolation, although admixture patterns of apparent hybrids were consistent with introgression of genes from introduced into resident populations. Our results suggest that both host–plant associations and endosymbionts are shaping the population genetic structure of sympatric psyllid populations associated with different non‐crop hosts. It is of future interest to explicitly examine vectorial capacity of the two populations and their potential hybrids, as population structure and hybridization might alter regional vector capacity and disease outbreaks.

Sequence-defined molecules are promising for data storage applications, but synthesizing long sequences is typically required to achieve a high data storage capacity. Here the authors synthesize a library of different sequence-defined tetramers and hexamers and demonstrate that mixtures of these short sequence-defined oligomers can store up to 64.5 bit.

Abstract Background Sickle cell disease (SCD) is a severe and devastating hematological disorder that affects over 100,000 persons in the USA and millions worldwide. Hydroxyurea is the primary disease-modifying therapy for the SCD, with proven benefits to reduce both short-term and long-term complications. Despite the well-described inter-patient variability in pharmacokinetics (PK), pharmacodynamics, and optimal dose, hydroxyurea is traditionally initiated at a weight-based dose with a subsequent conservative dose escalation strategy to avoid myelosuppression. Because the dose escalation process is time consuming and requires frequent laboratory checks, many providers default to a fixed dose, resulting in inadequate hydroxyurea exposure and suboptimal benefits for many patients. Results from a single-center trial of individualized, PK-guided dosing of hydroxyurea for children with SCD suggest that individualized dosing achieves the optimal dose more rapidly and provides superior clinical and laboratory benefits than traditional dosing strategies. However, it is not clear whether these results were due to individualized dosing, the young age that hydroxyurea treatment was initiated in the study, or both. The Hydroxyurea Optimization through Precision Study (HOPS) aims to validate the feasibility and benefits of this PK-guided dosing approach in a multi-center trial. Methods HOPS is a randomized, multicenter trial comparing standard vs. PK-guided dosing for children with SCD as they initiate hydroxyurea therapy. Participants (ages 6 months through 21 years), recruited from 11 pediatric sickle cell centers across the USA, are randomized to receive hydroxyurea either using a starting dose of 20 mg/kg/day (Standard Arm) or a PK-guided dose (Alternative Arm). PK data will be collected using a novel sparse microsampling approach requiring only 10 μL of blood collected at 3 time-points over 3 h. A protocol-guided strategy more aggressive protocols is then used to guide dose escalations and reductions in both arms following initiation of hydroxyurea. The primary endpoint is the mean %HbF after 6 months of hydroxyurea. Discussion HOPS will answer important questions about the clinical feasibility, benefits, and safety of PK-guided dosing of hydroxyurea for children with SCD with potential to change the treatment paradigm from a standard weight-based approach to one that safely and effectively optimize the laboratory and clinical response. Trial registration ClinicalTrials.gov NCT03789591 . Registered on 28 December 2018.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are established effective therapies in patients with ALK-rearranged advanced non-small-cell lung cancer (NSCLC). Upon progressive disease, patients normally receive a subsequent ALK TKI. However, when disease progression occurs in a limited number of sites, an oligoprogressive approach is a treatment option. In our case, FDG-PET/CT scan detected a progressive site in a patient with ceritinib therapy. Biopsy of the lesion was not possible because of its location. Progression was therefore confirmed by liquid biopsy with identification of the resistant subclone ALK G1202R. Definitive radiotherapy of the progressive site led to the disappearance of the ALK-resistant mutation. Meanwhile, ceritinib therapy was continued. The absence of disease both on repeated imaging and liquid biopsy indicates that eradication of a resistant subclone with an oligoprogressive treatment approach might be possible.

BACKGROUND: Evidence on the use of drugs during pregnancy in Switzerland is lacking. OBJECTIVES: To evaluate utilisation of prescribed drugs during pregnancy in outpatient care in Switzerland, focusing on treatments for pain, infections, gastro-oesophageal reflux, nausea/vomiting, and constipation. METHODS: We conducted a descriptive study using the Swiss Helsana claims database (2014–2018). We established a cohort of pregnancies by identifying deliveries and estimating the date of the last menstrual period. We identified claims for the following drugs during pregnancy; analgesics (opioids, paracetamol, and nonsteroidal anti-inflammatory drugs [NSAIDs]), oral antibiotics, antacids, proton pump inhibitors (PPIs), anti-nausea drugs (propulsives and 5HT3-antagonists), and laxatives. Within these drug groups we quantified exposure prevalence to the most prescribed drugs (to >1% of pregnancies) during pregnancy as well as to specific potentially teratogenic or fetotoxic drugs during specific risk periods. Results were extrapolated relative to the demographic distribution of the Swiss population. RESULTS: We identified an extrapolated population of 369,371 pregnancies, with a weighted mean maternal age of 32.0 years (weighted standard deviation 5.1). Analgesics were claimed in 34.5% (95% confidence interval [CI] 33.9–35.0%) of pregnancies, most frequently paracetamol (30.3%, 29.8–30.8%), followed by NSAIDs (8.6%, 8.3–8.8%), and opioids (2.6%, 2.4–2.8%). NSAIDs were claimed in 1.3% (1.2–1.4%) of pregnancies after week 24, and opioids were claimed in 1.3% (1.2–1.4%) in trimester 3. Antibiotics were dispensed in 26.3% (25.8–26.8%) of pregnancies, most frequently amoxicillin (14.6%, 95% CI 14.2–14.9%). Claims for potentially teratogenic or fetotoxic antibiotics during risk periods were each recorded in

OBJECTIVE: To analyse utilisation patterns of lipid-lowering drugs and the related costs in Switzerland between the years 2013 and 2019. METHODS: We conducted a retrospective descriptive study using administrative claims data of persons aged ≥18 years enrolled with the health insurance company Helsana. To enable statements at the Swiss population level, results were extrapolated according to age, sex and canton of residence. RESULTS: The overall prevalence of patients taking lipid-lowering drugs rose from 8.9% (n = 736,174) in 2013 to 11.6% (n = 841,682) in 2019, but varied markedly across regions, with highest values in Ticino and lowest values in Zurich. More than every third individual aged ≥65 years was treated with a lipid-lowering drug in 2019. Statins were by far the most commonly used drugs (>90% of prescriptions), followed by ezetimibe, fibrates and PCSK9 inhibitors. We observed a trend towards the prescription of more potent statins (atorvastatin, rosuvastatin) in recent years. Total costs of lipid-lowering drugs increased from CHF 222 million in 2013 to CHF 230 million in 2019 (+3.5%), whereas annual per capita costs decreased from CHF 302 in 2013 to CHF 273 in 2019 (−9.4%). CONCLUSION: The increasing use of lipid-lowering drugs reflects current therapeutic guidelines, but results in high costs for the healthcare system.

Successful peatland restoration requires a knowledge of peatland stratigraphy in order to understand the hydrological and ecological conditions under which peat formation occurred and to identify realistic objectives and measures for the specific site. So far, the ability to accurately identify peat deposits and lake sediments has been largely restricted to experts. To facilitate identification by others, we provide an identification key for common peatland deposits in Germany and introduce standardised portraits of 17 peat and six gyttja types with extensive descriptions and supporting photographs. We also provide information on the indicative value of the peatland deposits in terms of site conditions at the time of deposition.

Abstract Background Sarcopenia, the critical depletion of skeletal muscle mass, is an independent prognostic factor in several tumor entities for treatment-related toxicity and survival. In esophageal cancer, there have been conflicting results regarding the value of sarcopenia as prognostic factor, which may be attributed to the heterogeneous patient populations and the retrospective nature of previous studies. The aim of our study was therefore to determine the impact of sarcopenia on prospectively collected specific outcomes in a subgroup of patients treated within the phase III study SAKK 75/08 with trimodality therapy (induction chemotherapy, radiochemotherapy and surgery) for locally advanced esophageal cancer. Methods Sarcopenia was assessed by skeletal muscle index at the 3rd lumbar vertebra (L3) in cross-sectional computed tomography scans before induction chemotherapy, before radiochemotherapy and after neoadjuvant therapy in a subgroup of 61 patients from four centers in Switzerland. Sarcopenia was determined by previously established cut-off values (Martin et al., PMID: 23530101) and correlated with prospectively collected outcomes including treatment-related toxicity, postoperative morbidity, treatment feasibility and survival. Results Using the published cut-off values, the prevalence of sarcopenia increased from 29.5% before treatment to 63.9% during neoadjuvant therapy (p

Abstract Background A minority of breast cancer (BC) patients suffer from severe reaction to adjuvant radiotherapy (RT). Although deficient DNA double‐strand break repair is considered the main basis for the reactions, pretreatment identification of high‐risk patients has been challenging. Methods To retrospectively determine the etiology of severe local reaction to RT in a 39‐year‐old woman with BC, we performed next‐generation sequencing followed by further clinical and functional studies. Results We found a −4 intronic variant (c.2251‐4A>G) in trans with a synonymous (c.3576G>A) variant affecting the ATM DNA‐repair gene (NG_009830.1, NM_000051.3) which is linked to autosomal recessive ataxia–telangiectasia (A–T). We verified abnormal transcripts resulting from both variants, next to a minor wild‐type transcript leading to a residual ATM kinase activity and genomic instability. Follow‐up examination of the patient revealed no classic sign of A–T but previously unnoticed head dystonia and mild dysarthria, a family history of BC and late‐onset ataxia segregating with the variants. Additionally, her serum level of alpha‐fetoprotein (AFP) was elevated similar to A–T patients. Conclusion Considering the variable presentations of A–T and devastating impact of severe reactions to RT, we suggest a routine measurement of AFP in RT‐candidate BC patients followed by next‐generation sequencing with special attention to non‐canonical splice site and synonymous variants in ATM.

Abstract Background Concurrent chemoradiotherapy with cisplatin is standard for patients (pts) with loco-regionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) and for patients with resected SCCHN with high-risk features. The standard regimen includes 3-weekly cisplatin, but weekly regimens are often used to lower toxicity. Reaching a cumulative dose of ≥200 mg/m2 cisplatin was shown being associated with improved outcome. We herein investigated cumulative dose reached and toxicities between the 3-weekly and weekly cisplatin regimens with concurrent radiotherapy. Methods Multicentre, retrospective analysis of all patients undergoing combined RCT with cisplatin treated at 3 centres in Switzerland between 06/2008 and 12/2015. Results Three hundred fourteen pts. were included (3-weekly, N = 127; weekly, N = 187). Median cumulative cisplatin dose was 200 mg/m2 (IQR 150–300) for pts. treated with a 3-weekly schedule and 160 mg/m2 (120–240) for the weekly schedule, consequently more pts. treated with a 3-weekly schedule reached a cumulative dose ≥200 mg/m2 (75.6% vs. 47.1%, p

Abstract Background We present a rare case where distant metastasis of a low grade bladder tumor was observed. We carried out detailed genomic analysis and cell based experiments on patient tumor samples to study tumor evolution, possible cause of disease and provide personalized treatment strategies. Case presentation A man with a smoking history was diagnosed with a low-grade urothelial carcinoma of the bladder and a concurrent high-grade upper urinary tract tumor. Seven years later he had a lung metastasis. We carried out exome sequencing on all the patient’s tumors and peripheral blood (germline) to identify somatic variants. We constructed a phylogenetic tree to capture how the tumors are related and to identify somatic changes important for metastasis. Although distant metastasis of low-grade bladder tumor is rare, the somatic variants in the tumors and the phylogenetic tree showed that the metastasized tumor had a mutational profile most similar to the low grade urothelial carcinoma. The primary and the metastatic tumors shared several important mutations, including in the KMT2D and the RXRA genes. The metastatic tumor also had an activating MTOR mutation, which may be important for tumor metastasis. We developed a mutational signature to understand the biologic processes responsible for tumor development. The mutational signature suggests that the tumor mutations are associated with tobacco carcinogen exposure, which is concordant with the patient’s smoking history. We cultured cells from the lung metastasis to examine proliferation and signaling mechanisms in response to treatment. The mTOR inhibitor Everolimus inhibited downstream mTOR signaling and induced cytotoxicity in the metastatic tumor cells. Conclusion We used genomic analysis to examine a rare case of low grade bladder tumor metastasis to distant organ (lung). Our analysis also revealed exposure to carcinogens found is tobacco as a possible cause in tumor development. We further validated that the patient might benefit from mTOR inhibition as a potential salvage therapy in an adjuvant or recurrent disease setting.

Modeling studies have shown the importance of biogeophysical effects of deforestation on local climate conditions but have also highlighted the lack of agreement across different models. Recently, remote-sensing observations have been used to assess the contrast in albedo, evapotranspiration (ET), and land surface temperature (LST) between forest and nearby open land on a global scale. These observations provide an unprecedented opportunity to evaluate the ability of land surface models to simulate the biogeophysical effects of forests. Here, we evaluate the representation of the difference of forest minus open land (i.e., grassland and cropland) in albedo, ET, and LST in the Community Land Model version 4.5 (CLM4.5) using various remote-sensing and in situ data sources. To extract the local sensitivity to land cover, we analyze plant functional type level output from global CLM4.5 simulations, using a model configuration that attributes a separate soil column to each plant functional type. Using the separated soil column configuration, CLM4.5 is able to realistically reproduce the biogeophysical contrast between forest and open land in terms of albedo, daily mean LST, and daily maximum LST, while the effect on daily minimum LST is not well captured by the model. Furthermore, we identify that the ET contrast between forests and open land is underestimated in CLM4.5 compared to observation-based products and even reversed in sign for some regions, even when considering uncertainties in these products. We then show that these biases can be partly alleviated by modifying several model parameters, such as the root distribution, the formulation of plant water uptake, the light limitation of photosynthesis, and the maximum rate of carboxylation. Furthermore, the ET contrast between forest and open land needs to be better constrained by observations to foster convergence amongst different land surface models on the biogeophysical effects of forests. Overall, this study demonstrates the potential of comparing subgrid model output to local observations to improve current land surface models' ability to simulate land cover change effects, which is a promising approach to reduce uncertainties in future assessments of land use impacts on climate.

Abstract Background To evaluate the adverse events profile of oral prednisolone among adult asthma patients in the UK. Methods Using data from the UK-based Clinical Practice Research Datalink, we conducted a series of cohort studies to quantify incidence rates and incidence rate ratios, and a series of nested case-control analyses to estimate crude and adjusted odds ratios, of 11 different potential corticosteroid-related adverse events (bone-related conditions, hypertension, peptic ulcer, severe infections, herpes zoster, diabetes mellitus type 2, cataract, glaucoma, chronic kidney disease, affective disorders, and cardiovascular events). Results Between 165,900 and 269,368 asthma patients were included in each of the 11 cohorts, of whom between 836 and 16,192 developed an outcome of interest. Incidence rates per 1000 person-years of potential corticosteroid-related adverse events in patients with new current use of oral prednisolone ranged from 1.4 (95% confidence interval [CI], 1.0–1.8) for peptic ulcer to 78.0 (95% CI, 74.8–81.2) for severe infections. After adjusting for confounding, current oral prednisolone use was most strongly associated with an increased risk of severe infection, compared with non-use of prednisolone; OR 2.16 (95% CI, 2.05–2.27). There were smaller elevated risks of peptic ulcer, affective disorders, and cataract at higher doses, and marginally increased risks of herpes zoster, cardiovascular events, diabetes mellitus type 2, and bone related conditions, compared with non-use of prednisolone. We did not observe an association between oral prednisolone use and glaucoma, chronic kidney disease, or hypertension. Conclusion Oral prednisolone use is associated with infections, gastrointestinal, neuropsychiatric, ocular, cardiovascular, metabolic, and bone-related complications among adult asthma patients.

Designing molecular keys and combining advanced encryption standard cryptography with molecular steganography is a secure way for encoding messages. Here, the authors use the Ugi four-component reaction of perfluorinated acids to create a library of 500,000 molecular keys for encryption and decryption.

This best-practices article endorses incorporating service-learning into the foundational public speaking course. The article explains connections between service-learning and the rhetorical tradition, highlights pedagogical approaches that would benefit from a service-learning component, and discusses the benefits of service-learning for community partners and students. The remainder of the article focuses on how to implement service learning in a public speaking course, including reflection and assessment recommendations.