Prepping for climate change by introgressive hybridization.

Species and populations may adapt to climate change by microevolutionary processes. However, standing genetic variation can be insufficient for this to occur. An interesting new study of a system of rainbowfish species shows that intraspecific hybridization enriches gene pools with adaptive variation that may allow persistence in a changing climate.

PP2A catalytic subunit alpha is critically required for CD8+ T-cell homeostasis and antibacterial responses.

Although the functions of tyrosine phosphatases in T-cell biology have been extensively studied, our knowledge on the contribution of serine/threonine phosphatases in T cells remains poor. Protein phosphatase 2A (PP2A) is one of the most abundantly expressed serine/threonine phosphatases. It is important in thymocyte development and CD4+ T-cell differentiation. Utilizing a genetic model in which its catalytic subunit alpha isoform (PP2A Cα) is deleted in T cells, we investigated its contribution to CD8+ T-cell homeostasis and effector functions. Our results demonstrate that T-cell intrinsic PP2A Cα is critically required for CD8+ T-cell homeostasis in secondary lymphoid organs and intestinal mucosal site. Importantly, PP2A Cα-deficient CD8+ T cells exhibit reduced proliferation and survival. CD8+ T-cell antibacterial response is strictly dependent on PP2A Cα. Expression of Bcl2 transgene rescues CD8+ T-cell homeostasis in spleens, but not in intestinal mucosal site, nor does it restore defective antibacterial responses. Finally, proteomics and phosphoproteomics analyses reveal potential targets dependent on PP2A Cα, including mTORC1 and AKT. Thus, PP2A Cα is a key modulator of CD8+ T-cell homeostasis and effector functions.

Discrete class I molecules on brain endothelium differentially regulate neuropathology in experimental cerebral malaria.

Cerebral malaria is the deadliest complication that can arise from Plasmodium infection. CD8 T-cell engagement of brain vasculature is a putative mechanism of neuropathology in cerebral malaria. To define contributions of brain endothelial cell major histocompatibility complex (MHC) class I antigen-presentation to CD8 T cells in establishing cerebral malaria pathology, we developed novel H-2Kb LoxP and H-2Db LoxP mice crossed with Cdh5-Cre mice to achieve targeted deletion of discrete class I molecules, specifically from brain endothelium. This strategy allowed us to avoid off-target effects on iron homeostasis and class I-like molecules, which are known to perturb Plasmodium infection. This is the first endothelial-specific ablation of individual class-I molecules enabling us to interrogate these molecular interactions. In these studies, we interrogated human and mouse transcriptomics data to compare antigen presentation capacity during cerebral malaria. Using the Plasmodium berghei ANKA model of experimental cerebral malaria (ECM), we observed that H-2Kb and H-2Db class I molecules regulate distinct patterns of disease onset, CD8 T-cell infiltration, targeted cell death and regional blood-brain barrier disruption. Strikingly, ablation of either molecule from brain endothelial cells resulted in reduced CD8 T-cell activation, attenuated T-cell interaction with brain vasculature, lessened targeted cell death, preserved blood-brain barrier integrity and prevention of ECM and the death of the animal. We were able to show that these events were brain-specific through the use of parabiosis and created the novel technique of dual small animal MRI to simultaneously scan conjoined parabionts during infection. These data demonstrate that interactions of CD8 T cells with discrete MHC class I molecules on brain endothelium differentially regulate development of ECM neuropathology. Therefore, targeting MHC class I interactions therapeutically may hold potential for treatment of cases of severe malaria.

Cardiorenal Biomarkers, Canagliflozin, and Outcomes in Diabetic Kidney Disease: The CREDENCE Trial.

BACKGROUND: People with type 2 diabetes and albuminuria are at an elevated risk for cardiac and renal events. The optimal biomarkers to aid disease prediction and to understand the benefits of sodium-glucose cotransporter-2 inhibition remain unclear. METHODS: Among 2627 study participants in the CREDENCE trial (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), concentrations of NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T, growth differentiation factor-15, and IGFBP7 (insulin-like growth factor binding protein 7) were measured. The effect of canagliflozin on biomarker concentrations was evaluated. The prognostic potential of each biomarker on the primary outcome (a composite of end-stage kidney disease [dialysis, transplantation, or a sustained estimated glomerular filtration rate of <15 mL·min-1·1.73 m-2], doubling of the serum creatinine level, or renal death or cardiovascular death) was assessed. RESULTS: The median (quartiles 1 and 3) concentration of each biomarker was generally elevated: NT-proBNP, 180 ng/L (82, 442 ng/L); high-sensitivity cardiac troponin T, 19 ng/L (12, 29 ng/L); growth differentiation factor-15, 2595 ng/L (1852, 3775 ng/L); and IGFBP7, 121.8 ng/mL (105.4, 141.5 ng/mL). At 1 year, the biomarkers all rose by 6% to 29% in the placebo arm but only by 3% to 10% in the canagliflozin arm (all P<0.01 in multivariable linear mixed-effect models). Baseline concentrations of each biomarker were strongly predictive of cardiac and renal outcomes. When the biomarkers were analyzed together in a multimarker panel, individuals with high risk scores (hazard ratio [HR], 4.01 [95% CI, 2.52-6.35]) and moderate risk scores (HR, 2.39 [95% CI, 1.48-3.87]) showed a higher risk for the primary outcome compared with those with low risk scores. By 1 year, a 50% increase in NT-proBNP (HR, 1.11 [95% CI, 1.08-1.15]), high-sensitivity cardiac troponin T (HR, 1.86 [95% CI, 1.64-2.10]), growth differentiation factor-15 (HR, 1.45 [95% CI, 1.24-1.70]), and IGFBP7 (HR, 3.76 [95% CI, 2.54-5.56]) was associated with risk of the primary outcome. CONCLUSIONS: Multiple cardiorenal stress biomarkers are strongly prognostic in people with type 2 diabetes and albuminuria. Canagliflozin modestly reduced the longitudinal trajectory of rise in each biomarker. Change in the biomarker level in addition to the baseline level augments the primary outcome prediction. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02065791.

Charge Regulation at the Nanoscale as Evidenced from Light-Responsive Nanoemulsions.

Emulsions are indispensable in everyday life, and the demand for emulsions' diversity and control of properties is therefore substantial. As emulsions possess a high internal surface area, an understanding of the oil/water (o/w) interfaces at the molecular level is fundamental but often impaired by experimental limitations to probe emulsion interfaces in situ. Here, we have used light-responsive surfactants (butyl-AAP) that can photoisomerize between E and Z isomers by visible and UV light irradiation to tune the emulsion interfaces. This causes massive changes in the interface tension at the extended o/w interfaces in macroemulsions and a drastic shift in the surfactants' critical micelle concentration, which we show can be used to control both the stability and phase separation. Strikingly different from macroemulsions are nanoemulsions (RH ∼90 nm) as these are not susceptible to E/Z photoisomerization of the surfactants in terms of changes in their droplet size or ζ-potential. However, in situ second-harmonic scattering and pulsed-field gradient nuclear magnetic resonance (NMR) experiments show dramatic and reversible changes in the surface excess of surfactants at the nanoscopic interfaces. The apparent differences in ζ-potentials and surface excess provide evidence for a fixed charge to particle size ratio and the need for counterion condensation to renormalize the particle charge to a critical charge, which is markedly different compared to the behavior of very large particles in macroemulsions. Thus, our findings may have broader implications as the electrostatic stabilization of nanoparticles requires much lower surfactant concentrations, allowing for a more sustainable use of surfactants.

Cove-Edged Chiral Graphene Nanoribbons with Chirality-Dependent Bandgap and Carrier Mobility.

Graphene nanoribbons (GNRs) have garnered significant interest due to their highly customizable physicochemical properties and potential utility in nanoelectronics. Besides controlling widths and edge structures, the inclusion of chirality in GNRs brings another dimension for fine-tuning their optoelectronic properties, but related studies remain elusive owing to the absence of feasible synthetic strategies. Here, we demonstrate a novel class of cove-edged chiral GNRs (CcGNRs) with a tunable chiral vector (n,m). Notably, the bandgap and effective mass of (n,2)-CcGNR show a distinct positive correlation with the increasing value of n, as indicated by theory. Within this GNR family, two representative members, namely, (4,2)-CcGNR and (6,2)-CcGNR, are successfully synthesized. Both CcGNRs exhibit prominently curved geometries arising from the incorporated [4]helicene motifs along their peripheries, as also evidenced by the single-crystal structures of the two respective model compounds (1 and 2). The chemical identities and optoelectronic properties of (4,2)- and (6,2)-CcGNRs are comprehensively investigated via a combination of IR, Raman, solid-state NMR, UV-vis, and THz spectroscopies as well as theoretical calculations. In line with theoretical expectation, the obtained (6,2)-CcGNR possesses a low optical bandgap of 1.37 eV along with charge carrier mobility of ∼8 cm2 V-1 s-1, whereas (4,2)-CcGNR exhibits a narrower bandgap of 1.26 eV with increased mobility of ∼14 cm2 V-1 s-1. This work opens up a new avenue to precisely engineer the bandgap and carrier mobility of GNRs by manipulating their chiral vector.

Pressure-Induced Dislocations and Their Influence on Ionic Transport in Li+-Conducting Argyrodites.

The influence of the microstructure on the ionic conductivity and cell performance is a topic of broad scientific interest in solid-state batteries. The current understanding is that interfacial decomposition reactions during cycling induce local strain at the interfaces between solid electrolytes and the anode/cathode, as well as within the electrode composites. Characterizing the effects of internal strain on ion transport is particularly important, given the significant local chemomechanical effects caused by volumetric changes of the active materials during cycling. Here, we show the effects of internal strain on the bulk ionic transport of the argyrodite Li6PS5Br. Internal strain is reproducibly induced by applying pressures with values up to 10 GPa. An internal permanent strain is observed in the material, indicating long-range strain fields typical for dislocations. With increasing dislocation densities, an increase in the lithium ionic conductivity can be observed that extends into improved ionic transport in solid-state battery electrode composites. This work shows the potential of strain engineering as an additional approach for tuning ion conductors without changing the composition of the material itself.

A Super-Ionic Solid-State Block Copolymer Electrolyte.

Polymer solid-state electrolytes offer great promise for battery materials with high energy density, mechanical stability, and improved safety. However, their low ion conductivities have so far limited their potential applications. Here, it is shown for poly(ethylene oxide) block copolymers that the super-stoichiometric addition of lithium bis(trifluoromethanesulfonyl) imide (LiTFSI) as lithium salt leads to the formation of a crystalline PEO block copolymer phase with exceptionally high ion conductivities and low activation energies. The addition of LiTFSI further induces block copolymer phase transitions into bi-continuous Fddd and gyroid network morphologies, providing continuous 3D conduction pathways. Both effects lead to solid-state block copolymer electrolyte membranes with ion conductivities of up to 1·10-1 S cm-1 at 90 °C, decreasing only moderately to 4·10-2 S cm-1 at room temperature, and to >1·10-3 S cm-1 at -20 °C, corresponding to activation energies as low as 0.19 eV. The co-crystallization of PEO and LiTFSI with ether and carbonate solvents is observed to play a key role to realize a super-ionic conduction mechanism. The discovery of PEO super-ionic conductivity at high lithium concentrations opens a new pathway for fabrication of solid polymer electrolyte membranes with sufficiently high ion conductivities over a broad temperature range with widespread applications in electrical devices.

Vascular endothelial growth factors and risk of cardio-renal events: Results from the CREDENCE trial.

BACKGROUND: Circulating concentrations of vascular endothelial growth factor (VEGF) family members may be abnormally elevated in type 2 diabetes (T2D). The roles of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFLT-1), and VEGF-A in cardio-renal complications of T2D are not established. METHOD: The 2602 individuals with diabetic kidney disease (DKD) from the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial were randomized to receive canagliflozin or placebo and followed for incident cardio-renal outcomes. PlGF, sFLT-1, and VEGF-A were measured at baseline, year 1, and year 3. Primary outcome was a composite of end-stage kidney disease, doubling of the serum creatinine, or renal/cardiovascular death. Cox proportional hazard regression was used to investigate the association between biomarkers with adverse clinical events. RESULTS: At baseline, individuals with higher PlGF levels had more prevalent cardiovascular disease compared to those with lower values. Treatment with canagliflozin did not meaningfully change PlGF, sFLT-1, and VEGF-A concentrations at years 1 and 3. In a multivariable model, 1 unit increases in baseline log PlGF (hazard ratio [HR]: 1.76, 95% confidence interval [CI]: 1.23, 2.54, P-value = .002), sFLT-1 (HR: 3.34, [95% CI: 1.71, 6.52], P-value < .001), and PlGF/sFLT-1 ratio (HR: 4.83, [95% CI: 0.86, 27.01], P-value = .07) were associated with primary composite outcome, while 1 unit increase in log VEGF-A did not increase the risk of primary outcome (HR: 0.96 [95% CI: 0.81, 1.07]). Change by 1 year of each biomarker was also assessed: HR (95% CI) of primary composite outcome was 2.45 (1.70, 3.54) for 1 unit increase in 1-year concentration of log PlGF, 4.19 (2.18, 8.03) for 1 unit increase in 1-year concentration of log sFLT-1, and 21.08 (3.79, 117.4) for 1 unit increase in 1-year concentration of log PlGF/sFLT-1. Increase in 1-year concentrations of log VEGF-A was not associated with primary composite outcome (HR: 1.08, [95% CI: 0.93, 1.24], P-value = .30). CONCLUSIONS: People with T2D and DKD with elevated levels of PlGF, sFLT-1, and PlGF/sFLT-1 ratio were at a higher risk for cardiorenal events. Canagliflozin did not meaningfully decrease concentrations of PlGF, sFLT-1, and VEGF-A. CLINICAL TRIAL: CREDENCE, https://clinicaltrials.gov/ct2/show/NCT02065791.

Determining a urinary-specific antibiogram and risk factors of trimethoprim/sulfamethoxazole, ciprofloxacin and multidrug resistance among Enterobacterales in primary care.

BACKGROUND: Risk factors for ciprofloxacin or MDR in primary care urine specimens are not well defined. OBJECTIVES: We created a primary care-specific antibiogram for Escherichia coli isolates from cases with complicated and uncomplicated urinary tract infection (UTI) and evaluated risk factors for ciprofloxacin, trimethoprim/sulfamethoxazole and MDR among Enterobacterales. METHODS: We conducted a cross-sectional study to determine resistance and risk factors by collecting urine cultures from all patients (≥18 years) presenting with provider-suspected UTI at two primary care, safety-net clinics in Houston, TX, USA between November 2018 and March 2020. RESULTS: Among 1262 cultures, 308 cultures grew 339 uropathogens. Patients with Enterobacterales (n = 199) were mostly female (93.5%) with a mean age of 48.5 years. E. coli was the predominant uropathogen isolated (n = 187/339; 55%) and had elevated trimethoprim/sulfamethoxazole (43.6%) and ciprofloxacin (29.5%) resistance, low nitrofurantoin (1.8%) resistance, and no fosfomycin resistance. Among E. coli, 10.6% were ESBL positive and 24.9% had MDR. Birth outside the U.S.A., prior (2 year) trimethoprim/sulfamethoxazole resistance, and diabetes mellitus were associated with trimethoprim/sulfamethoxazole resistance. Prior (60 day) fluoroquinolone use, prior ciprofloxacin resistance and both diabetes mellitus and hypertension were strongly associated with ciprofloxacin resistance. Prior fluoroquinolone use and a history of resistance to any studied antibiotic were associated with MDR, while pregnancy was protective. CONCLUSIONS: We found elevated resistance to UTI-relevant antimicrobials and novel factors associated with resistance; these data can be incorporated into clinical decision tools to improve organism and drug concordance.

Quantifying 3D MR fingerprinting (3D-MRF) reproducibility across subjects, sessions, and scanners automatically using MNI atlases.

PURPOSE: Quantitative MRI techniques such as MR fingerprinting (MRF) promise more objective and comparable measurements of tissue properties at the point-of-care than weighted imaging. However, few direct cross-modal comparisons of MRF's repeatability and reproducibility versus weighted acquisitions have been performed. This work proposes a novel fully automated pipeline for quantitatively comparing cross-modal imaging performance in vivo via atlas-based sampling. METHODS: We acquire whole-brain 3D-MRF, turbo spin echo, and MPRAGE sequences three times each on two scanners across 10 subjects, for a total of 60 multimodal datasets. The proposed automated registration and analysis pipeline uses linear and nonlinear registration to align all qualitative and quantitative DICOM stacks to Montreal Neurological Institute (MNI) 152 space, then samples each dataset's native space through transformation inversion to compare performance within atlas regions across subjects, scanners, and repetitions. RESULTS: Voxel values within MRF-derived maps were found to be more repeatable (σT1 = 1.90, σT2 = 3.20) across sessions than vendor-reconstructed MPRAGE (σT1w = 6.04) or turbo spin echo (σT2w = 5.66) images. Additionally, MRF was found to be more reproducible across scanners (σT1 = 2.21, σT2 = 3.89) than either qualitative modality (σT1w = 7.84, σT2w = 7.76). Notably, differences between repeatability and reproducibility of in vivo MRF were insignificant, unlike the weighted images. CONCLUSION: MRF data from many sessions and scanners can potentially be treated as a single dataset for harmonized analysis or longitudinal comparisons without the additional regularization steps needed for qualitative modalities.

Genomic insights on conservation priorities for North Sea houting and European lake whitefish (Coregonus spp.).

Population genomics analysis holds great potential for informing conservation of endangered populations. We focused on a controversial case of European whitefish (Coregonus spp.) populations. The endangered North Sea houting is the only coregonid fish that tolerates oceanic salinities and was previously considered a species (C. oxyrhinchus) distinct from European lake whitefish (C. lavaretus). However, no firm evidence for genetic-based salinity adaptation has been available. Also, studies based on microsatellite and mitogenome data suggested surprisingly recent divergence (c. 2500 years bp) between houting and lake whitefish. These data types furthermore have provided no evidence for possible inbreeding. Finally, a controversial taxonomic revision recently classified all whitefish in the region as C. maraena, calling conservation priorities of houting into question. We used whole-genome and ddRAD sequencing to analyse six lake whitefish populations and the only extant indigenous houting population. Demographic inference indicated post-glacial expansion and divergence between lake whitefish and houting occurring not long after the Last Glaciation, implying deeper population histories than previous analyses. Runs of homozygosity analysis suggested not only high inbreeding (FROH up to 30.6%) in some freshwater populations but also FROH up to 10.6% in the houting prompting conservation concerns. Finally, outlier scans provided evidence for adaptation to high salinities in the houting. Applying a framework for defining conservation units based on current and historical reproductive isolation and adaptive divergence led us to recommend that the houting be treated as a separate conservation unit regardless of species status. In total, the results underscore the potential of genomics to inform conservation practices, in this case clarifying conservation units and highlighting populations of concern.

Natriuretic Peptides and Prognosis in Patients With Type 2 Diabetes Mellitus and High Risk for Cardiovascular Events.

BACKGROUND: The prognosis of individuals with and without an established heart failure (HF) diagnosis and similarly elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels is not well-known. METHODS AND RESULTS: CANVAS (Canagliflozin Cardiovascular Assessment Study) trial participants were stratified according to baseline NT-proBNP quartiles and history of HF at baseline. Adjusted event rates per 1000 patient-years of follow-up for hospitalizations for HF, cardiovascular mortality, and kidney events were assessed, and hazard ratios (HR) were calculated using Cox proportional hazard models. Of the 3507 participants with available NT-proBNP concentrations, 471 (13.4%) had history of HF. The incidence rate per 1000 patient-years for hospitalizations for HF increased across the NT-proBNP quartiles in patients with (0, 2.8, 13.4, and 40.1; P < .001) and without (1.8, 3.1, 6.0, and 19.1; P < .001) HF, with a significantly higher risk in patients with HF compared with those without (with HF, quartile 3 HR 9.28 [interquartile range (IQR) 1.15-75.05]; P = .04; without HF, quartile 4 HR 4.86 [95% CI, 2.08-11.35]; P < .001). A similar higher risk for kidney events was seen in HF patients (with HF, quartile 4 HR 6.94 [95% CI, 2.66-18.08]; P = .001; without HF, quartile 4 HR 4.85 [95% CI, 3.02-7.80]; P = .001). Similar trends were seen for cardiovascular mortality. CONCLUSIONS: Among patients with type 2 diabetes and cardiovascular risk, an elevated NT-proBNP level was associated with worse HF and kidney outcomes in general, regardless of history of HF; however, the presence of a clinical diagnosis of HF at baseline was associated with an incrementally higher risk, particularly in higher NT-proBNP quartiles.

Targeting cancer-associated fibroblasts in the bone marrow prevents resistance to CART-cell therapy in multiple myeloma.

Pivotal clinical trials of B-cell maturation antigen-targeted chimeric antigen receptor T (CART)-cell therapy in patients with relapsed/refractory multiple myeloma (MM) resulted in remarkable initial responses, which led to a recent US Food and Drug Administration approval. Despite the success of this therapy, durable remissions continue to be low, and the predominant mechanism of resistance is loss of CART cells and inhibition by the tumor microenvironment (TME). MM is characterized by an immunosuppressive TME with an abundance of cancer-associated fibroblasts (CAFs). Using MM models, we studied the impact of CAFs on CART-cell efficacy and developed strategies to overcome CART-cell inhibition. We showed that CAFs inhibit CART-cell antitumor activity and promote MM progression. CAFs express molecules such as fibroblast activation protein and signaling lymphocyte activation molecule family-7, which are attractive immunotherapy targets. To overcome CAF-induced CART-cell inhibition, CART cells were generated targeting both MM cells and CAFs. This dual-targeting CART-cell strategy significantly improved the effector functions of CART cells. We show for the first time that dual targeting of both malignant plasma cells and the CAFs within the TME is a novel strategy to overcome resistance to CART-cell therapy in MM.

Canagliflozin and iron metabolism in the CREDENCE trial.

BACKGROUND AND HYPOTHESIS: Studies in patients with heart failure have indicated that sodium-glucose cotransporter 2 (SGLT2) inhibitors increase iron use and enhance erythropoiesis. In this post-hoc analysis of the CREDENCE trial, we evaluated the effects of canagliflozin on iron metabolism in patients with chronic kidney disease (CKD) and whether the effects of canagliflozin on hemoglobin and cardiorenal outcomes were modified by iron deficiency. METHODS: We measured serum iron, total iron binding capacity (TIBC), transferrin saturation (TSAT) and ferritin at baseline and 12 months. The effects of canagliflozin, relative to placebo, on iron markers were assessed with analysis of covariance. Interactions between baseline iron deficiency, defined as TSAT < 20%, and the effects of canagliflozin on hemoglobin and cardiorenal outcomes were evaluated with mixed effect models and Cox regression models, respectively. RESULTS: Of 4401 participants randomized in CREDENCE, 2416 (54.9%) had iron markers measured at baseline, of whom 924 (38.2%) were iron deficient. Canagliflozin, compared to placebo, increased TIBC by 2.1% (95%CI 0.4-3.8; p = 0.014) and decreased ferritin by 11.5% (95%CI 7.1-15.7; p < 0.001) with no clear effect on serum iron or TSAT. Canagliflozin increased hemoglobin over the trial duration by 7.3 g/L (95% CI 6.2-8.5; p < 0.001) and 6.7 g/L (95% CI 5.2- 8.2; p < 0.001) in patients with and without iron deficiency, respectively (p-interaction = 0.38). The relative effect of canagliflozin on the primary outcome of doubling of serum creatinine, kidney failure or death due to cardiovascular disease or kidney failure (HR 0.70, 95%CI 0.56-0.87) was consistent regardless of iron deficiency (p-interaction 0.83), as were effects on other cardiovascular and mortality outcomes (all p-interactions ≥ 0.10). CONCLUSIONS: Iron deficiency is highly prevalent in patients with type 2 diabetes and CKD. Canagliflozin increased TIBC and decreased ferritin in patients with T2D and CKD, suggesting increased iron utilization, and improved hemoglobin levels and clinical outcomes regardless of iron deficiency.

Association of type III collagen turnover with cardiovascular outcomes and impact with canagliflozin in the CANVAS Program: A post hoc analysis.

AIM: To investigate type III collagen (COL III) turnover in participants from the CANVAS Program biomarker substudy. METHODS: Biomarkers of COL III formation (PRO-C3) and COL III degradation fragments (C3M and CTX-III) were assessed in baseline and year 3 plasma from patients enrolled in CANVAS, investigating the effect of canagliflozin in participants with type 2 diabetes. The clinical outcomes investigated in this study were hospitalization for heart failure, cardiovascular death and all-cause mortality. RESULTS: Higher levels of PRO-C3 and C3M at baseline were associated with an increased incidence of all investigated outcomes, whereas levels of CTX-III at baseline were not associated with any of the investigated outcomes. Levels of PRO-C3 decreased and levels of CTX-III increased following canagliflozin treatment. An increase from baseline to year 3 in PRO-C3 in the placebo arm was associated with an increased incidence of cardiovascular outcomes, and in all participants was associated with an increased risk of all-cause mortality. CONCLUSIONS: The changes in PRO-C3 and CTX-III reflect a shift in the dynamics of COL3 turnover following treatment with canagliflozin. These biomarkers are promising pharmacodynamic tools that can be used to monitor the impact of canagliflozin treatment and possibly other sodium-glucose co-transporter-2 inhibitors on tissue remodelling in future interventional trials.

Exploring Layered Disorder in Lithium-Ion-Conducting Li3Y1-xInxCl6.

Li3Y1-xInxCl6 undergoes a phase transition from trigonal to monoclinic via an intermediate orthorhombic phase. Although the trigonal yttrium containing the end member phase, Li3YCl6, synthesized by a mechanochemical route, is known to exhibit stacking fault disorder, not much is known about the monoclinic phases of the serial composition Li3Y1-xInxCl6. This work aims to shed light on the influence of the indium substitution on the phase evolution, along with the evolution of stacking fault disorder using X-ray and neutron powder diffraction together with solid-state nuclear magnetic resonance spectroscopy, studying the lithium-ion diffusion. Although Li3Y1-xInxCl6 with x ≤ 0.1 exhibits an ordered trigonal structure like Li3YCl6, a large degree of stacking fault disorder is observed in the monoclinic phases for the x ≥ 0.3 compositions. The stacking fault disorder materializes as a crystallographic intergrowth of faultless domains with staggered layers stacked in a uniform layer stacking, along with faulted domains with randomized staggered layer stacking. This work shows how structurally complex even the "simple" series of solid solutions can be in this class of halide-based lithium-ion conductors, as apparent from difficulties in finding a consistent structural descriptor for the ionic transport.

Submersion Injuries and the Cost of Injury Associated with Drowning Events in the United States, 2006-2015.

INTRODUCTION: The World Health Organization has reported submersion injuries as the third most common cause of death due to unintentional injury in the world. Greater detail in the rates, risk factors, and healthcare associated costs of submersion injuries could be instrumental in demonstrating the need for further funding and intervention. METHODS: The study was a cross-sectional analysis of a nationally representative dataset of inpatient and emergency department (ED) encounters between 2006 and 2015 in the United States (US). Healthcare utilization costs were provided within the datasets and adjusted to reflect actual charges and provider fees. Lastly, the final cost values were adjusted to the 2020 US dollar (USD) and summarized using a log adjusted mean. RESULTS: On average, there were 11,873 submersion injuries per year that presented to the ED in the US. Resulting in a rate where approximately 9 out of every 100,000 ED visits were associated with a submersion injury. Slightly more than 6% died in the ED, 24.2% were admitted, and 69.3% were discharged from the ED. In total, annual cost of submersion injuries in the US for ED care is approximately $12.5 million, inpatient care is approximately $27.5 million, and total annual healthcare cost exceeds $40 million. DISCUSSION: While these results only represent a fraction of the total cost associated with submersion injuries, it remains substantial and unchanged over the 10-year study period. Certain demographic groups showed higher rates of injury and disease burden, thus bearing a greater amount of the cost.

Wavy Graphene Nanoribbons Containing Periodic Eight-Membered Rings for Light-Emitting Electrochemical Cells.

Precision graphene nanoribbons (GNRs) offer distinctive physicochemical properties that are highly dependent on their geometric topologies, thereby holding great potential for applications in carbon-based optoelectronics and spintronics. While the edge structure and width control has been a popular strategy for engineering the optoelectronic properties of GNRs, non-hexagonal-ring-containing GNRs remain underexplored due to synthetic challenges, despite offering an equally high potential for tailored properties. Herein, we report the synthesis of a wavy GNR (wGNR) embedding periodic eight-membered rings into its carbon skeleton, which is achieved by the A2B2-type Diels-Alder polymerization between dibenzocyclooctadiyne (6) and dicyclopenta[e,l]pyrene-5,11-dione derivative (8), followed by a selective Scholl reaction of the obtained ladder-type polymer (LTP) precursor. The obtained wGNR, with a length of up to 30 nm, is thoroughly characterized by solid-state NMR, FT-IR, Raman, and UV-Vis spectroscopy with the support of DFT calculations. The non-planar geometry of wGNR efficiently prevents the inter-ribbon π-π aggregation, leading to photoluminescence in solution. Consequently, the wGNR can function as an emissive layer for organic light-emitting electrochemical cells (OLECs), offering a proof-of-concept exploration in implementing luminescent GNRs into optoelectronic devices. The fast-responding OLECs employing wGNR will pave the way for advancements in OLEC technology and other optoelectronic devices.

On the Discrepancy between Local and Average Structure in the Fast Na+ Ionic Conductor Na2.9Sb0.9W0.1S4.

Aliovalent substitution is a common strategy to improve the ionic conductivity of solid electrolytes for solid-state batteries. The substitution of SbS43- by WS42- in Na2.9Sb0.9W0.1S4 leads to a very high ionic conductivity of 41 mS cm-1 at room temperature. While pristine Na3SbS4 crystallizes in a tetragonal structure, the substituted Na2.9Sb0.9W0.1S4 crystallizes in a cubic phase at room temperature based on its X-ray diffractogram. Here, we show by performing pair distribution function analyses and static single-pulse 121Sb NMR experiments that the short-range order of Na2.9Sb0.9W0.1S4 remains tetragonal despite the change in the Bragg diffraction pattern. Temperature-dependent Raman spectroscopy revealed that changed lattice dynamics due to the increased disorder in the Na+ substructure leads to dynamic sampling causing the discrepancy in local and average structure. While showing no differences in the local structure, compared to pristine Na3SbS4, quasi-elastic neutron scattering and solid-state 23Na nuclear magnetic resonance measurements revealed drastically improved Na+ diffusivity and decreased activation energies for Na2.9Sb0.9W0.1S4. The obtained diffusion coefficients are in very good agreement with theoretical values and long-range transport measured by impedance spectroscopy. This work demonstrates the importance of studying the local structure of ionic conductors to fully understand their transport mechanisms, a prerequisite for the development of faster ionic conductors.