Accessing bands with extended quantum metric in kagome Cs2Ni3S4 through soft chemical processing.

Flat bands that do not merely arise from weak interactions can produce exotic physical properties, such as superconductivity or correlated many-body effects. The quantum metric can differentiate whether flat bands will result in correlated physics or are merely dangling bonds. A potential avenue for achieving correlated flat bands involves leveraging geometrical constraints within specific lattice structures, such as the kagome lattice; however, materials are often more complex. In these cases, quantum geometry becomes a powerful indicator of the nature of bands with small dispersions. We present a simple, soft-chemical processing route to access a flat band with an extended quantum metric below the Fermi level. By oxidizing Ni-kagome material Cs2Ni3S4 to CsNi3S4, we see a two orders of magnitude drop in the room temperature resistance. However, CsNi3S4 is still insulating, with no evidence of a phase transition. Using experimental data, density functional theory calculations, and symmetry analysis, our results suggest the emergence of a correlated insulating state of unknown origin.

Epidermal Growth Factor Receptor Signaling Governs the Host Inflammatory Response to Invasive Aspergillosis.

The epidermal growth factor receptor (EGFR) has been identified as an epithelial cell receptor for Mucorales fungi and Candida albicans . Blocking EGFR with small molecule inhibitors reduces disease severity in mouse models of mucormycosis and oropharyngeal candidiasis. In contrast, cases of invasive aspergillosis have been reported in cancer patients who were treated with EGFR inhibitors, suggesting that EGFR signaling may play a protective role in the host defense against this infection. Here, we analyzed transcriptomic data from the lungs of mice with invasive aspergillosis and found evidence that Aspergillus fumigatus infection activates multiple genes that are predicted to function in the EGFR signaling pathway. We also found that A. fumigatus infection activates EGFR in both a human small airway epithelial (HSAE) cell line and in the lungs of immunosuppressed mice. EGFR signaling in HSAE cells is required for maximal endocytosis of A. fumigatus and for fungal-induced proinflammatory cytokine and chemokine production. In a corticosteroid immunosuppressed mouse model of invasive pulmonary aspergillosis, inhibition of EGFR with gefitinib decreased whole lung chemokine levels and reduced accumulation of phagocytes in the lung, leading to a decrease in fungal killing, an increase in pulmonary fungal burden, and accelerated mortality. Thus, EGFR signaling is required for pulmonary epithelial cells to orchestrate the host innate immune defense against invasive aspergillosis in immunosuppressed hosts. Importance: When A. fumigatus infects the lungs, it invades epithelial cells that line the airways. During this process, the fungus interacts with epithelial cell receptors. This interaction stimulates epithelial cells to endocytose the fungus. It also induces these cells to secret proinflammatory cytokines and chemokines that recruit phagocytes to the site of infection where they can kill the fungus. Here, we show that in small airway epithelial cells, the epidermal growth factor receptor (EGFR) acts a sensor for A. fumigatus that triggers the production of chemokines in response to fungal infection. In corticosteroid-immunosuppressed mice, blocking EGFR with the kinase inhibitor, gefitinib reduces chemokine production in the lungs. This leads to decreased accumulation of neutrophils and dendritic cell in the lungs, reduced A. fumigatus killing, and increased mortality. These results provide a potential explanation as to why some cancer patients who are treated with EGFR inhibitors develop invasive aspergillosis.

Modeling the atrioventricular conduction axis using human pluripotent stem cell-derived cardiac assembloids.

The atrioventricular (AV) conduction axis provides electrical continuity between the atrial and ventricular chambers. The "nodal" cardiomyocytes populating this region (AV canal in the embryo, AV node from fetal stages onward) propagate impulses slowly, ensuring sequential contraction of the chambers. Dysfunction of AV nodal tissue causes severe disturbances in rhythm and contraction, and human models that capture its salient features are limited. Here, we report an approach for the reproducible generation of AV canal cardiomyocytes (AVCMs) with in vivo-like gene expression and electrophysiological profiles. We created the so-called "assembloids" composed of atrial, AVCM, and ventricular spheroids, which effectively recapitulated unidirectional conduction and the "fast-slow-fast" activation pattern typical for the vertebrate heart. We utilized these systems to reveal intracellular calcium mishandling as the basis of LMNA-associated AV conduction block. In sum, our study introduces novel cell differentiation and tissue construction strategies to facilitate the study of complex disorders affecting heart rhythm.

Space-Charge-Limited Current Measurements: A Problematic Technique for Metal Halide Perovskites.

Space-charge-limited current (SCLC) measurements play a crucial role in the electrical characterization of semiconductors, particularly for metal halide perovskites. Accurate reporting and analysis of SCLC are essential for gaining meaningful insights into charge transport and defect density in these systems. Unfortunately, performing SCLC measurements on perovskites is complicated by their mixed electronic-ionic conductivity. This complexity led to SCLC data often being incorrectly analyzed using simplified models unsuitable for these materials and reported without essential information about how the measurements were performed. In light of recently published SCLC data, common challenges in using SCLC measurements on perovskite materials are addressed, and solutions are discussed in this paper. The applicability of the often-used analytical models, the overlooked issues related to the mixed ionic-electronic conductivity of perovskites, and the complexity of creating single-carrier devices are investigated using drift-diffusion simulations. Finally, guidelines for more accurate reporting and improved analysis are provided.

Peripheral blood interferon responses to toll-like receptor 1/2 signaling associate with longer survival in men with metastatic prostate cancer treated with Sipleucel-T.

Mounting evidence links systemic innate immunity with cancer immune surveillance. In advanced metastatic castration resistant prostate cancer (mCRPC), Black patients have been found to have increased inflammatory markers and longer survival after sipuleucel-T (sip-T) therapy, an FDA-approved, autologous cell therapy. We hypothesized these differences may be explained by previously reported ancestral differences in pattern recognition receptor (PRR) signaling, which broadly governs innate inflammation to control adaptive immune cell activation, chemotaxis, and functionality. We discovered that PBMC interferon (IFN)-ß responses to TLR1/2, a sensor of bacterial and gut microbiome constituents, associated with significantly longer survival after sip-T therapy in two separate cohorts of men with mCRPC (discovery cohort: n=106, HR=0.12, p=0.019; validation cohort: n=28, HR<0.01, p=0.047). Higher IFN-ß induction after TLR1/2 stimulation was associated with lower hazard ratios compared to biomarkers of vaccine potency and other prognostic factors in mCRPC. TLR1/2 dependent cytokine induction was stronger in Black individuals (1.2-fold higher for IFN-ß; p=0.04) but was associated with survival independently of race or numbers of vaccine-induced tumor antigen-specific T cells. IFN-ß responses to TLR1/2 signaling correlated with increased numbers of IFN-ß producing T cells after broad, tumor antigen independent stimulation. Thus, peripheral innate immunity differs by race, may predict survival after sip-T, and associates with peripheral T cell functionality in men with mCRPC.

High-dose chemotherapy for patients with stage III breast cancer with homologous recombination deficiency: a discrete choice experiment among healthcare providers.

BACKGROUND AND PURPOSE: High-dose chemotherapy with autologous stem cell rescue (HDCT) is currently under investigation as a potential therapy for patients with stage III HER2-negative breast cancer with homologous recombination deficiency (HRD). In addition to survival, the impact on short- and long-term side effects might influence the uptake of HDCT by healthcare professionals. As part of the SUBITO trial, we investigated healthcare professionals' treatment (outcome) preferences for patients with HRD stage III HER2-negative breast cancer and established how healthcare professionals make trade-offs between these treatment outcomes. PATIENTS/MATERIAL AND METHODS: We conducted a discrete choice experiment in which healthcare professionals were asked to choose repeatedly between scenarios with two treatment options (HDCT or standard of care (SOC)) that varied in outcome with respect to 10-year overall survival (OS), short-term toxicity, long-term cognitive impairment, and premature menopause. We analysed treatment preferences, relative importance, and trade-offs using a multinomial logistic model. RESULTS AND INTERPRETATION: Thirty-five of the 151 dedicated breast cancer professionals with extensive experience in treating breast cancer patients completed the survey. The 10-year OS and long-term cognitive impairment were the most important attributes. The results indicate a requirement of 10.4% and 25.1% absolute additional improvement in the 10-year survival rate to justify accepting moderate or severe long-term cognitive impairment as a trade-off, respectively. Therefore, we found in our dataset that healthcare professionals expected a large improvement in 10-year OS to accept moderate to severe cognitive impairment. This information calls for further research into chemotherapy-related cognitive impairment, shared decision-making, and treatment preferences for patients with stage III breast cancer.

Engineered Bacteriophage-Polymer Nanoassemblies for Treatment of Wound Biofilm Infections.

The antibacterial efficacy and specificity of lytic bacteriophages (phages) make them promising therapeutics for treatment of multidrug-resistant bacterial infections. Restricted penetration of phages through the protective matrix of biofilms, however, may limit their efficacy against biofilm infections. Here, engineered polymers were used to generate noncovalent phage-polymer nanoassemblies (PPNs) that penetrate bacterial biofilms and kill resident bacteria. Phage K, active against multiple strains of Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), was assembled with cationic poly(oxanorbornene) polymers into PPNs. The PPNs retained phage infectivity, while demonstrating enhanced biofilm penetration and killing relative to free phages. PPNs achieved 3-log10 bacterial reduction (∼99.9%) against MRSA biofilms in vitro. PPNs were then incorporated into Poloxamer 407 (P407) hydrogels and applied onto in vivo wound biofilms, demonstrating controlled and sustained release. Hydrogel-incorporated PPNs were effective in a murine MRSA wound biofilm model, showing a 1.5-log10 reduction in bacterial load compared to a 0.5 log reduction with phage K in P407 hydrogel. Overall, this work showcases the therapeutic potential of phage K engineered with cationic polymers for treating wound biofilm infections.

Glutathione peroxidase 3 is a potential biomarker for konzo.

Konzo is a neglected paralytic neurological disease associated with food (cassava) poisoning that affects the world's poorest children and women of childbearing ages across regions of sub-Saharan Africa. Despite understanding the dietary factors that lead to konzo, the molecular markers and mechanisms that trigger this disease remain unknown. To identify potential protein biomarkers associated with a disease status, plasma was collected from two independent Congolese cohorts, a discovery cohort (n = 60) and validation cohort (n = 204), sampled 10 years apart and subjected to multiple high-throughput assays. We identified that Glutathione Peroxidase 3 (GPx3), a critical plasma-based antioxidant enzyme, was the sole protein examined that was both significantly and differentially abundant between affected and non-affected participants in both cohorts, with large reductions observed in those affected with konzo. Our findings raise the notion that reductions in key antioxidant mechanisms may be the biological risk factor for the development of konzo, particularly those mediated through pathways involving the glutathione peroxidase family.

Associations of fear of physical activity, coping style and self-reported exercise behavior in patients with chronic heart failure.

AIMS: Fear of physical activity (PA) is discussed as a barrier to regular exercise in patients with heart failure (HF), but HF-specific theoretical concepts are lacking. This study examined associations of fear of PA, heart-focused anxiety and trait anxiety with clinical characteristics and self-reported PA in outpatients with chronic HF. It was also investigated whether personality-related coping styles for dealing with health threats impact fear of PA via symptom perception. METHODS AND RESULTS: This cross-sectional study enrolled 185 HF outpatients from five hospitals (mean age 62 ± 11 years, mean ejection fraction 36.0 ± 12%, 24% women). Avoidance of PA, sports/exercise participation (yes/no) and the psychological characteristics were assessed by self-reports. Fear of PA was assessed by the Fear of Activity in Situations-Heart Failure (FActS-HF15) questionnaire. In multivariable regression analyses higher NYHA class (b = 0.26, p = 0.036) and a higher number of HF drugs including antidepressants (b = 0.25, p = 0.017) were independently associated with higher fear of PA, but not with heart-focused fear and trait anxiety. Of the three anxiety scores only increased fear of PA was independently associated with more avoidance behavior regarding PA (b = 0.45, SE = 0.06, p < 0.001) and with increased odds of no sports/exercise participation (OR = 1.34, 95% CI 1.03-1.74, p = 0.028). Attention towards cardiac symptoms and symptom distress were positively associated with fear of PA (p < 0.001), which explained higher fear of PA in patients with a vigilant (directing attention towards health threats) coping style (p = 0.004). CONCLUSIONS: Fear of PA assessed by the FActS-HF15 is a specific type of anxiety in patients with HF. Attention towards and being distressed by HF symptoms appear to play a central role in fear of PA, particularly in vigilant patients who are used to direct their attention towards health threats. These findings provide approaches for tailored interventions to reduce fear of PA and to increase PA in patients with HF. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02898246.

PKR activation-induced mitochondrial dysfunction in HIV-transgenic mice with nephropathy.

HIV disease remains prevalent in the USA and chronic kidney disease remains a major cause of morbidity in HIV-1-positive patients. Host double-stranded RNA (dsRNA)-activated protein kinase (PKR) is a sensor for viral dsRNA, including HIV-1. We show that PKR inhibition by compound C16 ameliorates the HIV-associated nephropathy (HIVAN) kidney phenotype in the Tg26 transgenic mouse model, with reversal of mitochondrial dysfunction. Combined analysis of single-nucleus RNA-seq and bulk RNA-seq data revealed that oxidative phosphorylation was one of the most downregulated pathways and identified signal transducer and activator of transcription (STAT3) as a potential mediating factor. We identified in Tg26 mice a novel proximal tubular cell cluster enriched in mitochondrial transcripts. Podocytes showed high levels of HIV-1 gene expression and dysregulation of cytoskeleton-related genes, and these cells dedifferentiated. In injured proximal tubules, cell-cell interaction analysis indicated activation of the pro-fibrogenic PKR-STAT3-platelet-derived growth factor (PDGF)-D pathway. These findings suggest that PKR inhibition and mitochondrial rescue are potential novel therapeutic approaches for HIVAN.

Enhancing radiotherapy response via intratumoral injection of a TLR9 agonist in autochthonous murine sarcomas.

Radiation therapy (RT) is frequently used to treat cancers, including soft-tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine oligodeoxynucleotide (CpG) enhances the response to RT in transplanted tumors, but the mechanisms of this enhancement remain unclear. Here, we used CRISPR/Cas9 and the chemical carcinogen 3-methylcholanthrene (MCA) to generate autochthonous soft-tissue sarcomas with high tumor mutation burden. Treatment with a single fraction of 20 Gy RT and 2 doses of CpG significantly enhanced tumor response, which was abrogated by genetic or immunodepletion of CD8+ T cells. To characterize the immune response to CpG+RT, we performed bulk RNA-Seq, single-cell RNA-Seq, and mass cytometry. Sarcomas treated with 20 Gy and CpG demonstrated increased CD8 T cells expressing markers associated with activation and proliferation, such as Granzyme B, Ki-67, and IFN-γ. CpG+RT also upregulated antigen presentation pathways on myeloid cells. Furthermore, in sarcomas treated with CpG+RT, TCR clonality analysis suggests an increase in clonal T cell dominance. Collectively, these findings demonstrate that CpG+RT significantly delays tumor growth in a CD8 T cell-dependent manner. These results provide a strong rationale for clinical trials evaluating CpG or other TLR9 agonists with RT in patients with soft-tissue sarcoma.

Creation of a predictive calculator to determine adequacy of occlusion of the woven endobridge (WEB) device in intracranial aneurysms-A retrospective analysis of the WorldWide WEB Consortium database.

BACKGROUND: Endovascular treatment with the woven endobridge (WEB) device has been widely utilized for managing intracranial aneurysms. However, predicting the probability of achieving adequate occlusion (Raymond-Roy classification 1 or 2) remains challenging. OBJECTIVE: Our study sought to develop and validate a predictive calculator for adequate occlusion using the WEB device via data from a large multi-institutional retrospective cohort. METHODS: We used data from the WorldWide WEB Consortium, encompassing 356 patients from 30 centers across North America, South America, and Europe. Bivariate and multivariate regression analyses were performed on a variety of demographic and clinical factors, from which predictive factors were selected. Calibration and validation were conducted, with variance inflation factor (VIF) parameters checked for collinearity. RESULTS: A total of 356 patients were included: 124 (34.8%) were male, 108 (30.3%) were elderly (≥65 years), and 118 (33.1%) were current smokers. Mean maximum aneurysm diameter was 7.09 mm (SD 2.71), with 112 (31.5%) having a daughter sac. In the multivariate regression, increasing aneurysm neck size (OR 0.706 [95% CI: 0.535-0.929], p = 0.13) and partial aneurysm thrombosis (OR 0.135 [95% CI: 0.024-0.681], p = 0.016) were found to be the only statistically significant variables associated with poorer likelihood of achieving occlusion. The predictive calculator shows a c-statistic of 0.744. Hosmer-Lemeshow goodness-of-fit test indicated a satisfactory model fit with a p-value of 0.431. The calculator is available at: https://neurodx.shinyapps.io/WEBDEVICE/. CONCLUSION: The predictive calculator offers a substantial contribution to the clinical toolkit for estimating the likelihood of adequate intracranial aneurysm occlusion by WEB device embolization.

7T-high resolution MRI-derived radiomic analysis for the identification of symptomatic intracranial atherosclerotic plaques.

INTRODUCTION: High-resolution magnetic resonance imaging (HR-MRI) allows for detailed visualization of intracranial atherosclerotic plaques. Radiomics can be used as a tool for objective quantification of the plaque's characteristics. We analyzed the radiomics features (RFs) obtained from 7 T HR-MRI of patients with intracranial atherosclerotic disease (ICAD) to determine distinct characteristics of culprit and non-culprit plaques. METHODS: Patients with stroke due to ICAD underwent HR-MRI. Culprit plaques in the vascular territory of the stroke were identified. Degree of stenosis, area degree of stenosis and plaque burden were calculated. A three-dimensional segmentation of the plaque was performed, and RFs were obtained. A machine learning model for prediction and identification of culprit plaques using significantly different RFs was evaluated. RESULTS: The study included 33 patients with ICAD as stroke etiology. Univariate analysis revealed 24 RFs in pre-contrast MRI, 21 in post-contrast MRI, 13 RFs that were different between pre and post contrast MRIs. Additionally, six shape-based RFs significantly differed from culprit and non-culprit plaques. The random forest model achieved an accuracy rate of 81% (88% sensitivity and 75% specificity) in identifying culprit plaques in the independent testing dataset. This model successfully identified the culprit plaques in all patients during the testing phase. DISCUSSION: Symptomatic plaques had a distinct signature RFs compared to other plaques within the same subject. A machine learning model built with RFs successfully identified the symptomatic atherosclerotic plaques in most cases. Radiomics is a promising tool for stratification of plaques in patients with ICAD.

Cu-Catalyzed Three-Component Alkene Carboamination: Mechanistic Insights and Rational Design to Overcome Limitations.

Herein, we report mechanistic investigations into the Cu-catalyzed three-component carboamination of alkenes with α-halo carbonyls and aryl amines via an oxocarbenium intermediate. Monitoring the reaction reveals the formation of transient atom transfer radical addition (ATRA) intermediates with both electron-neutral and deficient vinyl arenes as well as unactivated alkenes. Based on our experimental studies and density functional theory calculations, the oxocarbenium is generated through atom transfer and subsequent intramolecular substitution. Further, mechanistic factors that dictate the regioselectivity of the nucleophilic attack onto the oxocarbenium to afford the γ-amino ester, γ-iminolactone, or γ-lactone are discussed. A strategy to overcome scope limitation with respect to unactivated alkenes is developed using the mechanistic insights gained herein. Finally, we demonstrate that under modified conditions, our Cu catalyst enables the ATRA reaction between a variety of alkyl halides and vinyl arenes/α-olefins, and we present a one-pot, two-step carbofunctionalization with an array of nucleophiles through ATRA/SN2.

A chemoenzymatic method for simultaneous profiling N- and O-glycans on glycoproteins using one-pot format.

Glycosylation is generally characterized and controlled as a critical quality attribute for therapeutic glycoproteins because glycans can impact protein drug-product efficacy, half-life, stability, and safety. Analytical procedures to characterize N-glycans are relatively well established, but the characterization of O-glycans is challenging due to the complex workflows and lack of enzymatic tools. Here, we present a simplified chemoenzymatic method to simultaneously profile N- and O-glycans from the same sample using a one-pot format by mass spectrometry (MS). N-glycans were first released by PNGase F, followed by O-glycopeptide generation by proteinase K, selective N-glycan reduction, and O-glycan release by ß-elimination during permethylation of both N- and O-glycans. Glycan structural assignments and determination of N- to O-glycan ratio was obtained from the one-pot mass spectra. The streamlined, one-pot method is a reliable approach that will facilitate advanced characterizations for quality assessments of therapeutic glycoproteins.

Multi-phosphine-chelated iron-carbide clusters via redox-promoted ligand exchange on an inert hexa-iron-carbide carbonyl cluster, [Fe6(µ6-C)(µ2-CO)4(CO)12]2.

We report the reactivity, structures and spectroscopic characterization of reactions of phosphine-based ligands (mono-, di- and tri-dentate) with iron-carbide carbonyl clusters. Historically, the archetype of this cluster class, namely [Fe6(µ6-C)(µ2-CO)4(CO)12]2-, can be prepared on a gram-scale but is resistant to simple ligand substitution reactions. This limitation has precluded the relevance of iron-carbide clusters relating to organometallics, catalysis and the nitrogenase active site cluster. Herein, we aimed to derive a simple and reliable method to accomplish CO → L (where L = phosphine or other general ligands) substitution reactions without harsh reagents or multi-step synthetic strategies. Ultimately, our goal was ligand-based chelation of an Fe n (µ n -C) core to achieve more synthetic control over multi-iron-carbide motifs relevant to the nitrogenase active site. We report that the key intermediate is the PSEPT-non-conforming cluster [Fe6(µ6-C)(CO)16] (2: 84 electrons), which can be generated in situ by the outer-sphere oxidation of [Fe6(µ6-C)(CO)16]2- (1: closo, 86 electrons) with 2 equiv. of [Fc]PF6. The reaction of 2 with excess PPh3 generates a singly substituted neutral cluster [Fe5(µ5-C)(CO)14PPh3] (4), similar to the reported reactivity of the substitutionally active cluster [Fe5(µ5-C)(CO)15] with monodentate phosphines (Cooke & Mays, 1990). In contrast, the reaction of 2 with flexible, bidentate phosphines (DPPE and DPPP) generates a wide range of unisolable products. However, the rigid bidentate phosphine bis(diphenylphosphino)benzene (bdpb) disproportionates the cluster into non-ligated Fe3-carbide anions paired with a bdpb-supported Fe(ii) cation, which co-crystallize in [Fe3(µ3-CH)(µ3-CO)(CO)9]2[Fe(MeCN)2(bdpb)2] (6). A successful reaction of 2 with the tripodal ligand Triphos generates the first multi-iron-chelated, authentic carbide cluster of the formula [Fe4(µ4-C)(κ3-Triphos)(CO)10] (9). DFT analysis of the key (oxidized) intermediate 2 suggests that its (µ6-C)Fe6 framework remains fully intact but is distorted into an axially compressed, 'ruffled' octahedron distinct from the parent closo cluster 1. Oxidation of the cluster in non-coordinating solvent allows for the isolation and crystallization of the CO-saturated, intact closo-analogue [Fe6(µ6-C)(CO)17] (3), indicating that the intact (µ6-C)Fe6 motif is retained during initial oxidation with [Fc]PF6. Overall, we demonstrate that redox modulation beneficially 'bends' Wade-Mingo's rules via the generation of electron-starved (non-PSEPT) intermediates, which are the key intermediates in promoting facile CO → L substitution reactions in iron-carbide-carbonyl clusters.

Improving sustainability of a patient decision aid for systemic treatment of metastatic colorectal cancer: A qualitative study.

Objective: To improve sustainability of a patient decision aid for systemic treatment of metastatic colorectal cancer, we evaluated real-world experiences and identified ways to optimize decision aid content and future implementation. Methods: Semi-structured interviews with patients and medical oncologists addressed two main subjects: user experience and decision aid content. Content analysis was applied. Fifteen experts discussed the results and devised improvements based on experience and literature review. Results: Thirteen users were interviewed. They confirmed the relevance of the decision aid for shared decision making. Areas for improvement of content concerned; 1) outdated and missing information, 2) an imbalance in presentation of treatment benefits and harms, and 3) medical oncologists' expressed preference for a more center-specific or patient individualized decision aid, presenting a selection of the guideline recommended treatment options. Key points for improvement of implementation were better alignment within the care pathway, and clear instruction to users. Conclusion: We identified relevant opportunities for improvement of an existing decision aid and developed an updated version and accompanying implementation strategy accordingly. Innovation: This paper outlines an approach for continued decision aid and implementation strategy development which will add to sustainability. Implementation success of the improved decision aid is currently being studied in a multi-center mixed-methods implementation study.