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Immunoglobulin G 3 (IgG3) monoclonal antibodies (mAbs) are high-value scaffolds for developing novel therapies. Despite their wide-ranging therapeutic potential, IgG3 physicochemical properties and developability characteristics remain largely under-characterized. Protein-protein interactions elevate solution viscosity in high-concentration formulations, impacting physicochemical stability, manufacturability, and the injectability of mAbs. Therefore, in this manuscript, the key molecular descriptors and biophysical properties of a model anti-IL-8 IgG1 and its IgG3 ortholog are characterized. A computational and experimental framework was applied to measure molecular descriptors impacting their downstream developability. Findings from this approach underpin a detailed understanding of the molecular characteristics of IgG3 mAbs as potential therapeutic entities. This work is the first report examining the manufacturability of IgG3 for high-concentration mAb formulations. While poorer conformational and colloidal stability and elevated solution viscosity were observed for IgG3, future efforts controlling surface potential through sequence-engineering of solvent-accessible patches can be used to improve biophysical parameters that dictate mAb developability.
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Salbutamol is a common short-acting beta2-adrenergic agonist used in treatment of asthma and exercise-induced bronchoconstriction but also possesses anabolic and metabolic actions in skeletal muscle. As a chiral compound, salbutamol is a racemic 1:1 mixture of two enantiomers, (R)-salbutamol and (S)-salbutamol, which exhibit divergent pharmacokinetic and pharmacodynamic actions. Despite salbutamol being available for decades, information on the enantioselective disposition of salbutamol enantiomers in human skeletal muscle is absent. In this study, we determined concentrations of (R)-salbutamol and (S)-salbutamol by UHPLC-MS/MS in arterial plasma and vastus lateralis muscle samples from 12 lean young men 2½ and 7 h following ingestion of 24 mg oral salbutamol. Mean (range) arterial plasma concentrations were 10-fold higher (p < 0.001) for (S)-salbutamol than (R)-salbutamol, being 33(9-62) and 49(30-84) ng·mL-1 for (S)-salbutamol and 4 (1-6) and 4 (2-5) ng·mL-1 for (R)-salbutamol 2½ and 7 h following administration, respectively, reflecting faster elimination of the (R)-enantiomer. Mean (range) muscle concentrations were higher (p < 0.001) for (S)-salbutamol than (R)-salbutamol 2½ h (0.17 [0.1-0.26] vs. 0.04 [0.02-0.06]) and 7 h (0.31 [0.21-0.46] vs. 0.06 [0.04-0.12] ng·mgd.w. -1) after administration. However, muscle:plasma partition coefficient was two-fold higher (p < 0.001) for (R)-salbutamol than (S)-salbutamol 7 h following administration. These observations demonstrate that oral salbutamol exhibits enantioselective disposition in systemic circulation and muscle favoring the (S)-enantiomer but with higher relative partitioning of the (R)-enantiomer in skeletal muscle. Furthermore, the concentration-time profiles of salbutamol enantiomers are different in skeletal muscle and systemic circulation following oral ingestion. These findings have implications for the application of chiral switch (R)-salbutamol in doping control.
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Background: Weekly Steroids in Muscular Dystrophy (WSiMD) was a pilot study to evaluate once weekly prednisone in patients with Limb Girdle and Becker muscular dystrophy (LGMD and BMD, respectively). At study endpoint, there were trends towards increased lean mass, reduced fat mass, reduced creatine kinase and improved motor function. The investigation was motivated by studies in mouse muscular dystrophy models in which once weekly glucocorticoid exposure enhanced muscle strength and reduced fibrosis. Methods: WSiMD participants provided blood samples for aptamer serum profiling at baseline and after 6 months of weekly steroids. A subset completed magnetic resonance (MR) evaluation of muscle at study onset and endpoint. Results/Conclusions: At baseline compared to age and sex-matched healthy controls, the aggregate serum protein profile in the WSiMD cohort was dominated by muscle proteins, reflecting leak of muscle proteins into serum. Disease status produced more proteins differentially present in serum compared to steroid-treatment effect. Nonetheless, a response to prednisone was discernable in the WSiMD cohort, even at this low dose. Glucocorticoids downregulated muscle proteins and upregulated certain immune process- and matrix-associated proteins. Muscle MR fat fraction showed trends with functional status. The prednisone-responsive markers could be used in larger trial of prednisone efficacy.
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Fat embolism syndrome is a common occurrence after orthopedic trauma and surgery. Cerebral fat embolism (CFE) may arise after fat globules enter the arterial circulation. The neurological manifestations of CFE vary and generally carries a favorable outcome. A small number of reports exist regarding patients with CFE who experienced severe neurological deficits and significant edema on radiographic studies, and subsequently underwent decompressive hemicraniectomy (DHC), some of which had full neurological recoveries. Here, we present the case of a 21-year-old male who presented after a motorcycle accident with multiple orthopedic injuries, who after fixation did not awake from anesthesia. The patient was ultimately found to have cerebral fat emboli, and developed significant edema and swelling. The patient underwent DHC with subsequent cranioplasty and returned to his neurological baseline seven months after his initial injury. DHC for CFE has been described in a few cases with some patients have had substantive recoveries, including the present case. This case emphasizes the importance of promptly recognizing and reversing elevated intracranial pressures and the possibility of promising recoveries.
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This study examines the impact of India's export restrictions on domestic retail rice prices using a dynamic panel GARCH model. The findings suggest that export restrictions are not a sufficient condition to lower domestic prices. Export restrictions are associated with lower retail price volatility in the East Zone. Moreover, the international price transmission to a sample of Asian and African economies shows that all countries are vulnerable, but the degree and kinds of vulnerability differ. Rice exporters appear to be the most susceptible as domestic prices increase in these countries. Rice importers are also vulnerable because of price increases, but the increases are less than in countries where the private sector decides on import quantities.
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BACKGROUND: Schizophrenia is a mental disorder that causes considerable morbidity, whose risk largely results from genetic factors. Setd1a is a gene implicated in schizophrenia. OBJECTIVE: To study the gene expression changes found in heterozygous Setd1a± knockout mice in order to gain useful insight into schizophrenia pathogenesis. METHODS: We mined a single-cell RNA sequencing (scRNAseq) dataset from the prefrontal cortex (PFC) and striatum of Setd1a± mice and identified cell type-specific differentially expressed genes (DEGs) and differential transcript usage (DTU). DEGs and genes containing DTU found in each cell type were used to identify affected biological pathways using Ingenuity Pathway Analysis (IPA). RESULTS: We identified 273 unique DEGs across all cell types in PFC and 675 unique gene peaks containing DTU. In striatum, we identified 327 unique DEGs across all cell types and 8 unique gene peaks containing DTU. Key IPA findings from the analysis of DEGs found in PFC and striatum implicate processes involved in protein synthesis, mitochondrial function, cell metabolism, and inflammation. IPA analysis of genes containing DTU in PFC points to protein synthesis, as well as cellular activities involving intracellular signaling and neurotransmission. One canonical pathway, 'EIF2 Signaling', which is involved in the regulation of protein synthesis, was detected in PFC DEGs, striatum DEGs, and PFC genes containing DTU, drawing attention to its importance in schizophrenia pathophysiology. CONCLUSION: Processes involving protein synthesis in general and the 'EIF2 Signaling' pathway in particular could be targets for the development of new research strategies and biomarkers in schizophrenia.
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The formulation of high-concentration monoclonal antibody (mAb) solutions in low dose volumes for autoinjector devices poses challenges in manufacturability and patient administration due to elevated solution viscosity. Often many therapeutically potent mAbs are discovered, but their commercial development is stalled by unfavourable developability challenges. In this work, we present a systematic experimental framework for the computational screening of molecular descriptors to guide the design of 24 mutants with modified viscosity profiles accompanied by experimental evaluation. Our experimental observations using a model anti-IL8 mAb and eight engineered mutant variants reveal that viscosity reduction is influenced by the location of hydrophobic interactions, while targeting positively charged patches significantly increases viscosity in comparison to wild-type anti-IL-8 mAb. We conclude that most predicted in silico physicochemical properties exhibit poor correlation with measured experimental parameters for antibodies with suboptimal developability characteristics, emphasizing the need for comprehensive case-by-case evaluation of mAbs. This framework combining molecular design and triage via computational predictions with experimental evaluation aids the agile and rational design of mAbs with tailored solution viscosities, ensuring improved manufacturability and patient convenience in self-administration scenarios.
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Six Transmembrane Epithelial Antigen of Prostate 2 (STEAP2) belongs to a family of metalloreductases, which indirectly aid in uptake of iron and copper ions. Its role in hepatocellular carcinoma (HCC) remains to be characterized. Here, we report that STEAP2 expression was upregulated in HCC tumors compared with paired adjacent non-tumor tissues by RNA sequencing, RT-qPCR, Western blotting, and immunostaining. Public HCC datasets demonstrated upregulated STEAP2 expression in HCC and positive association with tumor grade. Transient and stable knockdown (KD) of STEAP2 in HCC cell lines abrogated their malignant phenotypes in vitro and in vivo, while STEAP2 overexpression showed opposite effects. STEAP2 KD in HCC cells led to significant alteration of genes associated with extracellular matrix organization, cell adhesion/chemotaxis, negative enrichment of an invasiveness signature gene set, and inhibition of cell migration/invasion. STEAP2 KD reduced intracellular copper levels and activation of stress-activated MAP kinases including p38 and JNK. Treatment with copper rescued the reduced HCC cell migration due to STEAP2 KD and activated p38 and JNK. Furthermore, treatment with p38 or JNK inhibitors significantly inhibited copper-mediated cell migration. Thus, STEAP2 plays a malignant-promoting role in HCC cells by driving migration/invasion via increased copper levels and MAP kinase activities. Our study uncovered a novel molecular mechanism contributing to HCC malignancy and a potential therapeutic target for HCC treatment.
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Carcinoma Hepatocelular , Movimiento Celular , Cobre , Neoplasias Hepáticas , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Cobre/metabolismo , Línea Celular Tumoral , Animales , Regulación Neoplásica de la Expresión Génica , Ratones , Progresión de la Enfermedad , Masculino , Oxidorreductasas/metabolismo , Oxidorreductasas/genética , FemeninoRESUMEN
Complement receptor 1 (CR1) is a membrane glycoprotein with a highly duplicated domain structure able to bind multiple ligands such as C3b and C4b, the activated fragments of complement components C3 and C4, respectively. We have previously used our knowledge of this domain structure to identify CSL040, a soluble extracellular fragment of CR1 containing the long homologous repeat (LHR) domains A, B, and C. CSL040 retains the ability to bind both C3b and C4b but is also a more potent complement inhibitor than other recombinant CR1-based therapeutics. To generate soluble CR1 variants with increased inhibitory potential across all three complement pathways, or variants with activity skewed to specific pathways, we exploited the domain structure of CR1 further by generating LHR domain duplications. We identified LHR-ABCC, a soluble CR1 variant containing a duplicated C3b-binding C-terminal LHR-C domain that exhibited significantly enhanced alternative pathway inhibitory activity in vitro compared to CSL040. Another variant, LHR-BBCC, containing duplications of both LHR-B and LHR-C with four C3b binding sites, was shown to have reduced classical/lectin pathway inhibitory activity compared to CSL040, but comparable alternative pathway activity. Interestingly, multiplication of the C4b-binding LHR-A domain resulted in only minor increases in classical/lectin pathway inhibitory activity. The CR1 duplication variants characterized in these in vitro potency assays, as well as in affinity in solution C3b and C4b binding assays, not only provides an opportunity to identify new therapeutic molecules but also additional mechanistic insights to the multiple interactions between CR1 and C3b/C4b.
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Complemento C3b , Dominios Proteicos , Humanos , Complemento C3b/metabolismo , Complemento C3b/química , Complemento C3b/genética , Receptores de Complemento 3b/metabolismo , Receptores de Complemento 3b/genética , Receptores de Complemento 3b/química , Complemento C4b/metabolismo , Complemento C4b/genética , Complemento C4b/química , Unión ProteicaRESUMEN
The vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are key regulators of blood vessel formation, including in tumors, where their deregulated function can promote the production of aberrant, leaky blood vessels, supporting tumor development. Here we investigated the VEGFR1 ligand VEGF-B, which we demonstrate to be expressed in tumor cells and in tumor stroma and vasculature across a range of tumor types. We examined the anti-VEGF-B-specific monoclonal antibody 2H10 in preclinical xenograft models of breast and colorectal cancer, in comparison with the anti-VEGF-A antibody bevacizumab. Similar to bevacizumab, 2H10 therapy was associated with changes in tumor blood vessels and intra-tumoral diffusion consistent with normalization of the tumor vasculature. Accordingly, treatment resulted in partial inhibition of tumor growth, and significantly improved the response to chemotherapy. Our studies indicate the importance of VEGF-B in tumor growth, and the potential of specific anti-VEGF-B treatment to inhibit tumor development, alone or in combination with established chemotherapies.
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The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is used as a ligation tool throughout chemical and biological sciences. Despite the pervasiveness of CuAAC, there is a need to develop more efficient methods to form 1,4-triazole ligated products with low loadings of Cu. In this paper, we disclose a mechanistic model for the ynamine-azide (3 + 2) cycloadditions catalyzed by copper(II) acetate. Using multinuclear nuclear magnetic resonance spectroscopy, electron paramagnetic resonance spectroscopy, and high-performance liquid chromatography analyses, a dual catalytic cycle is identified. First, the formation of a diyne species via Glaser-Hay coupling of a terminal ynamine forms a Cu(I) species competent to catalyze an ynamine-azide (3 + 2) cycloaddition. Second, the benzimidazole unit of the ynamine structure has multiple roles: assisting C-H activation, Cu coordination, and the formation of a postreaction resting state Cu complex after completion of the (3 + 2) cycloaddition. Finally, reactivation of the Cu resting state complex is shown by the addition of isotopically labeled ynamine and azide substrates to form a labeled 1,4-triazole product. This work provides a mechanistic basis for the use of mixed valency binuclear catalytic Cu species in conjunction with Cu-coordinating alkynes to afford superior reactivity in CuAAC reactions. Additionally, these data show how the CuAAC reaction kinetics can be modulated by changes to the alkyne substrate, which then has a predictable effect on the reaction mechanism.
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To determine whether body fat and body mass index (BMI) affect the energy cost of walking (Cw; J/kg/m), ventilation, and gas exchange data from 205 adults (115 females; percent body fat range = 3.0%-52.8%; BMI range = 17.5-43.2 kg/m2) were obtained at rest and during treadmill walking at 1.34 m/s to calculate gross and net Cw. Linear regression was used to assess relationships between body composition indices, Cw, and standing metabolic rate (SMR). Unpaired t-tests were used to assess differences between sex, and one-way ANOVA was used to assess differences by BMI categories: normal weight, <25.0 kg/m2; overweight, 25.0-29.9 km/m2; and obese, ≥30 kg/m2. Net Cw was not related to body fat percent, fat mass, or BMI (all R2 ≤ 0.011). Furthermore, mean net Cw was similar by sex (male: 2.19 ± 0.30 J/kg/m; female: 2.24 ± 0.37 J/kg/m, p = 0.35) and across BMI categories (normal weight: 2.23 ± 0.36 J/kg/m; overweight: 2.18 ± 0.33 J/kg/m; obese: 2.26 ± 0.31, p = 0.54). Gross Cw and SMR were inversely associated with percent body fat, fat mass, and BMI (all R2 between 0.033 and 0.270; all p ≤ 0.008). In conclusion, Net Cw is not influenced by body fat percentage, total body fat, and BMI and does not differ by sex.
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Índice de Masa Corporal , Metabolismo Energético , Caminata , Humanos , Masculino , Femenino , Adulto , Caminata/fisiología , Persona de Mediana Edad , Metabolismo Energético/fisiología , Tejido Adiposo/metabolismo , Tejido Adiposo/fisiología , Prueba de Esfuerzo/métodos , Consumo de Oxígeno/fisiología , Anciano , Obesidad/fisiopatología , Obesidad/metabolismo , Adulto JovenRESUMEN
Background: The incidence and mortality rates of hepatocellular carcinoma (HCC) among Hispanics in the United States are much higher than those of non-Hispanic whites. We conducted comprehensive multi-omics analyses to understand molecular alterations in HCC among Hispanic patients. Methods: Paired tumor and adjacent non-tumor samples were collected from 31 Hispanic HCC in South Texas (STX-Hispanic) for genomic, transcriptomic, proteomic, and metabolomic profiling. Additionally, serum lipids were profiled in 40 Hispanic and non-Hispanic patients with or without clinically diagnosed HCC. Results: Exome sequencing revealed high mutation frequencies of AXIN2 and CTNNB1 in STX Hispanic HCCs, suggesting a predominant activation of the Wnt/ß-catenin pathway. The TERT promoter mutation frequency was also remarkably high in the Hispanic cohort. Cell cycles and liver functions were identified as positively- and negatively-enriched, respectively, with gene set enrichment analysis. Gene sets representing specific liver metabolic pathways were associated with dysregulation of corresponding metabolites. Negative enrichment of liver adipogenesis and lipid metabolism corroborated with a significant reduction in most lipids in the serum samples of HCC patients. Two HCC subtypes from our Hispanic cohort were identified and validated with the TCGA liver cancer cohort. The subtype with better overall survival showed higher activity of immune and angiogenesis signatures, and lower activity of liver function-related gene signatures. It also had higher levels of immune checkpoint and immune exhaustion markers. Conclusions: Our study revealed some specific molecular features of Hispanic HCC and potential biomarkers for therapeutic management of HCC and provides a unique resource for studying Hispanic HCC.
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INTRODUCTION: In the era of next-generation sequencing, clinicians frequently encounter variants of unknown significance (VUS) in genetic testing. VUS may be reclassified over time as genetic knowledge grows. We know little about how best to approach VUS in the maturity-onset diabetes of the young (MODY). Therefore, our study aimed to determine the utility of reanalysis of previous VUS results in genetic confirmation of MODY. METHODS: A single-center retrospective chart review identified 85 subjects with a MODY clinical diagnosis. We reanalyzed genetic testing in 10 subjects with 14 unique VUS on MODY genes that was performed >3 years before the study. Demographic, clinical, and biochemical data was collected for those individuals. RESULTS: After reanalysis, 43% (6/14) of the gene variants were reclassified to a different category: 7% (1/14) were "likely pathogenic" and 36% (5/14) were "benign" or "likely benign." The reclassified pathogenic variant was in HNF1A and all reclassified benign variants were in HNF1A, HNF1B and PDX1. The median time between MODY testing and reclassification was 8 years (range: 4-10 years). CONCLUSION: In sum, iterative reanalyzing the genetic data from VUS found during MODY testing may provide high-yield diagnostic information. Further studies are warranted to identify the optimal time and frequency for such analyses.
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Importance: A new liver allocation policy was implemented by United Network for Organ Sharing (UNOS) in February 2020 with the stated intent of improving access to liver transplant (LT). There are growing concerns nationally regarding the implications this new system may have on LT costs, as well as access to a chance for LT, which have not been captured at a multicenter level. Objective: To characterize LT volume and cost changes across the US and within specific center groups and demographics after the policy implementation. Design, Setting, and Participants: This cross-sectional study collected and reviewed LT volume from multiple centers across the US and cost data with attention to 8 specific center demographics. Two separate 12-month eras were compared, before and after the new UNOS allocation policy: March 4, 2019, to March 4, 2020, and March 5, 2020, to March 5, 2021. Data analysis was performed from May to December 2022. Main Outcomes and Measures: Center volume, changes in cost. Results: A total of 22 of 68 centers responded comparing 1948 LTs before the policy change and 1837 LTs postpolicy, resulting in a 6% volume decrease. Transplants using local donations after brain death decreased 54% (P < .001) while imported donations after brain death increased 133% (P = .003). Imported fly-outs and dry runs increased 163% (median, 19; range, 1-75, vs 50, range, 2-91; P = .009) and 33% (median, 3; range, 0-16, vs 7, range, 0-24; P = .02). Overall hospital costs increased 10.9% to a total of $46â¯360â¯176 (P = .94) for participating centers. There was a 77% fly-out cost increase postpolicy ($10â¯600â¯234; P = .03). On subanalysis, centers with decreased LT volume postpolicy observed higher overall hospital costs ($41â¯720â¯365; P = .048), and specifically, a 122% cost increase for liver imports ($6â¯508â¯480; P = .002). Transplant centers from low-income states showed a significant increase in hospital (12%) and import (94%) costs. Centers serving populations with larger proportions of racial and ethnic minority candidates and specifically Black candidates significantly increased costs by more than 90% for imported livers, fly-outs, and dry runs despite lower LT volume. Similarly, costs increased significantly (>100%) for fly-outs and dry runs in centers from worse-performing health systems. Conclusions and Relevance: Based on this large multicenter effort and contrary to current assumptions, the new liver distribution system appears to place a disproportionate burden on populations of the current LT community who already experience disparities in health care. The continuous allocation policies being promoted by UNOS could make the situation even worse.
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Trasplante de Hígado , Obtención de Tejidos y Órganos , Trasplante de Hígado/economía , Humanos , Estudios Transversales , Estados Unidos , Obtención de Tejidos y Órganos/economía , Obtención de Tejidos y Órganos/legislación & jurisprudencia , Política de Salud , Masculino , Femenino , Listas de EsperaRESUMEN
Poly(ether ether ketone) (PEEK) was found to form gels in the benign solvent 1,3-diphenylacetone (DPA). Gelation of PEEK in DPA was found to form an interconnected, strut-like morphology composed of polymer axialites. To our knowledge, this is the first report of a strut-like morphology for PEEK aerogels. PEEK/DPA gels were prepared by first dissolving PEEK in DPA at 320 °C. Upon cooling to 50 °C, PEEK crystallizes and forms a gel in DPA. The PEEK/DPA phase diagram indicated that phase separation occurs by solid-liquid phase separation, implying that DPA is a good solvent for PEEK. The Flory-Huggins interaction parameter, calculated as χ12 = 0.093 for the PEEK/DPA system, confirmed that DPA is a good solvent for PEEK. PEEK aerogels were prepared by solvent exchanging DPA to water then freeze-drying. PEEK aerogels were found to have densities between 0.09 and 0.25 g/cm3, porosities between 80 and 93%, and surface areas between 200 and 225 m2/g, depending on the initial gel concentration. Using nitrogen adsorption analyses, PEEK aerogels were found to be mesoporous adsorbents, with mesopore sizes of about 8 nm, which formed between stacks of platelike crystalline lamellae. Scanning electron microscopy and X-ray scattering were utilized to elucidate the hierarchical structure of the PEEK aerogels. Morphological analysis found that the PEEK/DPA gels were composed of a highly nucleated network of PEEK axialites (i.e., aggregates of stacked crystalline lamellae). The highly connected axialite network imparted robust mechanical properties on PEEK aerogels, which were found to densify less upon freeze-drying than globular PEEK aerogel counterparts gelled from dichloroacetic acid (DCA) or 4-chlorphenol (4CP). PEEK aerogels formed from DPA were also found to have a modulus-density scaling that was far more efficient in supporting loads than the poorly connected aerogels formed from PEEK/DCA or PEEK/4CP solutions. The strut-like morphology in these new PEEK aerogels also significantly improved the modulus to a degree that is comparable to high-performance crosslinked aerogels based on polyimide and polyurea of comparable densities.
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BACKGROUND: Suicide safety plans can improve suicide-related coping skills and reduce suicidal thoughts and behaviours (STBs). However, little is known about their use and impact outside of treatment settings, where most suicidal crises will occur. The current study explored the prevalence of safety plan use among an online sample of help-seekers with lifetime STBs, and whether STBs and suicide-related coping differed between those with and without safety plans. An exploratory aim was to investigate barriers to safety plan use. METHOD: Participants (N = 1251) completed an online, anonymous survey at a mental health support website (Beyond Blue). The survey measured lifetime STBs, past-month suicidal ideation, suicide-related coping, help-seeking intentions and behaviour. RESULTS: Despite high levels of past-month suicidal ideation and past-year help-seeking, most participants (89.5 %) did not have a safety plan, and most of those were not familiar with the concept (70.5 %). Participants with safety plans reported a higher rate of past suicide attempts, but higher suicide-related coping and help-seeking behaviour. Among participants without safety plans, negative attitudes toward safety planning were positively associated with suicidal ideation and negatively associated with suicide-related coping. LIMITATIONS: Participants were primarily female, English-speaking visitors to a mental health support website. Cross-sectional design precludes conclusions being drawn about safety planning effectiveness over time. CONCLUSION: This study highlights the low prevalence of safety plan use among online help-seekers with lifetime STBs and the need to better promote safety planning as an intervention with autonomous benefits, including crisis preparedness and improved suicide-related coping skills.
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Adaptación Psicológica , Conducta de Búsqueda de Ayuda , Internet , Ideación Suicida , Intento de Suicidio , Humanos , Femenino , Masculino , Adulto , Australia , Persona de Mediana Edad , Intento de Suicidio/psicología , Intento de Suicidio/estadística & datos numéricos , Adulto Joven , Adolescente , Encuestas y Cuestionarios , Prevención del Suicidio , Aceptación de la Atención de Salud/psicología , Aceptación de la Atención de Salud/estadística & datos numéricos , Estudios TransversalesRESUMEN
The study aimed to provide quantitative information on the utilization of MRI transverse relaxation time constant (MRI-T2) of leg muscles in DMD clinical trials by developing multivariate disease progression models of Duchenne muscular dystrophy (DMD) using 6-min walk distance (6MWD) and MRI-T2. Clinical data were collected from the prospective and longitudinal ImagingNMD study. Disease progression models were developed by a nonlinear mixed-effect modeling approach. Univariate models of 6MWD and MRI-T2 of five muscles were developed separately. Age at assessment was the time metric. Multivariate models were developed by estimating the correlation of 6MWD and MRI-T2 model variables. Full model estimation approach for covariate analysis and five-fold cross validation were conducted. Simulations were performed to compare the models and predict the covariate effects on the trajectories of 6MWD and MRI-T2. Sigmoid Imax and Emax models best captured the profiles of 6MWD and MRI-T2 over age. Steroid use, baseline 6MWD, and baseline MRI-T2 were significant covariates. The median age at which 6MWD is half of its maximum decrease in the five models was similar, while the median age at which MRI-T2 is half of its maximum increase varied depending on the type of muscle. The models connecting 6MWD and MRI-T2 successfully quantified how individual characteristics alter disease trajectories. The models demonstrate a plausible correlation between 6MWD and MRI-T2, supporting the use of MRI-T2. The developed models will guide drug developers in using the MRI-T2 to most efficient use in DMD clinical trials.