Cerebral cavernous malformation is a vascular disease associated with activated RhoA signaling

Cerebral cavernous malformation (CCM) involves the homozygous inactivating mutations of one of three genes, ccm1, -2, or -3 resulting in hyperpermeable blood vessels in the brain. The CCM1, -2, and -3 proteins form a complex to organize the signaling networks controlling endothelial cell physiology including actin dynamics, tube formation, and adherens junctions. The common biochemical defect with the loss of CCM1, -2, or -3 is increased RhoA activity leading to the activation of Rho-associated coiled coil-forming kinase (ROCK). Inhibition of the ROCK rescues CCM endothelial cell dysfunction, suggesting that the inhibition of RhoA-ROCK signaling may be a therapeutic strategy to prevent or arrest the progression of the CCM lesions

Genome-wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease.

Identifying genetic variants associated with circulating protein concentrations (protein quantitative trait loci; pQTLs) and integrating them with variants from genome-wide association studies (GWAS) may illuminate the proteome's causal role in disease and bridge a knowledge gap regarding SNP-disease associations. We provide the results of GWAS of 71 high-value cardiovascular disease proteins in 6861 Framingham Heart Study participants and independent external replication. We report the mapping of over 16,000 pQTL variants and their functional relevance. We provide an integrated plasma protein-QTL database. Thirteen proteins harbor pQTL variants that match coronary disease-risk variants from GWAS or test causal for coronary disease by Mendelian randomization. Eight of these proteins predict new-onset cardiovascular disease events in Framingham participants. We demonstrate that identifying pQTLs, integrating them with GWAS results, employing Mendelian randomization, and prospectively testing protein-trait associations holds potential for elucidating causal genes, proteins, and pathways for cardiovascular disease and may identify targets for its prevention and treatment

A new measure for multi-professional medical team communication: design and methodology for multilingual measurement development

BackgroundAs implementation science in global health continues to evolve, there is a need for valid and reliable measures that consider diverse linguistic and cultural contexts. A standardized, reproducible process for multilingual measure development may improve accessibility and validity by participants in global health settings. To address this need, we propose a rigorous methodology for multilingual measurement development. We use the example of a novel measure of multi-professional team communication quality, a determinant of implementation efforts.MethodsThe development and translation of this novel bilingual measure is comprised of seven steps. In this paper, we describe a measure developed in English and Spanish, however, this approach is not language specific. Participants are engaged throughout the process: first, an interprofessional panel of experts and second, through cognitive interviewing for measure refinement. The steps of measure development included: (1) literature review to identify previous measures of team communication; (2) development of an initial measure by the expert panel; (3) cognitive interviewing in a phased approach with the first language (English); (4): formal, forward-backward translation process with attention to colloquialisms and regional differences in languages; (5) cognitive interviewing repeated in the second language (Spanish); (6) language synthesis to refine both instruments and unify feedback; and (7) final review of the refined measure by the expert panel.ResultsA draft measure to assess quality of multi-professional team communication was developed in Spanish and English, consisting of 52 questions in 7 domains. This measure is now ready for psychometric testing.ConclusionsThis seven-step, rigorous process of multilingual measure development can be used in a variety of linguistic and resource settings. This method ensures development of valid and reliable tools to collect data from a wide range of participants, including those who have historically been excluded due to language barriers. Use of this method will increase both rigor and accessibility of measurement in implementation science and advance equity in research and practice

Osteoinductive Nanocomposites for use as Bone Scaffold Materials Useful with 3D Printing

Worldwide, over 4.5 million bone tissue reconstructive surgical procedures are performed annually to treat bone defects. Due to bone infections, bone tumors, congenital disabilities, and fracture caused by traumatic injuries in which extensive bone mass is missing, lost, or damaged, there becomes a need to use materials to repair bone. Historically, doctors started repairing bone using brute force methods, for example, fixation using steel rods. Overtime, the materials, and technologies used to repair bone have progressed from using metal and ceramic implants, which completely replace bone to the current field of tissue engineering, which aims to leverage our body’s natural ability to heal and reform bone with the help of a 3D scaffold. Such an evolution is due to extensive research efforts to develop materials and regenerative therapies that lead to regenerative healing resulting in the bone as opposed to the permanent replacement of bone. The goal of this project is to develop materials to meet this need. The development of nanocomposites using calcium carbonate nanorods would be a cost-efficient method to initiate osteoinductivity. Incorporation of rod-shaped nanoparticles will also reinforce the polymer matrices and produce directionally dependent mechanical and barrier properties upon extrusion; these properties are interrelated to the material degradation. The addition of calcium carbonate nanoparticles will increase the melt viscosity of these polyesters. The investigating of these nanocomposites to establish the structure-property relationship will allow for nanocomposite design considering both bone scaffold performance, and fabrication using 3D printing

Cerebral cavernous malformation is a vascular disease associated with activated RhoA signaling

Cerebral cavernous malformation (CCM) involves the homozygous inactivating mutations of one of three genes, ccm1, -2, or -3 resulting in hyperpermeable blood vessels in the brain. The CCM1, -2, and -3 proteins form a complex to organize the signaling networks controlling endothelial cell physiology including actin dynamics, tube formation, and adherens junctions. The common biochemical defect with the loss of CCM1, -2, or -3 is increased RhoA activity leading to the activation of Rho-associated coiled coil-forming kinase (ROCK). Inhibition of the ROCK rescues CCM endothelial cell dysfunction, suggesting that the inhibition of RhoA-ROCK signaling may be a therapeutic strategy to prevent or arrest the progression of the CCM lesions

Rho Kinase Inhibition Rescues the Endothelial Cell Cerebral Cavernous Malformation Phenotype*

Cerebral cavernous malformations (CCM) are vascular lesions causing seizures and stroke. Mutations causing inactivation of one of three genes, ccm1, -2, or -3, are sufficient to induce vascular endothelial cell defects resulting in CCM. Herein, we show that loss of expression of the CCM1, -2, or -3 proteins causes a marked increase in expression of the GTPase RhoA. Live cell imaging with a RhoA-specific biosensor demonstrates increased RhoA activity with loss of CCM1, -2, or -3, with an especially pronounced RhoA activation in both the cytosol and the nucleus with loss of CCM1 expression. Increased RhoA activation was associated with Rho kinase-dependent phosphorylation of myosin light chain 2. Functionally, loss of CCM1, -2, or -3 inhibited endothelial cell vessel-like tube formation and extracellular matrix invasion, each of which is rescued by chemical inhibition or short hairpin RNA knockdown of Rho kinase. The findings, for the first time, define a signaling network for CCM1, -2, and -3 in CCM pathology, whereby loss of CCM1, -2, or -3 protein expression results in increased RhoA activity, with the activation of Rho kinase responsible for endothelial cell dysregulation. The results define Rho kinase as a therapeutic target to rescue endothelial cells from loss of CCM protein function

Author Correction: Genome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease

In the originally published version of this Article, financial support was not fully acknowledged. The sentence “KS was supported by the ‘Biomedical Research Program’ funds at Weill Cornell Medicine in Qatar, a program funded by the Qatar Foundation” has been added to the acknowledgement section in both the PDF and HTML versions of the Article

DataSheet_1_CritCom: assessment of quality of interdisciplinary communication around deterioration in pediatric oncologic patients.docx

BackgroundHigh-quality clinical care requires excellent interdisciplinary communication, especially during emergencies, and no tools exist to evaluate communication in critical care. We describe the development of a pragmatic tool focusing on interdisciplinary communication during patient deterioration (CritCom).MethodsThe preliminary CritCom tool was developed after a literature review and consultation with a multidisciplinary panel of global experts in communication, pediatric oncology, and critical care to review the domains and establish content validity iteratively. Face and linguistic validity were established through cognitive interviews, translation, and linguistic synthesis. We conducted a pilot study among an international group of clinicians to establish reliability and usability.ResultsAfter reviewing 105 potential survey items, we identified 52 items across seven domains. These were refined through cognitive interviews with 36 clinicians from 15 countries. CritCom was piloted with 433 clinicians (58% nurses, 36% physicians, and 6% other) from 42 hospitals in 22 countries. Psychometric testing guided the refinement of the items for the final tool. CritCom comprised six domains with five items each (30 total). The final tool has excellent reliability (Cronbach’s alpha 0.81-0.86), usability (93% agree or strongly agree that the tool is easy to use), and similar performance between English and Spanish tools. Confirmatory factor analysis was used to establish the final 6-domain structure.ConclusionsCritCom is a reliable and pragmatic bilingual tool to assess the quality of interdisciplinary communication around patient deterioration for children in diverse resource levels globally. Critcom results can be used to design and evaluate interventions to improve team communication.</p