Socioeconomic Influence on Surgical Management and Outcomes in Patients with Craniosynostosis - A Systematic Review.

OBJECTIVE: Disparities in insurance and socioeconomic status (SES) may impact surgical management and subsequent postoperative outcomes for patients with craniosynostosis. This systematic review summarizes the evidence on possible differences in surgical care, including procedure type, age at surgery, and differences in surgical outcomes such as complications, length of hospital stay, and child development based on SES. DESIGN: The databases Scopus, PubMed, and CINAHL were searched between May and July 2022. Following PICO criteria, studies included focused on patients diagnosed with craniosynostosis; corrective surgery for craniosynostosis; comparison of insurance, income, or zip code; and surgical management of postoperative outcomes. RESULTS: The initial search yielded 724 articles. After three stages of screening, 13 studies were included. Assessed outcomes included: type of procedure (6 articles), age at time of surgery (3 articles), post-operative complications (3 articles), referral delay (2 articles), length of stay (2 articles), hospital costs (2 articles), and child development (1 article). Of the studies with significant results, insurance type was the main SES variable of comparison. While some findings were mixed, these studies indicated that patients with public medical insurance were more likely to experience a delay in referral, undergo an open rather than minimally-invasive procedure, and have more complications, longer hospitalization, and higher medical charges. CONCLUSIONS: This study demonstrated that SES may be associated with several differences in the management of patients with craniosynostosis. Further investigation into the impact of SES on the management of patients with craniosynostosis is warranted to identify possible interventions that may improve overall care.

Phosphonoacetate Modifications Enhance the Stability and Editing Yields of Guide RNAs for Cas9 Editors.

CRISPR gene editing and control systems continue to emerge and inspire novel research and clinical applications. Advances in CRISPR performance such as optimizing the duration of activity in cells, tissues, and organisms, as well as limiting off-target activities, have been extremely important for expanding the utility of CRISPR-based systems. By investigating the effects of various chemical modifications in guide RNAs (gRNAs) at defined positions and combinations, we find that 2'-O-methyl-3'-phosphonoacetate (MP) modifications can be substantially more effective than 2'-O-methyl-3'-phosphorothioate (MS) modifications at the 3' ends of single-guide RNAs (sgRNAs) to promote high editing yields, in some instances showing an order of magnitude higher editing yield in human cells. MP-modified 3' ends are especially effective at promoting the activity of guide RNAs cotransfected with Cas messenger RNA (mRNA), as the gRNA must persist in cells until the Cas protein is expressed. We demonstrate such an MP enhancement for sgRNAs cotransfected with a BE4 mRNA for cytidine base editing and also demonstrate that MP at the 3' ends of prime editing guide RNAs (pegRNAs) cotransfected with PE2 mRNA can promote maximal prime editing yields. In the presence of serum, sgRNAs with MP-modified 3' ends showed marked improvements in editing efficiency over sgRNAs with MS-modified 3' ends codelivered with Cas9 mRNA and showed more modest improvements at enhancing the activity of transfected ribonucleoprotein (RNP) complexes. Our results suggest that MP should be considered as a performance-enhancing modification for the 3' ends of synthetic gRNAs, especially in situations where the guide RNAs may be susceptible to exonuclease-mediated degradation.

A Multifaceted Approach to Improve Physician Communication Scores.

Improving patient satisfaction scores has become a key focus of health-care organizations nationwide but can be a struggle for community hospitals with constrained resources, and particularly challenging for hospitalist programs due to provider variance and turnover. Using the framework of appreciative inquiry, we implemented a multipronged intervention including a rounding model whereby hospitalist leaders rounded on patients and relayed commentary back to their hospitalist providers. We communicated positive feedback preferentially over negative feedback to the entire hospitalist group through regular communication. Providers were encouraged to employ best practices including sitting with the patient, reviewing recommendations using teach back, and providing business cards. Scores improved in the physician communication category by approximately 1% annually from fiscal year 2015 through 2018, with our percentile rank improving 35 percentile points during that time. These findings indicate that a multifaceted approach including best practices is associated with improved patient experience regarding communication with physicians.

Cage-templated synthesis of highly stable palladium nanoparticles and their catalytic activities in Suzuki-Miyaura coupling.

We report the controlled synthesis of small palladium nanoparticles (PdNPs) with narrow particle size distribution (1.8 ± 0.2 nm) using an organic molecular cage as a template. The well-defined cage structure and thioether anchoring groups inside the cavity are critical for the formation of narrowly distributed PdNPs, offering a confined organic molecular environment and guiding PdNP nucleation and growth. The resulting encapsulated PdNPs are resistant to agglomeration and stable in solution exposed to air at room temperature. When provided with a protective cage shell with minimum surface coverage, such PdNPs are capable of catalyzing organic reactions, showing high catalytic activity in Suzuki-Miyaura coupling reactions.

Synthesis of Metallic Nanoparticles Using Closed-Shell Structures as Templates.

The synthesis and study of metallic nanoparticles are of continued and significant interest, with applications in materials science, catalysis, and medicine. The properties of metallic nanoparticles depend strongly on their particle size, shape, and interparticle distances. It is therefore desirable for the synthesis of metallic nanoparticles to be controlled for specific shapes and sizes. The rapid development in this research area has attracted intense interest from researchers with diverse expertise, and numerous methods towards the synthesis of monodisperse nanoparticles have been reported. In this Focus Review, we provide an overview of recent progress in the development of the template synthesis of metallic nanoparticles using closed-shell structures, including biological molecules/assemblies and cage molecules.

Improving CRISPR-Cas specificity with chemical modifications in single-guide RNAs.

CRISPR systems have emerged as transformative tools for altering genomes in living cells with unprecedented ease, inspiring keen interest in increasing their specificity for perfectly matched targets. We have developed a novel approach for improving specificity by incorporating chemical modifications in guide RNAs (gRNAs) at specific sites in their DNA recognition sequence ('guide sequence') and systematically evaluating their on-target and off-target activities in biochemical DNA cleavage assays and cell-based assays. Our results show that a chemical modification (2'-O-methyl-3'-phosphonoacetate, or 'MP') incorporated at select sites in the ribose-phosphate backbone of gRNAs can dramatically reduce off-target cleavage activities while maintaining high on-target performance, as demonstrated in clinically relevant genes. These findings reveal a unique method for enhancing specificity by chemically modifying the guide sequence in gRNAs. Our approach introduces a versatile tool for augmenting the performance of CRISPR systems for research, industrial and therapeutic applications.

Synthesis of Ultrafine and Highly Dispersed Metal Nanoparticles Confined in a Thioether-Containing Covalent Organic Framework and Their Catalytic Applications.

Covalent organic frameworks (COFs) with well-defined and customizable pore structures are promising templates for the synthesis of nanomaterials with controllable sizes and dispersity. Herein, a thioether-containing COF has been rationally designed and used for the confined growth of ultrafine metal nanoparticles (NPs). Pt or Pd nanoparticles (Pt NPs and Pd NPs) immobilized inside the cavity of the COF material have been successfully prepared at a high loading with a narrow size distribution (1.7 ± 0.2 nm). We found the crystallinity of the COF support and the presence of thioether groups inside the cavities are critical for the size-controlled synthesis of ultrafine NPs. The as-prepared COF-supported ultrafine Pt NPs and Pd NPs show excellent catalytic activity respectively in nitrophenol reduction and Suzuki-Miyaura coupling reaction under mild conditions and low catalyst loading. More importantly, they are highly stable and easily recycled and reused without loss of their catalytic activities. Such COF-supported size-controlled synthesis of nanoparticles will open a new frontier on design and preparation of metal NP@COF composite materials for various potential applications, such as catalysis and development of optical and electronic materials.

Synthesis of Small-Molecule/DNA Hybrids through On-Bead Amide-Coupling Approach.

Small molecule/DNA hybrids (SMDHs) have been considered as nanoscale building blocks for engineering 2D and 3D supramolecular DNA assembly. Herein, we report an efficient on-bead amide-coupling approach to prepare SMDHs with multiple oligodeoxynucleotide (ODN) strands. Our method is high yielding under mild and user-friendly conditions with various organic substrates and homo- or mixed-sequenced ODNs. Metal catalysts and moisture- and air-free conditions are not required. The products can be easily analyzed by LC-MS with accurate mass resolution. We also explored nanometer-sized shape-persistent macrocycles as novel multitopic organic linkers to prepare SMDHs. SMDHs bearing up to six ODNs were successfully prepared through the coupling of arylenethynylene macrocycles with ODNs, which were used to mediate the assembly of gold nanoparticles.

Synthesis of a Two-Dimensional Covalent Organic Monolayer through Dynamic Imine Chemistry at the Air/Water Interface.

A two-dimensional covalent organic monolayer was synthesized from simple aromatic triamine and dialdehyde building blocks by dynamic imine chemistry at the air/water interface (Langmuir-Blodgett method). The obtained monolayer was characterized by optical microscopy, scanning electron microscopy, and atomic force microscopy, which unambiguously confirmed the formation of a large (millimeter range), unimolecularly thin aromatic polyimine sheet. The imine-linked chemical structure of the obtained monolayer was characterized by tip-enhanced Raman spectroscopy, and the peak assignment was supported by spectra simulated by density functional theory. Given the modular nature and broad substrate scope of imine formation, the work reported herein opens up many new possibilities for the synthesis of customizable 2D polymers and systematic studies of their structure-property relationships.

Template synthesis of gold nanoparticles with an organic molecular cage.

We report a novel strategy for the controlled synthesis of gold nanoparticles (AuNPs) with narrow size distribution (1.9 ± 0.4 nm) through NP nucleation and growth inside the cavity of a well-defined three-dimensional, shape-persistent organic molecular cage. Our results show that both a well-defined cage structure and pendant thioether groups pointing inside the cavity are essential for the AuNP synthesis.

Design strategies for shape-persistent covalent organic polyhedrons (COPs) through imine condensation/metathesis.

A series of dialdehyde compounds were synthesized and reacted with the complementary triamines (either planar or pyramidal with a 109.5° vertex) in a 3:2 ratio to explore the structural requirements on the building blocks for the successful construction of shape-persistent, covalent organic polyhedrons (COPs). Structural variations in the building blocks included the distance and angle between the two reactive sites (aldehyde or amine functional groups) and the absence/presence of solubilizing chains. Computer modeling was utilized to determine and compare the thermodynamic stabilities of some of these COP structures. Furthermore, gas adsorption studies were performed to explore the potential of these molecular cages for gas separation, particularly carbon capture, applications.

DNA polymerase POLN participates in cross-link repair and homologous recombination.

All cells rely on DNA polymerases to duplicate their genetic material and to repair or bypass DNA lesions. In humans, 16 polymerases have been identified, and each bears specific functions in genome maintenance. We identified here the recently discovered polymerase POLN to be involved in repair of DNA cross-links. Such DNA lesions are highly toxic and are believed to be repaired by the sequential activity of nucleotide excision repair, translesion synthesis, and homologous recombination mechanisms. By functionally assaying its role in these processes, we unraveled an unexpected involvement of POLN in homologous recombination. Moreover, we obtained evidence for physical and functional interaction of POLN with factors belonging to the Fanconi anemia pathway, a master regulator of cross-link repair. Finally, we show that POLN interacts and cooperates in DNA repair with the helicase HEL308, which shares a common origin with POLN in the Drosophila mus308 gene. Our data indicate that this novel polymerase-helicase complex participates in homologous recombination repair and is essential for cellular protection against DNA cross-links.

The Fanconi anemia core complex is required for efficient point mutagenesis and Rev1 foci assembly.

Fanconi anemia (FA) is a chromosome instability syndrome characterized by congenital abnormalities, cellular hypersensitivity to DNA crosslinking agents, and heightened cancer risk. Eight of the thirteen identified FA genes encode subunits of a nuclear FA core complex that monoubiquitinates FANCD2 and FANCI to maintain genomic stability in response to replication stress. The FA pathway has been implicated in the regulation of error-prone DNA damage tolerance via an undefined molecular mechanism. Here, we show that the FA core complex is required for efficient spontaneous and UVC-induced point mutagenesis, independently of FANCD2 and FANCI. Consistent with the observed hypomutability of cells deficient in the FA core complex, we also demonstrate that these cells are impaired in the assembly of the error-prone translesion DNA synthesis polymerase Rev1 into nuclear foci. Consistent with a role downstream of the FA core complex and like known FA proteins, Rev1 is required to prevent DNA crosslinker-induced chromosomal aberrations in human cells. Interestingly, proliferating cell nuclear antigen (PCNA) monoubiquitination, known to contribute to Rev1 recruitment, does not require FA core complex function. Our results suggest a role for the FA core complex in regulating Rev1-dependent DNA damage tolerance independently of FANCD2, FANCI, and PCNA monoubiquitination.