The nasal spine suture: A novel approach for membrane stabilization.

BACKGROUND: Current evidence acknowledges guided bone regeneration (GBR) as a predictable therapeutic modality in the augmentation of a deficient alveolar ridge. Such deficiencies often reveal inadequate bone volume to support implant placement in a position amenable to prosthetic reconstruction. Additionally, an evolving body of literature demonstrates that membrane fixation may lead to improved clinical bone gain through positively influencing blood clot formation, stability, and the eventual osteogenic potential of the defect. Alternative benefits to membrane fixation, such as reduced graft displacement and reduction in wound micromotion, have also been cited as mechanisms for an increased regenerative response. METHODS AND RESULTS: The aim of this report was to present a case, including diagnosis, treatment, and follow-up for the reconstruction of a horizontal ridge deficiency. The patient's deficiency in ridge volume was found to be a developmental sequelae of lateral incisor agenesis, resulting in an underdeveloped midfacial region of the alveolar process subjacent to sites #7 and #10. The fixation protocol outlined in this report demonstrated adequate horizontal ridge augmentation to facilitate future prosthetic reconstruction with the use of implants. CONCLUSIONS: Numerous protocols have been established in an attempt to achieve effective barrier membrane stabilization for bone augmentation procedures. However, some techniques are poorly suited for the anatomically challenging region of the anterior maxilla. A case report describing the utilization of the anterior nasal spine for anchorage of a membrane-stabilizing suture may present a novel, safe, and effective technique for stabilizing the intended region of augmentation, as well as preventing graft migration beyond the membrane-maxilla interface. Key points Regarding guided bone regeneration (GBR) procedures, micromotion of the membrane or of the underlying particulate graft may negatively influence the volume of the augmented site. The ability to adequately stabilize the graft-membrane interface is recognized as a necessary prerequisite to predictably achieve optimal surgical outcomes. To the authors' knowledge, there is no clinical or scientific evidence regarding the use of the anterior nasal spine for membrane anchorage in maxillary GBR procedures, and thus a novel approach to membrane stabilization is introduced.

Artificial Intelligence for the Interventional Cardiologist: Powering and Enabling OCT Image Interpretation.

Intravascular optical coherence tomography (IVOCT) is a form of intra-coronary imaging that uses near-infrared light to generate high-resolution, cross-sectional, and 3D volumetric images of the vessel. Given its high spatial resolution, IVOCT is well-placed to characterise coronary plaques and aid with decision-making during percutaneous coronary intervention. IVOCT requires significant interpretation skills, which themselves require extensive education and training for effective utilisation, and this would appear to be the biggest barrier to its widespread adoption. Various artificial intelligence-based tools have been utilised in the most contemporary clinical IVOCT systems to facilitate better human interaction, interpretation and decision-making. The purpose of this article is to review the existing and future technological developments in IVOCT and demonstrate how they could aid the operator.

A genotyping array for the globally invasive vector mosquito, Aedes albopictus.

BACKGROUND: Although whole-genome sequencing (WGS) is the preferred genotyping method for most genomic analyses, limitations are often experienced when studying genomes characterized by a high percentage of repetitive elements, high linkage, and recombination deserts. The Asian tiger mosquito (Aedes albopictus), for example, has a genome comprising up to 72% repetitive elements, and therefore we set out to develop a single-nucleotide polymorphism (SNP) chip to be more cost-effective. Aedes albopictus is an invasive species originating from Southeast Asia that has recently spread around the world and is a vector for many human diseases. Developing an accessible genotyping platform is essential in advancing biological control methods and understanding the population dynamics of this pest species, with significant implications for public health. METHODS: We designed a SNP chip for Ae. albopictus (Aealbo chip) based on approximately 2.7 million SNPs identified using WGS data from 819 worldwide samples. We validated the chip using laboratory single-pair crosses, comparing technical replicates, and comparing genotypes of samples genotyped by WGS and the SNP chip. We then used the chip for a population genomic analysis of 237 samples from 28 sites in the native range to evaluate its usefulness in describing patterns of genomic variation and tracing the origins of invasions. RESULTS: Probes on the Aealbo chip targeted 175,396 SNPs in coding and non-coding regions across all three chromosomes, with a density of 102 SNPs per 1 Mb window, and at least one SNP in each of the 17,461 protein-coding genes. Overall, 70% of the probes captured the genetic variation. Segregation analysis found that 98% of the SNPs followed expectations of single-copy Mendelian genes. Comparisons with WGS indicated that sites with genotype disagreements were mostly heterozygotes at loci with WGS read depth < 20, while there was near complete agreement with WGS read depths > 20, indicating that the chip more accurately detects heterozygotes than low-coverage WGS. Sample sizes did not affect the accuracy of the SNP chip genotype calls. Ancestry analyses identified four to five genetic clusters in the native range with various levels of admixture. CONCLUSIONS: The Aealbo chip is highly accurate, is concordant with genotypes from WGS with high sequence coverage, and may be more accurate than low-coverage WGS.

Accelerating the open research agenda to solve global challenges.

Harnessing science-based policy is key to addressing global challenges like the biodiversity and climate crises. Open research principles underpin effective science-based policy, but the uptake of these principles is likely constrained by the politicisation, commoditisation and conflicting motives of stakeholders in the research landscape. Here, using the mission and vision statements from 129 stakeholders from across the research landscape, we explore alignment in open research principles between stakeholders. We find poor alignment between stakeholders, largely focussed around journals, societies and funders, all of which have low open research language-use. We argue that this poor alignment stifles knowledge flow within the research landscape, ultimately limiting the mobilisation of impactful science-based policy. We offer recommendations on how the research landscape could embrace open research principles to accelerate societies' ability to solve global challenges.

Factors influencing intraoperative and postoperative complication occurrence: A series of 1135 periodontal and implant-related surgeries.

OBJECTIVES: In periodontology, it is widely recognized that evidence characterizing the incidence and effect of treatment complications is lacking. The objective of this study was to assess the influence of operator-, procedure-, patient-, and site-associated factors on intraoperative and postoperative complication occurrence. MATERIAL AND METHODS: A single investigator reviewed records of patients treated by eight periodontics residents from July 2018 through June 2022. For each procedure, the investigator recorded each intraoperative and postoperative complication or indicated that no complication had occurred. These outcomes were analyzed against a panel of explanatory covariates. In addition, the severity of each postoperative complication was assessed using a standardized grading system. RESULTS: A total of 1135 procedures were included in the analysis. Intraoperative and postoperative complications were identified in 2.8% and 15.2% of procedures, respectively. The most common intraoperative complications were Schneiderian membrane perforation (1.3%) and gingival flap perforation/tear (1%), and the most common postoperative complications were dentin hypersensitivity (2.6%), excessive pain (2.5%), and infection (2.2%). Subepithelial connective tissue graft (odds ratio [OR]: 3.2, 95% confidence interval [CI]: 1.6, 6.1; p < .001), guided bone regeneration (OR: 3.0, 95% CI: 1.4, 6.5; p = .004), and guided bone regeneration with implant placement (OR: 3.1, 95% CI: 1.3, 7.6; p = .011) were associated with higher odds of postoperative complication, whereas lateral sinus elevation (OR: 102.5, 95% CI: 12.3, 852.9; p < .001), transalveolar sinus elevation (OR: 22.4, 95% CI: 2.2, 224.5; p = .008), open flap debridement (OR: 36.4, 95% CI: 3.0, 440.7; p = .005), and surgically facilitated orthodontic therapy (OR: 20.5, 95% CI: 1.2, 358.4; p = .039) were associated with higher odds of intraoperative complication occurrence. CONCLUSIONS: Consistent with previous reports, procedure type appears to be the predominant factor driving complication occurrence. As analyses of treatment complications increase, individualized risk-benefit assessments will become progressively meaningful for patients.

Long-Term Percutaneous Coronary Intervention Outcomes in Chronic Versus Acute Coronary Syndromes (TARGET All Comers Trial).

In the Targeted therapy with a localised abluminal coated, low-dose sirolimus-eluting, biodegreadable polymer coronary stent (TARGET; NCT02520180) All Comers trial the biodegradable polymer (BP) sirolimus-eluting FIREHAWK stent was noninferior to the durable polymer (DP) everolimus-eluting XIENCE stent with respect to target lesion failure (TLF) at 1 and 5 years; however, the long-term safety and efficacy in the setting of acute coronary syndromes (ACS) are not known. We sought to assess the long-term outcomes in ACS versus chronic coronary syndromes (CCS) with BP sirolimus-eluting stent (SES) versus DP everolimus-eluting stent (EES). The TARGET AC study was a multicenter, open-label, noninferiority trial of all comer patients randomly allocated 1:1 to BP SES or DP EES (stratified by ST-elevation myocardial infarction and study site). In this predefined substudy, the outcomes were compared based on clinical presentation (ACS vs CCS) and treatment allocation. A total of 1,653 patients were enrolled (728 with ACS and 922 with CCS), with 94% completing the 5-year follow-up. The baseline characteristics were well-matched between the 2 stent types; however, co-morbidities were more prevalent in the CCS than in the ACS population. TLF (15.5% vs 17.7%, p = 0.24), patient-oriented outcomes (32.0% vs 34.4%, p = 0.31), and stent thrombosis (4.1% vs 3.3%, p = 0.40) were similar between patients with ACS and patients with CCS. In the ACS cohort, the outcomes at 5 years for BP SES versus DP EES were similar for TLF (16.0% vs 14.9%, p = 0.70), ischemia-driven target lesion revascularization (5.6% vs 8.3%, p = 0.17), and definite/probable stent thrombosis (2.7% vs 4.6%, p = 0.18). The same was true for the CCS cohort, with 5-year outcomes for BP SES versus DP EES for TLF (18.0% vs 17.4%, p = 0.82), ischemia-driven target lesion revascularization (6.4% vs 5.0%, p = 0.37), and definite/probable stent thrombosis (3.0% vs 1.8%, p = 0.26). In conclusion, in the TARGET AC trial, 1 in 3 patients had a major adverse event at 5 years, irrespective of CCS or ACS presentation. Long-term, the BP sirolimus-eluting FIREHAWK stent was as safe and effective as the DP everolimus-eluting XIENCE stent across the spectrum of clinical presentations.

Capabilities and Limitations of Student-Led Free Vision Screening Programs in the United States.

Purpose: The Consortium of Student-Led Eye Clinics (CSLEC), founded in 2021, administered a comprehensive survey to document the types of services, most common diagnoses, and follow-up care protocols offered by student-led free vision screening programs (SLFVSP) in the United States. Methods: An 81-question institutional review board (IRB)-approved survey was administered to student-led vision screening eye clinics from October 1, 2022 to February 24, 2023. Results: Sixteen SLFVSPs were included in the final analysis, of which 81% (n = 13) conducted variations of fundoscopic examinations and 75% (n = 12) measured intraocular pressure. Cataracts and diabetic retinopathy were reported as the most frequent diagnoses by the majority of SLFVSPs (n = 9, 56%); non-mobile SLFVSPs more commonly reported cataract as a frequent diagnosis (P < 0.05). Most patients screened at participating programs were uninsured or met federal poverty guidelines. Prescription glasses were offered by 56% of the programs (n = 9). SLFVSPs that directly scheduled follow-up appointments reported higher attendance rates (66.5%) than those that only sent referrals (20%). Transportation was the most cited barrier for follow-up appointment attendance. Conclusions: SLFVSPs, one community vision screening initiative subtype, vary significantly in scope and capabilities of identifying vision threatening disease. The follow-up infrastructure is not uniformly robust and represents a key target for improving care delivery to at-risk populations. Translational Relevance: The CSLEC aims to develop a consensus-based standardization for the scope of screening services, offer guidelines for diagnostic criteria, promote real-time data stewardship, and identify means to improve follow-up care mechanisms in member communities.

Predictors of standardized in-service examination performance and residency outcomes in a graduate periodontics program.

PURPOSE/OBJECTIVES: The objectives of this study were to assess the influence of learner- and education-related factors on standardized in-service examination performance and determine whether in-service examination scores predict residency outcomes. METHODS: American Academy of Periodontology (AAP) In-service Examination (AIE) scores from 10 periodontics residency classes at a single center were recorded and compared against a panel of learner- and education-related variables using multiple linear regression models. Defined residency outcome measures were analyzed against AIE scores using binomial logistic regression. RESULTS: No evaluated learner- or education-related variable was a statistically significant predictor of AIE score in this study sample. Likewise, AIE score was not a statistically significant predictor of any assessed residency outcome. CONCLUSIONS: The AAP has performed a tremendous service to periodontics residents and programs by marshaling the leadership and expertise necessary to offer a professionally constructed assessment instrument. However, in the current study, no relationship could be identified between AIE score and any outcome, including first-attempt board certification. The AAP In-service Committee appears well situated to provide additional leadership focusing on exam implementation, which may enhance AIE value in competency decision making.

Percutaneous Coronary Interventions Using a Ridaforolimus-Eluting Stent in Patients at High Bleeding Risk.

BACKGROUND: Patients treated with percutaneous coronary intervention are often considered to be at a high bleeding risk (HBR). Drug-eluting stents have been shown to be superior to bare-metal stents in patients with HBR, even when patients were given abbreviated periods of dual antiplatelet therapy (DAPT). Short DAPT has not been evaluated with the EluNIR ridaforolimus-eluting stent. The aim of this study was to evaluate the safety and efficacy of a shortened period of DAPT following implantation of the ridaforolimus-eluting stent in patients with HBR. METHODS AND RESULTS: This was a prospective, multicenter, binational, single-arm, open-label trial. Patients were defined as HBR according to the LEADERS-FREE (Prospective Randomized Comparison of the BioFreedom Biolimus A9 Drug-Coated Stent versus the Gazelle Bare-Metal Stent in Patients at High Bleeding Risk) trial criteria. After percutaneous coronary intervention, DAPT was given for 1 month to patients presenting with stable angina. In patients presenting with an acute coronary syndrome, DAPT was given for 1 to 3 months, at the investigator's discretion. The primary end point was a composite of cardiac death, myocardial infarction, or stent thrombosis up to 1 year (Academic Research Consortium definite and probable). Three hundred fifteen patients undergoing percutaneous coronary intervention were enrolled, and 56.4% presented with acute coronary syndrome; 33.7% were receiving oral anticoagulation. At 1 year, the primary end point occurred in 15 patients (4.9%), meeting the prespecified performance goal of 14.1% (P<0.0001). Stent thrombosis (Academic Research Consortium definite and probable) occurred in 2 patients (0.6%). Bleeding Academic Research Consortium type 3 and 5 bleeding occurred in 6 patients (1.9%). CONCLUSIONS: We observed favorable results in patients with HBR who underwent percutaneous coronary intervention with a ridaforolimus-eluting stent and received shortened DAPT, including a low rate of ischemic events and low rate of stent thrombosis. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03877848.

A double-blind, randomised, placebo-controlled trial of the coronary sinus Reducer in refractory angina: design and rationale of the ORBITA-COSMIC trial.

The coronary sinus Reducer (CSR) is an hourglass-shaped device which creates an artificial stenosis in the coronary sinus. Whilst placebo-controlled data show an improvement in angina, these results are unreplicated and are the subject of further confirmatory research. The mechanism of action of this unintuitive therapy is unknown. The Coronary Sinus Reducer Objective Impact on Symptoms, MRI Ischaemia, and Microvascular Resistance (ORBITA-COSMIC) trial is a randomised, placebo-controlled, double-blind trial investigating the efficacy of the CSR. Patients with (i) established epicardial coronary artery disease, (ii) angina on maximally tolerated antianginal medication, (iii) evidence of myocardial ischaemia and (iv) no further options for percutaneous coronary intervention or coronary artery bypass grafting will be enrolled. Upon enrolment, angina and quality-of-life questionnaires, treadmill exercise testing and quantitative stress perfusion cardiac magnetic resonance (CMR) imaging will be performed. Participants will record their symptoms daily on a smartphone application throughout the trial. After a 2-week symptom assessment phase, participants will be randomised in the cardiac catheterisation laboratory to CSR or a placebo procedure. After 6 months of blinded follow-up, all prerandomisation tests will be repeated. A prespecified subgroup will undergo invasive coronary physiology assessment at prerandomisation and follow-up. The primary outcome is stress myocardial blood flow on CMR. Secondary outcomes include angina frequency, quality of life and treadmill exercise time. (ClinicalTrials.gov: NCT04892537).

Orbital Abscess Secondary to Nasolacrimal Duct Obstruction in an Extremely Preterm Infant.

Orbital abscesses are rarely encountered in children younger than 1 year. The literature is limited to isolated case reports and a few case series. Most such cases are reported in infants born at term, with the earliest reported gestational birth age at 34 weeks. Children are more prone to orbital cellulitis compared with adults due to their underdeveloped sinuses and immature immune systems, and the origin is most commonly an ethmoid sinus infection. Orbital cellulitis secondary to dacryocystitis is even less common, with only a few isolated cases reported in infants and children. Herein, the authors present a case of a large extraconal and intraconal orbital abscess secondary to nasolacrimal duct obstruction and dacryocystitis in an extremely preterm infant. We discuss the diagnosis and multidisciplinary management of this challenging case.

Peptide ligands targeting the vesicular stomatitis virus G (VSV-G) protein for the affinity purification of lentivirus particles.

The recent uptick in the approval of ex vivo cell therapies highlights the relevance of lentivirus (LV) as an enabling viral vector of modern medicine. As labile biologics, however, LVs pose critical challenges to industrial biomanufacturing. In particular, LV purification-currently reliant on filtration and anion-exchange or size-exclusion chromatography-suffers from long process times and low yield of transducing particles, which translate into high waiting time and cost to patients. Seeking to improve LV downstream processing, this study introduces peptides targeting the enveloped protein Vesicular stomatitis virus G (VSV-G) to serve as affinity ligands for the chromatographic purification of LV particles. An ensemble of candidate ligands was initially discovered by implementing a dual-fluorescence screening technology and a targeted in silico approach designed to identify sequences with high selectivity and tunable affinity. The selected peptides were conjugated on Poros resin and their LV binding-and-release performance was optimized by adjusting the flow rate, composition, and pH of the chromatographic buffers. Ligands GKEAAFAA and SRAFVGDADRD were selected for their high product yield (50%-60% of viral genomes; 40%-50% of HT1080 cell-transducing particles) upon elution in PIPES buffer with 0.65 M NaCl at pH 7.4. The peptide-based adsorbents also presented remarkable values of binding capacity (up to 3·109 TU per mL of resin, or 5·1011 vp per mL of resin, at the residence time of 1 min) and clearance of host cell proteins (up to a 220-fold reduction of HEK293 HCPs). Additionally, GKEAAFAA demonstrated high resistance to caustic cleaning-in-place (0.5 M NaOH, 30 min) with no observable loss in product yield and quality.

Early Endophthalmitis Incidence and Risk Factors after Glaucoma Surgery in the Medicare Population from 2016 to 2019.

PURPOSE: To determine early endophthalmitis incidence and risk factors after glaucoma surgeries in the Medicare population. DESIGN: Retrospective, longitudinal study. PARTICIPANTS: Medicare Fee-for-Service (FFS) and Medicare Advantage beneficiaries in the United States aged 65 years or older undergoing glaucoma surgery. METHODS: Medicare claims were used to identify all patients who underwent glaucoma, cataract, or combined cataract/glaucoma surgery from 2016 to 2019. Endophthalmitis cases within 42 days of the index surgery were identified using the diagnostic codes. Multivariable logistic regression models were used to evaluate factors associated with postoperative endophthalmitis. MAIN OUTCOME MEASURES: The 42-day postoperative endophthalmitis incidence and risk factors associated with endophthalmitis after glaucoma surgery. RESULTS: There were 466 928 glaucoma surgeries, of which 310 823 (66.6%) were combined with cataract surgery. Cataract surgeries alone (n = 8 460 360) served as a reference group. Microinvasive glaucoma surgeries constituted most glaucoma procedures performed (67.8%), followed by trabeculectomy (14.0%), tube shunt (10.9%), and other procedures (7.3%). There were 572 cases of endophthalmitis identified after all glaucoma surgeries. Endophthalmitis incidence after glaucoma, combined cataract/glaucoma, and cataract surgeries alone was 1.5 (95% confidence interval [CI], 1.3-1.7), 1.1 (95% CI, 1.0-1.2), and 0.8 (95% CI, 0.8-0.8) per 1000 procedures, respectively. The median day of diagnosis of endophthalmitis was later for glaucoma surgeries (16.5 days) compared with combined cataract/glaucoma or cataract surgeries alone (8 and 6 days, respectively). Compared with microinvasive glaucoma surgery (MIGS), tube shunts were the only surgery type to be a significant risk factor for endophthalmitis for both stand-alone (adjusted odds ratio [aOR], 1.8, P = 0.002) and combined surgery (aOR 1.8, P = 0.047). The other risk factor for both stand-alone (aOR 1.1, P = 0.001) and combined (aOR 1.06, P = 0.049) surgeries was the Charlson Comorbidity Index (CCI). Age (aOR 1.03, P = 0.004) and male gender (1.46, P = 0.001) were significant risk factors for combined cataract and glaucoma surgeries. CONCLUSIONS: Compared with cataract surgery, early endophthalmitis incidence was higher for both glaucoma and combined cataract/glaucoma surgeries, with the highest incidence among tube shunts. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Rational design and experimental evaluation of peptide ligands for the purification of adeno-associated viruses via affinity chromatography.

Adeno-associated viruses (AAVs) have acquired a central role in modern medicine as delivery agents for gene therapies targeting rare diseases. While new AAVs with improved tissue targeting, potency, and safety are being introduced, their biomanufacturing technology is lagging. In particular, the AAV purification pipeline hinges on protein ligands for the affinity-based capture step. While featuring excellent AAV binding capacity and selectivity, these ligands require strong acid (pH <3) elution conditions, which can compromise the product's activity and stability. Additionally, their high cost and limited lifetime has a significant impact on the price tag of AAV-based therapies. Seeking to introduce a more robust and affordable affinity technology, this study introduces a cohort of peptide ligands that (i) mimic the biorecognition activity of the AAV receptor (AAVR) and anti-AAV antibody A20, (ii) enable product elution under near-physiological conditions (pH 6.0), and (iii) grant extended reusability by withstanding multiple regenerations. A20-mimetic CYIHFSGYTNYNPSLKSC and AAVR-mimetic CVIDGSQSTDDDKIC demonstrated excellent capture of serotypes belonging to distinct clones/clades - namely, AAV1, AAV2, AAV5, AAV6, AAV8, and AAV9. This corroborates the in silico models documenting their ability to target regions of the viral capsid that are conserved across all serotypes. CVIDGSQSTDDDKIC-Toyopearl resin features binding capacity (≈1014 vp mL-1 ) and product yields (≈60%-80%) on par with commercial adsorbents, and purifies AAV2 from HEK293 and Sf9 cell lysates with high recovery (up to 78%), reduction of host cell proteins (up to 700-fold), and high transduction activity (up to 65%).

Ticagrelor inverse agonist activity at the P2Y12 receptor is non-reversible versus its endogenous agonist adenosine 5´-diphosphate.

BACKGROUND AND PURPOSE: Ticagrelor is labelled as a reversible, direct-acting platelet P2Y12 receptor (P2Y12 R) antagonist that is indicated clinically for the prevention of thrombotic events in patients with acute coronary syndrome (ACS). As with many antiplatelet drugs, ticagrelor therapy increases bleeding risk in patients, which may require platelet transfusion in emergency situations. The aim of this study was to further examine the reversibility of ticagrelor at the P2Y12 R. EXPERIMENTAL APPROACH: Studies were performed in human platelets, with P2Y12 R-stimulated GTPase activity and platelet aggregation assessed. Cell-based bioluminescence resonance energy transfer (BRET) assays were undertaken to assess G protein-subunit activation downstream of P2Y12 R activation. KEY RESULTS: Initial studies revealed that a range of P2Y12 R ligands, including ticagrelor, displayed inverse agonist activity at P2Y12 R. Only ticagrelor was resistant to washout and, in human platelet and cell-based assays, washing failed to reverse ticagrelor-dependent inhibition of ADP-stimulated P2Y12 R function. The P2Y12 R agonist 2MeSADP, which was also resistant to washout, was able to effectively compete with ticagrelor. In silico docking revealed that ticagrelor and 2MeSADP penetrated more deeply into the orthosteric binding pocket of the P2Y12 R than other P2Y12 R ligands. CONCLUSION AND IMPLICATIONS: Ticagrelor binding to P2Y12 R is prolonged and more akin to that of an irreversible antagonist, especially versus the endogenous P2Y12 R agonist ADP. This study highlights the potential clinical need for novel ticagrelor reversal strategies in patients with spontaneous major bleeding, and for bleeding associated with urgent invasive procedures.

Stem-cell derived neurosphere assay highlights the effects of viral infection on human cortical development.

Aberrant cortical development is a key feature of neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. Both genetic and environmental risk factors are thought to contribute to defects in cortical development; however, model systems that can capture the dynamic process of human cortical development are not well established. To address this challenge, we combined recent progress in induced pluripotent stem cell differentiation with advanced live cell imaging techniques to establish a novel three-dimensional neurosphere assay, amenable to genetic and environmental modifications, to investigate key aspects of human cortical development in real-time. For the first time, we demonstrate the ability to visualise and quantify radial glial extension and neural migration through live cell imaging. To show proof-of-concept, we used our neurosphere assay to study the effect of a simulated viral infection, a well-established environmental risk factor in neurodevelopmental disorders, on cortical development. This was achieved by exposing neurospheres to the viral mimic, polyinosinic:polycytidylic acid. The results showed significant reductions in radial glia growth and neural migration in three independent differentiations. Further, fixed imaging highlighted reductions in the HOPX-expressing outer radial glia scaffolding and a consequent decrease in the migration of CTIP2-expressing cortical cells. Overall, our results provide new insight into how infections may exert deleterious effects on the developing human cortex.

The mineralocorticoid receptor forms higher order oligomers upon DNA binding.

The prevailing model of steroid hormone nuclear receptor function assumes ligand-induced homodimer formation followed by binding to DNA hormone response elements (HREs). This model has been challenged by evidence showing that the glucocorticoid receptor (GR) forms tetramers upon ligand and DNA binding, which then drive receptor-mediated gene transactivation and transrepression. GR and the closely-related mineralocorticoid receptors (MR) interact to transduce corticosteroid hormone signaling, but whether they share the same quaternary arrangement is unknown. Here, we used a fluorescence imaging technique, Number & Brightness, to study oligomerization in a cell system allowing real-time analysis of receptor-DNA interactions. Agonist-bound MR forms tetramers in the nucleoplasm and higher order oligomers upon binding to HREs. Antagonists form intermediate-size quaternary arrangements, suggesting that large oligomers are essential for function. Divergence between MR and GR quaternary structure is driven by different functionality of known and new multimerization interfaces, which does not preclude formation of heteromers. Thus, influencing oligomerization may be important to selectively modulate corticosteroid signaling.

ACR Appropriateness Criteria® Preprocedural Planning for Transcatheter Aortic Valve Replacement: 2023 Update.

This document discusses preprocedural planning for transcatheter aortic valve replacement, evaluating the imaging modalities used in initial imaging for preprocedure planning under two variants 1) Preintervention planning for transcatheter aortic valve replacement: assessment of aortic root; and 2) Preintervention planning for transcatheter aortic valve replacement: assessment of supravalvular aorta and vascular access. US echocardiography transesophageal, MRI heart function and morphology without and with IV contrast, MRI heart function and morphology without IV contrast and CT heart function and morphology with IV contrast are usually appropriate for assessment of aortic root. CTA chest with IV contrast, CTA abdomen and pelvis with IV contrast, CTA chest abdomen pelvis with IV contrast are usually appropriate for assessment of supravalvular aorta and vascular access. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Comparison of the Biomechanics of the Mouse Astrocytic Lamina Cribrosa Between Glaucoma and Optic Nerve Crush Models.

Purpose: The strain response of the mouse astrocytic lamina (AL) to an ex vivo mechanical test was compared between two protocols: eyes that underwent sustained intraocular pressure (IOP) increase and eyes after optic nerve crush. Methods: Chronic IOP elevation was induced by microbead injection or the optic nerve was crushed in mice with widespread green fluorescence. After 3 days or 6 weeks, eyes were inflation tested by a published method of two-photon fluorescence to image the AL. Digital volume correlation was used to calculate strains. Optic nerve axon damage was also evaluated. Results: In the central AL but not the peripheral AL, four strains were greater in eyes at the 3-day glaucoma time point than control (P from 0.029 to 0.049, n = 8 eyes per group). Also, at this time point, five strains were greater in the central AL compared to the peripheral AL (P from 0.041 to 0.00003). At the 6-week glaucoma time point, the strains averaged across the specimen, in the central AL, and the peripheral AL were indistinguishable from the respective controls. Strains were not significantly different between controls and eyes 3 days or 6 weeks after crush (n = 8 and 16). Conclusions: We found alterations in the ex vivo mechanical behavior in eyes from mice with experimental glaucoma but not in those with crushed optic nerves. The results of this study demonstrate that significant axon injury does not directly affect mechanical behavior of the astrocytic lamina.