Stenting of a hepatic artery pseudoaneurysm rupture secondary to a celiac artery dissection.

Hepatic artery (HA) pseudoaneurysm rupture is a rare and potentially lethal pathology. We present the case of a celiac artery dissection complicated by an HA pseudoaneurysm rupture that was treated successfully with endovascular stenting. The patient's postoperative course was uncomplicated, and he was further evaluated for an underlying connective tissue disorder. There is no standard treatment for a ruptured HA pseudoaneurysm, although transarterial embolization is most frequently reported. This report demonstrates that self-expanding stent grafts are effective in the emergent repair of HA pseudoaneurysm rupture.

GUCY2C signaling limits dopaminergic neuron vulnerability to toxic insults.

Mitochondrial dysfunction and reactive oxygen species (ROS) accumulation within the substantia nigra pars compacta (SNpc) are central drivers of dopaminergic (DA) neuron death in Parkinson's disease (PD). Guanylyl cyclases and their second messenger cyclic (c)GMP support mitochondrial function, protecting against ROS and promoting cell survival in several tissues. However, the role of the guanylyl cyclase-cGMP axis in defining the vulnerability of DA neurons in the SNpc in PD remains unclear, in part due to the challenge of manipulating cGMP levels selectively in midbrain DA neurons. In that context, guanylyl cyclase C (GUCY2C), a receptor primarily expressed by intestinal epithelial cells, was discovered recently in midbrain DA neurons. Here, we demonstrate that GUCY2C promotes mitochondrial function, reducing oxidative stress and protecting DA neurons from degeneration in the 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) mouse model. GUCY2C is overexpressed in the SNpc in PD patients and in mice treated with MPTP, possibly reflecting a protective response to oxidative stress. Moreover, cGMP signaling protects against oxidative stress, mitochondrial impairment, and cell death in cultured DA neurons. These observations reveal a previously unexpected role for the GUCY2C-cGMP signaling axis in controlling mitochondrial dysfunction and toxicity in SNpc DA neurons, highlighting the therapeutic potential of targeting DA neuron GUCY2C to prevent neurodegeneration in PD.

Structure of the plant plastid-encoded RNA polymerase.

Chloroplast genes encoding photosynthesis-associated proteins are predominantly transcribed by the plastid-encoded RNA polymerase (PEP). PEP is a multi-subunit complex composed of plastid-encoded subunits similar to bacterial RNA polymerases (RNAPs) stably bound to a set of nuclear-encoded PEP-associated proteins (PAPs). PAPs are essential to PEP activity and chloroplast biogenesis, but their roles are poorly defined. Here, we present cryoelectron microscopy (cryo-EM) structures of native 21-subunit PEP and a PEP transcription elongation complex from white mustard (Sinapis alba). We identify that PAPs encase the core polymerase, forming extensive interactions that likely promote complex assembly and stability. During elongation, PAPs interact with DNA downstream of the transcription bubble and with the nascent mRNA. The models reveal details of the superoxide dismutase, lysine methyltransferase, thioredoxin, and amino acid ligase enzymes that are subunits of PEP. Collectively, these data provide a foundation for the mechanistic understanding of chloroplast transcription and its role in plant growth and adaptation.

Barriers and facilitators to establishing a clinical academic career in clinical education research in the UK: A focus group study.

In a rapidly changing healthcare environment, we need a robust evidence base to inform effective education and training. This study aimed to examine factors perceived to determine career progression in clinical education research in the UK. Six online focus groups were conducted, with 35 participants from a range of medical, dental, nursing, and allied health professions who identified as aspiring or early career clinical education researchers. Transcripts underwent thematic analysis. Two themes and associated subthemes were constructed to illustrate perceived factors impacting on career development: (1) A cultural challenge from clinical norms. Challenges included differences between the epistemological assumptions of biomedical and clinical research, and the underlying philosophy of education research, which is more closely aligned with the knowledge generation of the social sciences. This led to difficulty communicating the impact of education research to patient care. There were also blurred boundaries between education delivery and research, with the latter lacking a clearly defined group identity. (2) Structures, systems and relationships for career progression. Practical considerations included time and funding (or lack thereof), the opportunity to undertake formal training, networking and role models. This research highlights a number of systemic barriers and facilitators to careers in clinical education research and offers targets of intervention to enable a sustainable academic workforce in clinical education research.

Construction and validation of a medical career readiness inventory.

BACKGROUND: Medical students' preparedness for clinical practice is well researched, yet little is known on the extent to which students are being prepared for a medical career. This paper reports the construction of a short medical inventory titled eXploring medical sTudents' caReer reAdiness (XTRA) to measure students' career readiness based on Super's theory of career maturity. APPROACH: We designed an instrument consisting of a series of 5-point Likert-scale to identify participants competencies regarding career exploration and planning during their undergraduate studies. The instrument was completed by 348 medical students from 41 universities in the United Kingdom. We examined the validity and reliability of the instrument through Exploratory Factor Analysis, Cronbach's coefficient α and Pearson correlation. EVALUATION: Exploratory Factor Analysis revealed that 16 of the 20-items survey were aligned with the exploration stage of Super's theory: Crystallisation (Career goals), Specification (Career pathways) and Implementation (Career accomplishments). The four items that formed two separate statistical factors were specific to a current medical career in the UK. Internal reliability for Super's factor subscales were acceptable (α = 0.71 to α = 0.81). A significant positive relationship was found between students' overall rating of career readiness and the three factors, indicating construct validity. IMPLICATIONS: The XTRA Inventory is a short instrument with construct and content validity specifically designed to measure career readiness of medical students. Further work on its psychometric properties will help establish this inventory to be used as a guidance and career counselling tool by medical educators and educational institutions in developing career development programmes.

Sequencing by avidity enables high accuracy with low reagent consumption.

We present avidity sequencing, a sequencing chemistry that separately optimizes the processes of stepping along a DNA template and that of identifying each nucleotide within the template. Nucleotide identification uses multivalent nucleotide ligands on dye-labeled cores to form polymerase-polymer-nucleotide complexes bound to clonal copies of DNA targets. These polymer-nucleotide substrates, termed avidites, decrease the required concentration of reporting nucleotides from micromolar to nanomolar and yield negligible dissociation rates. Avidity sequencing achieves high accuracy, with 96.2% and 85.4% of base calls having an average of one error per 1,000 and 10,000 base pairs, respectively. We show that the average error rate of avidity sequencing remained stable following a long homopolymer.

GUCY2C signaling limits dopaminergic neuron vulnerability to toxic insults.

Mitochondrial dysfunction and reactive oxygen species (ROS) accumulation within the substantia nigra pars compacta (SNpc) are central drivers of dopaminergic (DA) neuron death in Parkinson's disease (PD). Guanylyl cyclases, and their second messengers cyclic (c)GMP, support mitochondrial function, protecting against ROS and promoting cell survival in a number of tissues. However, the role of the guanylyl cyclase-cGMP axis in defining the vulnerability of DA neurons in the SNpc in PD remains unclear, in part due to the challenge of manipulating cGMP levels selectively in midbrain DA neurons. In that context, guanylyl cyclase C (GUCY2C), a receptor primarily expressed by intestinal epithelial cells, was discovered recently in midbrain DA neurons. Here, we demonstrate that GUCY2C promotes mitochondrial function, reducing oxidative stress and protecting DA neurons from degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of neurodegeneration. GUCY2C is overexpressed in the SNpc in PD patients and in mice treated with MPTP, possibly reflecting a protective response to oxidative stress. Moreover, cGMP signaling protects against oxidative stress, mitochondrial impairment, and cell death in cultured DA neurons. These observations reveal a previously unexpected role for the GUCY2C-cGMP signaling axis in controlling mitochondrial dysfunction and toxicity in nigral DA neurons, highlighting the therapeutic potential of targeting DA neuron GUCY2C to prevent neurodegeneration in PD.

Analysis of Inclusive Gender, Sexuality and Sexual Orientation Data Elements in Academic Electronic Health Records.

Findings from an analysis of three vended academic electronic health records used in health science education are presented in this article. The quality assurance project examined the lexical and semantic fit and content coverage of gender, sexuality, and sexual orientation data elements within the academic electronic health records. A semantic comparative content analysis using a cognitive walkthrough was conducted as a means of comparing the ideal set of gender, sexuality, and sexual orientation data elements with those found in the three vended academic electronic health records. The results indicated a need for alignment to the research literature, expert consensus, and technical standards similar to what is expected for electronic health records used in clinical practice because of a lack of ideal state data elements. The findings align with ongoing issues with bias and disparities seen in the care of the lesbian, gay, bisexual, and transgender population and a lack of diverse, inclusive media and teaching technologies in health science education. The quality project and findings can inform academic electronic health record vendors on how they can create more inclusive systems and bring awareness to healthcare educators about the potential for implicit and explicit bias in their teaching technologies.

Use of Glycoprotein IIb-IIIa Inhibitors in Patients Undergoing Carotid Artery Stenting in the Vascular Quality Initiative.

BACKGROUND: Antiplatelet therapies with thromboxane inhibitors and adenosine 5'-diphosphate antagonists have been widely used following carotid artery stenting (CAS). However, these therapies may not apply to patients who are intolerant or present acutely. Glycoprotein IIb/IIIa inhibitors (GPI) are a proposed alternative therapy in these patients; however, their use has been limited due to concerns of increased risk for intracranial bleeding. Thus, this study aims to assess the safety profile of GPI in patients undergoing CAS. METHODS: All patients undergoing CAS in the Society of Vascular Surgery - Vascular Quality Initiative database from 2012 to 2021 was included and grouped into GPI versus non-GPI therapy (control). The primary outcome was in-hospital stroke or death, and secondary outcomes included in-hospital stroke/transient ischemic attack (TIA), death, myocardial infarction, and intracranial hemorrhage (ICH)/seizure. Patients were stratified by surgical approach (Transcarotid artery revascularization using flow reversal (TCAR) and transfemoral carotid artery stenting), and stepwise backward logistic regression analysis was conducted to evaluate major primary and secondary outcomes. RESULTS: A total of 50,628 patients underwent carotid revascularization. Of these, 4.4% of the patients received GPI. Mean age was similar between control versus GPI (71.35(9.67) vs. 71.36(10.20) years). Compared to the control group, patients who receive GPI are less likely to be on optimal medical therapy, including aspirin (83.0% vs. 88.1%), P2Y12 inhibitor (73.0% vs. 82.7%), and statin (82.3% vs. 86.0%) (All P < 0.05). In addition, patients in the GPI group were more likely to undergo TCAR for carotid revascularization (52.2% vs. 48.4%) for emergent/urgent (29.4% vs. 16.8%) and symptomatic indications (55.5% vs. 49.7%) (All P < 0.001). After stratifying by surgical approach, if patients underwent TFCAS and received a GPI, they were at increased odds of developing stroke/death (1.77(1.25-2.51)), death (odds ratio (OR) (95% CI): 1.67(1.07-2.61)), stroke/TIA (OR (95% confidence interval (CI)): 1.65(1.09-2.51)), and ICH/seizure (OR (95% CI): 2.13(1.23-3.68)) (All P < 0.05). No difference was seen in outcomes between the 2 groups if undergoing TCAR. CONCLUSIONS: Patients who receive GPI were more likely to be symptomatic at presentation and less likely to be medically optimized before their carotid revascularization. Transfemoral access in patients receiving GPI was associated with increased odds of morbidity and mortality. However, this was not observed if undergoing TCAR. TCAR can be considered for its overall favorable results in high-risk patients who are not medically optimized.

How to define clinical education research terminology: A glossary.

Clinical education research (ClinEdR) utilises diverse terminology, which can lead to confusion. A common language is essential for enhancing impact. An expert panel drawn from various workstreams within the National Institute for Health and Care Research (NIHR) Incubator for Clinical Education Research was tasked with reviewing an initial list of terms for the development of a glossary of terms in the field of ClinEdR. The glossary was populated with terms, definitions and foundational papers by the authors and peer-reviewed for accuracy. The glossary of terms developed for ClinEdR should enable researchers to use a common language, promoting consistency and improving communication. We anticipate this will be useful for ClinEdR students and early career researchers. The glossary could be integrated into educational research methods courses in ClinEdR, and through critical and reflective use, enhance the quality and subsequent impact of ClinEdR.

CryoEM and stability analysis of virus-like particles of potyvirus and ipomovirus infecting a common host.

Sweet potato feathery mottle virus (SPFMV) and Sweet potato mild mottle virus (SPMMV) are members of the genera Potyvirus and Ipomovirus, family Potyviridae, sharing Ipomoea batatas as common host, but transmitted, respectively, by aphids and whiteflies. Virions of family members consist of flexuous rods with multiple copies of a single coat protein (CP) surrounding the RNA genome. Here we report the generation of virus-like particles (VLPs) by transient expression of the CPs of SPFMV and SPMMV in the presence of a replicating RNA in Nicotiana benthamiana. Analysis of the purified VLPs by cryo-electron microscopy, gave structures with resolutions of 2.6 and 3.0 Å, respectively, showing a similar left-handed helical arrangement of 8.8 CP subunits per turn with the C-terminus at the inner surface and a binding pocket for the encapsidated ssRNA. Despite their similar architecture, thermal stability studies reveal that SPMMV VLPs are more stable than those of SPFMV.