Protocol for the SELECT study: a sequential mixed methods study of the selection of UK medical students into clinical academic training.

BACKGROUND: Internationally, there has been a move towards fostering diverse healthcare workforces that are representative of the patient populations they serve. Selection criteria for academic-clinicians often aim to capture skills and attributes that demonstrate both clinical and academic excellence. Currently, it is not known whether the selection criteria for early academic-clinical careers advantage or disadvantage certain ethnic or socioeconomic groups. The UK has a structured route of integrated clinical academic training with entry level training for newly qualified doctors administered through the 'Specialised Foundation Programme' which provides protected time for research within the first two years of postgraduate clinical training. In this study, we aim to identify what selection criteria are used within the UK Specialised Foundation Programme, and how these relate to demographic factors. METHODS: We will perform a mixed methods study consisting of a document analysis of person specifications and selection criteria used in the 2024 UK Specialised Foundation Programme, and a national cross-sectional survey of current medical students in the UK. We will obtain the person specifications, selection criteria, white space (open ended questions used during shortlisting) and interview questions and mark schemes from each Specialised Unit of Applications via information available on their websites or through Freedom of Information requests. Our survey will collect information relating to demographic data, selection criteria, and perceptions of specialised foundation programme selection. DISCUSSION: International literature has demonstrated inequity in academic markers used in selection of post-graduate clinicians and that disadvantages caused by selection can compound over time. As such it is important to understand what inequity exists within the selection of early academic-clinicians, as this can help inform more equitable selection practices and help nurture a more diverse academic-clinical workforce.

Balloon-expandable covered stenting of a large right hepatic artery aneurysm.

Hepatic artery aneurysms (HAAs) are rare visceral aneurysms with a high rupture rate. We report the case of an 88-year-old man with a 4.2-cm right HAA treated with covered stenting. Balloon-expandable covered stents effectively excluded the HAA with excellent proximal and distal seals. Our case is one of a limited number of reports on successfully repairing a hepatic aneurysm with a balloon-expandable stent graft. This case demonstrates that balloon expandable covered stenting is a viable approach in patients with appropriate anatomy and may be favorable in patients precluded from open bypass.

Multifocal, multiphenotypic tumours arising from an MTOR mutation acquired in early embryogenesis.

Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the wide dissemination of cells predisposed to disease within mature organs. We characterised the evolutionary history of four synchronous renal tumours from a 14-year-old girl using whole genome sequencing alongside single cell and bulk transcriptomic sequencing. Phylogenetic reconstruction timed the origin of all tumours to a multipotent embryonic cell committed to the right kidney, around 4 weeks post-conception. Biochemical and structural analysis of their shared MTOR mutation, absent from normal tissues, demonstrates enhanced protein flexibility, enabling a FAT domain hinge to dramatically increase activity of mTORC1 and mTORC2. Developmental mutations, not usually detected in traditional genetic screening, have vital clinical importance in guiding prognosis, targeted treatment, and family screening decisions for paediatric tumours.

The Rochester Protocol for Living Donor Liver Transplantation of Unresectable Colorectal Liver Metastasis: A 5-Year Report on Selection, Approval, and Outcomes.

Living donor liver transplantation (LDLT) is a treatment option for select patients with unresectable colorectal liver metastasis (uCRLM). We describe our center's experience of patient selection, insurance approval, and outcomes after LDLT after first referral in March 2019. Of the 206 evaluated patients, twenty-three underwent LDLT. We found that patients who were referred earlier in their oncologic course were more likely to be eligible for transplantation. After completion of the Rochester Protocol for LDLT eligibility, recipients had a median delay of care of 10 days (IQR 0-36) related to insurance appeal, with six patients (30%) having a delay longer than 30 days. LDLT recipients had an overall survival proportion of 100% and 91% at 1, and 3 years; and a recurrence-free survival proportion of 100% and 40%, at 1 and 3 years, respectively. All donors underwent right hepatectomy, of which only one donor had a Clavien-Dindo IIIa complication and readmission. There was no donor mortality. We assert that multidisciplinary care and strict patient selection through the Rochester Protocol were paramount to our center's success. In the appropriately selected patient, LDLT for uCRLM may be justified, and patients should be referred to transplant oncology centers for evaluation.

Pan-lysyl oxidase inhibition disrupts fibroinflammatory tumor stroma, rendering cholangiocarcinoma susceptible to chemotherapy.

BACKGROUND: Cholangiocarcinoma (CCA) features highly desmoplastic stroma that promotes structural and functional resistance to therapy. Lysyl oxidases (LOX, LOXL1-4) catalyze collagen cross-linking, thereby increasing stromal rigidity and facilitating therapeutic resistance. Here, we evaluate the role of lysyl oxidases in stromal desmoplasia and the effects of pan-lysyl oxidase (pan-LOX) inhibition in CCA. METHODS: Resected CCA and normal liver specimens were analyzed from archival tissues. Spontaneous and orthotopic murine models of intrahepatic CCA (iCCA) were used to assess the impact of the pan-LOX inhibitor PXS-5505 in treatment and correlative studies. The functional role of pan-LOX inhibition was interrogated through in vivo and ex vivo assays. RESULTS: All 5 lysyl oxidases are upregulated in CCA and reduced lysyl oxidase expression is correlated with an improved prognosis in resected patients with CCA. Spontaneous and orthotopic murine models of intrahepatic cholangiocarcinoma upregulate all 5 lysyl oxidase isoforms. Pan-LOX inhibition reversed mechanical compression of tumor vasculature, resulting in improved chemotherapeutic penetrance and cytotoxic efficacy. The combination of chemotherapy with pan-LOX inhibition increased damage-associated molecular pattern release, which was associated with improved antitumor T-cell responses. Pan-LOX inhibition downregulated macrophage invasive signatures in vitro, rendering tumor-associated macrophages more susceptible to chemotherapy. Mice bearing orthotopic and spontaneously occurring intrahepatic cholangiocarcinoma tumors exhibited delayed tumor growth and improved survival following a combination of pan-LOX inhibition with chemotherapy. CONCLUSIONS: CCA upregulates all 5 lysyl oxidase isoforms, and pan-LOX inhibition reverses tumor-induced mechanical forces associated with chemotherapy resistance to improve chemotherapeutic efficacy and reprogram antitumor immune responses. Thus, combination therapy with pan-LOX inhibition represents an innovative therapeutic strategy in CCA.

Transplantation in the Pandemic Era: Perspectives on the Utilization of COVID-19 Positive Organs.

BACKGROUND: At early stages of the pandemic, most organ procurements organizations considered COVID-19 infected donors to be ineligible for organ donation. The aim of this survey is to describe the current practices of the utilization of COVID-19 positive organs donors among American Society of Transplant Surgeons (ASTS) members. METHODS: An anonymous 40-question redcap survey was emailed to ASTS members from June to August 2022. RESULTS: One hundred forty-nine surveys from 10 countries were included for analysis. The majority of the responders were men (66.7%) from North America (95%) and identified as transplant surgeons (68.5%). Most work at academic institutions (76.5%). Almost all responders (94%) were willing to accept an organ from a donor with a history of COVID-19 who tested negative at the time of donation, however, there was no consensus on the length of time after the disease was resolved. Approximately 70% indicated they accept organs from asymptomatic donors with active disease. Only 32 responders indicated they would accept an organ from an individual with a history of "severe" COVID-19 infection and less than one third of the responders would accept an organ from a donor who died from COVID-19 infection. Interestingly, 80% indicated they have protocols at their institution to guide the acceptance of such organs. DISCUSSION: Despite new evidence that the transmission of COVID-19 in non-lung organs is extremely rare, the results of this survey suggest significant heterogeneity in practice and perceptions of the use of COVID-19 positive organs across international centers. We suggest that the implementation of a standardized protocol is of paramount importance to continue safe transplant activity.

Progression-Free Survival for Liver Transplant vs Alternative Therapy in Unresectable Colorectal Liver Metastasis.

This cohort study compares survival outcomes between patients with unresectable colorectal liver metastasis who received chemotherapy-based multimodal therapy and patients who underwent liver transplant.

The cryoEM structure of the Hendra henipavirus nucleoprotein reveals insights into paramyxoviral nucleocapsid architectures.

We report the first cryoEM structure of the Hendra henipavirus nucleoprotein in complex with RNA, at 3.5 Å resolution, derived from single particle analysis of a double homotetradecameric RNA-bound N protein ring assembly exhibiting D14 symmetry. The structure of the HeV N protein adopts the common bi-lobed paramyxoviral N protein fold; the N-terminal and C-terminal globular domains are bisected by an RNA binding cleft containing six RNA nucleotides and are flanked by the N-terminal and C-terminal arms, respectively. In common with other paramyxoviral nucleocapsids, the lateral interface between adjacent Ni and Ni+1 protomers involves electrostatic and hydrophobic interactions mediated primarily through the N-terminal arm and globular domains with minor contribution from the C-terminal arm. However, the HeV N multimeric assembly uniquely identifies an additional protomer-protomer contact between the Ni+1 N-terminus and Ni-1 C-terminal arm linker. The model presented here broadens the understanding of RNA-bound paramyxoviral nucleocapsid architectures and provides a platform for further insight into the molecular biology of HeV, as well as the development of antiviral interventions.

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.

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.

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.