Genomic Landscape of Adenocarcinomas Across the Gastroesophageal Junction: Moving on from the Siewert Classification.

OBJECTIVE: To investigate how the Siewert classification of gastroesophageal junction adenocarcinomas correlates with genomic profiles. SUMMARY/BACKGROUND DATA: Current staging and treatment guidelines recommend that tumors with an epicenter less than 2 cm into the gastric cardia be treated as esophageal cancers, while tumors with epicenter greater than 2 cm into the cardia be staged and treated as gastric cancers. To date, however, few studies have compared the genomic profiles of the 3 Siewert classification groups to validate this distinction. METHODS: Using targeted tumor sequencing data on patients with adenocarcinoma of the gastroesophageal junction previously treated with surgery at our institution, we compared genomic features across Siewert classification groups. RESULTS: A total of 350 patients were included: 121 had Siewert type I, 170 type II, and 59 type III. Comparisons by Siewert location revealed that Siewert type I and II were primarily characterized as the chromosomal instability (CIN) molecular subtype and displayed Barrett's metaplasia and p53 and cell cycle pathway dysregulation. Siewert type III tumors, by contrast, were more heterogeneous, including higher proportions of microsatellite instability (MSI) and genomically stable (GS) tumors and more frequently displayed ARID1A and somatic CDH1 alterations, signet ring cell features, and poor differentiation. Overall, Siewert type I and II tumors demonstrated greater genomic overlap with lower esophageal tumors, while Siewert type III tumors shared genomic features with gastric tumors. CONCLUSIONS: Overall, our results support recent updates in treatment and staging guidelines. Ultimately, however, molecular rather than anatomic classification may prove more valuable in determining staging, treatment, and prognosis.

Judicial Opinion 130.

Opinion 130 deals with a Request for an Opinion asking the Judicial Commission to clarify whether the genus name Rhodococcus Zopf 1891 (Approved Lists 1980) is illegitimate. The Request is approved and an answer is given. The name Rhodococcus Zopf 1891 (Approved Lists 1980) is illegitimate because it is a later homonym of the validly published cyanobacterial name Rhodococcus Hansgirg 1884. The Judicial Commission also clarifies that it has the means to resolve such cases by conserving a name over an earlier homonym. It is concluded that the name Rhodococcus Zopf 1891 (Approved Lists 1980) is significantly more important than the name Rhodococcus Hansgirg 1884 and therefore the former is conserved over the latter. This makes the name Rhodococcus Zopf 1891 (Approved Lists 1980) legitimate.

The anion photoelectron spectrum and diabatization of tetrazolyl.

The potential energy surface of tetrazolyl [cyclic (N4CH)] has a conical intersection seam between the two lowest-energy electronic states near the ground state minimum geometry. This work treats that molecule. The potential energy surfaces used in this study are based on a least-squares fitting procedure that includes ab initio energies, energy gradients, and derivative couplings described using polynomials up to fourth-order and ab initio data obtained from multireference configuration interaction wave functions. A five-electronic-state description was generated with a root mean square absolute energy error of 9.6 cm-1, compared to 326.8 cm-1 when only second-order terms were used. The time-independent multimode vibronic coupling in the KDC approximation was used to simulate and analyze the anion ultraviolet photoelectron spectrum of tetrazolide.

Evaluation of the critical warzone experiences scale among Gulf War I-era veterans: Associations with PTSD symptoms, depressive symptoms, and suicidal thoughts and behaviors.

Prior research has established the psychometric properties of the Critical Warzone Experiences (CWE) scale among post-9/11 Iraq/Afghanistan-era veterans; however, the psychometric properties of the CWE among Gulf War I-era veterans have not yet been established. The first objective of the present study was to examine the psychometric properties of the CWE among Gulf War I-era veterans. The second objective was to test the hypothesis that the CWE would have a significant indirect effect on suicidal thoughts and behaviors via posttraumatic stress disorder (PTSD) and depressive symptoms. To test these hypotheses, a survey packet that included the CWE and measures of PTSD symptoms, depressive symptoms, and suicidal thoughts and behaviors was administered to 1,153 Gulf War I-era veterans. Consistent with prior research in post-9/11 Iraq/Afghanistan-era veterans, the CWE exhibited good internal consistency (α = .85), a unidimensional factor structure (RMSEA = .056, CFI = .959, SRMR = .033; average factor loading = .69), and good concurrent validity with PTSD (r = .47, p < .001) and depressive (r = .31, p < .001) symptoms among Gulf War I-era veterans. Additionally, as hypothesized, a significant indirect effect from the CWE to suicidal thoughts and behaviors via PTSD and depressive symptoms (ß = .35, p < .001) was also observed. Taken together, our findings provide strong support for using the CWE with Gulf War I-era veterans.

All-Soft-Tissue Meniscus Allograft Transplantation With Circumferential Suture Tape Augmentation to Mitigate Hoop Stress and Promote Centralization.

Meniscus allograft transplantation (MAT) is a technically challenging procedure. Bone plugs, slot techniques, and all-soft-tissue fixation techniques have been described in the past. Each technique comes with advantages and disadvantages. Native menisci have circumferential collagen fibers to help resist hoop stress during loading cycles. Although hoop stress resistance is a known function of the menisci, its recreation in MAT has only been targeted indirectly through anatomic root placement. The authors describe the use of a high-tensile suture tape (i.e. InternalBrace) to promote centralization by directly mitigating hoop stresses through recreation of peripheral meniscus tensioning in MAT.

Major adverse foot events and functional mobility deficits associated with diabetic neuropathy and nephropathy.

Aim: The purpose is to determine the risk ratios (RR) for both major adverse foot events (MAFEs) and the presence of moderate and severe functional mobility deficits in participants with diabetic peripheral neuropathy across the stages of chronic kidney disease (CKD). Methods: We studied 284 participants with diabetes mellitus, peripheral neuropathy, and CKD. MAFEs including foot fracture, ulcerations, Charcot neuropathic arthropathy (CN), osteomyelitis, and minor foot amputations were collected from foot x-ray reports in the medical records of 152 participants; functional mobility deficits were assessed in 132 participants using the modified physical performance test (mPPT). Moderate mobility deficit was categorized as mPPT scores 22-29 and severe mobility deficit as < 22. Unadjusted and adjusted (age, body weight, race, HbA1c) RR were calculated across each stage of CKD, with stage 1 CKD used as the reference group. Results: The RR for neuropathic foot fracture, CN, and diabetic foot ulceration remained consistent across CKD stages. The RR of minor amputation is greater in CKD stages 4 and 5. The RR of moderate or severe mobility deficit is greater in CKD stages 3 and 5 and in CKD stages 3, 4, and 5, respectively. An inverse association was observed between MAFE prevalence and mPPT scores across CKD stages. Conclusion: Major adverse foot events and functional mobility deficits are prevalent in individuals with DPN and diabetic kidney disease. The risks for minor foot amputation and functional mobility deficits increase as early as stage 3 CKD and increase further in stages 4 and 5.

Meniscal Transplant surgery or Optimised Rehabilitation full randomised trial (MeTeOR2): a study protocol.

INTRODUCTION: Pain and disability after meniscectomy can be a substantial lifelong problem. There are few treatment options, especially for young people. Non-surgical management (rehabilitation) is an option but increasingly surgeons are performing meniscal allograft transplants (MATs) for these individuals. However, this is still an uncommon procedure, and availability and usage of MAT vary widely both in the UK and internationally. It is not known which treatment option is the most effective and cost-effective. METHODS AND ANALYSIS: The Meniscal Transplant surgery or Optimised Rehabilitation trial is an international, multicentre, randomised controlled trial. The aim is to compare the clinical and cost effectiveness of MAT versus an optimised package of individualised, progressive, rehabilitation that we have called personalised knee therapy (PKT).Participants will be recruited from sites across the UK, Australia, Canada and Belgium. The planned 144 participants provide at least 90% power to detect a 10-point difference in the Knee injury and Osteoarthritis Outcome Score (KOOS4) at 24-months post randomisation (primary outcome). A prospectively planned economic evaluation will be conducted from a healthcare system and personal social services perspective. Secondary outcome data including health utility, occupational status, sports participation, mental well-being, further treatment, and adverse events will be collected at 3, 6, 12, 18, and 24 months. Analysis will be on an intention-to-treat basis and reported in-line with the Consolidated Standards of Reporting Trials statement. ETHICS AND DISSEMINATION: The trial was approved by the London-Bloomsbury Research Ethics Committee on 19 August 2022 (22/LO/0327) and Northern Sydney Local Health District Human Research Ethics Committee, NSW, Australia on the 13 March 2023 (2022/ETH01890).Trial results will be disseminated via peer-reviewed publications, presentations at international conferences, in lay summaries and using social media as appropriate.This protocol adheres to the recommended Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist. TRIAL REGISTRATION NUMBER: ISRCTN87336549.

Efficient site-specific integration of large genes in mammalian cells via continuously evolved recombinases and prime editing.

Methods for the targeted integration of genes in mammalian genomes suffer from low programmability, low efficiencies or low specificities. Here we show that phage-assisted continuous evolution enhances prime-editing-assisted site-specific integrase gene editing (PASSIGE), which couples the programmability of prime editing with the ability of recombinases to precisely integrate large DNA cargoes exceeding 10 kilobases. Evolved and engineered Bxb1 recombinase variants (evoBxb1 and eeBxb1) mediated up to 60% donor integration (3.2-fold that of wild-type Bxb1) in human cell lines with pre-installed recombinase landing sites. In single-transfection experiments at safe-harbour and therapeutically relevant sites, PASSIGE with eeBxb1 led to an average targeted-gene-integration efficiencies of 23% (4.2-fold that of wild-type Bxb1). Notably, integration efficiencies exceeded 30% at multiple sites in primary human fibroblasts. PASSIGE with evoBxb1 or eeBxb1 outperformed PASTE (for 'programmable addition via site-specific targeting elements', a method that uses prime editors fused to recombinases) on average by 9.1-fold and 16-fold, respectively. PASSIGE with continuously evolved recombinases is an unusually efficient method for the targeted integration of genes in mammalian cells.

Photostasis and photosynthetic adaptation to polar life.

Photostasis is the light-dependent maintenance of energy balance associated with cellular homeostasis in photoautotrophs. We review evidence that illustrates how photosynthetic adaptation in polar photoautrophs such as aquatic green algae, cyanobacteria, boreal conifers as well as terrestrial angiosperms exhibit an astonishing plasticity in structure and function of the photosynthetic apparatus. This plasticity contributes to the maintenance of photostasis, which is essential for the long-term survival in the seemingly inhospitable Antarctic and Arctic habitats. However, evidence indicates that polar photoautrophic species exhibit different functional solutions for the maintenance of photostasis. We suggest that this reflects, in part, the genetic diversity symbolized by inherent genetic redundancy characteristic of polar photoautotrophs which enhances their survival in a thermodynamically challenging environment.

A typology of internationally qualified dentists in the United Kingdom.

Introduction: The Global Strategy for Human Resources for Health 2030, requires member states to half their dependency on an international workforce by 2030. In order to design policies towards that goal, country-specific research on migration motivations of the health workforce is required. The United Kingdom (UK) is a net importer of health professionals and whilst there is a body of research on doctors' and nurses' migration, there is no research on the migration motivations of migrant dentists in the UK. This research explored the migration motivations of internationally qualified dentists (IQDs) in the UK and presents a typology to understand the global migration of dentists in the context of oral health workforce. Methods: The paper presents qualitative data from semi-structured interviews conducted between August 2014 and October 2017, of IQDs working in the United Kingdom. The topic guide for interviews was informed by the literature, with new themes added inductively. A phenomenological approach involving an epistemological stance of interpretivism, was used with framework analysis. Results: A total of 38 internationally qualified dentists (M = 18, F = 20), migrating from the five World Health Organization regions, and working in general practice, NHS hospitals and in community dental services across the four nations of the UK were interviewed. Seven types of internationally qualified dentists were identified working in the UK. They were livelihood migrants, career-orientated migrants, dependant migrants, backpacker migrants, commuter migrants, undocumented migrants, and education-tourist migrant. The categories were based on their migration motivations, which were complex, multifactorial, and included personal, professional, national, and international drivers. The typology, based on their migration motivations, offered a structured, comprehensive understanding of the migrant dental workforce. This typology involving dentists provides additional dimensions to commuter and undocumented migrants described in the context of other health professionals. The education-tourist migrant is a new category proposed as an extension to existing typology in health professional migration. Conclusions: The typology of internationally qualified dentists has congruency with other health professionals' typology in categories previously described and demonstrates that each of these categories are complex, fluid and change in response to policy changes. The new category of education-tourist migrant along with oral health dimensions of commuter and undocumented migrants adds to the existing typology in health professional migration.

Making assessment a team sport: a qualitative study of facilitated group feedback in internal medicine residency.

Purpose: Competency-based medical education relies on feedback from workplace-based assessment (WBA) to direct learning. Unfortunately, WBAs often lack rich narrative feedback and show bias towards Medical Expert aspects of care. Building on research examining interactive assessment approaches, the Queen's University Internal Medicine residency program introduced a facilitated, team-based assessment initiative ("Feedback Fridays") in July 2017, aimed at improving holistic assessment of resident performance on the inpatient medicine teaching units. In this study, we aim to explore how Feedback Fridays contributed to formative assessment of Internal Medicine residents within our current model of competency-based training. Method: A total of 53 residents participated in facilitated, biweekly group assessment sessions during the 2017 and 2018 academic year. Each session was a 30-minute facilitated assessment discussion done with one inpatient team, which included medical students, residents, and their supervising attending. Feedback from the discussion was collected, summarized, and documented in narrative form in electronic WBA forms by the program's assessment officer for the residents. For research purposes, verbatim transcripts of feedback sessions were analyzed thematically. Results: The researchers identified four major themes for feedback: communication, intra- and inter-personal awareness, leadership and teamwork, and learning opportunities. Although feedback related to a broad range of activities, it showed strong emphasis on competencies within the intrinsic CanMEDS roles. Additionally, a clear formative focus in the feedback was another important finding. Conclusions: The introduction of facilitated team-based assessment in the Queen's Internal Medicine program filled an important gap in WBA by providing learners with detailed feedback across all CanMEDS roles and by providing constructive recommendations for identified areas for improvement.

Objectif: La formation médicale fondée sur les compétences s'appuie sur la rétroaction faite lors de l'évaluation des apprentissages par observation directe dans le milieu de travail. Malheureusement, les évaluations dans le milieu de travail omettent souvent de fournir une rétroaction narrative exhaustive et privilégient les aspects des soins relevant de l'expertise médicale. En se basant sur la recherche ayant étudié les approches d'évaluation interactive, le programme de résidence en médecine interne de l'Université Queen's a introduit en juillet 2017 une initiative d'évaluation facilitée et en équipe (« Les vendredis rétroaction ¼), visant à améliorer l'évaluation holistique du rendement des résidents dans les unités d'enseignement clinique en médecine interne. Dans cette étude, nous visons à explorer comment ces « vendredis rétroaction ¼ ont contribué à l'évaluation formative des résidents en médecine interne dans le cadre de notre modèle actuel de formation axée sur les compétences. Méthode: Au total, 53 résidents ont participé à des séances d'évaluation de groupe facilitées et bi-hebdomadaires au cours de l'année universitaire 2017-2018. Chaque séance consistait en une discussion d'évaluation facilitée de 30 minutes menée avec une équipe de l'unité de soins, qui comprenait des étudiants en médecine, des résidents et le médecin superviseur. Les commentaires issus de la discussion ont été recueillis, résumés et documentés sous forme narrative dans des formulaires électroniques d'observation directe dans le milieu de travail par le responsable de l'évaluation du programme de résidence. À des fins de recherche, les transcriptions verbatim des séances de rétroaction ont été analysées de façon thématique. Résultats: Les chercheurs ont identifié quatre thèmes principaux pour les commentaires : la communication, la conscience intra- et interpersonnelle, le leadership et le travail d'équipe, et les occasions d'apprentissage. Bien que la rétroaction concerne un large éventail d'activités, elle met fortement l'accent sur les compétences liées aux rôles intrinsèques de CanMEDS. De plus, le fait que la rétroaction avait un rôle clairement formatif est une autre constatation importante. Conclusions: L'introduction de l'évaluation en équipe facilitée dans le programme de médecine interne à Queen's a comblé une lacune importante dans l'apprentissage par observation directe dans le milieu de travail en fournissant aux apprenants une rétroaction détaillée sur tous les rôles CanMEDS et en formulant des recommandations constructives sur les domaines à améliorer.

Survivorship after adolescent and young adult cancer: Models of care, disparities, and opportunities.

Survivors of adolescent and young adult (AYA, age 15-39 years at diagnosis) cancer are a growing population with the potential to live for many decades after treatment completion. Survivors of AYA cancer are at risk for adverse long-term outcomes including chronic conditions, secondary cancers, impaired fertility, poor psychosocial health and health behaviors, and financial toxicity. Further, survivors of AYA cancer from racially minoritized and low socio-economic status populations experience disparities in these outcomes, including lower long-term survival. Despite these known risks, most survivors of AYA cancer do not receive routine survivorship follow-up care, and research on delivering high-quality, evidence-based survivorship care to these patients is lacking. The need for survivorship care was initially advanced in 2006 by the Institute of Medicine. In 2019, the Quality of Cancer Survivorship Care Framework (QCSCF) was developed to provide an evidence-based framework to define key components of optimal survivorship care. In this commentary focused on survivors of AYA cancer, we apply the QCSCF framework to describe models of care that can be adapted for their unique needs, multi-level factors limiting equitable access to care, and opportunities to address these factors to improve short- and long-term outcomes in this vulnerable population.

Reduced Protein Import via TIM23 SORT Drives Disease Pathology in TIMM50-Associated Mitochondrial Disease.

TIMM50 is a core subunit of the TIM23 complex, the mitochondrial inner membrane translocase responsible for the import of pre-sequence-containing precursors into the mitochondrial matrix and inner membrane. Here we describe a mitochondrial disease patient who is homozygous for a novel variant in TIMM50 and establish the first proteomic map of mitochondrial disease associated with TIMM50 dysfunction. We demonstrate that TIMM50 pathogenic variants reduce the levels and activity of endogenous TIM23 complex, which significantly impacts the mitochondrial proteome, resulting in a combined oxidative phosphorylation (OXPHOS) defect and changes to mitochondrial ultrastructure. Using proteomic data sets from TIMM50 patient fibroblasts and a TIMM50 HEK293 cell model of disease, we reveal that laterally released substrates imported via the TIM23SORT complex pathway are most sensitive to loss of TIMM50. Proteins involved in OXPHOS and mitochondrial ultrastructure are enriched in the TIM23SORT substrate pool, providing a biochemical mechanism for the specific defects in TIMM50-associated mitochondrial disease patients. These results highlight the power of using proteomics to elucidate molecular mechanisms of disease and uncovering novel features of fundamental biology, with the implication that human TIMM50 may have a more pronounced role in lateral insertion than previously understood.

Protein translation rate determines neocortical neuron fate.

The mammalian neocortex comprises an enormous diversity regarding cell types, morphology, and connectivity. In this work, we discover a post-transcriptional mechanism of gene expression regulation, protein translation, as a determinant of cortical neuron identity. We find specific upregulation of protein synthesis in the progenitors of later-born neurons and show that translation rates and concomitantly protein half-lives are inherent features of cortical neuron subtypes. In a small molecule screening, we identify Ire1α as a regulator of Satb2 expression and neuronal polarity. In the developing brain, Ire1α regulates global translation rates, coordinates ribosome traffic, and the expression of eIF4A1. Furthermore, we demonstrate that the Satb2 mRNA translation requires eIF4A1 helicase activity towards its 5'-untranslated region. Altogether, we show that cortical neuron diversity is generated by mechanisms operating beyond gene transcription, with Ire1α-safeguarded proteostasis serving as an essential regulator of brain development.

Long non-coding RNA TUG1 is downregulated in Friedreich's ataxia.

Friedreich's ataxia is a neurodegenerative disorder caused by reduced frataxin levels. It leads to motor and sensory impairments and has a median life expectancy of around 35 years. As the most common inherited form of ataxia, Friedreich's ataxia lacks reliable, non-invasive biomarkers, prolonging and inflating the cost of clinical trials. This study proposes TUG1, a long non-coding RNA, as a promising blood-based biomarker for Friedreich's ataxia, which is known to regulate various cellular processes. In a previous study using a frataxin knockdown mouse model, we observed several hallmark Friedreich's ataxia symptoms. Building on this, we hypothesized that a dual-source approach-comparing the data from peripheral blood samples from Friedreich's ataxia patients with tissue samples from affected areas in Friedreich's ataxia knockdown mice, tissues usually unattainable from patients-would effectively identify robust biomarkers. A comprehensive reanalysis was conducted on gene expression data from 183 age- and sex-matched peripheral blood samples of Friedreich's ataxia patients, carriers and controls and 192 tissue data sets from Friedreich's ataxia knockdown mice. Blood and tissue samples underwent RNA isolation and quantitative reverse transcription polymerase chain reaction, and frataxin knockdown was confirmed through enzyme-linked immunosorbent assays. Tug1 RNA interaction was explored via RNA pull-down assays. Validation was performed in serum samples on an independent set of 45 controls and 45 Friedreich's ataxia patients and in blood samples from 66 heterozygous carriers and 72 Friedreich's ataxia patients. Tug1 and Slc40a1 emerged as potential blood-based biomarkers, confirmed in the Friedreich's ataxia knockdown mouse model (one-way ANOVA, P ≤ 0.05). Tug1 was consistently downregulated after Fxn knockdown and correlated strongly with Fxn levels (R 2 = 0.71 during depletion, R 2 = 0.74 during rescue). Slc40a1 showed a similar but tissue-specific pattern. Further validation of Tug1's downstream targets strengthened its biomarker candidacy. In additional human samples, TUG1 levels were significantly downregulated in both whole blood and serum of Friedreich's ataxia patients compared with controls (Wilcoxon signed-rank test, P < 0.05). Regression analyses revealed a negative correlation between TUG1 fold-change and disease onset (P < 0.0037) and positive correlations with disease duration and functional disability stage score (P < 0.04). This suggests that elevated TUG1 levels correlate with earlier onset and more severe cases. This study identifies TUG1 as a potential blood-based biomarker for Friedreich's ataxia, showing consistent expression variance in human and mouse tissues related to disease severity and key Friedreich's ataxia pathways. It correlates with frataxin levels, indicating its promise as an early, non-invasive marker. TUG1 holds potential for Friedreich's ataxia monitoring and therapeutic development, meriting additional research.

The effect of factors from different time points on psychological readiness following ACL reconstruction.

OBJECTIVE: The purpose of this study was to examine factors correlated with psychological readiness to return to activity after ACLR. DESIGN: cross sectional study. SETTING: controlled laboratory. PARTICIPANTS: 164 patients (82 M/82 F, 22.5 ± 8.9yr, 171.6 ± 11.0 cm, 77.4 ± 18.6 kg, 8.6 ± 3.4 months post-ACLR) participated in this study after a primary, isolated, and uncomplicated ACLR. MAIN OUTCOME MEASURES: ACL Return to Sport Index (ACL-RSI). RESULTS: ACL-RSI scores demonstrated a weak positive correlation with activity level at the time of injury and a fair positive correlation with activity level at the time of post-operative testing (p-values: 0.004, <0.001). ACL-RSI scores showed a statistically significant fair negative correlation with pain and a moderate negative correlation with kinesiophobia during rehabilitation (p-values: <0.001, <0.001). There was no statistical significance between ACL-RSI and the surgical variables (p-value range: 0.10-0.61). CONCLUSIONS: Outcomes from testing during postoperative rehabilitation were most correlated with psychological readiness to return to activity after ACLR. Increased pain and kinesiophobia were associated with a decreased psychological readiness. Increased activity level prior to injury and activity level at the time of testing during rehabilitation were both correlated with increased psychological readiness. Psychological readiness to return to activity may need to be customized based on potentially modifiable patient-specific factors during the post-operative rehabilitation.

Pseudo-outbreak of Parengyodontium album related to contaminated saline used in specimen processing in the microbiology laboratory.

We report a cluster of nine isolates of Parengyodontium album recovered from four patients who had surgical tissue specimens processed after dilution with a multi-use diluent saline solution. P. album was also identified from a non-clinical sample on agar prepared with the same lot number of saline solution. Our epidemiological investigation revealed this to represent a pseudo-outbreak related to contaminated saline used to process specimens in the microbiology laboratory.