Radiomics Analysis of Contrast-Enhanced Breast MRI for Optimized Modelling of Virtual Prognostic Biomarkers in Breast Cancer.

Objective: Breast cancer clinical stage and nodal status are the most clinically significant drivers of patient management, in combination with other pathological biomarkers, such as estrogen receptor (ER), progesterone receptor or human epidermal growth factor receptor 2 (HER2) receptor status and tumor grade. Accurate prediction of such parameters can help avoid unnecessary intervention, including unnecessary surgery. The objective was to investigate the role of magnetic resonance imaging (MRI) radiomics for yielding virtual prognostic biomarkers (ER, HER2 expression, tumor grade, molecular subtype, and T-stage). Materials and Methods: Patients with primary invasive breast cancer who underwent dynamic contrast-enhanced (DCE) breast MRI between July 2013 and July 2016 in a single center were retrospectively reviewed. Age, N-stage, grade, ER and HER2 status, and Ki-67 (%) were recorded. DCE images were segmented and Haralick texture features were extracted. The Bootstrap Lasso feature selection method was used to select a small subset of optimal texture features. Classification of the performance of the final model was assessed with the area under the receiver operating characteristic curve (AUC). Results: Median age of patients (n = 209) was 49 (21-79) years. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the model for differentiating N0 vs N1-N3 was: 71%, 79%, 76%, 74%, 75% [AUC = 0.78 (95% confidence interval (CI) 0.72-0.85)], N0-N1 vs N2-N3 was 81%, 59%, 24%, 95%, 62% [AUC = 0.74 (95% CI 0.63-0.85)], distinguishing HER2(+) from HER2(-) was 79%, 48%, 34%, 87%, 56% [AUC = 0.64 (95% CI 0.54-0.73)], high nuclear grade (grade 2-3) vs low grade (grades 1) was 56%, 88%, 96%, 29%, 61% [AUC = 0.71 (95% CI 0.63-0.80)]; and for ER (+) vs ER(-) status the [AUC=0.67 (95% CI 0.59-0.76)]. Radiomics performance in distinguishing triple-negative vs other molecular subtypes was [0.60 (95% CI 0.49-0.71)], and Luminal A [0.66 (95% CI 0.56-0.76)]. Conclusion: Quantitative radiomics using MRI contrast texture shows promise in identifying aggressive high grade, node positive triple negative breast cancer, and correlated well with higher nuclear grades, higher T-stages, and N-positive stages.

Infection with mpox virus via the genital mucosae increases shedding and transmission in the multimammate rat (Mastomys natalensis).

The 2022 mpox virus (MPXV) outbreak was sustained by human-to-human transmission; however, it is currently unclear which factors lead to sustained transmission of MPXV. Here we present Mastomys natalensis as a model for MPXV transmission after intraperitoneal, rectal, vaginal, aerosol and transdermal inoculation with an early 2022 human outbreak isolate (Clade IIb). Virus shedding and tissue replication were route dependent and occurred in the presence of self-resolving localized skin, lung, reproductive tract or rectal lesions. Mucosal inoculation via the rectal, vaginal and aerosol routes led to increased shedding, replication and a pro-inflammatory T cell profile compared with skin inoculation. Contact transmission was higher from rectally inoculated animals. This suggests that transmission might be sustained by increased susceptibility of the anal and genital mucosae for infection and subsequent virus release.

Using the Traditional Ex Vivo Whole Blood Model to Discriminate Bacteria by Their Inducible Host Responses.

Whole blood models are rapid and versatile for determining immune responses to inflammatory and infectious stimuli, but they have not been used for bacterial discrimination. Staphylococcus aureus, S. epidermidis and Escherichia coli are the most common causes of invasive disease, and rapid testing strategies utilising host responses remain elusive. Currently, immune responses can only discriminate between bacterial 'domains' (fungi, bacteria and viruses), and very few studies can use immune responses to discriminate bacteria at the species and strain level. Here, whole blood was used to investigate the relationship between host responses and bacterial strains. Results confirmed unique temporal profiles for the 10 parameters studied: IL-6, MIP-1α, MIP-3α, IL-10, resistin, phagocytosis, S100A8, S100A8/A9, C5a and TF3. Pairwise analysis confirmed that IL-6, resistin, phagocytosis, C5a and S100A8/A9 could be used in a discrimination scheme to identify to the strain level. Linear discriminant analysis (LDA) confirmed that (i) IL-6, MIP-3α and TF3 could predict genera with 95% accuracy; (ii) IL-6, phagocytosis, resistin and TF3 could predict species at 90% accuracy and (iii) phagocytosis, S100A8 and IL-10 predicted strain at 40% accuracy. These data are important because they confirm the proof of concept that host biomarker panels could be used to identify bacterial pathogens.

Impaired innate and adaptive immune responses to BNT162b2 SARS-CoV-2 vaccination in systemic lupus erythematosus.

Understanding the immune responses to SARS-CoV-2 vaccination is critical to optimizing vaccination strategies for individuals with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here, we comprehensively analyzed innate and adaptive immune responses in 19 patients with SLE receiving a complete 2-dose Pfizer-BioNTech mRNA vaccine (BNT162b2) regimen compared with a control cohort of 56 healthy control (HC) volunteers. Patients with SLE exhibited impaired neutralizing antibody production and antigen-specific CD4+ and CD8+ T cell responses relative to HC. Interestingly, antibody responses were only altered in patients with SLE treated with immunosuppressive therapies, whereas impairment of antigen-specific CD4+ and CD8+ T cell numbers was independent of medication. Patients with SLE also displayed reduced levels of circulating CXC motif chemokine ligands, CXCL9, CXCL10, CXCL11, and IFN-γ after secondary vaccination as well as downregulation of gene expression pathways indicative of compromised innate immune responses. Single-cell RNA-Seq analysis reveals that patients with SLE showed reduced levels of a vaccine-inducible monocyte population characterized by overexpression of IFN-response transcription factors. Thus, although 2 doses of BNT162b2 induced relatively robust immune responses in patients with SLE, our data demonstrate impairment of both innate and adaptive immune responses relative to HC, highlighting a need for population-specific vaccination studies.

Establishing a framework for best practices for quality assurance and quality control in untargeted metabolomics.

BACKGROUND: Quality assurance (QA) and quality control (QC) practices are key tenets that facilitate study and data quality across all applications of untargeted metabolomics. These important practices will strengthen this field and accelerate its success. The Best Practices Working Group (WG) within the Metabolomics Quality Assurance and Quality Control Consortium (mQACC) focuses on community use of QA/QC practices and protocols and aims to identify, catalogue, harmonize, and disseminate current best practices in untargeted metabolomics through community-driven activities. AIM OF REVIEW: A present goal of the Best Practices WG is to develop a working strategy, or roadmap, that guides the actions of practitioners and progress in the field. The framework in which mQACC operates promotes the harmonization and dissemination of current best QA/QC practice guidance and encourages widespread adoption of these essential QA/QC activities for liquid chromatography-mass spectrometry. KEY SCIENTIFIC CONCEPTS OF REVIEW: Community engagement and QA/QC information gathering activities have been occurring through conference workshops, virtual and in-person interactive forum discussions, and community surveys. Seven principal QC stages prioritized by internal discussions of the Best Practices WG have received participant input, feedback and discussion. We outline these stages, each involving a multitude of activities, as the framework for identifying QA/QC best practices. The ultimate planned product of these endeavors is a "living guidance" document of current QA/QC best practices for untargeted metabolomics that will grow and change with the evolution of the field.

Skeletal stability of inter-molar mandibular distraction osteogenesis in growing patients.

INTRODUCTION: The aim of this retrospective study was to firstly assess the stability of surgical advancement using inter-molar mandibular distraction osteogenesis (IMDO) and secondly to assess the impact of the surgical intervention on subsequent mandibular growth in patients with residual growth. METHODS: The sample consisted of 17 (13F and 4M) consecutively treated patients who underwent IMDO and orthodontic treatment. Cephalometric analysis was performed at three time points: T0 prior to distraction; T1 post-distraction immediately prior to surgical removal of the distractors; and T2 following completion of orthodontic treatment when the final lateral cephalogram was taken (0.86-4.37 years after T1). Statistical comparison of lower facial height, mandibular length, growth, condylar position and anterior mandibular rotation was performed. RESULTS: No association was found between changes in any of the cephalometric measurements and the length of the follow-up interval. The anterior mandibular segment underwent clockwise rotation during distraction and recovered to near its pre-distraction angulation during remodelling. An increase in the lower facial height of 1.88 ± 2.81mm also occurred during distraction (T0-T1) and was maintained during the follow-up period (T1-T2). Post-distraction (T1-T2) growth of lower facial height (p value 0.872) and mandibular length (p value 0.251) showed no association when compared to an untreated control group and an overall reduction in growth was reported. CONCLUSIONS: IMDO was highly stable within a follow-up period of 2.3 ± 0.9 years; however, growth appears to have been inhibited.

Magnetic resonance imaging improves diagnosis of placenta accreta spectrum requiring hysterectomy compared to ultrasound.

BACKGROUND: Magnetic resonance imaging has been used increasingly as an adjunct for ultrasound imaging for placenta accreta spectrum assessment and preoperative surgical planning, but its value has not been established yet. The ultrasound-based placenta accreta index is a well-validated standardized approach for placenta accreta spectrum evaluation. Placenta accreta spectrum-magnetic resonance imaging markers have been outlined in a joint guideline from the Society of Abdominal Radiology and the European Society of Urogenital Radiology. OBJECTIVE: This study aimed to compare placenta accreta spectrum-magnetic resonance imaging parameters with the ultrasound-based placenta accreta index in pregnancies at high risk for placenta accreta spectrum and to assess the additional diagnostic value of magnetic resonance imaging for placenta accreta spectrum that requires a cesarean hysterectomy. STUDY DESIGN: This was a single-center, retrospective study of pregnant patients who underwent magnetic resonance imaging, in addition to ultrasonography, because of suspected placenta accreta spectrum. The ultrasound-based placenta accreta index and placenta accreta spectrum-magnetic resonance imaging parameters were obtained. Student's t test and Fisher's exact test were used to compare the groups in terms of the primary outcome (hysterectomy vs no hysterectomy). The diagnostic performance of magnetic resonance imaging and the ultrasound-based placenta accreta index was assessed using multivariable logistic regressions, receiver operating characteristics curves, the DeLong test, McNemar test, and the relative predictive value test. RESULTS: A total of 82 patients were included in the study, 41 of whom required a hysterectomy. All patients who underwent a hysterectomy met the International Federation of Gynecology and Obstetrics clinical evidence of placenta accreta spectrum at the time of delivery. Multiple parameters of the ultrasound-based placenta accreta index and placenta accreta spectrum-magnetic resonance imaging were able to predict hysterectomy, and the parameter of greatest dimension of invasion by magnetic resonance imaging was the best quantitative predictor. At 96% sensitivity for hysterectomy, the cutoff values were 3.5 for the ultrasound-based placenta accreta index and 2.5 cm for the greatest dimension of invasion by magnetic resonance imaging. Using this sensitivity, the parameter of greatest dimension of invasion measured by magnetic resonance imaging had higher specificity (P=.0016) and a higher positive predictive value (P=.0018) than the ultrasound-based placenta accreta index, indicating an improved diagnostic threshold. CONCLUSION: In a suspected high-risk group for placenta accreta spectrum, magnetic resonance imaging identified more patients who will not need a hysterectomy than when using the ultrasound-based placenta accrete index only. Magnetic resonance imaging has the potential to aid patient counseling, surgical planning, and delivery timing, including preterm delivery decisions for patients with placenta accreta spectrum requiring hysterectomy.

A co-design living labs philosophy of practice for end-to-end research design to translation with people with lived-experience of mental ill-health and carer/family and kinship groups.

There is increased recognition that people with lived-experience of mental ill-health ought to be centred in research design, implementation and translation, and quality improvement and program evaluation of services. There is also an increased focus on ways to ensure that co-design processes can be led by people with lived-experience of mental ill-health. Despite this, there remains limited explanation of the physical, social, human, and economic infrastructure needed to create and sustain such models in research and service settings. This is particularly pertinent for all health service sectors (across mental and physical health and social services) but more so across tertiary education settings where research generation occurs for implementation and translation activities with policy and services. The Co-Design Living Labs program was established in 2017 as an example of a community-based embedded approach to bring people living with trauma and mental ill-health and carers/family and kinship group members together with university-based researchers to drive end-to-end research design to translation in mental healthcare and research sectors. The program's current membership is near to 2000 people. This study traces the evolution of the program in the context of the living labs tradition of open innovation. It overviews the philosophy of practice for working with people with lived-experience and carer/family and kinship group members-togetherness by design. Togetherness by design centres on an ethical relation of being-for that moves beyond unethical and transactional approaches of being-aside and being-with, as articulated by sociologist Zygmunt Bauman. The retrospective outlines how an initial researcher-driven model can evolve and transform to become one where people with lived-experience of mental ill-health and carer/family kinship group members hold clear decision-making roles, share in power to enact change, and move into co-researcher roles within research teams. Eight mechanisms are presented in the context of an explanatory theoretical model of change for co-design and coproduction, which are used to frame research co-design activities and provide space for continuous learning and evolution of the Co-Design Living Labs program.

Metabolomics 2022 workshop report: state of QA/QC best practices in LC-MS-based untargeted metabolomics, informed through mQACC community engagement initiatives.

INTRODUCTION: The Metabolomics Quality Assurance and Quality Control Consortium (mQACC) organized a workshop during the Metabolomics 2022 conference. OBJECTIVES: The goal of the workshop was to disseminate recent findings from mQACC community-engagement efforts and to solicit feedback about a living guidance document of QA/QC best practices for untargeted LC-MS metabolomics. METHODS: Four QC-related topics were presented. RESULTS: During the discussion, participants expressed the need for detailed guidance on a broad range of QA/QC-related topics accompanied by use-cases. CONCLUSIONS: Ongoing efforts will continue to identify, catalog, harmonize, and disseminate QA/QC best practices, including outreach activities, to establish and continually update QA/QC guidelines.

Enhancing survivorship and growth of juvenile Montipora capitata using the Hawaiian collector urchin Tripneustes gratilla.

The biodiversity of coral reef habitats is rapidly declining due to the effects of anthropogenic climate change, prompting the use of active restoration as a mitigation strategy. Sexual propagation can maintain or enhance genetic diversity in restoration of these ecosystems, but these approaches suffer from a range of inefficiencies in rearing and husbandry. Algal overgrowth of juveniles is a major bottleneck in the production of sexually propagated corals that may be alleviated by co-culture with herbivores. We reared juvenile Montipora capitata alongside juvenile native Hawaiian collector urchins, Tripneustes gratilla, for 15 weeks and documented significant ecological benefits of co-culture. Urchin treatments significantly increased the survivorship of coral aggregates (14%) and individual settlers (24%). We also documented a significant increase in coral growth in the presence of urchins. These results demonstrate the utility of microherbivory in promoting coral growth and survivorship in ex situ conditions, providing valuable insight for restoration pipelines of native Hawaiian coral species.

A scoping review of cardiovascular risk factor screening rates in general or family practice attendees living with severe mental ill-health.

BACKGROUND: Primary care is essential to address the unmet physical health needs of people with severe mental ill-health. Continued poor cardiovascular health demands improved screening and preventive care. No previous reviews have examined primary care cardiovascular screening rates for people living with severe mental ill-health; termed in the literature "severe mental illness". METHODS: A scoping review following Joanna Briggs Institute methodology was conducted. Cardiovascular risk factor screening rates in adults with severe mental ill-health were examined in general or family practices (as the main delivery sites of primary care). Literature published between 2001 and 2023 was searched using electronic databases including Medline, Embase, Web of Science, PsychINFO and CINAHL. Two reviewers independently screened titles and abstracts and conducted a full-text review. The term "severe mental illness" was applied as the term applied in the literature over the past decades. Study information, participant details and cardiovascular risk factor screening rates for people with 'severe mental illness' were extracted and synthesised. RESULTS: Thirteen studies were included. Nine studies were from the United Kingdom and one each from Canada, Spain, New Zealand and the Netherlands. The general and/or family practice cardiovascular disease screening rates varied considerably across studies, ranging from 0 % to 75 % for people grouped within the term "severe mental illness". Lipids and blood pressure were the most screened risk factors. CONCLUSIONS: Cardiovascular disease screening rates in primary care settings for adults living with severe mental ill-health varied considerably. Tailored and targeted cardiovascular risk screening will enable more comprehensive preventive care to improve heart health outcomes and address this urgent health inequity.

Small Intestinal Permeability and Metabolomic Profiles in Feces and Plasma Associate With Clinical Response in Patients With Active Psoriatic Arthritis Participating in a Fecal Microbiota Transplantation Trial: Exploratory Findings From the FLORA Trial.

OBJECTIVE: We investigated intestinal permeability and fecal, plasma, and urine metabolomic profiles in methotrexate-treated active psoriatic arthritis (PsA) and how this related to clinical response following one sham or fecal microbiota transplantation (FMT). METHODS: This exploratory study is based on the FLORA trial cohort, in which 31 patients with moderate-to-high peripheral PsA disease activity, despite at least 3 months of methotrexate-treatment, were included in a 26-week, double-blind, 1:1 randomized, sham-controlled trial. Participants were randomly allocated to receive either one healthy donor FMT (n = 15) or sham (n = 16) via gastroscopy. The primary trial end point was the proportion of treatment failures through 26 weeks. We performed a lactulose-to-mannitol ratio (LMR) test at baseline (n = 31) and at week 26 (n = 26) to assess small intestinal permeability. Metabolomic profiles in fecal, plasma, and urine samples collected at baseline, weeks 4, 12, and 26 were measured using 1 H Nuclear Magnetic Resonance. RESULTS: Trial failures (n = 7) had significantly higher LMR compared with responders (n = 19) at week 26 (0.027 [0.017-0.33]) vs. 0.012 [0-0.064], P = 0.013), indicating increased intestinal permeability. Multivariate analysis revealed a significant model for responders (n = 19) versus failures (n = 12) at all time points based on their fecal (P < 0.0001) and plasma (P = 0.005) metabolomic profiles, whereas urine metabolomic profiles did not differ between groups (P = 1). Fecal N-acetyl glycoprotein GlycA correlated with Health Assessment Questionnaire Disability Index (coefficient = 0.50; P = 0.03) and fecal propionate correlated with American College of Rheumatology 20 response at week 26 (coefficient = 27, P = 0.02). CONCLUSION: Intestinal permeability and fecal and plasma metabolomic profiles of patients with PsA were associated with the primary clinical trial end point, failure versus responder.

A mixed-methods evaluation of the impacts of an online Carer wellbeing and connection program.

Objective: To evaluate a facilitated, 90-min session, delivered for four weeks, Online Carer Wellbeing and Connection Program in Victoria, Australia. Methods: One hundred and three carers took part in the evaluation. Eighty-six completed both pre- and post-program surveys evaluating program impacts on psychological distress, perceived loneliness, and social support. Qualitative interviews were conducted (n = 76) post-program for experiential data. Findings: Paired samples t-tests showed significant decreases between pre- and post-program for psychological distress (M = 25.10, SD = 7.08; M = 22.00, SD = 6.57; t(85) = 4.88, p = 0.000), perceived loneliness (M = 6.69, SD = 1.89; M = 6.14, SD = 1.76; t(85) = 3.45, p = 0.000) and perceived social support (M = 8.31, SD = 2.48; M = 8.83, SD = 2.21; t(85) = -2.54, p = 0.013). Thematic analysis identified positive experiences and the mechanisms of action (or the ingredients for program success) as: 1. Delivery by a trained facilitator; 2. Provision of respite for person being cared for during meetings; 3. Technical assistance; 4. Online modality; 5. Inclusivity; 6. Diversity of experience; 7. Shared understanding; 8. Safety; 9. Emotional release; 10. Reflection, and; 11. Self-care practices. Innovation: A model illustrating the mechanisms of action based on the findings of the mixed-methods evaluation is presented to support wider implementation and translation. Conclusion: The online program effectively reduced psychological distress and loneliness and improved carer wellbeing.

Comparative outcomes and risk analysis after cone repair or tricuspid valve replacement for Ebstein's anomaly.

Objective: Ebstein's anomaly is a rare congenital heart malformation for which surgical and medical management are still controversial. The cone repair has transformed surgical outcomes in many of these patients. We aimed to present our results on the outcomes of patients with Ebstein's anomaly who underwent a cone repair or tricuspid valve replacement. Methods: A total of 85 patients who underwent a cone repair (mean age, 16.5 years) or tricuspid valve replacement (mean age, 40.8 years) between 2006 and 2021 were included. Univariate, multivariate, and Kaplan-Meier analyses were used to evaluate operative and long-term outcomes. Results: Residual/recurrent greater than mild-to-moderate tricuspid regurgitation at discharge was higher after cone repair compared with tricuspid valve replacement (36% vs 5%; P = .010). However, at last follow-up, the risk of greater than mild-to-moderate tricuspid regurgitation was not different between groups (35% in the cone group vs 37% in the tricuspid valve replacement group; P = .786). The tricuspid valve replacement group had a higher risk of tricuspid valve reoperation (37% vs 9%; P = .005) and tricuspid stenosis (21% vs 0%; P = .002) compared with the cone repair group. Kaplan-Meier freedom from reintervention was 97%, 91%, and 91% at 2, 4, and 6 years after cone repair, respectively, and 84%, 74%, and 68% at 2, 4, and 6 years after tricuspid valve replacement, respectively (P = .0191). At last follow-up, right ventricular function was significantly worse from baseline in the tricuspid valve replacement group (P = .0294). There were no statistical differences between age-stratified cohorts or surgeon volume in the cone repair group. Conclusions: The cone procedure offers excellent results, with stable tricuspid valve function and low reintervention and death rates at last follow-up. The rate of greater than mild-to-moderate residual tricuspid regurgitation at discharge was higher after cone repair compared with tricuspid valve replacement, but this did not expose the patient to a higher risk of reoperation or death at last follow-up. Tricuspid valve replacement was associated with a significantly higher risk of tricuspid valve reoperation and tricuspid valve stenosis, and worse right ventricular function at last follow-up.

Longitudinal assessment of placental perfusion in normal and hypertensive pregnancies using pseudo-continuous arterial spin-labeled MRI: preliminary experience.

OBJECTIVES: To evaluate longitudinal placental perfusion using pseudo-continuous arterial spin-labeled (pCASL) MRI in normal pregnancies and in pregnancies affected by chronic hypertension (cHTN), who are at the greatest risk for placental-mediated disease conditions. METHODS: Eighteen normal and 23 pregnant subjects with cHTN requiring antihypertensive therapy were scanned at 3 T using free-breathing pCASL-MRI at 16-20 and 24-28 weeks of gestational age. RESULTS: Mean placental perfusion was 103.1 ± 48.0 and 71.4 ± 18.3 mL/100 g/min at 16-20 and 24-28 weeks respectively in normal pregnancies and 79.4 ± 27.4 and 74.9 ± 26.6 mL/100 g/min in cHTN pregnancies. There was a significant decrease in perfusion between the first and second scans in normal pregnancies (p = 0.004), which was not observed in cHTN pregnancies (p = 0.36). The mean perfusion was not statistically different between normal and cHTN pregnancies at both scans, but the absolute change in perfusion per week was statistically different between these groups (p = 0.044). Furthermore, placental perfusion was significantly lower at both time points (p = 0.027 and 0.044 respectively) in the four pregnant subjects with cHTN who went on to have infants that were small for gestational age (52.7 ± 20.4 and 50.4 ± 20.9 mL/100 g/min) versus those who did not (85 ± 25.6 and 80.0 ± 25.1 mL/100 g/min). CONCLUSION: pCASL-MRI enables longitudinal assessment of placental perfusion in pregnant subjects. Placental perfusion in the second trimester declined in normal pregnancies whereas it remained unchanged in cHTN pregnancies, consistent with alterations due to vascular disease pathology. Perfusion was significantly lower in those with small for gestational age infants, indicating that pCASL-MRI-measured perfusion may be an effective imaging biomarker for placental insufficiency. CLINICAL RELEVANCE STATEMENT: pCASL-MRI enables longitudinal assessment of placental perfusion without administering exogenous contrast agent and can identify placental insufficiency in pregnant subjects with chronic hypertension that can lead to earlier interventions. KEY POINTS: • Arterial spin-labeled (ASL) magnetic resonance imaging (MRI) enables longitudinal assessment of placental perfusion without administering exogenous contrast agent. • ASL-MRI-measured placental perfusion decreased significantly between 16-20 week and 24-28 week gestational age in normal pregnancies, while it remained relatively constant in hypertensive pregnancies, attributed to vascular disease pathology. • ASL-MRI-measured placental perfusion was significantly lower in subjects with hypertension who had a small for gestational age infant at 16-20-week gestation, indicating perfusion as an effective biomarker of placental insufficiency.

Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation in type I interferon and cytokine responses in COVID-19.

Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19) and is influenced by host genetics. To understand mechanisms of inflammation, animal models that reflect genetic diversity and clinical outcomes observed in humans are needed. We report a mouse panel comprising the genetically diverse Collaborative Cross (CC) founder strains crossed to human ACE2 transgenic mice (K18-hACE2) that confers susceptibility to SARS-CoV-2. Infection of CC x K18-hACE2 resulted in a spectrum of survival, viral replication kinetics, and immune profiles. Importantly, in contrast to the K18-hACE2 model, early type I interferon (IFN-I) and regulated proinflammatory responses were required for control of SARS-CoV-2 replication in PWK x K18-hACE2 mice that were highly resistant to disease. Thus, virus dynamics and inflammation observed in COVID-19 can be modeled in diverse mouse strains that provide a genetically tractable platform for understanding anti-coronavirus immunity.

Clinical Outcomes of Adult Fontan-Associated Liver Disease and Combined Heart-Liver Transplantation.

BACKGROUND: The impact of Fontan-associated liver disease (FALD) on post-transplant mortality and indications for combined heart-liver transplant (CHLT) in adult Fontan patients remains unknown. OBJECTIVES: The purpose of this study was to assess the impact of FALD on post-transplant outcomes and compare HT vs CHLT in adult Fontan patients. METHODS: We performed a retrospective-cohort study of adult Fontan patients who underwent HT or CHLT across 15 centers. Inclusion criteria were as follows: 1) Fontan; 2) HT/CHLT referral; and 3) age ≥16 years at referral. Pretransplant FALD score was calculated using the following: 1) cirrhosis; 2) varices; 3) splenomegaly; or 4) ≥2 paracenteses. RESULTS: A total of 131 patients (91 HT and 40 CHLT) were included. CHLT recipients were more likely to be older (P = 0.016), have a lower hemoglobin (P = 0.025), require ≥2 diuretic agents pretransplant (P = 0.051), or be transplanted in more recent decades (P = 0.001). Postmatching, CHLT demonstrated a trend toward improved survival at 1 year (93% vs 74%; P = 0.097) and improved survival at 5 years (86% vs 52%; P = 0.041) compared with HT alone. In patients with a FALD score ≥2, CHLT was associated with improved survival (1 year: 85% vs 62%; P = 0.044; 5 years: 77% vs 42%; P = 0.019). In a model with transplant decade and FALD score, CHLT was associated with improved survival (HR: 0.33; P = 0.044) and increasing FALD score was associated with worse survival (FALD score: 2 [HR: 14.6; P = 0.015], 3 [HR: 22.2; P = 0.007], and 4 [HR: 27.8; P = 0.011]). CONCLUSIONS: Higher FALD scores were associated with post-transplant mortality. Although prospective confirmation of our findings is necessary, compared with HT alone, CHLT recipients were older with higher FALD scores, but had similar survival overall and superior survival in patients with a FALD score ≥2.

Morbidity and Mortality in Adult Fontan Patients After Heart or Combined Heart-Liver Transplantation.

BACKGROUND: An increasing number of adult Fontan patients require heart transplantation (HT) or combined heart-liver transplant (CHLT); however, data regarding outcomes and optimal referral time remain limited. OBJECTIVES: The purpose of this study was to define survivorship post-HT/CHLT and predictors of post-transplant mortality, including timing of referral, in the adult Fontan population. METHODS: A retrospective cohort study of adult Fontan patients who underwent HT or CHLT across 15 centers in the United States and Canada was performed. Inclusion criteria included the following: 1) Fontan; 2) HT/CHLT referral; and 3) age ≥16 years at the time of referral. Date of "failing" Fontan was defined as the earliest of the following: worsening fluid retention, new ascites, refractory arrhythmia, "failing Fontan" diagnosis by treating cardiologist, or admission for heart failure. RESULTS: A total of 131 patients underwent transplant, including 40 CHLT, from 1995 to 2021 with a median post-transplant follow-up time of 1.6 years (Q1 0.35 years, Q3 4.3 years). Survival was 79% at 1 year and 66% at 5 years. Survival differed by decade of transplantation and was 87% at 1 year and 76% at 5 years after 2010. Time from Fontan failure to evaluation (HR/year: 1.23 [95% CI: 1.11-1.36]; P < 0.001) and markers of failure, including NYHA functional class IV (HR: 2.29 [95% CI: 1.10-5.28]; P = 0.050), lower extremity varicosities (HR: 3.92 [95% CI: 1.68-9.14]; P = 0.002), and venovenous collaterals (HR: 2.70 [95% CI: 1.17-6.20]; P = 0.019), were associated with decreased post-transplant survival at 1 year in a bivariate model that included transplant decade. CONCLUSIONS: In our multicenter cohort, post-transplant survival improved over time. Late referral after Fontan failure and markers of failing Fontan physiology, including worse functional status, lower extremity varicosities, and venovenous collaterals, were associated with post-transplant mortality.

Pathobionts in the tumour microbiota predict survival following resection for colorectal cancer.

BACKGROUND AND AIMS: The gut microbiota is implicated in the pathogenesis of colorectal cancer (CRC). We aimed to map the CRC mucosal microbiota and metabolome and define the influence of the tumoral microbiota on oncological outcomes. METHODS: A multicentre, prospective observational study was conducted of CRC patients undergoing primary surgical resection in the UK (n = 74) and Czech Republic (n = 61). Analysis was performed using metataxonomics, ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), targeted bacterial qPCR and tumour exome sequencing. Hierarchical clustering accounting for clinical and oncological covariates was performed to identify clusters of bacteria and metabolites linked to CRC. Cox proportional hazards regression was used to ascertain clusters associated with disease-free survival over median follow-up of 50 months. RESULTS: Thirteen mucosal microbiota clusters were identified, of which five were significantly different between tumour and paired normal mucosa. Cluster 7, containing the pathobionts Fusobacterium nucleatum and Granulicatella adiacens, was strongly associated with CRC (PFDR = 0.0002). Additionally, tumoral dominance of cluster 7 independently predicted favourable disease-free survival (adjusted p = 0.031). Cluster 1, containing Faecalibacterium prausnitzii and Ruminococcus gnavus, was negatively associated with cancer (PFDR = 0.0009), and abundance was independently predictive of worse disease-free survival (adjusted p = 0.0009). UPLC-MS analysis revealed two major metabolic (Met) clusters. Met 1, composed of medium chain (MCFA), long-chain (LCFA) and very long-chain (VLCFA) fatty acid species, ceramides and lysophospholipids, was negatively associated with CRC (PFDR = 2.61 × 10-11); Met 2, composed of phosphatidylcholine species, nucleosides and amino acids, was strongly associated with CRC (PFDR = 1.30 × 10-12), but metabolite clusters were not associated with disease-free survival (p = 0.358). An association was identified between Met 1 and DNA mismatch-repair deficiency (p = 0.005). FBXW7 mutations were only found in cancers predominant in microbiota cluster 7. CONCLUSIONS: Networks of pathobionts in the tumour mucosal niche are associated with tumour mutation and metabolic subtypes and predict favourable outcome following CRC resection. Video Abstract.