An online case-based teaching and assessment program on clinical history-taking skills and reasoning using simulated patients in response to the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has created unprecedented challenges for medical students and educators worldwide. Groups 1, 2 and 3 of year 3, semester 2 medical students at the Royal College of Surgeons in Ireland (n = 275) had only completed 2, 5 and 7 weeks, respectively, of their scheduled 10-week clinical medicine and surgery attachments, prior to the Irish shutdown of all in-person non-essential activities, including medical student education. METHODS: We developed and delivered an online case-based program, focused on history-taking skills and clinical reasoning, using simulated patients and video technologies. 12 tutorials were delivered over 6 weeks to 35 subgroups of 8 students in line with program learning outcomes. Both simulated patients (n = 36), and tutors (n = 45, from retired clinical professors to newly graduated physicians), were rapidly upskilled in Blackboard Collaborate and Microsoft Teams, and also in the provision of constructive feedback. We evaluated this newly developed program by the following three criteria: student attendance, achieved grades, and student feedback. RESULTS: Attendance at the 12 tutorials was higher amongst group 1 and 2 students (75 and 73%) by comparison with group 3 students (60%) (p = < 0.001). Of the 273 students that sat the Year 3 Semester 2 online long case assessment, 93% were successful. Despite group 1 students having the least prior clinical experience, results were similar to those of groups 2 and 3 (1st honors, 2nd honors, pass, and fail grades for group 1, 39%, 33%, 23% and 6%; group 2, 34%, 41%, 17% and 8%; group 3, 39%, 25%, 28% and 7%) (p = 0.48). An increased attendance rate at tutorials was associated with higher numbers of honors grades (p = < 0.001). Anonymous feedback from the students demonstrated considerable satisfaction with program: > 85% agreed that the online program was interactive and very educational. CONCLUSIONS: Use of online video technology, tutors of varied experience, and simulated patients were demonstrated to replicate patient encounters, and to facilitate the development of clinical skills remotely during the COVID-19 pandemic.

Analysis with the exome array identifies multiple new independent variants in lipid loci.

It has been hypothesized that low frequency (1-5% minor allele frequency (MAF)) and rare (<1% MAF) variants with large effect sizes may contribute to the missing heritability in complex traits. Here, we report an association analysis of lipid traits (total cholesterol, LDL-cholesterol, HDL-cholesterol triglycerides) in up to 27 312 individuals with a comprehensive set of low frequency coding variants (ExomeChip), combined with conditional analysis in the known lipid loci. No new locus reached genome-wide significance. However, we found a new lead variant in 26 known lipid association regions of which 16 were >1000-fold more significant than the previous sentinel variant and not in close LD (six had MAF <5%). Furthermore, conditional analysis revealed multiple independent signals (ranging from 1 to 5) in a third of the 98 lipid loci tested, including rare variants. Addition of our novel associations resulted in between 1.5- and 2.5-fold increase in the proportion of heritability explained for the different lipid traits. Our findings suggest that rare coding variants contribute to the genetic architecture of lipid traits.

Central arteriovenous anastomosis for the treatment of patients with uncontrolled hypertension (the ROX CONTROL HTN study): a randomised controlled trial.

BACKGROUND: Hypertension contributes to cardiovascular morbidity and mortality. We assessed the safety and efficacy of a central iliac arteriovenous anastomosis to alter the mechanical arterial properties and reduce blood pressure in patients with uncontrolled hypertension. METHODS: We enrolled patients in this open-label, multicentre, prospective, randomised, controlled trial between October, 2012, and April, 2014. Eligible patients had baseline office systolic blood pressure of 140 mm Hg or higher and average daytime ambulatory blood pressure of 135 mm Hg or higher systolic and 85 mm Hg or higher diastolic despite antihypertensive treatment. Patients were randomly allocated in a 1:1 ratio to undergo implantation of an arteriovenous coupler device plus current pharmaceutical treatment or to maintain current treatment alone (control). The primary endpoint was mean change from baseline in office and 24 h ambulatory systolic blood pressure at 6 months. Analysis was by modified intention to treat (all patients remaining in follow-up at 6 months). This trial is registered with ClinicalTrials.gov, number NCT01642498. FINDINGS: 83 (43%) of 195 patients screened were assigned arteriovenous coupler therapy (n=44) or normal care (n=39). Mean office systolic blood pressure reduced by 26·9 (SD 23·9) mm Hg in the arteriovenous coupler group (p<0·0001) and by 3·7 (21·2) mm Hg in the control group (p=0·31). Mean systolic 24 h ambulatory blood pressure reduced by 13·5 (18·8) mm Hg (p<0·0001) in arteriovenous coupler recipients and by 0·5 (15·8) mm Hg (p=0·86) in controls. Implantation of the arteriovenous coupler was associated with late ipsilateral venous stenosis in 12 (29%) of 42 patients and was treatable with venoplasty or stenting. INTERPRETATION: Arteriovenous anastomosis was associated with significantly reduced blood pressure and hypertensive complications. This approach might be a useful adjunctive therapy for patients with uncontrolled hypertension. FUNDING: ROX Medical.

Central iliac arteriovenous anastomosis for hypertension: targeting mechanical aspects of the circulation.

Raised blood pressure is the leading attributable risk factor for global morbidity and mortality. Real world data demonstrates that half of treated patients are at elevated cardiovascular risk because of inadequately controlled BP. In addition to pharmacotherapy, certain interventional strategies to reduce blood pressure and cardiovascular risk in hypertension can be considered according to international guidelines. One of the newer technologies entering this field is a proprietary arteriovenous coupler device that forms a fixed flow arteriovenous conduit in the central vasculature. In this review, we examine the development of and rationale for the creation of a central arteriovenous anastomosis in patients with hypertension and review the proposed mechanisms by which it may ameliorate hypertension. We critically review the clinical trial evidence base to date and postulate on future therapeutic directions.

Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.

Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.

The thrill of success: central arterial-venous anastomosis for hypertension.

Excess blood pressure remains the most important risk factor for cardiovascular and renal disease. Poly pharmacy has been proved safe and effective under clinical trial circumstances; however, the majority of patients fail to sustain pharmaceutical persistence and adherence. The opportunity to offer patients a treatment or device in addition or perhaps instead of drug therapy alone may significantly broaden the options for patients and allow greater success in hypertensive therapy. In this review, we examine the potential of a fixed-volume central arterial-venous anastomosis to reduce blood pressure in hypertensive patients, review possible mechanisms by which the anastomosis may reduce blood pressure, and consider the unique clinical trial opportunities posed by this therapy.

Plant-based diets-impacts of consumption of little or no animal-source foods on human health.

The world, in 2024, faces both climate and biodiversity crises, and the food system does contribute significantly to these crises. For some, the solution is simple - intakes of animal source foods (ASFs) should be considerably reduced, and consumption of plant-source foods (PSFs) should be greatly increased. Advocates for such a dietary transformation express confidence that plant-based diets will not only benefit planetary health, but will provide nutrient adequacy for all, and will also result in considerable protection from chronic non-communicable diseases (NCDs). However, as described in this perspective, the dramatic reductions in ASFs, entailed by many plant-based diets, will worsen already prevalent micronutrient and protein deficiencies. The protections provided by plant-based diets against NCDs appear to be more strongly associated with reduced intakes of calories and salt, and increased intakes of fruit, vegetables, nuts and whole grains, rather than with reduced intakes of ASFs. Any possible absolute adverse effects of red and processed meat consumption on NCDs are very small and uncertain. Other ASFs either appear to have no impact on NCDs (poultry meat and eggs), or are associated with protections against obesity, cardiovascular events, brain disorders and some cancers (seafood and dairy). Rigorous randomized controlled trials of all newly proposed environmentally-protective plant-based diets are required, so as to provide clear-cut evidence of micronutrient and protein adequacy, with or without, supplementation, fortification and/or biofortification. In the meantime, dietary guidelines should advise moderating excessive consumption, rather than substantially limiting or excluding ASFs from the human diet.

Unacceptable use of substandard metrics in policy decisions which mandate large reductions in animal-source foods.

Many recent very influential reports, including those from the Global Burden of Disease (GBD) Risk Factor Collaborators, the EAT-Lancet Commission on Food, Planet, Health, and the Lancet Countdown on Health and Climate Change, have recommended dramatic reductions or total exclusion of animal-source foods, particularly ruminant products (red meat and dairy), from the human diet. They strongly suggest that these dietary shifts will not only benefit planetary health but also human health. However, as detailed in this perspective, there are grounds for considerable concern in regard to the quality and transparency of the input data, the validity of the assumptions, and the appropriateness of the statistical modelling, used in the calculation of the global health estimates, which underpin the claimed human health benefits. The lessor bioavailability of protein and key micronutrients from plant-source foods versus animal-source foods was not adequately recognised nor addressed in any of these reports. Furthermore, assessments of bias and certainty were either limited or absent. Despite many of these errors and limitations being publically acknowledged by the GBD and the EAT-Lancet authors, no corrections have been applied to the published papers. As a consequence, these reports continue to erroneously influence food policy decisions and international dietary guidelines, such as the World Wildlife Fund's Livewell Diet, and the Nordic Nutrition Recommendations 2023.

Genome-wide analysis of blood pressure variability and ischemic stroke.

BACKGROUND AND PURPOSE: Visit-to-visit variability in blood pressure (vBP) is associated with ischemic stroke. We sought to determine whether such variability has genetic causes and whether genetic variants associated with BP variability are also associated with ischemic stroke. METHODS: A Genome Wide Association Study (GWAS) for loci influencing BP variability was undertaken in 3802 individuals from the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) study, in which long-term visit-to-visit and within-visit BP measures were available. Because BP variability is strongly associated with ischemic stroke, we genotyped the sentinel single nucleotide polymorphism in an independent ischemic stroke population comprising 8624 cases and 12 722 controls and in 3900 additional (Scandinavian) participants from the ASCOT study to replicate our findings. RESULTS: The ASCOT discovery GWAS identified a cluster of 17 correlated single nucleotide polymorphisms within the NLGN1 gene (3q26.31) associated with BP variability. The strongest association was with rs976683 (P=1.4×10(-8)). Conditional analysis of rs976683 provided no evidence of additional independent associations at the locus. Analysis of rs976683 in patients with ischemic stroke found no association for overall stroke (odds ratio, 1.02; 95% CI, 0.97-1.07; P=0.52) or its subtypes: cardioembolic (odds ratio, 1.07; 95% CI, 0.97-1.16; P=0.17), large vessel disease (odds ratio, 0.98; 95% CI, 0.89-1.07; P=0.60), and small vessel disease (odds ratio, 1.07; 95% CI, 0.97-1.17; P=0.19). No evidence for association was found between rs976683 and BP variability in the additional (Scandinavian) ASCOT participants (P=0.18). CONCLUSIONS: We identified a cluster of single nucleotide polymorphisms at the NLGN1 locus showing significant association with BP variability. Follow-up analyses did not support an association with risk of ischemic stroke and its subtypes.

Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5' region of Uromodulin (UMOD; rs13333226, combined P value of 3.6 × 10⁻¹¹). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial.

IMPORTANCE: Most patients with cardiovascular disease (CVD) do not take recommended medications long-term. The use of fixed-dose combinations (FDCs) improves adherence in several clinical areas. Previous trials of cardiovascular FDCs have assessed short-term effects compared with placebo or no treatment. OBJECTIVE: To assess whether FDC delivery of aspirin, statin, and 2 blood pressure-lowering agents vs usual care improves long-term adherence to indicated therapy and 2 major CVD risk factors, systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C). DESIGN, SETTING, AND PARTICIPANTS: The UMPIRE trial, a randomized, open-label, blinded-end-point trial among 2004 participants with established CVD or at risk of CVD enrolled July 2010-July 2011 in India and Europe. The trial follow-up concluded in July 2012. INTERVENTIONS: Participants were randomly assigned (1:1) to an FDC-based strategy (n=1002) containing either (1) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 50 mg atenolol or (2) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 12.5 mg hydrochlorothiazide or to usual care (n=1002). MAIN OUTCOMES AND MEASURES: Adherence to medication (defined as self-reported use of antiplatelet, statin, and ≥2 BP-lowering medications) and changes in SBP and LDL-C from baseline. RESULTS: At baseline, mean BP was 137/78 mm Hg, LDL-C was 91.5 mg/dL, and 1233 (61.5%) of 2004 participants reported use of antiplatelet, statin, and 2 or more BP-lowering medications. Median follow-up was 15 months (interquartile range, 12-18 months). The FDC group had improved adherence vs usual care (86% vs 65%; relative risk [RR] of being adherent, 1.33; 95% CI, 1.26-1.41; P < .001) with concurrent reductions in SBP (-2.6 mm Hg; 95% CI, -4.0 to -1.1 mm Hg; P < .001) and LDL-C (-4.2 mg/dL; 95% CI, -6.6 to -1.9 mg/dL; P < .001) at the end of the study. Although there was consistency of effects across predefined subgroups, evidence existed of larger benefits in patients with lower adherence at baseline. In this subgroup of 727 participants (36%), adherence at the end of study was 77% vs 23% (RR, 3.35; 95% CI, 2.74-4.09; P < .001 for interaction), SBP was reduced by 4.9 mm Hg (95% CI 7.3-2.6 mm Hg; P = .01 for interaction), and LDL-C was reduced by 6.7 mg/dL (95% CI, 10.5-2.8 mg/dL; P = .11 for interaction). There were no significant differences in serious adverse events or cardiovascular events (50 [5%] in the FDC group and 35 [3.5%] in the usual care group; RR, 1.45; 95% CI, 0.94-2.24; P=.09) between the groups. CONCLUSIONS AND RELEVANCE: Among patients with or at high risk of CVD, use of an FDC strategy for blood pressure, cholesterol, and platelet control vs usual care resulted in significantly improved medication adherence at 15 months and statistically significant but small improvements in SBP and LDL-C. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01057537.

Engineered 3D Immuno-Glial-Neurovascular Human Brain Model.

Patient-specific, human-based cellular models that integrate biomimetic BBB, immune, and myelinated neuron components are critically needed to enable translationally relevant and accelerated discovery of neurological disease mechanisms and interventions. By engineering a brain-mimicking 3D hydrogel and co-culturing all six major brain cell types derived from patient iPSCs, we have constructed, characterized, and utilized a multicellular integrated brain (miBrain) immuno-glial-neurovascular model with in vivo- like hallmarks. As proof of principle, here we utilized the miBrain to model Alzheimer's Disease pathologies associated with APOE4 genetic risk. APOE4 miBrains differentially exhibit amyloid aggregation, tau phosphorylation, and astrocytic GFAP. Unlike the co-emergent fate specification of glia and neurons in organoids, miBrains integrate independently differentiated cell types in a modular system with unique utility for elucidating cell-type specific contributions to pathogenesis. We here harness this feature to identify that risk factor APOE4 in astrocytes promotes tau pathogenesis and neuronal dysregulation through crosstalk with microglia. One-Sentence Summary: A novel patient-specific brain model with BBB, neuronal, immune, and glial components was developed, characterized, and harnessed to model Alzheimer's Disease-associated pathologies and APOE4 genetic risk.

Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a).

We carried out a genome-wide association study (GWAS) of LDL-c response to statin using data from participants in the Collaborative Atorvastatin Diabetes Study (CARDS; n = 1,156), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT; n = 895), and the observational phase of ASCOT (n = 651), all of whom were prescribed atorvastatin 10 mg. Following genome-wide imputation, we combined data from the three studies in a meta-analysis. We found associations of LDL-c response to atorvastatin that reached genome-wide significance at rs10455872 (P = 6.13 × 10(-9)) within the LPA gene and at two single nucleotide polymorphisms (SNP) within the APOE region (rs445925; P = 2.22 × 10(-16) and rs4420638; P = 1.01 × 10(-11)) that are proxies for the ε2 and ε4 variants, respectively, in APOE. The novel association with the LPA SNP was replicated in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial (P = 0.009). Using CARDS data, we further showed that atorvastatin therapy did not alter lipoprotein(a) [Lp(a)] and that Lp(a) levels accounted for all of the associations of SNPs in the LPA gene and the apparent LDL-c response levels. However, statin therapy had a similar effect in reducing cardiovascular disease (CVD) in patients in the top quartile for serum Lp(a) levels (HR = 0.60) compared with those in the lower three quartiles (HR = 0.66; P = 0.8 for interaction). The data emphasize that high Lp(a) levels affect the measurement of LDL-c and the clinical estimation of LDL-c response. Therefore, an apparently lower LDL-c response to statin therapy may indicate a need for measurement of Lp(a). However, statin therapy seems beneficial even in those with high Lp(a).

Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.

Blood lipids are important cardiovascular disease (CVD) risk factors with both genetic and environmental determinants. The Whitehall II study (n=5592) was genotyped with the gene-centric HumanCVD BeadChip (Illumina). We identified 195 SNPs in 16 genes/regions associated with 3 major lipid fractions and 2 apolipoprotein components at p<10(-5), with the associations being broadly concordant with prior genome-wide analysis. SNPs associated with LDL cholesterol and apolipoprotein B were located in LDLR, PCSK9, APOB, CELSR2, HMGCR, CETP, the TOMM40-APOE-C1-C2-C4 cluster, and the APOA5-A4-C3-A1 cluster; SNPs associated with HDL cholesterol and apolipoprotein AI were in CETP, LPL, LIPC, APOA5-A4-C3-A1, and ABCA1; and SNPs associated with triglycerides in GCKR, BAZ1B, MLXIPL, LPL, and APOA5-A4-C3-A1. For 48 SNPs in previously unreported loci that were significant at p<10(-4) in Whitehall II, in silico analysis including the British Women's Heart and Health Study, BRIGHT, ASCOT, and NORDIL studies (total n>12,500) revealed previously unreported associations of SH2B3 (p<2.2x10(-6)), BMPR2 (p<2.3x10(-7)), BCL3/PVRL2 (flanking APOE; p<4.4x10(-8)), and SMARCA4 (flanking LDLR; p<2.5x10(-7)) with LDL cholesterol. Common alleles in these genes explained 6.1%-14.7% of the variance in the five lipid-related traits, and individuals at opposite tails of the additive allele score exhibited substantial differences in trait levels (e.g., >1 mmol/L in LDL cholesterol [approximately 1 SD of the trait distribution]). These data suggest that multiple common alleles of small effect can make important contributions to individual differences in blood lipids potentially relevant to the assessment of CVD risk. These genes provide further insights into lipid metabolism and the likely effects of modifying the encoded targets therapeutically.

Aligned Gelatin Microribbon Scaffolds with Hydroxyapatite Gradient for Engineering the Bone-Tendon Interface.

Injuries of the bone-to-tendon interface, such as rotator cuff and anterior cruciate ligament tears, are prevalent musculoskeletal injuries, yet effective methods for repair remain elusive. Tissue engineering approaches that use cells and biomaterials offer a promising potential solution for engineering the bone-tendon interface, but previous strategies require seeding multiple cell types and use of multiphasic scaffolds to achieve zonal-specific tissue phenotype. Furthermore, mimicking the aligned tissue morphology present in native bone-tendon interface in three-dimensional (3D) remains challenging. To facilitate clinical translation, engineering bone-tendon interface using a single cell source and one continuous scaffold with alignment cues would be more attractive but has not been achieved before. To address these unmet needs, in this study, we develop an aligned gelatin microribbon (µRB) hydrogel scaffold with hydroxyapatite nanoparticle (HA-np) gradient for guiding zonal-specific differentiation of human mesenchymal stem cell (hMSC) to mimic the bone-tendon interface. We demonstrate that aligned µRBs led to cell alignment in 3D, and HA gradient induced zonal-specific differentiation of mesenchymal stem cells that resemble the transition at the bone-tendon interface. Short chondrogenic priming before exposure to osteogenic factors further enhanced the mimicry of bone-cartilage-tendon transition with significantly improved tensile moduli of the resulting tissues. In summary, aligned gelatin µRBs with HA gradient coupled with optimized soluble factors may offer a promising strategy for engineering bone-tendon interface using a single cell source. Impact statement Our 3D macroporous microribbon hydrogel platform with alignment cues zonally integrated with hydroxyapatite nanoparticles enables differentiation across the bone-tendon interface within a continuous scaffold. While most interfacial scaffolds heretofore rely on composites and multilayer approaches, we present a continuous scaffold utilizing a single cell source. The synergy of niche cues with human mesenchymal stem cell (hMSC) culture leads to an over 45-fold enhancement in tensile modulus in culture. We further demonstrate that priming hMSCs towards the chondrogenic lineage can enhance the differential osteogenesis. Relying on a single cell source could enhance zone integration and scaffold integrity, along with practical benefits.

Engineering multicellular living systems-a Keystone Symposia report.

The ability to engineer complex multicellular systems has enormous potential to inform our understanding of biological processes and disease and alter the drug development process. Engineering living systems to emulate natural processes or to incorporate new functions relies on a detailed understanding of the biochemical, mechanical, and other cues between cells and between cells and their environment that result in the coordinated action of multicellular systems. On April 3-6, 2022, experts in the field met at the Keystone symposium "Engineering Multicellular Living Systems" to discuss recent advances in understanding how cells cooperate within a multicellular system, as well as recent efforts to engineer systems like organ-on-a-chip models, biological robots, and organoids. Given the similarities and common themes, this meeting was held in conjunction with the symposium "Organoids as Tools for Fundamental Discovery and Translation".

Tissue Doppler E/E' ratio is a powerful predictor of primary cardiac events in a hypertensive population: an ASCOT substudy.

AIMS: Patients with controlled hypertension are at risk of future cardiac events, but predicting first events remains difficult. We hypothesized that modern echocardiographic measures of left ventricular diastolic function may be more sensitive than traditional echocardiographic methods of risk prediction and set out to test this in a cohort of patients with well-controlled hypertension. METHODS AND RESULTS: Conventional and tissue Doppler echocardiography was performed on 980 participants in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). All subjects had hypertension, but no known cardiac disease. Cardiac events were defined as fatal and non-fatal myocardial infarction (including silent myocardial infarction), coronary revascularization procedures, new-onset angina (stable or unstable), fatal and non-fatal heart failure, and life-threatening arrhythmias. Analysis was performed by a single, blinded observer. There were 56 primary cardiac events during 4.2 +/- 0.7 years follow-up. The ratio of transmitral Doppler early filling velocity to tissue Doppler early diastolic mitral annular velocity (E/E') was the strongest predictor of first cardiac events in Cox-proportional hazards models. Following adjustment for covariates, a unit rise in the E/E' ratio was associated with a 17% increment in risk of a cardiac event (HR 1.17, CI 1.05-1.29; P = 0.003). CONCLUSION: Tissue Doppler E/E', a non-invasive estimate of left atrial filling pressure, independently predicts primary cardiac events in a hypertensive population and out-performed traditional echocardiographic measures in this moderately sized, well-treated hypertensive population. E/E' represents a simple, effective tool for assessing cardiac risk in a hypertensive population.

Pneumomediastinum following endobronchial ultrasound and transbronchial needle aspirate (EBUS-TBNA) sampling of mediastinal lymph nodes.

A 72-year-old female patient underwent endobronchial ultrasound and transbronchial needle aspirate sampling of mediastinal lymph nodes to investigate a middle lobe abnormality following an urgent referral. CT imaging completed the following day demonstrated a pneumomediastinum. At clinical review, the patient remained clinically stable and no intervention was required.

Negative Transpulmonary Pressure Disrupts Airway Morphogenesis by Suppressing Fgf10.

Mechanical forces are increasingly recognized as important determinants of cell and tissue phenotype and also appear to play a critical role in organ development. During the fetal stages of lung morphogenesis, the pressure of the fluid within the lumen of the airways is higher than that within the chest cavity, resulting in a positive transpulmonary pressure. Several congenital defects decrease or reverse transpulmonary pressure across the developing airways and are associated with a reduced number of branches and a correspondingly underdeveloped lung that is insufficient for gas exchange after birth. The small size of the early pseudoglandular stage lung and its relative inaccessibility in utero have precluded experimental investigation of the effects of transpulmonary pressure on early branching morphogenesis. Here, we present a simple culture model to explore the effects of negative transpulmonary pressure on development of the embryonic airways. We found that negative transpulmonary pressure decreases branching, and that it does so in part by altering the expression of fibroblast growth factor 10 (Fgf10). The morphogenesis of lungs maintained under negative transpulmonary pressure can be rescued by supplementing the culture medium with exogenous FGF10. These data suggest that Fgf10 expression is regulated by mechanical stress in the developing airways. Understanding the mechanical signaling pathways that connect transpulmonary pressure to FGF10 can lead to the establishment of novel non-surgical approaches for ameliorating congenital lung defects.