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.

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.

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.

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".

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.

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.

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.

Omega-3 index and blood pressure responses to eating foods naturally enriched with omega-3 polyunsaturated fatty acids: a randomized controlled trial.

Diets low in seafood omega-3 polyunsaturated fatty acids (PUFAs) are very prevalent. Such diets have recently been ranked as the sixth most important dietary risk factor-1.5 million deaths and 33 million disability-adjusted life-years worldwide are attributable to this deficiency. Wild oily fish stocks are insufficient to feed the world's population, and levels of eicosapentaenoic acid and docosahexaenoic acid (DHA) in farmed fish have more than halved in the last 20 years. Here we report on a double-blinded, controlled trial, where 161 healthy normotensive adults were randomly allocated to eat at least three portions/week of omega-3-PUFA enriched (or control) chicken-meat, and to eat at least three omega-3-PUFA enriched (or control) eggs/week, for 6 months. We show that regular consumption of omega-3-PUFA enriched chicken-meat and eggs significantly increased the primary outcome, the red cell omega-3 index (mean difference [98.75% confidence interval] from the group that ate both control foods, 1.7% [0.7, 2.6]). Numbers of subjects with a very high-risk omega-3 index (index < 4%) were more than halved amongst the group that ate both enriched foods. Furthermore, eating the enriched foods resulted in clinically relevant reductions in diastolic blood pressure (- 3.1 mmHg [- 5.8, - 0.3]). We conclude that chicken-meat and eggs, naturally enriched with algae-sourced omega-3-PUFAs, may serve as alternative dietary sources of these essential micronutrients. Unlike many lifestyle interventions, long-term population health benefits do not depend on willingness of individuals to make long-lasting difficult dietary changes, but on the availability of a range of commonly eaten, relatively inexpensive, omega-3-PUFA enriched foods.

Varying solvent type modulates collagen coating and stem cell mechanotransduction on hydrogel substrates.

Type I collagen is the most abundant extracellular matrix protein in the human body and is commonly used as a biochemical ligand for hydrogel substrates to support cell adhesion in mechanotransduction studies. Previous protocols for conjugating collagen I have used different solvents; yet, how varying solvent pH and composition impacts the efficiency and distribution of these collagen I coatings remains unknown. Here, we examine the effect of varying solvent pH and type on the efficiency and distribution of collagen I coatings on polyacrylamide hydrogels. We further evaluate the effects of varying solvent on mechanotransduction of human mesenchymal stem cells (MSCs) by characterizing cell spreading and localization of Yes-Associated Protein (YAP), a key transcriptional regulator of mechanotransduction. Increasing solvent pH to 5.2 and above increased the heterogeneity of coating with collagen bundle formation. Collagen I coating highly depends on the solvent type, with acetic acid leading to the highest conjugation efficiency and most homogeneous coating. Compared to HEPES or phosphate-buffered saline buffer, acetic acid-dissolved collagen I coatings substantially enhance MSC adhesion and spreading on both glass and polyacrylamide hydrogel substrates. When acetic acid was used for collagen coatings, even the low collagen concentration (1 µg/ml) induced robust MSC spreading and nuclear YAP localization on both soft (3 kPa) and stiff (38 kPa) substrates. Depending on the solvent type, stiffness-dependent nuclear YAP translocation occurs at a different collagen concentration. Together, the results from this study validate the solvent type as an important parameter to consider when using collagen I as the biochemical ligand to support cell adhesion.

Extracellular matrix type modulates mechanotransduction of stem cells.

Extracellular matrix (ECM) is comprised of different types of proteins, which change in composition and ratios during morphogenesis and disease progression. ECM proteins provide cell adhesion and impart mechanical cues to the cells. Increasing substrate stiffness has been shown to induce Yes-associated protein (YAP) translocation from the cytoplasm to the nucleus, yet these mechanistic studies used fibronectin only as the biochemical cue. How varying the types of ECM modulates mechanotransduction of stem cells remains largely unknown. Using polyacrylamide hydrogels with tunable stiffness as substrates, here we conjugated four major ECM proteins commonly used for cell adhesion: fibronectin, collagen I, collagen IV and laminin, and assessed the effects of varying ECM type and density on YAP translocation in human mesenchymal stem cells (hMSCs). For all four ECM types, increasing ECM ligand density alone can induce YAP nuclear translocation without changing substrate stiffness. The ligand threshold for such biochemical ligand-induced YAP translocation differs across ECM types. While stiffness-dependent YAP translocation can be induced by all four ECM types, each ECM requires a different optimized ligand density for this to occur. Using antibody blocking, we further identified integrin subunits specifically involved in mechanotransduction of different ECM types. Finally, we demonstrated that altering ECM type further modulates hMSC osteogenesis without changing substrate stiffness. These findings highlight the important role of ECM type in modulating mechanotransduction and differentiation of stem cells, and call for future mechanistic studies to further elucidate the role of changes in ECM compositions in mediating mechanotransduction during morphogenesis and disease progression. STATEMENT OF SIGNIFICANCE: Our study addresses a critical gap of knowledge in mechanobiology. Increasing substrate stiffness has been shown to induce nuclear YAP translocation, yet only on fibronectin-coated substrates. However, extracellular matrix (ECM) is comprised of different protein types. How varying the type of ECM modulates stem cell mechanotransduction remains largely unknown. We here reveal that the choice of ECM type can directly modulate stem cell mechanotransduction, filling this critical gap. This work has broad impacts in mechanobiology and biomaterials, as it provides the first evidence that varying ECM type can impact YAP translocation independent of substrate stiffness, opening doors for a more rational biomaterials design tuning ECM properties to control cell fate for promoting normal development and for preventing disease progression.

Associations and effects of omega-3 polyunsaturated fatty acids on cognitive function and mood in healthy adults: a protocol for a systematic review of observational and interventional studies.

INTRODUCTION: The association between long-chain omega-3 polyunsaturated fatty acids (PUFAs), brain health, cognitive function and mood has been the subject of intensive research. Marine-derived omega-3 PUFAs, such as docosahexaenoic acid and eicosapentaenoic acid, are highly concentrated in neuronal membranes and affect brain function. Many studies have found that consumption of omega-3 PUFAs is associated with lower risk of cognitive or mood dysfunction. However, other studies have demonstrated no beneficial effects. There appears to be inconsistent findings from both epidemiological and randomised controlled trial (RCT) studies. The aim of this review is to compile the previous literature and establish the efficacy of omega-3 PUFAs in enhancing cognitive performance and mood in healthy adults. METHODS AND ANALYSIS: Prospective cohort studies, RCTs, controlled clinical trials, controlled before and after studies, interrupted time series with a minimum of 3 months duration will be eligible for inclusion. Studies on healthy adults over the age of 18, where the intervention/exposure of interest is omega-3 PUFAs will be included. The outcomes of interest are cognition and mood. Studies will be eligible for inclusion if they measure changes in cognitive function or mood, or the risk of developing cognitive or mood disorders using validated tools and assessments. Relevant search terms and keywords will be used to generate a systematic search in Cochrane Library, MEDLINE, EMBASE, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Scopus and the grey literature. Two independent reviewers will screen studies for eligibility. Risk of bias in cohort and non-randomised studies will be assessed using the ROBINS-I tool. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials will be used for RCTs. If there are sufficient data, a meta-analysis will be conducted. ETHICS AND DISSEMINATION: This systematic review does not involve primary data collection and therefore formal ethical approval is not required. Results will be disseminated through peer reviewed publications, conference presentations and the popular press. PROSPERO REGISTRATION NUMBER: CRD42018080800.

Hydrogels with enhanced protein conjugation efficiency reveal stiffness-induced YAP localization in stem cells depends on biochemical cues.

Polyacrylamide hydrogels have been widely used in stem cell mechanotransduction studies. Conventional conjugation methods of biochemical cues to polyacrylamide hydrogels suffer from low conjugation efficiency, which leads to poor attachment of human pluripotent stem cells (hPSCs) on soft substrates. In addition, while it is well-established that stiffness-dependent regulation of stem cell fate requires cytoskeletal tension, and is mediated through nuclear translocation of transcription regulator, Yes-associated protein (YAP), the role of biochemical cues in stiffness-dependent YAP regulation remains largely unknown. Here we report a method that enhances the conjugation efficiency of biochemical cues on polyacrylamide hydrogels compared to conventional methods. This modified method enables robust hPSC attachment, proliferation and maintenance of pluripotency across varying substrate stiffness (3 kPa-38 kPa). Using this hydrogel platform, we demonstrate that varying the types of biochemical cues (Matrigel, laminin, GAG-peptide) or density of Matrigel can alter stiffness-dependent YAP localization in hPSCs. In particular, we show that stiffness-dependent YAP localization is overridden at low or high density of Matrigel. Furthermore, human mesenchymal stem cells display stiffness-dependent YAP localization only at intermediate fibronectin density. The hydrogel platform with enhanced conjugation efficiency of biochemical cues provides a powerful tool for uncovering the role of biochemical cues in regulating mechanotransduction of various stem cell types.

Biochemical Ligand Density Regulates Yes-Associated Protein Translocation in Stem Cells through Cytoskeletal Tension and Integrins.

Different tissue types are characterized by varying stiffness and biochemical ligands. Increasing substrate stiffness has been shown to trigger Yes-associated protein (YAP) translocation from the cytoplasm to the nucleus, yet the role of ligand density in modulating mechanotransduction and stem cell fate remains largely unexplored. Using polyacrylamide hydrogels coated with fibronectin as a model platform, we showed that stiffness-induced YAP translocation occurs only at intermediate ligand densities. At low or high ligand densities, YAP localization is dominated by ligand density independent of substrate stiffness. We further showed that ligand density-induced YAP translocation requires cytoskeleton tension and αVß3-integrin binding. Finally, we demonstrate that increasing ligand density alone can enhance osteogenic differentiation regardless of matrix stiffness. Together, the findings from the present study establish ligand density as an important parameter for modulating stem cell mechanotransduction and differentiation, which is mediated by integrin clustering, focal adhesion, and cytoskeletal tension.

Reaching cardiovascular prevention guideline targets with a polypill-based approach: a meta-analysis of randomised clinical trials.

OBJECTIVE: The aim of this study was to determine the effect of polypill-based care on the achievement of 2016 European Society of Cardiology (ESC) guideline targets for blood pressure (BP), low-density lipoprotein (LDL) cholesterol and antiplatelet therapy. METHODS: We conducted an individual participant data meta-analysis of three randomised clinical trials that compared a strategy using a polypill containing aspirin, statin and antihypertensive therapy with usual care in patients with a prior cardiovascular disease (CVD) event or who were at high risk of their first event. Overall, the trials included 3140 patients from Australia, England, India, Ireland, the Netherlands and New Zealand (75% male, mean age 62 years and 76% with a prior CVD event). The primary outcome for this study was the proportion of people achieving ESC guideline targets for BP, LDL and antiplatelet therapy. RESULTS: Those randomised to polypill-based care were more likely than those receiving usual care to achieve recommended targets for BP (62% vs 58%, risk ratio (RR) 1.08, 95% CI 1.02 to 1.15), LDL (39% vs 34%, RR 1.13, 95% CI 1.02 to 1.25) and all three targets for BP, LDL and adherence to antiplatelet therapy (the latter only applicable to those with a prior CVD event) simultaneously (24% vs 19%, RR 1.27, 95% CI 1.10 to 1.47) at 12 months. There was no difference between groups in antiplatelet adherence (96% vs 96%, RR 1.00, 95% CI 0.98 to 1.01). There was heterogeneity by baseline treatment intensity such that treatment effects increased with the fewer the number of treatments being taken at baseline: for patients taking 3, 2 and 0-1 treatment modalities the RRs for reaching all three guideline goals simultaneously were 1.10 (95% CI 0.94 to 1.30, 22% vs 20%), 1.62 (95% CI 1.09 to 2.42, 27% vs 17%) and 3.07 (95% CI 1.77 to 5.33, 35% vs 11%), respectively. CONCLUSIONS: Polypill-based therapy significantly improved the achievement of all three ESC targets for BP, LDL and antiplatelet therapy compared with usual care, particularly among those undertreated at baseline.

Trial of feasibility and acceptability of routine low-dose aspirin versus Early Screening Test indicated aspirin for pre-eclampsia prevention (TEST study): a multicentre randomised controlled trial.

OBJECTIVE: Evaluate the feasibility and acceptability of routine aspirin in low-risk women, compared with screening-test indicated aspirin for the prevention of pre-eclampsia and fetal growth restriction. DESIGN: Multicentre open-label feasibility randomised controlled trial. SETTING: Two tertiary maternity hospitals in Dublin, Ireland. PARTICIPANTS: 546 low-risk nulliparous women completed the study. INTERVENTIONS: Women underwent computerised randomisation to: Group 1-routine aspirin 75 mg from 11 until 36 weeks; Group 2-no aspirin and; Group 3-aspirin based on the Fetal Medicine Foundation screening test. PRIMARY AND SECONDARY OUTCOME MEASURES: (1) Proportion agreeing to participate; (2) compliance with protocol; (3) proportion where first trimester uterine artery Doppler was obtainable and; (4) time taken to issue a screening result. Secondary outcomes included rates of pre-eclampsia and small-for-gestational-age fetuses. RESULTS: 546 were included in the routine aspirin (n=179), no aspirin (n=183) and screen and treat (n=184) groups. 546 of 1054 were approached (51.8%) and enrolled. Average aspirin adherence was 90%. The uterine artery Doppler was obtained in 98.4% (181/184) and the average time to obtain a screening result was 7.6 (0-26) days. Of those taking aspirin, vaginal spotting was greater; n=29 (15.1%), non-aspirin n=28 (7.9%), OR 2.1 (95% CI 1.2 to 3.6). Postpartum haemorrhage >500 mL was also greater; aspirin n=26 (13.5%), no aspirin n=20 (5.6%), OR 2.6 (95% CI 1.4 to 4.8). CONCLUSION: Low-risk nulliparous women are open to taking aspirin in pregnancy and had high levels of adherence. Aspirin use was associated with greater rates of vaginal bleeding. An appropriately powered randomised controlled trial is now required to address the efficacy and safety of universal low-dose aspirin in low-risk pregnancy compared with a screening approach. TRIAL REGISTRATION NUMBER: ISRCTN (15191778); Post-results.

Genetic variants in PPARGC1B and CNTN4 are associated with thromboxane A2 formation and with cardiovascular event free survival in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).

BACKGROUND AND AIMS: Elevated urinary 11-dehydro thromboxane B2 (TxB2), a measure of thromboxane A2 formation in vivo, predicts future atherothrombotic events. To further understand this relationship, the genetic determinants of 11-dehydro TxB2 and their associations with cardiovascular morbidity were investigated in this study. METHODS: Genome-wide and targeted genetic association studies of urinary 11-dehydro TxB2 were conducted in 806 Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) participants. RESULTS: The strongest associations were in PPARGC1B (rs4235745, rs32582, rs10515638) and CNTN4 (rs10510230, rs4684343), these 5 single nucleotide polymorphisms (SNPs) were independently associated with 11-dehydro TxB2 formation. Haplotypes of 11-dehydro TxB2 increasing alleles for both PPARGC1B and CNTN4 were significantly associated with 11-dehydro TxB2, explaining 5.2% and 4.5% of the variation in the whole cohort, and 8.8% and 7.9% in participants not taking aspirin, respectively. In a second ASCOT population (n = 6199), addition of these 5 SNPs significantly improved the covariate-only Cox proportional hazards model for cardiovascular events (chisq = 14.7, p=0.01). Two of the risk alleles associated with increased urinary 11-dehydro TxB2 were individually associated with greater incidences of cardiovascular events - rs10515638 (HR = 1.31, p=0.01) and rs10510230 (HR = 1.25, p=0.007); effect sizes were larger in those not taking aspirin. CONCLUSIONS: PPARGC1B and CNTN4 genotypes are associated with elevated thromboxane A2 formation and with an excess of cardiovascular events. Aspirin appears to blunt these associations. If specific protection of PPARGC1B and CNTN4 variant carriers by aspirin is confirmed by additional studies, PPARGC1B and CNTN4 genotyping could potentially assist in clinical decision making regarding the use of aspirin in primary prevention.

Central Iliac Arteriovenous Anastomosis for Uncontrolled Hypertension: One-Year Results From the ROX CONTROL HTN Trial.

Creation of a central iliac arteriovenous anastomosis using a novel nitinol coupler device results in an immediate, significant reduction of blood pressure (BP). We present efficacy and safety findings at 12 months post-coupler insertion. This open-label, multicenter, prospective, randomized trial enrolled patients with a baseline office systolic BP ≥140 mm Hg and average daytime ambulatory BP ≥135/85 mm Hg. Subjects were randomly allocated to coupler implantation and continuing previous pharmacotherapy or to maintain previous treatment alone. At 12 months, 39 patients who had coupler therapy were included in the intention-to-treat analysis. Office-based systolic BP reduced by 25.1±23.3 mm Hg (baseline, 174±18 mm Hg; P<0.0001) post-coupler placement, and office diastolic BP reduced by 20.8±13.3 mm Hg (baseline, 100±13 mm Hg; P<0.0001). Mean 24-hour ambulatory BP reduced by 12.6±17.4/15.3±9.7 mm Hg (P<0.0001 for both). In a prespecified subset of patients who failed to respond adequately to prior renal denervation, coupler therapy led to highly significant reduction in office systolic/diastolic BP (30.7/24.1 mm Hg) and significant reduction in 24-hour ambulatory systolic/diastolic BP (12.4/14.4 mm Hg) at 12 months (n=9). After coupler therapy, 14 patients (33%) developed ipsilateral venous stenosis; all were treated successfully with venous stenting. These findings confirm the importance of arterial mechanics in the pathophysiology of hypertension and support the clinical use of a central iliac arteriovenous anastomosis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01642498.