Mineralocorticoid Receptor Antagonism Prevents Aortic Plaque Progression and Reduces Left Ventricular Mass and Fibrosis in Patients With Type 2 Diabetes and Chronic Kidney Disease: The MAGMA Trial.

BACKGROUND: Persistent mineralocorticoid receptor activation is a pathologic response in type 2 diabetes and chronic kidney disease. Whereas mineralocorticoid receptor antagonists are beneficial in reducing cardiovascular complications, direct mechanistic pathways for these effects in humans are lacking. METHODS: The MAGMA trial (Mineralocorticoid Receptor Antagonism Clinical Evaluation in Atherosclerosis) was a randomized, double-blind, placebo-controlled trial in patients with high-risk type 2 diabetes with chronic kidney disease (not receiving dialysis) on maximum tolerated renin-angiotensin system blockade. The primary end point was change in thoracic aortic wall volume, expressed as absolute or percent value (ΔTWV or ΔPWV), using 3T magnetic resonance imaging at 12 months. Secondary end points were changes in left ventricle (LV) mass; LV fibrosis, measured as a change in myocardial native T1; and 24-hour ambulatory and central aortic blood pressures. Tertiary end points included plasma proteomic changes in 7596 plasma proteins using an aptamer-based assay. RESULTS: A total of 79 patients were randomized to placebo (n=42) or 25 mg of spironolactone daily (n=37). After a modified intent-to-treat, including available baseline data of study end points, patients who completed the trial protocol were included in the final analyses. At the 12-month follow-up, the average change in PWV was 7.1±10.7% in the placebo group and 0.87±10.0% in the spironolactone group (P=0.028), and ΔTWV was 1.2±1.7 cm3 in the placebo group and 0.037±1.9 cm3 in the spironolactone group (P=0.022). Change in LV mass was 3.1±8.4 g in the placebo group and -5.8±8.4 g in the spironolactone group (P=0.001). Changes in LV T1 values were significantly different between the placebo and spironolactone groups (26.0±41.9 ms in the placebo group versus a decrease of -10.1±36.3 ms in the spironolactone group; P=6.33×10-4). Mediation analysis revealed that the spironolactone effect on thoracic aortic wall volume and myocardial mass remained significant after adjustment for ambulatory and central blood pressures. Proteomic analysis revealed a dominant effect of spironolactone on pathways involving oxidative stress, inflammation, and leukocyte activation. CONCLUSIONS: Among patients with diabetes with moderate to severe chronic kidney disease at elevated cardiovascular risk, treatment with spironolactone prevented progression of aortic wall volume and resulted in regression of LV mass and favorable alterations in native T1, suggesting amelioration of left-ventricular fibrosis. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02169089.

The validation of computed tomography derived radiodensity measurements of bone healing using histopathology.

BACKGROUND: The early identification of delayed bone healing or a non-union is vital for prompt treatment and superior patient outcomes. Current techniques rely heavily on operator skill for interpretation and hence their reliability and repeatability may be inconsistent. This study assessed the application of computed tomography (CT) derived densiometric measurements as a quantitative tool for the assessment of bone healing. METHODS: This prospective, longitudinal, method comparison study was performed using a recognised sheep tibial ostectomy model. Secondary bone healing was assessed at 2, 4, 6, and 8 weeks after the ostectomy was performed. CT densiometric measures of bone healing (Hounsfield units) were taken of the cis, trans, cranial and caudal cortices relative to the bone plate, with histological measurements (percentage of ossification) sourced from the same areas. Cis cortical densiometric data points were excluded from analysis due to significant beam hardening artefact from the bone plate (P < 0.001). A univariable linear regression was performed on the remaining data using averaged radiodensity (independent variable) and histomorphometric (dependent variable) measurements. RESULTS: The two measurements were significantly correlated (R2 = 0.623, P = 0.020) with a clear positive trend identified. CONCLUSION: This study suggests that radiodensity measurements may be a useful diagnostic and management tool for the monitoring of indirect bone healing.

Thickness and design features of clinical cranial implants-what should automated methods strive to replicate?

PURPOSE: New deep learning and statistical shape modelling approaches aim to automate the design process for patient-specific cranial implants, as highlighted by the MICCAI AutoImplant Challenges. To ensure applicability, it is important to determine if the training data used in developing these algorithms represent the geometry of implants designed for clinical use. METHODS: Calavera Surgical Design provided a dataset of 206 post-craniectomy skull geometries and their clinically used implants. The MUG500+ dataset includes 29 post-craniectomy skull geometries and implants designed for automating design. For both implant and skull shapes, the inner and outer cortical surfaces were segmented, and the thickness between them was measured. For the implants, a 'rim' was defined that transitions from the repaired defect to the surrounding skull. For unilateral defect cases, skull implants were mirrored to the contra-lateral side and thickness differences were quantified. RESULTS: The average thickness of the clinically used implants was 6.0 ± 0.5 mm, which approximates the thickness on the contra-lateral side of the skull (relative difference of -0.3 ± 1.4 mm). The average thickness of the MUG500+ implants was 2.9 ± 1.0 mm, significantly thinner than the intact skull thickness (relative difference of 2.9 ± 1.2 mm). Rim transitions in the clinical implants (average width of 8.3 ± 3.4 mm) were used to cap and create a smooth boundary with the skull. CONCLUSIONS: For implant modelers or manufacturers, this shape analysis quantified differences of cranial implants (thickness, rim width, surface area, and volume) to help guide future automated design algorithms. After skull completion, a thicker implant can be more versatile for cases involving muscle hollowing or thin skulls, and wider rims can smooth over the defect margins to provide more stability. For clinicians, the differing measurements and implant designs can help inform the options available for their patient specific treatment.

Unraveling the Role of Sex in Endothelial Cell Dysfunction: Evidence From Lineage Tracing Mice and Cultured Cells.

BACKGROUND: Biological sex differences play a vital role in cardiovascular diseases, including atherosclerosis. The endothelium is a critical contributor to cardiovascular pathologies since endothelial cells (ECs) regulate vascular tone, redox balance, and inflammatory reactions. Although EC activation and dysfunction play an essential role in the early and late stages of atherosclerosis development, little is known about sex-dependent differences in EC. METHODS: We used human and mouse aortic EC as well as EC-lineage tracing (Cdh5-CreERT2 Rosa-YFP [yellow fluorescence protein]) atherosclerotic Apoe-/- mice to investigate the biological sexual dimorphism of the EC functions in vitro and in vivo. Bioinformatics analyses were performed on male and female mouse aortic EC and human lung and aortic EC. RESULTS: In vitro, female human and mouse aortic ECs showed more apoptosis and higher cellular reactive oxygen species levels than male EC. In addition, female mouse aortic EC had lower mitochondrial membrane potential (ΔΨm), lower TFAM (mitochondrial transcription factor A) levels, and decreased angiogenic potential (tube formation, cell viability, and proliferation) compared with male mouse aortic EC. In vivo, female mice had significantly higher lipid accumulation within the aortas, impaired glucose tolerance, and lower endothelial-mediated vasorelaxation than males. Using the EC-lineage tracing approach, we found that female lesions had significantly lower rates of intraplaque neovascularization and endothelial-to-mesenchymal transition within advanced atherosclerotic lesions but higher incidents of missing EC lumen coverage and higher levels of oxidative products and apoptosis. RNA-seq analyses revealed that both mouse and human female EC had higher expression of genes associated with inflammation and apoptosis and lower expression of genes related to angiogenesis and oxidative phosphorylation than male EC. CONCLUSIONS: Our study delineates critical sex-specific differences in EC relevant to proinflammatory, pro-oxidant, and angiogenic characteristics, which are entirely consistent with a vulnerable phenotype in females. Our results provide a biological basis for sex-specific proatherosclerotic mechanisms.

Accuracy of Orbital Shape Reconstruction-Comparative Analysis of Errors in Implant Shape Versus Implant Positioning: A Cadaveric Study.

INTRODUCTION: Orbital blowout fractures are commonly reconstructed with implants shaped to repair orbital cavity defects, restore ocular position and projection, and correct diplopia. Orbital implant shaping has traditionally been performed manually by surgeons, with more recent use of computer-assisted design (CAD). Accuracy of implant placement is also key to reconstruction. This study compares the placement accuracy of orbital implants, testing the hypothesis that CAD-shaped implants indexed to patient anatomy will better restore orbit geometry compared with manually shaped implants and manually placed implants. METHODS: The placement accuracy of orbital implants was assessed within a cadaveric blowout fracture model (3 skulls, 6 orbits) via 3-dimensional CT analysis. Defects were repaired with 4 different techniques: manually placed-manually shaped composite (titanium-reinforced porous polyethylene), manually placed CAD composite, indexed placed CAD composite, and indexed placed CAD titanium mesh. RESULTS: Implant placement accuracy differed significantly with the implant preparation method ( P =0.01). Indexing significantly improved the placement accuracy ( P =0.002). Indexed placed titanium mesh CAD implants (1.42±0.33 mm) were positioned significantly closer to the intact surface versus manually placed-manually shaped composite implants (2.12±0.39 mm). DISCUSSION: Computer-assisted design implants indexed to patient geometry yielded average errors below the acceptable threshold (2 mm) for enophthalmos and diplopia. This study highlights the importance of adequately indexing CAD-designed implants to patient geometry to ensure accurate orbital reconstructions.

Specialized Pro-resolving Mediator Improves Vascular Relaxation via Formyl Peptide Receptor-2.

BACKGROUND: The resolution of inflammation is an active phenomenon important for switching off inflammatory processes once the harmful stimuli are removed and facilitate the return to homeostasis. Specialized pro-resolving mediators (SPMs), such as lipoxin A4, resolvin D1, and resolvin E1, derived from ω-3 or ω-6 polyunsaturated fatty acids, are crucial for the resolution of inflammation. We hypothesized that SPMs are decreased in hypertension which contributes to the acetylcholine-induced contraction in resistance arteries, which are well known to be mediated by leukotrienes and prostaglandins. Moreover, treatment with SPMs will decrease this contraction via formyl peptide receptor-2 (FPR-2) in resistance arteries from spontaneously hypertensive rats (SHR). METHODS AND RESULTS: We performed a comprehensive eicosanoid lipid panel analysis, and our data showed for the first time that precursors of SPMs are decreased in SHR, limiting the production of SPMs and resolution of inflammation in vivo. This phenomenon was associated with an increase in lipid peroxidation in resistance arteries. Although SPMs did not abolish acetylcholine-induced contraction, these lipid mediators improved endothelial function in arteries from SHR via FPR-2 activation at nanomolar concentrations. SPMs also buffered TNF-α-induced reactive oxygen species generation in endothelial cells from C57Bl/6 mice. CONCLUSIONS: We suggest that FPR-2 and SPMs could be revealed as a new target or therapeutic agent to improve vascular function in arteries from hypertensive rats.

Safety evaluation of the Guardian device on the common carotid artery in sheep.

Background: Pulse pressure intensity in middle-aged adults is a risk factor for dementia. The Guardian device (The Brain Protection Company, Sydney, Australia) has been developed to reduce pulse pressure, as a potential therapy. Objectives: The aim of this study was to evaluate the safety of the Guardian, a novel pulse modulation device designed to reduce the intensity of the pulse pressure that penetrates into the cerebral small vessels. The Guardian is a helix that gently wraps around the common carotid artery (CCA) to slightly change its shape, to absorb pulsatility, without lowering flow. Methods: The Guardian was implanted bilaterally on the CCAs of 10 mature sheep for chronic implant periods of 3, 6 or 8 months. The ratio of internal device diameter to outer diameter of the CCA varied from 63% to 92% (n = 20). The implant position on the vessel was marked surgically at implant. Gross pathology and histopathology of the CCA were examined at 3- and 6-months post explant. Most devices were explanted using open surgery, however minimally invasive surgical explant techniques were examined in 2 animals to assess the potential of this approach for explant in humans if required. Results: The Guardian was successfully implanted with no adverse events, and minimally invasive explant appeared to be viable for removal. Following implant, the device was surrounded by a thin fibrous capsule, with similar pathology at 3- and 6-months. Minimal or no movement was observed. CCA sections appeared histologically normal, with no evidence of thrombosis, stenosis, fibrosis, chronic inflammatory response, or vessel degeneration. Conclusions: The feasibility of surgical implantation and biomaterial safety of the Guardian was confirmed over 8 months. Minimally invasive explant of the Guardian has the potential to be viable. Further work is required to demonstrate efficacy in vitro and/or in vivo before evaluation in humans.

Decision-Making in Adult Cranial Vault Reconstruction.

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Define and classify different types of cranial defects 2. Compare both autologous and alloplastic options for reconstruction 3. Develop an optimal approach for cranial vault reconstruction in various clinical scenarios. SUMMARY: Defects of the cranium result from various causes, including traumatic loss, neurosurgical intervention, skull tumors, and infection. Cranial vault reconstruction aims to restore both the structural integrity and surface morphology of the skull. To ensure a successful outcome, the choice of appropriate cranioplasty reconstruction will vary primarily based on the cause, location, and size of the defect. Other relevant factors that must be considered include adequacy of soft-tissue coverage, presence of infection, and previous or planned radiation therapy. This article presents an algorithm for the reconstruction of various cranial defects using both autologous and alloplastic techniques, with a comparison of their advantages and disadvantages.

SARS-CoV-2 seroprevalence in healthcare workers in a tertiary healthcare network in Victoria, Australia.

BACKGROUND: Healthcare workers (HCW) are exposed to an increased risk of COVID-19 through direct contact with patients and patient environments. We calculated the; seroprevalence of SARS-CoV-2 in HCW at Eastern Health, a tertiary healthcare network in Victoria, and assessed associations with demographics, work location and role. METHODS: A cross-sectional cohort study of HCW at Eastern Health was conducted. Serum was analysed for the presence of antibodies to SARS-CoV-2, and all participants completed; an online survey collecting information on demographics, place of work, role, and exposures; to COVID-19. Seroprevalence was calculated as the proportion participants with SARS-CoV-2; antibodies out of all tested individuals. RESULTS: The crude seroprevalence of SARS-CoV-2 antibodies in this study was 2.17% (16/736). Thirteen of the 16 (81.2%) positive cases had previously been diagnosed with COVID-19 by PCR: the seroprevalence in the group not previously diagnosed with COVID by PCR was 0.42% (3/720). Having direct contact with COVID-19 patients did not increase the likelihood of having positive serology. A prior history of symptoms consistent with COVID-19 was associated with a higher likelihood of having positive serology (OR 17.2, p = 0.006, 95%CI: 2.25-131.55). CONCLUSION: Our calculated seroprevalence of 2.17% is higher than estimated in the general Australian population, but lower than that reported in HCW internationally. The; majority of those with positive serology in our study had previously been diagnosed with COVID-19 by PCR based testing. Seropositivity was not associated with interaction with COVID-19 positive patients, highlighting effective infection prevention and control practices within the workplace.

The investigation of bone fracture healing under intramembranous and endochondral ossification.

After trauma, fractured bone starts healing directly through bone union or indirectly through callus formation process. Intramembranous and endochondral ossification are two commonly known mechanisms of indirect healing. The present study investigated the bone fracture healing under intramembranous and endochondral ossification by developing theoretical models in conjunction with performing a series of animal experiments. Using experimentally determined mean bone densities in sheep tibia stabilized by the Locking Compression Plate (LCP) fixation system, the research outcomes showed that intramembranous and endochondral ossification can be described by Hill Function with two unique sets of function parameters in mechanical stimuli mediated fracture healing. Two different thresholds exist within the range of mechanical simulation index which could trigger significant intramembranous and endochondral ossification, with a relatively higher bone formation rate of endochondral ossification than that of intramembranous ossification. Furthermore, the increase of flexibility of the LCP system and the use of titanium LCP could potentially promote uniform bone formation across the fracture gap, ultimately better healing outcomes.

The common carotid artery provides significant pressure wave dampening in the young adult sheep.

BACKGROUND: It has been established that the central elastic arteries of the mammalian circulation dampen the high pulse pressure emanating from the left ventricle, so that the pulsations in distal arterioles, such as in the cerebral circulation, are of lower amplitude than more centrally. However, the contribution of the common carotid artery (CCA) to protection of the cerebral microvasculature from high pulse pressure is not known, specifically to what extent viscoelastic energy dissipation in the arterial wall might contribute to the shock absorbing function of the large conduit arteries. METHODS: Young adult sheep (n = 6) were anaesthetised and their CCAs (n = 7) exposed. Pressure catheters were inserted 10-15 cm apart, proximally and distally in the CCA; a flow probe was placed proximally on the vessel. RESULTS: The median dp/dtmax on the pressure rise of the arterial wave upstroke for the proximal CCA was 619 mm Hg/s and for the distal CCA it was significantly lower, at 197 mm Hg/s (p = 0.0156; n = 7). The median pulse pressure of the proximal CCA was 24 mm Hg/s; distal pulse pressure was significantly lower, at 18 mm Hg/s (p = 0.0156; n = 7). The median flow rate was 0.97 L/min with an interquartile range from 0.51 to 1.15 L/min. CONCLUSIONS: The native CCA in the young adult sheep is an effective "pressure dampener" in the arterial circulation, reducing both pressure slope and pulse pressure, most likely via viscous dampening in the arterial wall.

Unified biophysical mechanism for cell-shape oscillations and cell ingression.

We describe a mechanochemical and percolation cascade that augments myosin's regulatory network to tune cytoskeletal forces. Actomyosin forces collectively generate cytoskeletal forces during cell oscillations and ingression, which we quantify by elastic percolation of the internally driven, cross-linked actin network. Contractile units can produce relatively large, oscillatory forces that disrupt crosslinks to reduce cytoskeletal forces. A (reverse) Hopf bifurcation switches contractile units to produce smaller, steady forces that enhance crosslinking and consequently boost cytoskeletal forces to promote ingression. We describe cell-shape changes and cell ingression in terms of intercellular force imbalances along common cell junctions.

Tropoelastin Implants That Accelerate Wound Repair.

A novel, pure, synthetic material is presented that promotes the repair of full-thickness skin wounds. The active component is tropoelastin and leverages its ability to promote new blood vessel formation and its cell recruiting properties to accelerate wound repair. Key to the technology is the use of a novel heat-based, stabilized form of human tropoelastin which allows for tunable resorption. This implantable material contributes a tailored insert that can be shaped to the wound bed, where it hydrates to form a conformable protein hydrogel. Significant benefits in the extent of wound healing, dermal repair, and regeneration of mature epithelium in healthy pigs are demonstrated. The implant is compatible with initial co-treatment with full- and split-thickness skin grafts. The implant's superiority to sterile bandaging, commercial hydrogel and dermal regeneration template products is shown. On this basis, a new concept for a prefabricated tissue repair material for point-of-care treatment of open wounds is provided.

Cell Sheet Morphogenesis: Dorsal Closure in Drosophila melanogaster as a Model System.

Dorsal closure is a key process during Drosophila morphogenesis that models cell sheet movements in chordates, including neural tube closure, palate formation, and wound healing. Closure occurs midway through embryogenesis and entails circumferential elongation of lateral epidermal cell sheets that close a dorsal hole filled with amnioserosa cells. Signaling pathways regulate the function of cellular structures and processes, including Actomyosin and microtubule cytoskeletons, cell-cell/cell-matrix adhesion complexes, and endocytosis/vesicle trafficking. These orchestrate complex shape changes and movements that entail interactions between five distinct cell types. Genetic and laser perturbation studies establish that closure is robust, resilient, and the consequence of redundancy that contributes to four distinct biophysical processes: contraction of the amnioserosa, contraction of supracellular Actomyosin cables, elongation (stretching?) of the lateral epidermis, and zipping together of two converging cell sheets. What triggers closure and what the emergent properties are that give rise to its extraordinary resilience and fidelity remain key, extant questions.

Correlating in Vitro Solubilization and Supersaturation Profiles with in Vivo Exposure for Lipid Based Formulations of the CETP Inhibitor CP-532,623.

Lipid based formulations (LBFs) are a promising formulation strategy for many poorly water-soluble drugs and have been shown previously to enhance the oral exposure of CP-532,623, an oral cholesteryl ester transfer protein inhibitor. In the current study, an in vitro lipid digestion model was used to probe the relationship between drug solubilization and supersaturation on in vitro dispersion and digestion of LBF containing long chain (LC) lipids and drug absorption in vivo. After in vitro digestion of LBF based on LC lipids, the proportion of CP-532,623 maintained in the solubilized state in the aqueous phase of the digest was highest in formulations containing Kolliphor RH 40, and in most cases outperformed equivalent formulations based on MC lipids. Subsequent administration of the LC-LBFs to beagle dogs resulted in reasonable correlation between concentrations of CP-532,623 measured in the aqueous phase of the in vitro digest after 30 min digestion and in vivo exposure (AUC); however, the LC-LBFs required greater in vitro drug solubilization to elicit similar in vivo exposure when compared to previous studies with MC-LBF. Although post digestion solubilization was enhanced in LC-LBF compared to MC-LBF, equilibrium solubility studies of CP-532,623 in the aqueous phase isolated from blank lipid digestion experiments revealed that equilibrium solubility was also higher, and therefore supersaturation lower. A revised correlation based on supersaturation in the digest aqueous phase and drug absorption was therefore generated. A single, linear correlation was evident for both LC- and MC-LBF containing Kolliphor RH 40, but this did not extend to formulations based on other surfactants. The data suggest that solubilization and supersaturation are significant drivers of drug absorption in vivo, and that across formulations with similar formulation composition good correlation is evident between in vitro and in vivo measures. However, across dissimilar formulations, solubilization and supersaturation alone are not sufficient to explain drug exposure and other factors also likely play a role.

Quantifying dorsal closure in three dimensions.

Dorsal closure is an essential stage of Drosophila embryogenesis and is a powerful model system for morphogenesis, wound healing, and tissue biomechanics. During closure, two flanks of lateral epidermis close an eye-shaped dorsal opening that is filled with amnioserosa. The two flanks of lateral epidermis are zipped together at each canthus ("corner" of the eye). Actomyosin-rich purse strings are localized at each of the two leading edges of lateral epidermis ("lids" of the eye). Here we report that each purse string indents the dorsal surface at each leading edge. The amnioserosa tissue bulges outward during the early-to-mid stages of closure to form a remarkably smooth, asymmetric dome indicative of an isotropic and uniform surface tension. Internal pressure of the embryo and tissue elastic properties help to shape the dorsal surface.

Lymphatic Transport and Lymphocyte Targeting of a Triglyceride Mimetic Prodrug Is Enhanced in a Large Animal Model: Studies in Greyhound Dogs.

In previous studies, a triglyceride (TG) mimetic prodrug of the model immunomodulator mycophenolic acid (MPA) was shown to significantly enhance lymphatic transport of MPA-related species in the rat. The rat gastrointestinal tract, however, is somewhat different from that in higher order species such as dogs and humans and may underestimate lymphatic transport. Here the effectiveness of the prodrug strategy has been examined in conscious greyhound dogs, the GI physiology of which is more representative of that in humans. The bioavailability and lymphatic transport of free MPA and total MPA related materials were examined following oral administration of the parent drug (MPA) and the prodrug (2-MPA-TG) to both thoracic lymph duct cannulated and intact (noncannulated) greyhound dogs. The enrichment of free MPA in lymph nodes and lymph-derived lymphocytes was also determined to examine the efficiency of drug targeting to potential sites of action within the lymph. Via biochemical integration into a series of site-specific metabolic processes, the prodrug markedly increased (288-fold) lymphatic transport of total MPA related material (present as re-esterified 2-MPA-TG) when compared to the parent MPA and the extent of lymphatic transport was significantly greater in the dog (36.4% of the dose recovered in lymph) when compared to the previous data in the rat (13.4% of the dose). Conversion from 2-MPA-TG derivatives to parent MPA occurred in vivo, resulting in a marked increase in MPA concentrations in lymph nodes (5-6-fold) and lymph lymphocytes (21-fold), when compared to animals administered the parent drug. In conclusion, the data demonstrate that the TG prodrug of MPA facilitates efficient delivery of MPA to the lymphatic system in dogs and suggest that the TG prodrug strategy may more effectively facilitate targeted delivery in large animals than in rats.

Interpretative comments specifically suggesting specialist referral increase the detection of familial hypercholesterolaemia.

Familial hypercholesterolaemia (FH) is an under-diagnosed inherited condition characterised by elevated low density lipoprotein (LDL)-cholesterol and premature coronary artery disease. The requesting general practitioner of individuals with extremely elevated LDL-cholesterol measured by St John of God Pathology receives an interpretative comment on the lipid results highlighting possible FH. We sought to determine whether specifically recommending referral to the regional Lipid Disorders Clinic (LDC) increased referral and FH detection rates. A prospective case-control study of individuals with LDL-cholesterol ≥6.5 mmol/L was conducted. All individuals received an interpretative comment highlighting the possibility of FH. The cases comment also suggested LDC referral, and a subset of cases received the LDC's fax number (fax-cases) in addition. There were 231 individuals with an LDL-cholesterol ≥6.5 mmol/L; 96 (42%) controls and 135 (58%) cases, of which 99 were fax-cases. Twenty-four (18%) cases were referred to clinic compared with eight (8%) controls (p = 0.035). After specialist review and genetic testing, four probable and four definite FH individuals were detected amongst controls, compared with seven possible, eight probable and nine definite FH amongst cases. Genetic testing was performed in 31 (94%) individuals, 13 (42%) had a causative mutation identified. Interpretative commenting specifically recommending specialist review augments the detection of FH in the community.

Plasma Ion Activated Expanded Polytetrafluoroethylene Vascular Grafts with a Covalently Immobilized Recombinant Human Tropoelastin Coating Reducing Neointimal Hyperplasia.

Expanded polytetrafluoroethylene (ePTFE) vascular conduits with less than or equal to 6 mm internal diameter typically occlude due to a combination of thrombus formation and neointimal hyperplasia. We hypothesized that by layering the polymerized elastin precursor, human tropoelastin, in the synthetic vessel lumen we could mimic the internal elastic lamina and so maintain low thrombogenicity while significantly reducing smooth muscle cell proliferation. The luminal surfaces of ePTFE conduits were activated with plasma immersion ion implantation (PIII) treatment to facilitate covalent attachment of tropoelastin. Multilayered tropoelastin vessels (2TE) enhanced endothelial cell attachment and proliferation in vitro and were superior to materials lacking the protein. In an ovine carotid interposition model of graft compatibility, partially tropoelastin coated vessels (1TE) thrombosed at a greater rate than control ePTFE, but 2TE maintained the same patency as controls. 2TE showed a significant reduction in neointimal area down to 9.7 ± 5.2% (p < 0.05) in contrast to 32.3 ± 3.9% for ePTFE alone. This reduction was due to a halving of the number of smooth muscle cells present and a corresponding reduction in their proliferation. 2TE, but not 1TE, enhanced the vascular compatibility of these materials: while both tropoelastin presentations increased in vitro endothelialization, only 2TE displayed the dual benefits of maintained hemocompatibility and simultaneously suppressed neointimal hyperplasia in vivo. We conclude that 2TE surface modification provides a significant improvement over ePTFE vascular conduits in a pilot large animal model study and presents an attractive path toward clinical applications for reduced diameter vessels.

Patient-Specific Orbital Implants: Development and Implementation of Technology for More Accurate Orbital Reconstruction.

Fracture of the orbital floor is commonly seen in facial trauma. Accurate anatomical reconstruction of the orbital floor contour is challenging. The authors demonstrate a novel method to more precisely reconstruct the orbital floor on a 50-year-old female who sustained an orbital floor fracture following a fall. Results of the reconstruction show excellent reapproximation of the native orbital floor contour and complete resolution of her enopthalmos and facial asymmetry.