Hybrid approach to postmyocardial infarction ventricular septal defect repair

Postinfarction ventricular septal rupture is a rare and devastating complication of myocardial infarction. Despite attempts at acute surgical and percutaneous defect closure, morbidity and mortality remain high. Herein, we describe a hybrid surgical and catheter-based approach to defect closure in a 63-year-old woman with postinfarction ventricular septal rupture and cardiogenic shock.     

CALLA-positive myeloma: an aggressive subtype with poor survival

Detailed immunotyping was carried out on 21 direct myeloma bone marrow aspirates and eight human myeloma cell lines. Four previously untreated common acute lymphoblastic leukemia antigen (CALLA)-positive myeloma patients were identified and six of eight cell lines (75%) were also positive. CALLA positivity, as part of an immature B phenotype, was found to correlate with very aggressive clinical disease: median survival six months v 56 months for the CALLA-negative group.     

[11C]5-HTP and microPET are not suitable for pharmacodynamic studies in the rodent brain

The PET tracer [¹¹C]5-hydroxytryptophan ([¹¹C]5-HTP), which is converted to [¹¹C]5-hydroxytryptamine ([¹¹C]5-HT) by aromatic amino acid decarboxylase (AADC), is thought to measure 5-HT synthesis rates. But can we measure these synthesis rates by kinetic modeling of [¹¹C]5-HTP in rat? Male rats were scanned with [¹¹C]5-HTP (60 minutes) after different treatments. Scans included arterial blood sampling and metabolite analysis. 5-HT synthesis rates were calculated by a two-tissue compartment model (2TCM) with irreversible tracer trapping or Patlak analysis. Carbidopa (inhibitor peripheral AADC) dose-dependently increased [¹¹C]5-HTP brain uptake, but did not influence 2TCM parameters. Therefore, 10 mg/kg carbidopa was applied in all subsequent study groups. These groups included treatment with NSD 1015 (general AADC inhibitor) or p-chlorophenylalanine (PCPA, inhibitor of tryptophan hydroxylase, TPH). In addition, the effect of a low-tryptophan (Trp) diet was investigated. NSD 1015 or Trp depletion did not affect any model parameters, but PCPA reduced [¹¹C]5-HTP uptake, and the k₃. This was unexpected as NSD 1015 directly inhibits the enzyme converting [¹¹C]5-HTP to [¹¹C]5-HT, suggesting that trapping of radioactivity does not distinguish between parent tracer and its metabolites. As different results have been acquired in monkeys and humans, [¹¹C]5-HTP-PET may be suitable for measuring 5-HT synthesis in primates, but not in rodents.     

A Randomised Controlled Trial of complete denture impression materials

Objectives

There is continuing demand for non-implant prosthodontic treatment and yet there is a paucity of high quality Randomised Controlled Trial (RCT) evidence for best practice. The aim of this research was to provide evidence for best practice in prosthodontic impressions by comparing two impression materials in a double-blind, randomised, crossover, controlled, clinical trial.

Methods

Eighty-five patients were recruited, using published eligibility criteria, to the trial at Leeds Dental Institute, UK. Each patient received two sets of dentures; made using either alginate or silicone impressions. Randomisations determined the order of assessment and order of impressions. The primary outcome was patient blinded preference for unadjusted dentures. Secondary outcomes were patient preference for the adjusted dentures, rating of comfort, stability and chewing efficiency, experience of each impression, and an OHIP-EDENT questionnaire.

Results

Seventy-eight (91.8%) patients completed the primary assessment. 53(67.9%) patients preferred dentures made from silicone impressions while 14(17.9%) preferred alginate impressions. 4(5.1%) patients found both dentures equally satisfactory and 7 (9.0%) found both equally unsatisfactory. There was a 50% difference in preference rates (in favour of silicone) (95%CI 32.7–67.3%, p < 0.0001).

Conclusion

There is significant evidence that dentures made from silicone impressions were preferred by patients.

Clinical significance

Given the strength of the clinical findings within this paper, dentists should consider choosing silicone rather than alginate as their material of choice for secondary impressions for complete dentures.Trial Registration: ISRCTN 01528038.This article forms part of a project for which the author (TPH) won the Senior Clinical Unilever Hatton Award of the International Assocation for Dental Research, Capetown, South Africa, June 2014.     

Childhood violence exposure and social deprivation are linked to adolescent threat and reward neural function

BackgroundChildhood adversity is, unfortunately, highly prevalent and strongly associated with later psychopathology. Recent theories posit that two dimensions of early adversity, threat and deprivation, have distinct effects on brain development. The current study evaluated whether violence exposure (threat) and social deprivation (deprivation) were associated with adolescent amygdala and ventral striatum activation, respectively, in a prospective, well-sampled, longitudinal cohort using a pre-registered, open science approach.MethodsOne hundred and sixty-seven adolescents from the Fragile Families and Child Wellbeing Study completed functional magnetic resonance imaging (fMRI) scanning. Prospective longitudinal data from ages 3, 5 and 9 years were used to create indices of childhood violence exposure and social deprivation. We evaluated whether these dimensions were associated with adolescent brain function in response to threatening and rewarding faces.ResultsChildhood violence exposure was associated with decreased amygdala habituation (i.e. more sustained activation) and activation to angry faces in adolescence, whereas childhood social deprivation was associated with decreased ventral striatum activation to happy faces in adolescence. These associations held when adjusting for the other dimension of adversity (e.g., adjusting for social deprivation when examining associations with violence exposure), the interaction of the two dimensions of adversity, gender, internalizing psychopathology, and current life stress.ConclusionsConsistent with recent theories, different forms of early adversity were associated with region-specific differences in brain activation.     

An evaluation of a national mass media campaign to raise public awareness of possible lung cancer symptoms in England in 2016 and 2017

Background A two-phase ‘respiratory symptoms’ mass media campaign was conducted in 2016 and 2017 in England raising awareness of cough and worsening shortness of breath as symptoms warranting a general practitioner (GP) visit.Method A prospectively planned pre–post evaluation was done using routinely collected data on 15 metrics, including GP attendance, GP referral, emergency presentations, cancers diagnosed (five metrics), cancer stage, investigations (two metrics), outpatient attendances, inpatient admissions, major lung resections and 1-year survival. The primary analysis compared 2015 with 2017. Trends in metrics over the whole period were also considered. The effects of the campaign on awareness of lung cancer symptoms were evaluated using bespoke surveys.Results There were small favourable statistically significant and clinically important changes over 2 years in 11 of the 15 metrics measured, including a 2.11% (95% confidence interval 1.02–3.20, p < 0.001) improvement in the percentage of lung cancers diagnosed at an early stage. However, these changes were not accompanied by increases in GP attendances. Furthermore, the time trends showed a gradual change in the metrics rather than steep changes occurring during or after the campaigns.Conclusion There were small positive changes in most metrics relating to lung cancer diagnosis after this campaign. However, the pattern over time challenges whether the improvements are wholly attributable to the campaign. Given the importance of education on cancer in its own right, raising awareness of symptoms should remain important. However further research is needed to maximise the effect on health outcomes.Subject terms: Translational research, Epidemiology     

From the Cover: Symmetric tangled Platonic polyhedra

Conventional embeddings of the edge-graphs of Platonic polyhedra, {f, z}, where f, z denote the number of edges in each face and the edge-valence at each vertex, respectively, are untangled in that they can be placed on a sphere (S2) such that distinct edges do not intersect, analogous to unknotted loops, which allow crossing-free drawings of S1 on the sphere. The most symmetric (flag-transitive) realizations of those polyhedral graphs are those of the classical Platonic polyhedra, whose symmetries are *2fz, according to Conway’s two-dimensional (2D) orbifold notation (equivalent to Schönflies symbols I_h, O_h, and T_d). Tangled Platonic {f, z} polyhedra—which cannot lie on the sphere without edge-crossings—are constructed as windings of helices with three, five, seven,… strands on multigenus surfaces formed by tubifying the edges of conventional Platonic polyhedra, have (chiral) symmetries 2fz (I, O, and T), whose vertices, edges, and faces are symmetrically identical, realized with two flags. The analysis extends to the “θ_z” polyhedra, {2,z}. The vertices of these symmetric tangled polyhedra overlap with those of the Platonic polyhedra; however, their helicity requires curvilinear (or kinked) edges in all but one case. We show that these 2fz polyhedral tangles are maximally symmetric; more symmetric embeddings are necessarily untangled. On one hand, their topologies are very constrained: They are either self-entangled graphs (analogous to knots) or mutually catenated entangled compound polyhedra (analogous to links). On the other hand, an endless variety of entanglements can be realized for each topology. Simpler examples resemble patterns observed in synthetic organometallic materials and clathrin coats in vivo.

Two-dimensional topology, graph theory, and non-Euclidean geometry offer a useful view of the rich universe of chemical structures. In this paper, we combine Platonic geometry and two-dimensional topology to derive theoretical families of “tangled” or “catenated” polyhedra, whose faces are threaded by edges. (We will clarify our nomenclature later on.) The resulting structures are worth knowing for their own sake, since they are the most symmetric entanglements of the regular (Platonic) polyhedra in three-dimensional space, with symmetrically equivalent faces, edges, and vertices. They are also promising candidates for (supra)molecular assemblies. For example, tangled symmetric structures are a feature of finite metal-organic molecules (1–5) and infinite catenated inorganic compounds, coordination polymers, covalent organic frameworks (COFs), and metal-organic frameworks (MOFs) (6–12).The phenomenon of entanglement is central to the mathematical field of knot theory (13). Equivalent tangled nets are “isotopic” and interchangeable by any distortion of the net edges and vertices as long as edges don’t pass through each other. Tangling is therefore a structural phenomenon that lies between geometrically congruent structures, which allow rigid-body rotations or translations only, and topologically equivalent (homeomorphic) structures, which can be interchanged by arbitrary distortions, including “phantom moves” of edges through each other. In common with modern understanding of polyhedra as combinatorial structures (14), we describe polyhedra via the net of edges and vertices, allowing faces to self-intersect. However, we do not insist that edges follow shortest paths between vertices, allowing edges to tangle. For example, tangled cubes share the topology of the conventional Platonic cube, but many different “isotopes” are possible, whose rings of four edges—bounding the cube “faces”—are threaded by edges in different ways (some examples can be found in ref. 15). The occurrence of tangled two- and three-periodic nets at the molecular scale in synthetic chemical materials, particularly MOFs, has led to a number of fundamental studies of tangles of infinite periodic nets (10, 16–19). In contrast, surprisingly little is known about allowed symmetries of finite nets, with the exception of the “trivial” (untangled) symmetric (e.g., Platonic and Archimedean) polyhedra and studies of symmetric embeddings of knots and links (20–22). Graph topologies of the five Platonic polyhedral nets are given by their Schläfli symbols, {f, z}, where f describes the number of edges per face and z the number of faces per vertex (z), including {3, 3} (tetrahedron), {3, 4} (octahedron), {4, 3} (cube), {3, 5} (icosahedron), and {5, 3} (dodecahedron). We describe the familiar regular embeddings of these nets, with straight edges, as (capitalized) “Platonic” embeddings and arbitrary embeddings of {f, z} nets as “platonic”. The former are “flag-transitive” embeddings of {f, z} nets with symmetrically identical faces, edges, and vertices; their point-group symmetries are (for our purposes) most simply denoted by Conway’s orbifold symbols *2fz (23). The orbifolds refer to the symmetries of spherical embeddings of the Platonic polyhedra, formed by blowing the polyhedra into a ball, bounded by a sphere centered on the polyhedron. The radius of that sphere can be adjusted so that all polyhedral vertices lie on its surface and edges form arcs of great circles joining those vertices. Conway symbols *2fz describe the asymmetric domain of those spherical Platonic polyhedra: spherical triangles bounded by geodesic mirror arcs (on great circles) subtending angles on the sphere of π2, πf, and πz. The geodesic edges coincide with the intersections of mirror planes of the Platonic polyhedron with the sphere, passing through face centers, vertices, and midedges, giving Schönflies point-group symbols, T_d, O_h, and I_h (for {3, 3}, {4, 3} or {3, 4}, and {5, 3} or {3, 5}, respectively) (24).Graph topologies of the nets of platonic polyhedra are constrained by Euler’s formula for polyhedra, which can be expressed as 0≤(f−2)(z−2)<4, where f and z are positive integers. That relation admits additional solutions, notably, the {2, 3} “θ-polyhedron,” with a pair of three-valent vertices and three lens-shaped faces. That net can be embedded in space with symmetry *223, in which case its three edges describe curved meridians from pole to pole. More generally, θ_z-polyhedra, with vertices at both poles joined by z meridians, are admissible solutions. For convenience, we include the θ_z-polyhedra among platonic examples. All of these platonic {f, z} polyhedra can be embedded as “regular” (Platonic) polyhedra, with reflection symmetry *2fz.The most symmetric “irregular” polyhedra are referred to as “chiral polytopes” in ref. 25. So-called chiral polytopes are almost, but not quite, regular: Like regular polyhedra, they have edge-, vertex-, and face-transitive embeddings. However, in contrast to regular cases which have a single flag, chiral polytopes have two distinct flags, each with separate orbits. Any flag of one type is necessarily adjacent to a flag of the other, and their union describes an asymmetric domain of the chiral embedding (25). (Three-dimensional chiral polytopes differ from better-known chiral polyhedra, such as the snub cube, although both are geometrically chiral.) Chiral polytopes, with straight edges, include either an infinite number of finite (skew) faces or a finite number of infinite (helical) faces (25), Here, we show that specific entanglements of {f, z} polyhedra, whose nets share the topologies of Platonic polyhedra, can be realized with symmetries 2fz, which contain rotation axes only (Schönflies point-group symbols T, O, and I for {3, 3}, {4, 3} or {3, 4}, and {5, 3} or {3, 5}, respectively). The edge-net of a tangled platonic {f, z} polyhedron cannot be morphed into that of its untangled Platonic analog without phantom crossings, where edges pass through each other. Like chiral polytopes, these tangled polyhedra have just two flags; they are therefore the most symmetric nontrivial embeddings of entangled platonic graphs, whose trivial entanglements are the Platonic *2fz polyhedral embeddings.Embeddings of Platonic {f, z} polyhedra with no crossed edges are possible on the sphere; their edges can therefore be traced in the plane without edge-crossings (e.g., via stereographic projection). These regular embeddings are classified as “untangled,” analogous to the trivial unknot, which can be drawn in the plane (or on the sphere) without edge-crossings. In contrast, like knots, planar drawings of tangled net embeddings contain edge-crossings, and crossing-free embeddings are possible only on higher-genus surfaces. Tangled embeddings of polyhedral nets {f, z} are less symmetric than their untangled, regular analogs. Earlier studies of tangled nets of the tetrahedron, octahedron, and cube, generated as reticulations of the relevant {f, z} nets on the torus, established that all such “toroidal polyhedra” are topologically chiral (26, 27), allowing a pair of distinct isotopes related to each other by a reflection. Further, those toroidal polyhedra are, without exception, rather asymmetric compared with their untangled embeddings. Their chirality ensures that they are devoid of reflections (so their orbifold symbols exclude the * character) and have multiple flags. The most symmetric toroidal tetrahedra, cubes, and octahedra can be realized with orbifolds 222 (D₂), 422 (D₄), and 622 (D₆), respectively (28), with six, six, and four distinct flags. Here, we show that the most symmetric {f, z} (nontrivially) tangled polyhedral nets can be embedded in space with chiral symmetry 2fz, provided their edges are curved (or suitably kinked), so that they have just two flags, analogous to chiral polytopes. Since the most symmetric regular embeddings of polyhedral graphs {f, z}, with symmetry *2fz, are untangled, these 2fz cases are the most symmetric possible embeddings of (nontrivial) polyhedral entanglements.     

A genetic polymorphism for translocator protein 18?kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation

Second-generation radioligands for translocator protein (TSPO), an inflammation marker, are confounded by the codominant rs6971 polymorphism that affects binding affinity. The resulting three groups are homozygous for high-affinity state (HH), homozygous for low-affinity state (LL), or heterozygous (HL). We tested if in vitro binding to leukocytes distinguished TSPO genotypes and if genotype could affect clinical studies using the TSPO radioligand [¹¹C]PBR28. In vitro binding to leukocytes and [¹¹C]PBR28 brain imaging were performed in 27 human subjects with known TSPO genotype. Specific [³H]PBR28 binding was measured in prefrontal cortex of 45 schizophrenia patients and 47 controls. Leukocyte binding to PBR28 predicted genotype in all subjects. Brain uptake was ∼40% higher in HH than HL subjects. Specific [³H]PBR28 binding in LL controls was negligible, while HH controls had ∼80% higher binding than HL controls. After excluding LL subjects, specific binding was 16% greater in schizophrenia patients than controls. This difference was insignificant by itself (P=0.085), but was significant after correcting for TSPO genotype (P=0.011). Our results show that TSPO genotype influences PBR28 binding in vitro and in vivo. Correcting for this genotype increased statistical power in our postmortem study and is recommended for in vivo positron emission tomography studies.