1H detection and dynamic nuclear polarization-enhanced NMR of Aß1-42 fibrils.

Several publications describing high-resolution structures of amyloid-ß (Aß) and other fibrils have demonstrated that magic-angle spinning (MAS) NMR spectroscopy is an ideal tool for studying amyloids at atomic resolution. Nonetheless, MAS NMR suffers from low sensitivity, requiring relatively large amounts of samples and extensive signal acquisition periods, which in turn limits the questions that can be addressed by atomic-level spectroscopic studies. Here, we show that these drawbacks are removed by utilizing two relatively recent additions to the repertoire of MAS NMR experiments-namely, 1H detection and dynamic nuclear polarization (DNP). We show resolved and sensitive two-dimensional (2D) and three-dimensional (3D) correlations obtained on 13C,15N-enriched, and fully protonated samples of M0Aß1-42 fibrils by high-field 1H-detected NMR at 23.4 T and 18.8 T, and 13C-detected DNP MAS NMR at 18.8 T. These spectra enable nearly complete resonance assignment of the core of M0Aß1-42 (K16-A42) using submilligram sample quantities, as well as the detection of numerous unambiguous internuclear proximities defining both the structure of the core and the arrangement of the different monomers. An estimate of the sensitivity of the two approaches indicates that the DNP experiments are currently ∼6.5 times more sensitive than 1H detection. These results suggest that 1H detection and DNP may be the spectroscopic approaches of choice for future studies of Aß and other amyloid systems.

Structural characterization of E22G Aß1-42 fibrils via1H detected MAS NMR.

Amyloid fibrils have been implicated in the pathogenesis of several neurodegenerative diseases, the most prevalent example being Alzheimer's disease (AD). Despite the prevalence of AD, relatively little is known about the structure of the associated amyloid fibrils. This has motivated our studies of fibril structures, extended here to the familial Arctic mutant of Aß1-42, E22G-Aß1-42. We found E22G-AßM0,1-42 is toxic to Escherichia coli, thus we expressed E22G-Aß1-42 fused to the self-cleavable tag NPro in the form of its EDDIE mutant. Since the high surface activity of E22G-Aß1-42 makes it difficult to obtain more than sparse quantities of fibrils, we employed 1H detected magic angle spinning (MAS) nuclear magnetic resonance (NMR) experiments to characterize the protein. The 1H detected 13C-13C methods were first validated by application to fully protonated amyloidogenic nanocrystals of GNNQQNY, and then applied to fibrils of the Arctic mutant of Aß, E22G-Aß1-42. The MAS NMR spectra indicate that the biosynthetic samples of E22G-Aß1-42 fibrils comprise a single conformation with 13C chemical shifts extracted from hCH, hNH, and hCCH spectra that are very similar to those of wild type Aß1-42 fibrils. These results suggest that E22G-Aß1-42 fibrils have a structure similar to that of wild type Aß1-42.

Tau induces formation of α-synuclein filaments with distinct molecular conformations.

Recent structural investigation of amyloid filaments extracted from human patients demonstrated that the ex vivo filaments associated with different disease phenotypes adopt diverse molecular conformations, which are different from those of in vitro amyloid filaments. A very recent cryo-EM structural study also revealed that ex vivo α-synuclein filaments extracted from multiple system atrophy patients adopt distinct molecular structures from those of in vitro α-synuclein filaments, suggesting the presence of co-factors for α-synuclein aggregation in vivo. Here, we report structural characterizations of α-synuclein filaments formed in the presence of a potential co-factor, tau, using cryo-EM and solid-state NMR. Our cryo-EM structure of the tau-promoted α-synuclein filaments reveals some similarities to one of the previously reported polymorphs of in vitro α-synuclein filaments in the core region, while illustrating distinct conformations in the N- and C-terminal regions. The structural study highlights the conformational plasticity of α-synuclein filaments and the importance of the co-factors, requiring additional structural investigation of not only more ex vivo α-synuclein filaments, but also in vitro α-synuclein filaments formed in the presence of diverse co-factors. The comparative structural analyses will help better understand molecular basis of diverse structures of α-synuclein filaments and possible relevance of each structure to the disease phenotype.

Structural Characterization of Cardiac Ex Vivo Transthyretin Amyloid: Insight into the Transthyretin Misfolding Pathway In Vivo.

Structural characterization of misfolded protein aggregates is essential to understanding the molecular mechanism of protein aggregation associated with various protein misfolding disorders. Here, we report structural analyses of ex vivo transthyretin aggregates extracted from human cardiac tissue. Comparative structural analyses of in vitro and ex vivo transthyretin aggregates using various biophysical techniques revealed that cardiac transthyretin amyloid has structural features similar to those of in vitro transthyretin amyloid. Our solid-state nuclear magnetic resonance studies showed that in vitro amyloid contains extensive nativelike ß-sheet structures, while other loop regions including helical structures are disrupted in the amyloid state. These results suggest that transthyretin undergoes a common misfolding and aggregation transition to nativelike aggregation-prone monomers that self-assemble into amyloid precipitates in vitro and in vivo.

Disruption of the CD Loop by Enzymatic Cleavage Promotes the Formation of Toxic Transthyretin Oligomers through a Common Transthyretin Misfolding Pathway.

Amyloid formation of full-length TTR involves dissociation of the native tetramers into misfolded monomers that self-assemble into amyloid. In addition to the full-length TTR, C-terminal fragments including residues 49-127 were also observed in vivo, implying the presence of additional misfolding pathways. It was previously proposed that a proteolytic cleavage might lead to the formation of the C-terminal fragment TTR amyloid. Here, we report mechanistic studies of misfolding and aggregation of a TTR variant (G53A) in the absence and presence of a serine protease. A proteolytic cleavage of G53A in the CD loop (K48 and T49) with agitation promoted TTR misfolding and aggregation, suggesting that the proteolytic cleavage may lead to the aggregation of the C-terminal fragment (residues 49-127). To gain more detailed insights into TTR misfolding promoted by proteolytic cleavage, we investigated structural changes in G53A TTR in the presence and absence of trypsin. Our combined biophysical analyses revealed that the proteolytic cleavage accelerated the formation of spherical small oligomers, which exhibited cytotoxic activities. However, the truncated TTR appeared to maintain native-like structures, rather than the C-terminal fragment (residues 49-127) being released and unfolded from the native state. In addition, our solid-state nuclear magnetic resonance and Fourier transform infrared structural studies showed that the two aggregates derived from the full-length and cleaved TTR exhibited nearly identical molecular structural features, suggesting that the proteolytic cleavage in the CD loop destabilizes the native tetrameric structure and accelerates oligomer formation through a common TTR misfolding and aggregation mechanism rather than through a distinct molecular mechanism.

Atomic Resolution Structure of Monomorphic Aß42 Amyloid Fibrils.

Amyloid-ß (Aß) is a 39-42 residue protein produced by the cleavage of the amyloid precursor protein (APP), which subsequently aggregates to form cross-ß amyloid fibrils that are a hallmark of Alzheimer's disease (AD). The most prominent forms of Aß are Aß1-40 and Aß1-42, which differ by two amino acids (I and A) at the C-terminus. However, Aß42 is more neurotoxic and essential to the etiology of AD. Here, we present an atomic resolution structure of a monomorphic form of AßM01-42 amyloid fibrils derived from over 500 (13)C-(13)C, (13)C-(15)N distance and backbone angle structural constraints obtained from high field magic angle spinning NMR spectra. The structure (PDB ID: 5KK3 ) shows that the fibril core consists of a dimer of Aß42 molecules, each containing four ß-strands in a S-shaped amyloid fold, and arranged in a manner that generates two hydrophobic cores that are capped at the end of the chain by a salt bridge. The outer surface of the monomers presents hydrophilic side chains to the solvent. The interface between the monomers of the dimer shows clear contacts between M35 of one molecule and L17 and Q15 of the second. Intermolecular (13)C-(15)N constraints demonstrate that the amyloid fibrils are parallel in register. The RMSD of the backbone structure (Q15-A42) is 0.71 ± 0.12 Å and of all heavy atoms is 1.07 ± 0.08 Å. The structure provides a point of departure for the design of drugs that bind to the fibril surface and therefore interfere with secondary nucleation and for other therapeutic approaches to mitigate Aß42 aggregation.

LONG-TERM NONOPERATIVE RATE OF THYROID NODULES WITH BENIGN RESULTS ON THE AFIRMA GENE EXPRESSION CLASSIFIER.

OBJECTIVE: The primary objective was to assess the operative rate in patients with a benign result from the Afirma gene expression classifier (GEC) during long-term follow-up at nonacademic medical facilities. The secondary endpoint of this study was the treating physician's opinion regarding the safety of GEC use compared to the hypothetical situation of providing thyroid nodule management without the GEC. METHODS: This was a retrospective study of nonacademic medical practices utilizing the GEC. Those clinicians utilizing the GEC testing who had three or more 'benign' results during the data collection period (September 2010 through June 2014) were invited to participate. Operative status and patient demographics were documented for patients with GEC testing at least 36 months (± 3 months) prior to the date of data collection. A survey also was administered to the treating physicians to assess their perceived safety of using the GEC in patient care. RESULTS: During 36 months (± 3 months) of follow-up, 17 of 98 patients (17.3%) with a 'benign' GEC result underwent surgery. Within the first 2 years after a 'benign' GEC, 88% of surgeries were performed. Regarding safety of the GEC, the treating physicians reported that patient safety was improved by using the GEC compared to not using the GEC in 78 of 91 cases (86%). CONCLUSION: It appears that a 'benign' result on the GEC is associated with a reduction in the rate of thyroid surgeries compared to published data when patients are followed for 36 months after testing. A nonoperative approach to follow-up was felt to be a safe alternative to diagnostic surgery by the majority of responsible physicians in the study. ABBREVIATIONS: AUS = atypia of undetermined significance FLUS = follicular lesion of undetermined significance FN = follicular neoplasm FNA = fine-needle aspiration GEC = gene expression classifier.

Who explicitly requests the ordering of computed tomography for emergency department patients? A multicenter prospective study.

Emergency department (ED) computed tomography (CT) use has increased substantially in recent years, resulting in increased radiation exposure for patients. Few studies have assessed which parties contribute to CT ordering in the ED. The objective of this study was to determine the proportion of CT scans ordered due to explicit requests by various stakeholders in ED patient care. This is a prospective, observational study performed at three university hospital EDs. CT scans ordered during research assistant hours were eligible for inclusion. Attending emergency physicians (EPs) completed standardized data forms to indicate all parties who had explicitly requested that a specific CT be performed. Forms were completed before the CT results were known in order to minimize bias. Data were obtained from 77 EPs regarding 944 CTs. The parties most frequently requesting CTs were attending EPs (82.0 %, 95 % CI 79.4-84.3), resident physicians (28.6 %, 95 % CI 25.8-31.6), consulting physicians (24.4 %, 95 % CI 21.7-27.2), and admitting physicians (3.9 %, 95 % CI 2.9-5.4). In the 168 instances in which the attending EP did not explicitly request the CT, requests most commonly came from consulting physicians (51.2 %, 95 % CI 43.7-58.6), resident physicians in the ED (39.9 %, 95 % CI 32.8-47.4), and admitting physicians (8.9 %, 95 % CI 5.5-14.2). EPs were the sole party requesting CT in 46.2 % of cases while multiple parties were involved in 39.0 %. Patients, families, and radiologists were uncommon sources of such requests. Emergency physicians requested the majority of CTs, though nearly 20 % were actually not desired by them. Admitting, consulting, and resident physicians in the ED were important contributors to CT utilization.

Using a map-based assessment tool for the development of cost-effective WFD river basin action programmes in a changing climate.

For the 2nd and 3rd river basin management cycles (2015-2027) of the Water Framework Directive (WFD), EU Member States are required to fully integrate climate change into the process of river basin management planning (RBMP). Complying with the main WFD objective of achieving 'good ecological status' in all water bodies in Denmark requires Programmes of Measures (PoMs) to reduce nitrogen (N) pollution from point and diffuse sources. Denmark is among the world's most intensively farmed countries and in spite of thirty years of significant policy actions to reduce diffuse nutrient emissions, there is still a need for further reductions. In addition, the impacts of climate change are projected to lead to a situation where nutrient loads will have to be reduced still further in comparison to current climate conditions. There is an urgent need to address this challenge in WFD action programmes in order to develop robust and cost-effective adaptation strategies for the next WFD RBMP cycles. The aim of this paper is to demonstrate and discuss how a map-based PoMs assessment tool can support the development of adaptive and cost-effective strategies to reduce N losses in the Isefjord and Roskilde Fjord River Basin in the north east of Denmark. The tool facilitates assessments of the application of agri-environmental measures that are targeted towards low retention agricultural areas, where limited or no surface and subsurface N reduction takes place. Effects of climate change on nitrate leaching were evaluated using the dynamic agro-ecosystem model 'Daisy'. Results show that nitrate leaching rates increase by approx. 25% under current management practices. This impact outweighs the expected total N reduction effect of Baseline 2015 and the first RBMP in the case study river basin. The particular PoMs investigated in our study show that WFD N reduction targets can be achieved by targeted land use changes on approx. 4% of the agricultural area under current climate conditions and approx. 9% of the agricultural area, when projected climate change impacts on nitrate leaching rates are included in the assessment. The study highlights the potential of the PoMs assessment tool to assist in evaluation of alternative WFD RBMP scenarios to achieve spatially targeted and cost-effective reductions of N loads at catchment scale in the context of a changing climate.

Evaluation of malnutrition in orthopaedic surgery.

Malnutrition can increase the risk of surgical site infection in both elective spine surgery and total joint arthroplasty. Obesity and diabetes are common comorbid conditions in patients who are malnourished. Despite the relatively high incidence of nutritional disorders among patients undergoing elective orthopaedic surgery, the evaluation and management of malnutrition is not generally well understood by practicing orthopaedic surgeons. Serologic parameters such as total lymphocyte count, albumin level, prealbumin level, and transferrin level have all been used as markers for nutrition status. In addition, anthropometric measurements, such as calf and arm muscle circumference or triceps skinfold, and standardized scoring systems, such as the Rainey-MacDonald nutritional index, the Mini Nutritional Assessment, and institution-specific nutritional scoring tools, are useful to define malnutrition. Preoperative nutrition assessment and optimization of nutritional parameters, including tight glucose control, normalization of serum albumin, and safe weight loss, may reduce the risk of perioperative complications, including infection.

Neurohypophyseal response to fluid resuscitation with hypertonic saline during septic shock in rats.

Septic shock is a serious condition with a consequent drop in blood pressure and inadequate tissue perfusion. Small-volume resuscitation with hypertonic saline (HS) has been proposed to restore physiological haemodynamics during haemorrhagic and endotoxic shock. In the present study, we sought to determine the effects produced by an HS infusion in rats subjected to caecal ligation and perforation (CLP). Male Wistar rats were randomly grouped and submitted to either CLP or sham surgery. Either HS (7.5% NaCl, 4 ml kg(-1) i.v.) or isotonic saline (IS; 0.9% NaCl, 4 ml kg(-1) i.v.) was administered 6 h after CLP. Recordings of mean arterial pressure and heart rate were made during this protocol. Moreover, measurements of electrolyte, vasopressin and oxytocin secretion were analysed after either the HS or the IS treatment. Six hours after CLP, we observed a characteristic decrease in mean arterial pressure that occurs after CLP. The HS infusion in these rats produced a transient elevation of the plasma sodium concentration and osmolality and increased plasma vasopressin and oxytocin levels. Moreover, the HS infusion could restore the mean arterial pressure after CLP, which was completely blunted by the previous injection of the vasopressin but not the oxytocin antagonist. The present study demonstrated that rats subjected to CLP and an infusion of hypertonic saline respond with secretion of neurohypophyseal hormones and a transient increase in blood pressure mediated by the V(1) receptor.

Diamond rotors.

The resolution of magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectra remains bounded by the spinning frequency, which is limited by the material strength of MAS rotors. Since diamond is capable of withstanding 1.5-2.5x greater MAS frequencies, compared to state-of-the art zirconia, we fabricated rotors from single crystal diamond. When combined with bearings optimized for spinning with helium gas, diamond rotors could achieve the highest MAS frequencies to date. Furthermore, the excellent microwave transmission properties and thermal conductivity of diamond could improve sensitivity enhancements in dynamic nuclear polarization (DNP) experiments. The fabrication protocol we report involves novel laser micromachining and produced rotors that presently spin at ωr/2π = 111.000 ±â€¯0.004 kHz, with stable spinning up to 124 kHz, using N2 gas as the driving fluid. We present the first proton-detected 13C/15N MAS spectra recorded using diamond rotors, a critical step towards studying currently inaccessible ex-vivo protein samples with MAS NMR. Previously, the high aspect ratio of MAS rotors (∼10:1) precluded fabrication of MAS rotors from diamond.

3D-printed stators & drive caps for magic-angle spinning NMR.

3D printing has evolved into an invaluable tool for rapid and cost-effective production of intricate parts. In this paper we describe 3D printing and other rapid prototyping methods to fabricate 3.2 mm stators and drive caps for use in magic angle spinning (MAS) NMR experiments. These components can be fabricated with the assistance of computer-aided design (CAD) software and at a fraction of the cost of commercial parts. Additionally, we show that the performance of these 3D printed stators and drive caps is comparable to commercially available systems and that they have significant advantages over their machined counterparts.

Reconstruction of Mastoid Cortex Defects with Hydroxyapatite Cement for Negative Sequelae of Mastoidectomy.

OBJECTIVES: Mastoid cortex defects resulting from mastoidectomy surgery can rarely lead to negative sequelae, including unsightly post-auricular depression and discomfort. This study sought to evaluate the use of hydroxyapatite cement (HAC) to reconstruct mastoidectomy cortex defects. METHODS: Retrospective chart review was undertaken for all patients that underwent reconstruction of the mastoid cortex using HAC at a single tertiary medical center between 2013 and 2019. Collected data included demographics, indications for mastoidectomy, complications, and associated symptom status. RESULTS: Twenty-nine patients that underwent mastoid cortex repair using HAC were included, and ten of these underwent mastoid revision in a secondary procedure to reconstruct the mastoid cortex with a specific goal to eliminate negative signs and symptoms. There were no associated postoperative complications and no instances of post-auricular depression following repair. All cases of secondary reconstruction resolved the primary signs and symptoms that prompted mastoid revision. CONCLUSIONS: HAC mastoid cortex reconstruction may be a safe and effective method to resolve negative sequelae resulting from previous mastoidectomy defects. Also, upfront HAC mastoid cortex reconstruction appears viable in select instances as an option to prevent potential future complications.

Surgery for Cholesteatomatous Labyrinthine Fistula.

OBJECTIVE: There is uncertainty regarding the ideal surgical management of cholesteatomatous labyrinthine fistulae. The objective was to review the published evidence to determine whether a difference exists in hearing outcome for cholesteatoma matrix removal or matrix exteriorization. DATA SOURCES: Systematic MEDLINE and Web of Science searches identified publications describing hearing results after cholesteatoma matrix removal or matrix exteriorization. REVIEW METHODS: Three reviewers appraised the studies for quality, level of evidence, and extracted data. Fistula characteristics such as single-site, multisite, size, grade, and follow-up time were extracted for subanalyses, and when appropriate, data were pooled for statistical analysis. RESULTS: Twenty-eight articles met inclusion criteria, and the level of evidence was judged no better than level 3b. There was no difference in hearing preservation detected between matrix removal and exteriorization (87% for matrix removal, 95% CI, 0.82-0.90; 95% for exteriorization, 95% CI, 0.85-0.98). An analysis of the individual cohort studies that compared these groups directly did not show a difference in calculated odds ratio (OR), 0.96 (95% CI, 0.66-1.40). CONCLUSION: The level of evidence on which to base surgical decision making related to cholesteatomatous labyrinthine fistula is poor, and the data do not demonstrate significant differences in hearing outcomes based on surgical technique.

Highly Oriented Atomically Thin Ambipolar MoSe2 Grown by Molecular Beam Epitaxy.

Transition metal dichalcogenides (TMDCs), together with other two-dimensional (2D) materials, have attracted great interest due to the unique optical and electrical properties of atomically thin layers. In order to fulfill their potential, developing large-area growth and understanding the properties of TMDCs have become crucial. Here, we have used molecular beam epitaxy (MBE) to grow atomically thin MoSe2 on GaAs(111)B. No intermediate compounds were detected at the interface of as-grown films. Careful optimization of the growth temperature can result in the growth of highly aligned films with only two possible crystalline orientations due to broken inversion symmetry. As-grown films can be transferred onto insulating substrates, allowing their optical and electrical properties to be probed. By using polymer electrolyte gating, we have achieved ambipolar transport in MBE-grown MoSe2. The temperature-dependent transport characteristics can be explained by the 2D variable-range hopping (2D-VRH) model, indicating that the transport is strongly limited by the disorder in the film.

Linking climate change mitigation and coastal eutrophication management through biogas technology: Evidence from a new Danish bioenergy concept.

The interest in sustainable bioenergy solutions has gained great importance in Europe due to the need to reduce GHG emissions and to meet environmental policy targets, not least for the protection of groundwater and surface water quality. In the Municipality of Solrød in Denmark, a novel bioenergy concept for anaerobic co-digestion of food industry residues, manure and beach-cast seaweed has been developed and tested in order to quantify the potential for synergies between climate change mitigation and coastal eutrophication management in the Køge Bay catchment. The biogas plant, currently under construction, was designed to handle an annual input of up to 200,000 t of biomass based on four main fractions: pectin wastes, carrageenan wastes, manure and beach-cast seaweed. This paper describes how this bioenergy concept can contribute to strengthening the linkages between climate change mitigation strategies and Water Framework Directive (WFD) action planning. Our assessments of the projected biogas plant indicate an annual reduction of GHG emissions of approx. 40,000 t CO2 equivalents, corresponding to approx. 1/3 of current total GHG emissions in the Municipality of Solrød. In addition, nitrogen and phosphorous loads to Køge Bay are estimated to be reduced by approx. 63 t yr.(-1) and 9 tyr.(-1), respectively, contributing to the achievement of more than 70% of the nutrient reduction target set for Køge Bay in the first WFD river basin management plan. This study shows that anaerobic co-digestion of the specific food industry residues, pig manure and beach-cast seaweed is feasible and that there is a very significant, cost-effective GHG and nutrient loading mitigation potential for this bioenergy concept. Our research demonstrates how an integrated planning process where considerations about the total environment are integrated into the design and decision processes can support the development of this kind of holistic bioenergy solutions.

Numerical correction of anti-symmetric aberrations in single HRTEM images of weakly scattering 2D-objects.

Here, we present a numerical post-processing method for removing the effect of anti-symmetric residual aberrations in high-resolution transmission electron microscopy (HRTEM) images of weakly scattering 2D-objects. The method is based on applying the same aberrations with the opposite phase to the Fourier transform of the recorded image intensity and subsequently inverting the Fourier transform. We present the theoretical justification of the method, and its verification based on simulated images in the case of low-order anti-symmetric aberrations. Ultimately the method is applied to experimental hardware aberration-corrected HRTEM images of single-layer graphene and MoSe2 resulting in images with strongly reduced residual low-order aberrations, and consequently improved interpretability. Alternatively, this method can be used to estimate by trial and error the residual anti-symmetric aberrations in HRTEM images of weakly scattering objects.

Atomic scale microstructure and properties of Se-deficient two-dimensional MoSe2.

We study the atomic scale microstructure of nonstoichiometric two-dimensional (2D) transition metal dichalcogenide MoSe2-x by employing aberration-corrected high-resolution transmission electron microscopy. We show that a Se-deficit in single layers of MoSe2 grown by molecular beam epitaxy gives rise to a dense network of mirror-twin-boundaries (MTBs) decorating the 2D-grains. With the use of density functional theory calculations, we further demonstrate that MTBs are thermodynamically stable structures in Se-deficient sheets. These line defects host spatially localized states with energies close to the valence band minimum, thus giving rise to enhanced conductance along straight MTBs. However, electronic transport calculations show that the transmission of hole charge carriers across MTBs is strongly suppressed due to band bending effects. We further observe formation of MTBs during in situ removal of Se atoms by the electron beam of the microscope, thus confirming that MTBs appear due to Se-deficit, and not coalescence of individual grains during growth. At a very high local Se-deficit, the 2D sheet becomes unstable and transforms to a nanowire. Our results on Se-deficient MoSe2 suggest routes toward engineering the properties of 2D transition metal dichalcogenides by deviations from the stoichiometric composition.

Superannuation retirement balances: a surprising outcome.

AIM: Although the guaranteed superannuation system is believed by many to provide a safe and adequate source of funds in retirement, some will be unpleasantly surprised. The aim of this paper is to demonstrate the significant effect of the economic cycle on the final accumulated balance in superannuation retirement accounts. METHOD: A Monte Carlo simulation is used to illustrate the variance in outcomes that can be expected for a hypothetical individual. RESULTS: The expected accumulated superannuation balances for two hypothetical individuals are estimated. The spread of outcomes is used to illustrate the problem of using only the mean of the distribution as a predictor of wealth in the retirement years. CONCLUSIONS: Many retirees rely on superannuation to fund their retirement. However regular contributions to superannuation does not ensure a predictable outcome, and active management of contributions is required if retirement goals are to be met.