Potential Implications of Slowing Disease Progression in Amyloid-Positive Early Alzheimer's Disease: Estimates from Real-World Data.

BACKGROUND: Emerging therapies have shown promising results for slowing the progression of Alzheimer's disease (AD). However, the potential impact of these therapies on real-world outcomes remains to be explored. OBJECTIVE: To examine the impact of slowing AD progression on functional abilities and behavioral symptoms. DESIGN: Retrospective observational study. SETTING: Data from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) in the United States (06/2005-11/2021, primary analysis) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (09/2005-03/2022, sensitivity analysis) were used. PARTICIPANTS: Individuals with mild cognitive impairment (MCI) or mild dementia, Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score 0.5-9.0 (inclusive; first visit defined as the index date), and confirmed amyloid positivity were identified in NACC. In ADNI, individuals with at least one clinical center visit with a clinical assessment of MCI or mild dementia and confirmed amyloid positivity were identified. MEASUREMENTS: Hypothetical effects of slowing disease progression as assessed by CDR-SB on functional and behavioral outcomes including the Functional Activities Questionnaire (FAQ) score, Neuropsychiatric Inventory Questionnaire (NPI-Q) score, and the probability of complete dependence over five years were evaluated using multivariable regression among NACC participants, separately for the subgroups with MCI and mild dementia at baseline, respectively. For the ADNI sensitivity analysis, the hypothetical effects of slowing disease progression were evaluated for FAQ score using multivariable regression among the MCI participants only. RESULTS: Compared with natural disease progression, slowing progression by 20% over five years for NACC participants with MCI and mild dementia, respectively, would result in 1.7-point (10.8%) and 1.6-point (12.9%) less deterioration based on FAQ; 0.5-point (20.3%) and 0.5-point (19.3%) less deterioration based on NPI-Q; 4.7 percentage-point (22.2%) and 10.1 percentage-point (21.6%) lower probability of complete dependence. Among ADNI participants, delaying disease progression by 20% or 30% over 4 years would avert deterioration based on FAQ of 1.1 points (20.4%) and 1.6 points (29.6%), respectively, compared to natural disease progression. CONCLUSIONS: Slowing early AD progression could result in preservation of functional and behavioral attributes and functional autonomy for longer.

Impact of Differential Rates of Disease Progression in Amyloid-Positive Early Alzheimer's Disease: Findings from a Longitudinal Cohort Analysis.

BACKGROUND: There is limited literature regarding the impact of differential rates of disease progression on longitudinal outcomes in individuals with early Alzheimer's disease (AD) and confirmed brain amyloid pathology. OBJECTIVES: To describe the underlying characteristics and long-term outcomes associated with different rates of disease progression among amyloid-positive individuals with early symptomatic AD. DESIGN: Retrospective observational study. SETTING: Data from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) in the United States (06/2005-11/2021). PARTICIPANTS: Individuals with a clinical assessment of mild cognitive impairment or dementia and Clinical Dementia Rating® Dementia Staging Instrument Sum of Boxes (CDR-SB) score 0.5-9.0 (inclusive; first visit defined as the index date) and confirmed amyloid positivity. Participants were stratified into No Progression (change ≤0), Slower Progression (0< change <2.0 points), Median Progression (2.0-point change), and Faster Progression (change >2.0 points) cohorts based on the observed distribution of changes in CDR-SB score between the index and first subsequent visit. MEASUREMENTS: For each cohort, the functional and neuropsychiatric outcomes were described at index and each subsequent visit for up to five years, and least-square (LS) mean changes from baseline were estimated using linear mixed-effects models adjusting for baseline demographic and clinical characteristics. RESULTS: Among 1,263 participants included in the analysis, the mean±standard deviation (SD) age at index was 72.7±9.7 years and 55.3% were males. Demographic characteristics and comorbidity profiles at index were similar across cohorts. However, at index, the Faster Progression (N=279) cohort had higher CDR-SB and Functional Assessment Questionnaire (FAQ) scores compared with the No Progression (N=474), Slower Progression (N=297), and Median Progression (N=213) cohorts. Adjusting for baseline characteristics, at year 5 after index the FAQ score increased by 23.6 points for Faster Progression cohort and 10.4, 15.8, and 19.2 points for the No, Slower, and Median Progression cohorts, respectively. The corresponding increases in Neuropsychiatric Inventory Questionnaire (NPI-Q) scores were 6.7 points for the Faster Progression cohort, and by 1.3, 3.1, and 8.3 points, for the No, Slower, and Median Progression cohorts, respectively. CONCLUSIONS: Despite similar demographic and clinical profiles at baseline, amyloid-positive individuals with greater deterioration based on CDR-SB early in the AD trajectory continue to experience worse functional and behavioral outcomes over time than those with more gradual deterioration in this metric.

Optimizing the structure of acene clusters.

We present a study of the potential energy surface of anthracene, tetracene, and pentacene clusters with up to 30 molecules. We have applied the basin-hopping Monte Carlo algorithm to clusters of acene molecules in order to find their lowest energy states. The acene molecules are described by the polymer-consistent force field-interface force field. We present the structures with the lowest observed energy, and we discuss the relative stability and accessibility of structures corresponding to local energy minima.

Revisiting Mt Fuji's groundwater origins with helium, vanadium and environmental DNA tracers.

Known locally as the water mountain, for millennia Japan's iconic Mt Fuji has provided safe drinking water to millions of people via a vast network of groundwater and freshwater springs. Groundwater, which is recharged at high elevations, flows down Fuji's flanks within three basaltic aquifers, ultimately forming countless pristine freshwater springs among Fuji's foothills. Here we challenge the current conceptual model of Fuji being a simple system of laminar groundwater flow with little to no vertical exchange between its three aquifers. This model contrasts strongly with Fuji's extreme tectonic instability due to its unique location on top of the only known continental trench-trench-trench triple junction, its complex geology and its unusual microbial spring water communities. On the basis of a unique combination of microbial environmental DNA, vanadium and helium tracers, we provide evidence for prevailing deep circulation and a previously unknown deep groundwater contribution to Fuji's freshwater springs. The most substantial deep groundwater upwelling has been found along Japan's most tectonically active region, the Fujikawa-kako Fault Zone. Our findings broaden the hydrogeological understanding of Fuji and demonstrate the vast potential of combining environmental DNA, on-site noble gas and trace element analyses for groundwater science.

Computation of the solid-liquid interfacial free energy in hard spheres by means of thermodynamic integration.

We used a thermodynamic integration scheme, which is specifically designed for disordered systems, to compute the interfacial free energy of the solid-liquid interface in the hard-sphere model. We separated the bulk contribution to the total free energy from the interface contribution, performed a finite-size scaling analysis, and obtained for the (100)-interface γ=0.591(11)k_{B}Tσ^{-2}.

A CRISPR-Cas9 tool to explore the genetics of Bacillus subtilis phages.

Here, we present pRH030, a new CRISPR-Cas9 tool for the genetic engineering of Bacillus phages and beyond. It is based on the Streptococcus pyogenes cas9 with its native constitutive promoter, tracrRNA, and a gRNA precursor. The constitutive expression of Cas9 was conducive to the inactivation of viral attackers and enhanced phage mutagenesis efficiency up to 100%. The gRNA precursor can be built up to an artificial CRISPR array with up to 5 spacers (target sequences) assembled from ordinary oligonucleotides and directly cloned into pRH030. Required time and resources remain comparable to a single gRNA cloning. These properties make pRH030 an attractive new system for the modification of Bacillus phages and qualify it for research beyond genetic construction.

[Unmet research and developmental needs in ophthalmology : A consensus-based road map of the European Vision Institute for 2019-2025]. / Forschungs- und Entwicklungsbedarf in der Augenheilkunde ("Unmet needs") : Ein konsensbasierter Fahrplan des European Vision Institute (EVI) für die Jahre 2019 bis 2025.

PURPOSE: To define unmet needs in ophthalmology which can realistically be addressed in the next years (2019-2025) and to describe potential avenues for research to address these challenges. METHODS: Outcomes of a consensus process within the European Vision Institute (EVI, Brussels) are outlined. Disease areas which are discussed comprise glaucoma, retinal dystrophies, diabetic retinopathy, dry eye disease, corneal diseases, cataract and refractive surgery. RESULTS: Unmet needs in the mentioned disease areas are discussed and realistically achievable research projects outlined. CONCLUSION: Considerable progress can be made in the field of ophthalmology and patient-relevant outcomes in the near future.

High-density percolation on the modified Bethe lattice.

High-density percolation is the formation of a system spanning cluster of vertices with at least m occupied neighbors. We discuss high-density percolation on the modified Bethe lattice in terms of the theory of large random graphs with arbitrary degree distributions. Using the formalism of generating functions, we derive expressions for the cluster size distribution, the percolation threshold, the percolation probability, and the mean size of finite clusters. We show that the critical exponents ß=γ=1. Additionally, numerical solutions and simulation results for the percolation probability and mean size of finite clusters are compared for illustration.

Growth of films with anisotropic particles: Simulations and rate equations.

By means of computer simulations and kinetic rate equations, we study the formation of a film of rod-like particles which are deposited on a substrate. The rod-rod interactions are hard with a short-range attraction of variable strength and width, and the rod-substrate interactions favor lying rods with a variable strength. For a rod aspect ratio of 5 and deposition of up to an equivalent of one monolayer of standing rods, we demonstrate a rich variety of growth modes upon variation of the three interaction parameters. We formulate rate equations for the time evolution of densities of islands composed of standing, lying, and mixed rods. Input parameters such as diffusion constants, island capture numbers, and rod reorientation free energies are extracted from simulations, while rod reorientation attempt frequencies remain as free parameters. Numerical solutions of the rate equations in a simple truncation show rough qualitative agreement with the simulations for the early stage of film growth but an extension to later stages requires to go significantly beyond this simple truncation.

Preoperative serum uric acid predicts incident acute kidney injury following cardiac surgery.

BACKGROUND: Acute kidney injury (AKI) following cardiac surgery is a frequent complication and several risk factors increasing its incidence have already been characterized. This study evaluates the influence of preoperative increased serum uric acid (SUA) levels in comparison with other known risk factors on the incidence of AKI following cardiac surgery. METHODS: During a period of 5 month, 247 patients underwent elective coronary artery bypass grafting, valve replacement/ repair or combined bypass and valve surgery. Datas were prospectively analyzed. Primary endpoint was the incidence of AKI as defined by the AKI criteria comparing patients with preoperative serum uric acid (SUA) levels below versus above the median. Multivariate logistic regression analysis was used to identify independent predictors of postoperative AKI. RESULTS: Thirty (12.1%) of the 247 patients developed postoperative AKI, 24 of 30 (80%) had preoperative SUA- levels above the median (≥373 µmol/l) (OR: 4.680, CI 95% 1.840; 11.904, p = 0.001). In the multivariate analysis SUA levels above the median (OR: 5.497, CI 95% 1.772; 17.054, p = 0.003), cardiopulmonary bypass (CPB) time > 90 min (OR: 4.595, CI 95% 1.587; 13.305, p = 0.005), cardiopulmonary bypass (CPB) > 30 kg/m2 (OR: 3.208, CI 95% 1.202; 8.562; p = 0.02), and preoperative elevated serum-creatinine levels (OR: 1.015, CI 95% 1.001; 1.029, p = 0.04) were independently associated with postoperative AKI. CONCLUSIONS: Serum uric acid is an independent risk marker for AKI after cardiac surgery. From all evaluated factors it showed the highest odds ratio.

Guidelines versus reality: is coronary stent application in three-vessel disease standard or the exception?

The national guidelines for treatment of chronic coronary heart disease (CHD) recommend surgical coronary aortic bypass grafting (CABG) rather than percutaneous coronary intervention (PCI) for patients with a coronary three-vessel disease. The epidemiology of three-vessel CHD and data about the application of different revascularisation strategies raise suspicion of deviation from the guidelines in the treatment of those patients. Claims data containing records of almost 10 million patients of the largest German statutory health insurance fund (Techniker Krankenkasse) were utilised to measure adherence to the guidelines for treatment of groups of patients with one-, two-, and three-vessel CHD, respectively. The impact of age, sex, and comorbidity on each patient's revascularisation procedure was investigated as well. There was no significant difference in the rate of PCI between the groups. In conclusion, the hypothesis that patients with a coronary three-vessel disease are not always treated according to the recommendations of the national guidelines could not be disproved by this study. Finally, the results of this study suggest that the best revascularisation strategy for each patient with two- and three-vessel disease should be decided upon by an interdisciplinary discussion between both cardiologists and cardiac surgeons.

Elastic properties of the nematic phase in hard ellipsoids of short aspect ratio.

We present a Monte Carlo simulation study of suspensions of hard ellipsoids of revolution. Based on the spatial fluctuations of the orientational order, we have computed the Frank elastic constants for prolate and oblate ellipsoids and compared them to the affine transformation model. The affine transformation model predicts the right order of magnitude of the twist and bend constant but not of the splay constant. In addition, we report the observation of a stable nematic phase at an aspect ratio as low as 2.5.

Monolayers of hard rods on planar substrates. II. Growth.

Growth of hard-rod monolayers via deposition is studied in a lattice model using rods with discrete orientations and in a continuum model with hard spherocylinders. The lattice model is treated with kinetic Monte Carlo simulations and dynamic density functional theory while the continuum model is studied by dynamic Monte Carlo simulations equivalent to diffusive dynamics. The evolution of nematic order (excess of upright particles, "standing-up" transition) is an entropic effect and is mainly governed by the equilibrium solution, rendering a continuous transition [Paper I, M. Oettel et al., J. Chem. Phys. 145, 074902 (2016)]. Strong non-equilibrium effects (e.g., a noticeable dependence on the ratio of rates for translational and rotational moves) are found for attractive substrate potentials favoring lying rods. Results from the lattice and the continuum models agree qualitatively if the relevant characteristic times for diffusion, relaxation of nematic order, and deposition are matched properly. Applicability of these monolayer results to multilayer growth is discussed for a continuum-model realization in three dimensions where spherocylinders are deposited continuously onto a substrate via diffusion.

Isotropic-nematic transition and cholesteric phases of helical Yukawa rods.

We present a Monte Carlo simulation study of helical Yukawa rods as a model for chiral liquid crystal mesogens. To simulate the cholesteric phase, we introduce a new simulation method that uses soft walls and self-determined boundary conditions. We observe that the isotropic-nematic phase transition is shifted to lower volume fractions with decreasing salt concentration as well as with increasing internal pitch of the rods. For particular sets of interaction parameters, the sense of the cholesteric pitch inverts, i.e., depending on concentration, mesogens of a given handedness can produce cholesteric phases of both chiral senses.

[Complex regional pain syndrome following distal fractures of the radius : Epidemiology, pathophysiological models, diagnostics and therapy]. / Komplexes regionales Schmerzsyndrom nach distaler Radiusfraktur : Aktuelle Epidemiologie, pathophysiologische Modelle, Diagnostik und Therapie.

The complex regional pain syndrome (CRPS) still represents an incompletely etiologically understood complication following fractures of the distal radius. The incidence of CRPS following fractures of the distal radius varies between 1 % and 37 %. Pathophysiologically, a complex interaction of inflammatory, somatosensory, motor and autonomic changes is suspected, leading to a persistent maladaptive response and sensitization of the central and peripheral nervous systems with development of the corresponding symptoms. Decisive for the diagnostics are a detailed patient medical history and a clinical hand surgical, neurological and pain-related examination with confirmation of the Budapest criteria. Among the types of apparatus used for diagnostics, 3­phase bone scintigraphy and temperature measurement have a certain importance. A multimodal therapy started as early as possible is the most promising approach for successful treatment. As part of a multimodal rehabilitation the main focus of therapy lies on pain relief and functional aspects.

Monolayers of hard rods on planar substrates. I. Equilibrium.

The equilibrium properties of hard rod monolayers are investigated in a lattice model (where position and orientation of a rod are restricted to discrete values) as well as in an off-lattice model featuring spherocylinders with continuous positional and orientational degrees of freedom. Both models are treated using density functional theory and Monte Carlo simulations. Upon increasing the density of rods in the monolayer, there is a continuous ordering of the rods along the monolayer normal ("standing up" transition). The continuous transition also persists in the case of an external potential which favors flat-lying rods in the monolayer. This behavior is found in both the lattice and the continuum models. For the lattice model, we find very good agreement between the results from the specific DFT used (lattice fundamental measure theory) and simulations. The properties of lattice fundamental measure theory are further illustrated by the phase diagrams of bulk hard rods in two and three dimensions.

Visualizing retinoic acid morphogen gradients.

Morphogens were originally defined as secreted signaling molecules that diffuse from local sources to form concentration gradients, which specify multiple cell fates. More recently morphogen gradients have been shown to incorporate a range of mechanisms including short-range signal activation, transcriptional/translational feedback, and temporal windows of target gene induction. Many critical cell-cell signals implicated in both embryonic development and disease, such as Wnt, fibroblast growth factor (Fgf), hedgehog (Hh), transforming growth factor beta (TGFb), and retinoic acid (RA), are thought to act as morphogens, but key information on signal propagation and ligand distribution has been lacking for most. The zebrafish provides unique advantages for genetics and imaging to address gradients during early embryonic stages when morphogens help establish major body axes. This has been particularly informative for RA, where RA response elements (RAREs) driving fluorescent reporters as well as Fluorescence Resonance Energy Transfer (FRET) reporters of receptor binding have provided evidence for gradients, as well as regulatory mechanisms that attenuate noise and enhance gradient robustness in vivo. Here we summarize available tools in zebrafish and discuss their utility for studying dynamic regulation of RA morphogen gradients, through combined experimental and computational approaches.

Suitability and Usability of Claims Data for Review of Guidelines for the Treatment of Chronic Heart Failure.

Background: Guidelines have special importance in medicine, however, it is questionable to what extent these recommendations are applied in daily care, and under which conditions claims data can be used for verification of guideline adherence. Method: Advantages and limitations of claims data for verification of guidelines compliance in the therapeutic area as well as the guidelines themselves were analysed and critically assessed. To substantiate these results, claims data of a major German health insurance fund (Techniker Krankenkasse) were analysed. Results: 104 236 patients were identified. With certain limitations, claims data are useful for verifying guideline adherence; it could be shown that in pharmacotherapy the beta-adrenergic receptor blocker was used to the highest extent (70.5%). In contrast, only 56.4% of patients were treated with pure ACE inhibitors and ACE combined preparation. Conclusion: In order to validate guideline adherence by means of claims data analyses, a number of conditions relating to the database, the therapeutic area and the guidelines themselves have to be considered. Guideline recommendations, which, for example, are based on clinical data, cannot be reviewed by using claims data. Despite these limitations, claims data provide a suitable tool for reviewing selected guideline recommendations. They show that the current use of pharmacotherapy as well as clinical and diagnostic interventions might be increased in accordance with the guideline recommendations.

Structural Transition in a Fluid of Spheroids: A Low-Density Vestige of Jamming.

A thermodynamically equilibrated fluid of hard spheroids is a simple model of liquid matter. In this model, the coupling between the rotational degrees of freedom of the constituent particles and their translations may be switched off by a continuous deformation of a spheroid of aspect ratio t into a sphere (t=1). We demonstrate, by experiments, theory, and computer simulations, that dramatic nonanalytic changes in structure and thermodynamics of the fluids take place, as the coupling between rotations and translations is made to vanish. This nonanalyticity, reminiscent of a second-order liquid-liquid phase transition, is not a trivial consequence of the shape of an individual particle. Rather, free volume considerations relate the observed transition to a similar nonanalyticity at t=1 in structural properties of jammed granular ellipsoids. This observation suggests a deep connection to exist between the physics of jamming and the thermodynamics of simple fluids.

[Impact of guideline adherence on mortality in treatment of left heart failure]. / Auswirkung einer leitliniengerechten Behandlung auf die Mortalität bei Linksherzinsuffizienz.

BACKGROUND: The German national guidelines on chronic heart failure provide treatment recommendations to physicians and reflect the current level of evidence; however, it is questionable to what extent these recommendations are applied in the routine practice and what the effect of guideline adherence on mortality is. METHODS: In this study the claims data of a major German health insurance fund collected over a period of 4 years were analyzed. Using binary logistic regression and Cox regression analyses the influence of drug prescriptions, diagnostic measures, influenza vaccination, the New York Heart Association (NYHA) status, the age and gender on mortality were examined. RESULTS: The study population consisted of 85,465 heart failure patients. Approximately 60 % of the drugs were prescribed according to the guidelines. There was a positive correlation between a higher NYHA status and mortality with an odds ratio (OR) of 3.264. Especially pharmacotherapy with angiotensin-converting enzyme (ACE) inhibitors and beta blockers according to the guidelines was associated with a lower mortality rate (OR 0.448 resp. 0.444). Also patients diagnosed using echocardiography at regular intervals showed a lower risk of dying (OR 0.314). CONCLUSION: The results of this large sample could confirm the results of clinical trials that a therapy according to the guidelines has a significant impact on mortality. By analyzing the claims data evidence was found that in the treatment of heart failure patients the medical results could be improved by adherence to guideline recommendations.