Accessing activity and viscoelastic properties of artificial and living systems from passive measurement.

Living systems are complex dynamic entities that operate far from thermodynamic equilibrium. Their active, non-equilibrium behaviour requires energy to drive cellular organization and dynamics. Unfortunately, most statistical mechanics approaches are not valid in non-equilibrium situations, forcing researchers to use intricate and often invasive methods to study living processes. Here we experimentally demonstrate that an observable termed mean back relaxation quantifies the active mechanics of living cells from passively observed particle trajectories. The mean back relaxation represents the average trajectory of a particle after a recent motion and is calculated from three-point probabilities. We show that this parameter allows the detection of broken detailed balance in confined systems. We experimentally observe that it provides access to the non-equilibrium generating energy and viscoelastic properties of artificial bulk materials and living cells. These findings suggest that the mean back relaxation can function as a marker of non-equilibrium dynamics and is a non-invasive avenue to determine viscoelastic material properties from passive measurements.

A novel gradient echo data based vein segmentation algorithm and its application for the detection of regional cerebral differences in venous susceptibility.

Accurate segmentation of cerebral venous vasculature from gradient echo data is of central importance in several areas of neuroimaging such as for the susceptibility-based assessment of brain oxygenation or planning of electrode placement in deep brain stimulation. In this study, a vein segmentation algorithm for single- and multi-echo gradient echo data is proposed. First, susceptibility maps, true susceptibility-weighted images, and, in the multi-echo case, R2* maps were generated from the gradient echo data. These maps were filtered with an inverted Hamming filter to suppress background contrast as well as artifacts from field inhomogeneities at the brain boundaries. A shearlet-based scale-wise representation was generated to calculate a vesselness function and to generate segmentations based on local thresholding. The accuracy of the proposed algorithm was evaluated for different echo times and image resolutions using a manually generated reference segmentation and two vein segmentation algorithms (Frangi vesselness-based, recursive vesselness filter) as a reference with the Dice and Cohen's coefficients as well as the modified Hausdorff distance. The Frangi-based and recursive vesselness filter methods were significantly outperformed with regard to all error metrics. Applying the algorithm, susceptibility differences likely related to differences in blood oxygenation between superficial and deep venous territories could be demonstrated.

Measuring capabilities in health and physical activity promotion: a systematic review.

BACKGROUND: The capability approach by Amartya Sen and Martha Nussbaum has gained increasing attention in the field of public health. As it combines individual, social and structural factors and shifts the focus of attention from the actual behavior towards available options for health behaviors that people can actually choose from, it may help advance our understanding of complex health issues. OBJECTIVES: The aim of this article is to identify and describe tools available to measure capabilities within the context of health, with a specific focus on capabilities for health-enhancing physical activity. METHOD: We conducted a systematic literature review using 11 databases covering scientific journal articles published in English or German between the years 2000 and 2020 with a focus on capabilities for health or physical activity. RESULTS: We found a total of 51 articles meeting our inclusion criteria. Four articles measured capabilities using qualitative methods, one combined qualitative and quantitative methods, while the rest used quantitative methods. We identified a total 11 different capability questionnaires, all showing moderate to good validity/reliability. Only one questionnaire and one interview-based tool specifically dealt with capabilities for health enhancing physical activity. CONCLUSION: Although we were able to identify measurement tools for capabilities in health, this review has shown that there is no generic tool available for the measurement across all population- and age-groups, and tools focusing on physical activity are scarce. However, our results can be used as guide for future projects that aim at measuring capabilities.

Return to work and lost earnings after acute respiratory distress syndrome: a 5-year prospective, longitudinal study of long-term survivors.

BACKGROUND: Delayed return to work is common after acute respiratory distress syndrome (ARDS), but has undergone little detailed evaluation. We examined factors associated with the timing of return to work after ARDS, along with lost earnings and shifts in healthcare coverage. METHODS: Five-year, multisite prospective, longitudinal cohort study of 138 2-year ARDS survivors hospitalised between 2004 and 2007. Employment and healthcare coverage were collected via structured interview. Predictors of time to return to work were evaluated using Fine and Grey regression analysis. Lost earnings were estimated using Bureau of Labor Statistics data. RESULTS: Sixty-seven (49%) of the 138 2-year survivors were employed prior to ARDS. Among 64 5-year survivors, 20 (31%) never returned to work across 5-year follow-up. Predictors of delayed return to work (HR (95% CI)) included baseline Charlson Comorbidity Index (0.77 (0.59 to 0.99) per point; p=0.04), mechanical ventilation duration (0.67 (0.55 to 0.82) per day up to 5 days; p<0.001) and discharge to a healthcare facility (0.49 (0.26 to 0.93); p=0.03). Forty-nine of 64 (77%) 5-year survivors incurred lost earnings, with average (SD) losses ranging from US$38 354 (21,533) to US$43 510 (25,753) per person per year. Jobless, non-retired survivors experienced a 33% decrease in private health insurance and concomitant 37% rise in government-funded coverage. CONCLUSIONS: Across 5-year follow-up, nearly one-third of previously employed ARDS survivors never returned to work. Delayed return to work was associated with patient-related and intensive care unit/hospital-related factors, substantial lost earnings and a marked rise in government-funded healthcare coverage. These important consequences emphasise the need to design and evaluate vocation-based interventions to assist ARDS survivors return to work.

Quantitative susceptibility mapping and 23 Na imaging-based in vitro characterization of blood clotting kinetics.

Blood clotting is a fundamental biochemical process in post-hemorrhagic hemostasis. Although the varying appearance of coagulating blood in T1 - and T2 -weighted images is widely used to qualitatively determine bleeding age, the technique permits only a rough discrimination of coagulation stages, and it remains difficult to distinguish acute and chronic hemorrhagic stages because of low T1 - and T2 -weighted signal intensities in both instances. To investigate new biomedical parameters for magnetic resonance imaging-based characterization of blood clotting kinetics, sodium imaging and quantitative susceptibility mapping (QSM) were compared with conventional T1 - and T2 -weighted imaging, as well as with biochemical hemolysis parameters. For this purpose, a blood-filled spherical agar phantom was investigated daily for 14 days, as well as after 24 days at 7 T after initial preparation with fresh blood. T1 - and T2 -weighted sequences, a three-dimensional (3D) gradient echo sequence and a density-adapted 3D radial projection reconstruction pulse sequence for 23 Na imaging were applied. For hemolysis estimations, free hemoglobin and free potassium concentrations were measured photometrically and with the direct ion-selective electrode method, respectively, in separate heparinized whole-blood samples along the same timeline. Initial mean susceptibility was low (0.154 ± 0.020 ppm) and increased steadily during the course of coagulation to reach up to 0.570 ± 0.165 ppm. The highest total sodium (NaT) values (1.02 ± 0.06 arbitrary units) in the clot were observed initially, dropped to 0.69 ± 0.13 arbitrary units after one day and increased again to initial values. Compartmentalized sodium (NaS) showed a similar signal evolution, and the NaS/NaT ratio steadily increased over clot evolution. QSM depicts clot evolution in vitro as a process associated with hemoglobin accumulation and transformation, and enables the differentiation of the acute and chronic coagulation stages. Sodium imaging visualizes clotting independent of susceptibility and seems to correspond to clot integrity. A combination of QSM and sodium imaging may enhance the characterization of hemorrhage.

Joblessness and Lost Earnings after Acute Respiratory Distress Syndrome in a 1-Year National Multicenter Study.

RATIONALE: Following acute respiratory distress syndrome (ARDS), joblessness is common but poorly understood. OBJECTIVES: To evaluate the timing of return to work after ARDS, and associated risk factors, lost earnings, and changes in healthcare coverage Methods: Over 12-month longitudinal follow-up, ARDS survivors from 43 U.S. ARDSNet hospitals provided employment and healthcare coverage data via structured telephone interviews. Factors associated with the timing of return to work were assessed using Fine and Gray regression analysis. Lost earnings were estimated using Bureau of Labor Statistics data. MEASUREMENTS AND MAIN RESULTS: Of 922 consenting survivors, 386 (42%) were employed before ARDS (56% male; mean ± SD age, 45 ± 13 yr), with seven dying by 12-month follow-up. Of 379 previously employed 12-month survivors, 166 (44%) were jobless at 12-month follow-up. Accounting for competing risks of death and retirement, half of enrolled and previously employed survivors returned to work by 13 weeks after hospital discharge, with 68% ever returning by 12 months. Delays in return to work were associated with longer hospitalization and older age among nonwhite survivors. Over 12-month follow-up, 274 (71%) survivors accrued lost earnings, averaging $26,949 ± $22,447 (60% of pre-ARDS annual earnings). Jobless survivors experienced a 14% (95% confidence interval, 5-22%; P = 0.002) absolute decrease in private health insurance (from 44% pre-ARDS) and a 16% (95% confidence interval, 7-24%; P < 0.001) absolute increase in Medicare and Medicaid (from 33%). CONCLUSIONS: At 12 months after ARDS, nearly one-half of previously employed survivors were jobless. Post-ARDS joblessness is associated with readily identifiable patient and hospital variables and accompanied by substantial lost earnings and a shift toward government-funded healthcare coverage.

Suitable reference tissues for quantitative susceptibility mapping of the brain.

PURPOSE: Since quantitative susceptibility mapping (QSM) quantifies magnetic susceptibility relative to a reference value, a suitable reference tissue has to be available to compare different subjects and stages of disease. METHODS: To find such a suitable reference tissue for QSM of the brain, melanoma patients with and without brain metastases were measured. Twelve reference regions were chosen and assessed for stability of susceptibility values with respect to multiple intra-individual and inter-individual measurements, age, and stage of disease. RESULTS: Cerebrospinal fluid (CSF), the internal capsule and one region in the splenium of the corpus callosum are the regions with the smallest standard deviations of the mean susceptibility value. The mean susceptibility is 0.010 ± 0.014 ppm for CSF in the atrium of the lateral ventricles (csfpost ), -0.060 ± 0.019 ppm for the posterior limb of the internal capsule (ci2), and -0.008 ± 0.019 ppm for the splenium of the corpus callosum. csfpost and ci2 show nearly no dependence on age or stage of disease, whereas some other regions, e.g., the red nucleus, show moderate dependence on age or disease. CONCLUSION: The internal capsule and CSF appear to be the most suitable reference regions for QSM of the brain in the melanoma patients studied. Both showed virtually no dependence on age or disease and small variations among patients. Magn Reson Med 78:204-214, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Whole-exome sequencing improves the diagnosis yield in sporadic infantile spasm syndrome.

Infantile spasms syndrome (ISs) is characterized by clinical spasms with ictal electrodecrement, usually occurring before the age of 1 year and frequently associated with cognitive impairment. Etiology is widely heterogeneous, the cause remaining elusive in 40% of patients. We searched for de novo mutations in 10 probands with ISs and their parents using whole-exome sequencing (WES). Patients had neither consanguinity nor family history of epilepsy. Common causes of ISs were excluded by brain magnetic resonance imaging (MRI), metabolic screening, array-comparative genomic hybridization (CGH) and testing for mutations in CDKL5, STXBP1, and for ARX duplications. We found a probably pathogenic mutation in four patients. Missense mutations in SCN2A (p.Leu1342Pro) and KCNQ2 (p.Ala306Thr) were found in two patients with no history of epilepsy before the onset of ISs. The p.Asn107Ser missense mutation of ALG13 had been previously reported in four females with ISs. The fourth mutation was an in-frame deletion (p.Phe110del) in NR2F1, a gene whose mutations cause intellectual disability, epilepsy, and optic atrophy. In addition, we found a possibly pathogenic variant in KIF3C that encodes a kinesin expressed during neural development. Our results confirm that WES improves significantly the diagnosis yield in patients with sporadic ISs.

Genetic counselling difficulties and ethical implications of incidental findings from array-CGH: a 7-year national survey.

Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.

Incidental findings on array comparative genomic hybridization: detection of carrier females of dystrophinopathy without any family history.

Array comparative genomic hybridization (aCGH) has progressively replaced conventional karyotype in the diagnostic strategy of intellectual disability (ID) and congenital malformations. This technique increases not only the diagnostic rate but also the possibility of finding unexpected variants unrelated to the indication of referral, namely incidental findings. The incidental finding of copy number variants (CNVs) located in X-linked genes in girls addresses the crucial question of genetic counseling in the family. We report here five cases of CNVs involving the dystrophin gene detected by aCGH in girls referred for developmental delay, without any family history of dystrophinopathy. The rearrangements included three in-frame deletions; one maternally and two paternally inherited, and two frameshift duplications: one de novo and one from undetermined inheritance. In two cases, the deletion identified in a girl was transmitted by the asymptomatic father. In the case of the maternally inherited deletion, prenatal diagnosis of dystrophinopathy was proposed for an ongoing pregnancy, whereas the cause of developmental delay in the index case remained unknown. Through these cases, we discussed the challenges of genetic counseling in the family, regarding the predictive issues for male individuals at risk for a muscular dystrophy without precise knowledge of the clinical consequences of some CNVs in the DMD gene.

Assessing Air Pollutant-Induced, Health-Related External Costs in the Context of Nonmarginal System Changes: A Review.

Marginal analysis is the usual approach to environmental economic assessment, for instance, of health-related external costs due to energy-associated air pollutant emissions. However, nonlinearity exists in all steps of their assessment, i.e., atmospheric dispersion, impact assessment, and monetary valuation. Dedicated assessments thus appear necessary when evaluating large systems or their changes such as in green accounting or the implications of economy-wide energy transitions. Corresponding approaches are reviewed. Tools already exist that allow assessing a marginal change (e.g., one power plant's emissions) for different background emission scenarios that merely need to be defined and implemented. When assessing nonmarginal changes, the top-down approach is considered obsolete, and four variants of the bottom-up approach with different application domains were identified. Variants 1 and 2 use precalculated external cost factors with different levels of sophistication, suitable for energy systems modeling, optimizing for social (i.e., private and external) costs. Providing more reliable results due to more detailed modeling, emission sources are assessed individually or jointly in variants 3 and 4, respectively. Aiming at considering nonlinearity more fully and simultaneously following marginal analysis principles, I propose a variant 3-based approach, subdividing an aggregate (i.e., a nonmarginal change) into several smaller changes. Its strengths and drawbacks, notably the associated effort, are discussed.

Health-related external cost assessment in Europe: methodological developments from ExternE to the 2013 Clean Air Policy Package.

"Getting the prices right" through internalizing external costs is a guiding principle of environmental policy making, one recent example being the EU Clean Air Policy Package released at the end of 2013. It is supported by impact assessments, including monetary valuation of environmental and health damages. For over 20 years, related methodologies have been developed in Europe in the Externalities of Energy (ExternE) project series and follow-up activities. In this study, we aim at analyzing the main methodological developments over time from the 1990s until today with a focus on classical air pollution-induced human health damage costs. An up-to-date assessment including the latest European recommendations is also applied. Using a case from the energy sector, we identify major influencing parameters: differences in exposure modeling and related data lead to variations in damage costs of up to 21%; concerning risk assessment and monetary valuation, differences in assessing long-term exposure mortality risks together with assumptions on particle toxicity explain most of the observed changes in damage costs. These still debated influencing parameters deserve particular attention when damage costs are used to support environmental policy making.

Pregnancy outcomes of prenatally diagnosed Turner syndrome: a French multicenter retrospective study including a series of 975 cases.

OBJECTIVES: The objectives of this study were to report pregnancy outcomes after prenatal diagnosis of Turner syndrome (TS) and to compare and assess termination of pregnancy rates during two periods. The intervals selected were before and after 1997 when multidisciplinary centers for prenatal diagnosis (MCPDs) were established in France. METHODS: A database of 975 cases of TS diagnosed between 1980 and 2012 was created from 21 French cytogenetics laboratories. For each case, the karyotype indication, maternal age, year of prenatal testing, sampling procedure, karyotype, associated ultrasound findings, and outcomes were recorded. RESULTS: Karyotypes were mainly performed because of abnormal sonographic findings (84%). Before 1997, there were no changes in the rate of termination (90%) of affected fetuses. After 1997, the rate fell to 80%. This decrease was mainly observed in cases of mosaicism, incidental diagnosis, and in later gestations. US abnormalities were more likely to be associated with a full 45,X karyotype. CONCLUSION: There was an evolution in the way genetic counseling was performed following prenatal diagnosis of Turner syndrome that coincided with the opening of MCPDs in France. This resulted in a decrease in the rate of termination of affected fetuses.

A French collaborative survey of 272 fetuses with 22q11.2 deletion: ultrasound findings, fetal autopsies and pregnancy outcomes.

OBJECTIVE: The 22q11.2 deletion (del22q11.2) is one of the most common microdeletions. We performed a collaborative, retrospective analysis in France of prenatal diagnoses and outcomes of fetuses carrying the del22q11.2. METHODS: A total of 272 fetuses were included. Data on prenatal diagnosis, ultrasound findings, pathological features, outcomes and inheritance were analyzed. RESULTS: The mean time of prenatal diagnosis was 25.6 ± 6 weeks of gestation. Most of the diagnoses (86.8%) were prompted by abnormal ultrasound findings [heart defects (HDs), in 83.8% of cases]. On fetal autopsy, HDs were again the most common disease feature, but thymus, kidney abnormalities and facial dysmorphism were also described. The deletion was inherited in 27% of cases. Termination of pregnancy (TOP) occurred in 68.9% of cases and did not appear to depend on the inheritance status. However, early diagnosis was associated with a higher TOP rate. CONCLUSION: This is the largest cohort of prenatal del22q11.2 diagnoses. As in postnatally diagnosed cases, HDs were the most frequently observed abnormalities. However, thymus and kidney abnormalities and polyhydramnios should also be screened for in the prenatal diagnosis of del22q11.2. Only the time of diagnosis appeared to be strongly associated with the pregnancy outcome: the earlier the diagnosis, the higher the TOP rate.

Progress challenges and opportunities for the re-engineering of trans-AT polyketide synthases.

Polyketides are a structurally and functionally diverse family of bioactive natural products that are used extensively as pharmaceuticals and agrochemicals. In bacteria these molecules are biosynthesized by giant, multi-functional enzymatic complexes, termed modular polyketide synthases (PKSs), that function in assembly-line like fashion to fuse and tailor simple carboxylic acid monomers into a vast array of elaborate chemical scaffolds. Modifying PKSs through targeted synthase re-engineering is a promising approach for accessing functionally-optimized polyketides. Due to their highly mosaic architectures the recently identified trans-AT family of modular synthases appear inherently more amenable to re-engineering than their well studied cis-AT counterparts. Here, we review recent progress in the re-engineering of trans-AT PKSs, summarize opportunities for harnessing the biosynthetic potential of these systems, and highlight challenges that such re-engineering approaches present.

Characterizing intracellular mechanics via optical tweezers-based microrheology.

Intracellular organization is a highly regulated homeostatic state maintained to ensure eukaryotic cells' correct and efficient functioning. Thanks to decades of research, vast knowledge of the proteins involved in intracellular transport and organization has been acquired. However, how these influence and potentially regulate the intracellular mechanical properties of the cell is largely unknown. There is a deep knowledge gap between the understanding of cortical mechanics, which is accessible by a series of experimental tools, and the intracellular situation that has been largely neglected due to the difficulty of performing intracellular mechanics measurements. Recently, tools required for such quantitative and localized analysis of intracellular mechanics have been introduced. Here, we review how these approaches and the resulting viscoelastic models lead the way to a full mechanical description of the cytoplasm, which is instrumental for a quantitative characterization of the intracellular life of cells.

Fungal traits help to understand the decomposition of simple and complex plant litter.

Litter decomposition is a key ecosystem process, relevant for the release and storage of nutrients and carbon in soil. Soil fungi are one of the dominant drivers of organic matter decomposition, but fungal taxa differ substantially in their functional ability to decompose plant litter. Knowledge is mostly based on observational data and subsequent molecular analyses and in vitro studies have been limited to forest ecosystems. In order to better understand functional traits of saprotrophic soil fungi in grassland ecosystems, we isolated 31 fungi from a natural grassland and performed several in vitro studies testing for i) leaf and wood litter decomposition, ii) the ability to use carbon sources of differing complexity, iii) the enzyme repertoire. Decomposition strongly varied among phyla and isolates, with Ascomycota decomposing the most and Mucoromycota decomposing the least. The phylogeny of the fungi and their ability to use complex carbon were the most important predictors for decomposition. Our findings show that it is crucial to understand the role of individual members and functional groups within the microbial community. This is an important way forward to understand the role of microbial community composition for the prediction of litter decomposition and subsequent potential carbon storage in grassland soils.

Trapped tidal currents generate freely propagating internal waves at the Arctic continental slope.

Energetic tidal currents in the Arctic play an important role in local mixing processes, but they are primarily confined to the shelves and continental slopes due to topographic trapping north of their critical latitude. Recent studies employing idealized models have suggested that the emergence of higher harmonic tidal waves along these slopes could serve as a conduit for tidal energy transmission into the Arctic Basin. Here we provide observational support from an analysis of yearlong observations from three densely-instrumented oceanographic moorings spanning 30 km across the continental slope north of Svalbard ([Formula: see text]81.3[Formula: see text]N). Full-depth current records show strong barotropic diurnal tidal currents, dominated by the K[Formula: see text] constituent. These sub-inertial currents vary sub-seasonally and are strongest at the 700-m isobath due to the topographic trapping. Coinciding with the diurnal tide peak in summer 2019, we observe strong baroclinic semidiurnal currents exceeding 10 cm s[Formula: see text] between 500 m and 1000 m depth about 10 km further offshore at the outer mooring. In this semidiurnal band, we identify super-inertial K[Formula: see text] waves, and present evidence that their frequency, timing, polarization, propagation direction and depths are consistent with the generation as higher harmonics of the topographically trapped K[Formula: see text] tide at the continental slope.

Descemet Membrane Endothelial Keratoplasty and Triple Descemet Membrane Endothelial Keratoplasty in Eyes With Macular Comorbidity.

PURPOSE: The aim of this study was to evaluate results after Descemet membrane endothelial keratoplasty (DMEK) and DMEK with cataract surgery (triple DMEK) in eyes with endothelial dysfunction and concomitant macular pathology. METHODS: A monocentric, prospective clinical observational study of patients who underwent DMEK or triple DMEK surgery at the Department of Ophthalmology, University Hospital Düsseldorf, Germany, from June 2013 to February 2016 was conducted. Sex, age, best-corrected visual acuity (BCVA), central corneal thickness, endothelial cell density, and central retinal thickness in the 1 millimeter zone were analyzed. RESULTS: A total of 209 eyes were included in the study. Forty-two eyes (20.1%) had vision-limiting concomitant maculopathies. These were age-related macular degeneration (n = 17, 8.1%), epiretinal gliosis (n = 13, 6.2%), chronic macular edema (n = 7, 3.3%), macular holes (n = 3, 1.4%), and macular scarring (n = 2, 1.0%). BCVA significantly increased in patients without maculopathy from 0.6 ± 0.33 logMAR to 0.1 ± 0.15 logMAR ( P < 0.001) and also in patients with maculopathy from 0.9 ± 0.38 logMAR to 0.27 ± 0.23 logMAR 12 months postoperatively ( P < 0.001). There was a significant central retinal thickness increase of 34.1 µm 6 weeks after triple DMEK in the central 1-mm zone ( P = 0.011). This increase was insignificant after DMEK. Postoperative macular edema occurred in 5.9% of cases after DMEK and 8.1% after triple DMEK, which was not significantly different. CONCLUSIONS: DMEK and triple DMEK significantly increase BCVA in eyes with concomitant maculopathy. Postoperative macular edema is a common disorder after lamellar keratoplasty; therefore, prophylactic treatment with nonsteroidal antiinflammatory drugs should be considered. Maculopathies did not predispose the development of postoperative macular edema.