The adaptability of the ion-binding site by the Ag(I)/Cu(I) periplasmic chaperone SilF.

The periplasmic chaperone SilF has been identified as part of an Ag(I) detoxification system in Gram-negative bacteria. Sil proteins also bind Cu(I) but with reported weaker affinity, therefore leading to the designation of a specific detoxification system for Ag(I). Using isothermal titration calorimetry, we show that binding of both ions is not only tighter than previously thought but of very similar affinities. We investigated the structural origins of ion binding using molecular dynamics and QM/MM simulations underpinned by structural and biophysical experiments. The results of this analysis showed that the binding site adapts to accommodate either ion, with key interactions with the solvent in the case of Cu(I). The implications of this are that Gram-negative bacteria do not appear to have evolved a specific Ag(I) efflux system but take advantage of the existing Cu(I) detoxification system. Therefore, there are consequences for how we define a particular metal resistance mechanism and understand its evolution in the environment.

The effect of (neo)adjuvant chemotherapy on long-term survival outcomes in patients with invasive lobular breast cancer treated with endocrine therapy: A retrospective cohort study.

BACKGROUND: Despite histological and molecular differences between invasive lobular carcinoma (ILC) and invasive carcinoma of no special type, according to national treatment guidelines no distinction is made regarding the use of (neo)adjuvant chemotherapy. Studies on the long-term outcome of chemotherapy in patients with ILC are scarce and show inconclusive results. METHODS: All patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative ILC with an indication for chemotherapy treated with adjuvant endocrine therapy were selected from the Erasmus Medical Center Breast Cancer database. Cox proportional hazards models were used to estimate the effect of chemotherapy on recurrence-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS). RESULTS: A total of 520 patients were selected, of whom 379 were treated with chemotherapy and 141 were not. Patients in the chemotherapy group were younger (51 vs. 61 years old; p < .001), had a higher T status (T3+, 33% vs. 14%; p < .001), and more often had lymph node involvement (80% vs. 49%; p < .001) in comparison to the no-chemotherapy group. After adjusting for confounders, chemotherapy treatment was not associated with better RFS (hazard ratio [HR], 1.20; 95% confidence interval [CI], 0.63-2.31), BCSS (HR, 1.24; 95% CI, 0.60-2.58), or OS (HR, 0.97; 95% CI, 0.56-1.66). This was also reflected by adjusted Cox survival curves in the chemotherapy versus no-chemotherapy group for RFS (75% vs. 79%), BCSS (80% vs. 84%), and OS (72% vs. 71%). CONCLUSIONS: Chemotherapy is not associated with improved RFS, BCSS, or OS for patients with ER+/HER2- ILC treated with adjuvant endocrine therapy and with an indication for chemotherapy.

Fully Automated Valve Segmentation for Blood Flow Assessment From 4D Flow MRI Including Automated Cardiac Valve Tracking and Transvalvular Velocity Mapping.

BACKGROUND: Automated 4D flow MRI valvular flow quantification without time-consuming manual segmentation might improve workflow. PURPOSE: Compare automated valve segmentation (AS) to manual (MS), and manually corrected automated segmentation (AMS), in corrected atrioventricular septum defect (c-AVSD) patients and healthy volunteers, for assessing net forward volume (NFV) and regurgitation fraction (RF). STUDY TYPE: Retrospective. POPULATION: 27 c-AVSD patients (median, 23 years; interquartile range, 16-31 years) and 24 healthy volunteers (25 years; 12.5-36.5 years). FIELD STRENGTH/SEQUENCE: Whole-heart 4D flow MRI and cine steady-state free precession at 3T. ASSESSMENT: After automatic valve tracking, valve annuli were segmented on time-resolved reformatted trans-valvular velocity images by AS, MS, and AMS. NFV was calculated for all valves, and RF for right and left atrioventricular valves (RAVV and LAVV). NFV variation (standard deviation divided by mean NFV) and NFV differences (NFV difference of a valve vs. mean NFV of other valves) expressed internal NFV consistency. STATISTICAL TESTS: Comparisons between methods were assessed by Wilcoxon signed-rank tests, and intra/interobserver variability by intraclass correlation coefficients (ICCs). P < 0.05 was considered statistically significant, with multiple testing correction. RESULTS: AMS mean analysis time was significantly shorter compared with MS (5.3 ± 1.6 minutes vs. 9.1 ± 2.5 minutes). MS NFV variation (6.0%) was significantly smaller compared with AMS (6.3%), and AS (8.2%). Median NFV difference of RAVV, LAVV, PV, and AoV between segmentation methods ranged from -0.7-1.0 mL, -0.5-2.8 mL, -1.1-3.6 mL, and - 3.1--2.1 mL, respectively. Median RAVV and LAVV RF, between 7.1%-7.5% and 3.8%-4.3%, respectively, were not significantly different between methods. Intraobserver/interobserver agreement for AMS and MS was strong-to-excellent for NFV and RF (ICC ≥0.88). DATA CONCLUSION: MS demonstrates strongest internal consistency, followed closely by AMS, and AS. Automated segmentation, with or without manual correction, can be considered for 4D flow MRI valvular flow quantification. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 3.

Evaluating a Phase-Specific Approach to Aortic Flow: A 4D Flow MRI Study.

BACKGROUND: Aortic flow parameters can be quantified using 4D flow MRI. However, data are sparse on how different methods of analysis influence these parameters and how these parameters evolve during systole. PURPOSE: To assess multiphase segmentations and multiphase quantification of flow-related parameters in aortic 4D flow MRI. STUDY TYPE: Prospective. POPULATION: 40 healthy volunteers (50% male, 28.9 ± 5.0 years) and 10 patients with thoracic aortic aneurysm (80% male, 54 ± 8 years). FIELD STRENGTH/SEQUENCE: 4D flow MRI with a velocity encoded turbo field echo sequence at 3 T. ASSESSMENT: Phase-specific segmentations were obtained for the aortic root and the ascending aorta. The whole aorta was segmented in peak systole. In all aortic segments, time to peak (TTP; for flow velocity, vorticity, helicity, kinetic energy, and viscous energy loss) and peak and time-averaged values (for velocity and vorticity) were calculated. STATISTICAL TESTS: Static vs. phase-specific models were assessed using Bland-Altman plots. Other analyses were performed using phase-specific segmentations for aortic root and ascending aorta. TTP for all parameters was compared to TTP of flow rate using paired t-tests. Time-averaged and peak values were assessed using Pearson correlation coefficient. P < 0.05 was considered statistically significant. RESULTS: In the combined group, velocity in static vs. phase-specific segmentations differed by 0.8 cm/sec for the aortic root, and 0.1 cm/sec (P = 0.214) for the ascending aorta. Vorticity differed by 167 sec-1 mL-1 (P = 0.468) for the aortic root, and by 59 sec-1 mL-1 (P = 0.481) for the ascending aorta. Vorticity, helicity, and energy loss in the ascending aorta, aortic arch, and descending aorta peaked significantly later than flow rate. Time-averaged velocity and vorticity values correlated significantly in all segments. DATA CONCLUSION: Static 4D flow MRI segmentation yields comparable results as multiphase segmentation for flow-related parameters, eliminating the need for time-consuming multiple segmentations. However, multiphase quantification is necessary for assessing peak values of aortic flow-related parameters. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3.

Comprehensive sex-specific and age-dependent analysis of 4D-flow MRI assessed aortic blood flow-related parameters in normal subjects using single-vendor MR systems and single-vendor software.

BACKGROUND: Aortic blood flow characterization by 4D flow MRI is increasingly performed in aneurysm research. A limited number of studies have established normal values that can aid the recognition of abnormal flow at an early stage. This study aims to establish additional sex-specific and age-dependent reference values for flow-related parameters in a large cohort of healthy adults. METHODS: 212 volunteers were included, and 191 volunteers completed the full study protocol. All underwent 4D flow MRI of the entire aorta. Quantitative values for velocity, vorticity, helicity, as well as total, circumferential, and axial wall shear stress [WSS] were determined for the aortic root [AoR], ascending aorta [AAo], aortic arch [AoA], descending [DAo], suprarenal [SRA], and infrarenal aorta [IRA]. Vorticity and helicity were indexed for segment volume (mL). RESULTS: The normal values were estimated per sex- and age-group, where significant differences between males (M) and females (F) were found only for specific age groups. More specifically, the following variables were significantly different after applying the false discovery rate correction for multiple testing: 1) velocity in the AAo and DAo in the 60-70 years age group (mean±SD: (M) 47.0 ± 8.2cm/s vs. (F) 38.4 ± 6.9cm/s, p=0.001 and, (M) 55.9 ± 9.9cm/s vs. (F) 46.5 ± 5.5cm/s, p=0.002), 2) normalized vorticity in AoR in the 50-59 years age group ((M) 27539 ± 5042s-1mL-1 vs. (F) 30849 ± 7285s-1mL-1, p=0.002), 3) axial WSS in the Aao in the 18-29 age group ((M) 1098 ± 203 mPa vs. (F) 921 ± 121 mPa, p=0.002). Good to strong negative correlations with age were seen for almost all variables, in different segments, and for both sexes. CONCLUSION: This study describes reference values for aortic flow-related parameters as acquired by 4D flow MRI. We observed limited differences between males and females. A negative relationship with age was seen for almost all flow-related parameters and segments.

Electrokinetic properties of NaCl solution via molecular dynamics simulations with scaled-charge electrolytes.

Scaling ionic charges has become an alternative to polarizable force fields for representing indirect charge transfer effects in molecular simulations. In our work, we apply molecular dynamics simulations to investigate the properties of NaCl aqueous solutions in homogeneous and confined media. We compare classical integer- and scaled-charge force fields for the ions. In the bulk, we validate the force fields by computing equilibrium and transport properties and comparing them with experimental data. Integer-charge ions overestimate dielectric saturation and ionic association. Both force fields present an excess in ion-ion correlation, which leads to a deviation in the ionic conductivity at higher ionic strengths. Negatively charged quartz is used to simulate the confinement effect. Electrostatic interactions dominate counter-ion adsorption. Full-charge ions have stronger and more defined adsorption planes. We obtain the electroosmotic mobility of the solution by combining the shear plane location from non-equilibrium simulations with the ionic distribution from equilibrium simulations. From the Helmholtz-Smoluchowski equation, the zeta potential and the streaming potential coupling coefficient are computed. From an atomic-scale perspective, our molecular dynamics simulations corroborate the hypothesis of maximum packing of the Stern layer, which results in a stable and non-zero zeta potential at high salinity. The scaled-charge model representation of both properties is in excellent qualitative and quantitative agreement with experimental data. With our work, we demonstrate how useful and precise simple scaled-charge models for electrolytes can be to represent complex systems, such as the electrical double layer.

Validity of Cardiopulmonary Exercise Testing for Assessing Aerobic Capacity in Neuromuscular Diseases.

OBJECTIVES: To determine the content validity of cardiopulmonary exercise testing (CPET) for assessing peak oxygen uptake (VO2peak) in neuromuscular diseases (NMD). DESIGN: Baseline assessment of a randomized controlled trial. SETTING: Academic hospital. PARTICIPANTS: Eighty-six adults (age: 58.0±13.9 y) with Charcot-Marie-Tooth disease (n=35), postpolio syndrome (n=26), or other NMD (n=25). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: Workload, gas exchange variables, heart rate, and ratings of perceived exertion were measured during CPET on a cycle ergometer, supervised by an experienced trained assessor. Muscle strength of the knee extensors was assessed isometrically with a fixed dynamometer. Criteria for confirming maximal cardiorespiratory effort during CPET were established during 3 consensus meetings of an expert group. The percentage of participants meeting these criteria was assessed to quantify content validity. RESULTS: The following criteria were established for maximal cardiorespiratory effort: a plateau in oxygen uptake (VO2plateau) as the primary criterion, or 2 of 3 secondary criteria: (1) peak respiratory exchange ratio (RERpeak) ≥1.10 (2), peak heart rate ≥85% of predicted maximal heart rate; and (3) peak rating of perceived exertion (RPEpeak) ≥17 on the 6-20 Borg scale. These criteria were attained by 71 participants (83%). VO2plateau, RERpeak ≥1.10, peak heart rate ≥85%, and RPEpeak ≥17 were attained by 31%, 73%, 69%, and 72% of the participants, respectively. Peak workload, VO2peak, and knee extension muscle strength were significantly higher, and body mass index was lower (all P<.05), in participants with maximal cardiorespiratory effort than other participants. CONCLUSIONS: Most people with NMD achieved maximal cardiorespiratory effort during CPET. This study provides high quality evidence of sufficient content validity of VO2peak as a maximal aerobic capacity measure. Content validity may be lower in more severely affected people with lower physical fitness.

Generalised models of the vertebrate eye.

PURPOSE: To present a set of closed-form analytical equations to create a consistent eye model balance based on clinically measured input parameters in a single step. These models complement the existing iterative approaches in the literature. METHODS: Two different approaches are presented, both considering the cornea and lens as equivalent thin lenses. The first, called the Gaussian model, starts by defining the refractive error as the difference between the axial power (or dioptric distance) and the whole eye power, which can be expanded by filling in the formulas for each power. The resulting equation can be solved for either the refractive error, axial length, corneal power, lens power or the distance between the cornea and the lens as a function of the other four parameters. The second approach uses vergence calculations to provide alternative expressions, assuming that the refractive error is located at the corneal plane. Both models are explored for a biometric range typically found in adult human eyes. RESULTS: The Gaussian and vergence models each instantly balance the input data into a working eye model over the human physiological range and far beyond as demonstrated in various examples. The equations of the Gaussian model are more complicated, while the vergence model experiences more singularities, albeit in trivial or highly unlikely parameter combinations. CONCLUSIONS: The proposed equations form a flexible and robust platform to create eye models from clinical data. Possible applications lie in creating animal eye models or providing a generic reference for real biometric data and the relationships between the ocular dimensions.

Estimating the astigmatic power of the crystalline lens and eye from ocular biometry.

PURPOSE: To estimate the astigmatic power of the crystalline lens and the whole eye without phakometry using a set of linear equations and to provide estimates for the astigmatic powers of the crystalline lens surfaces. METHODS: Linear optics expresses astigmatic powers in the form of matrices and uses paraxial optics and a 4 × 4 ray transfer matrix to generalise Bennett's method comprehensively to include astigmatic elements. Once this is established, the method is expanded to estimate the contributions of the front and back lens surfaces. The method is illustrated using two examples. The first example is of an astigmatic model eye and compares the calculated results to the original powers. In the second example, the method is applied to the biometry of a real eye with large lenticular astigmatism. RESULTS: When the calculated powers for the astigmatic model eye were compared to the actual powers, the difference in the power of the eye was 0.03 0.13 0.04 T D $$ {\left(0.03\kern0.5em 0.13\kern0.5em 0.04\right)}^{\mathrm{T}}\ \mathrm{D} $$ (where T represents the matrix transpose) and for the crystalline lens, the difference was 0.08 0.29 0.08 T D $$ {\left(0.08\kern0.5em 0.29\kern0.5em 0.08\right)}^{\mathrm{T}}\ \mathrm{D} $$ (power vector format). A second example applies the method to a real eye, obtaining lenticular astigmatism of -5.84 × 175. CONCLUSIONS: The method provides an easy-to-code way of estimating the astigmatic powers of the crystalline lens and the eye.

The influence of variations in ocular biometric and optical parameters on differences in refractive error.

PURPOSE: To present a paraxial method to estimate the influence of variations in ocular biometry on changes in refractive error (S) at a population level and apply this method to literature data. METHODS: Error propagation was applied to two methods of eye modelling, referred to as the simple method and the matrix method. The simple method defines S as the difference between the axial power and the whole-eye power, while the matrix method uses more accurate ray transfer matrices. These methods were applied to literature data, containing the mean ocular biometry data from the SyntEyes model, as well as populations of premature infants with or without retinopathy, full-term infants, school children and healthy and diabetic adults. RESULTS: Applying these equations to 1000 SyntEyes showed that changes in axial length provided the most important contribution to the variations in refractive error (57%-64%), followed by lens power/gradient index power (16%-31%) and the anterior corneal radius of curvature (10%-13%). All other components of the eye contributed <4%. For young children, the largest contributions were made by variations in axial length, lens and corneal power for the simple method (67%, 23% and 8%, respectively) and by variations in axial length, gradient lens power and anterior corneal curvature for the matrix method (55%, 21% and 14%, respectively). During myopisation, the influence of variations in axial length increased from 54.5% to 73.4%, while changes in corneal power decreased from 9.82% to 6.32%. Similarly, for the other data sets, the largest contribution was related to axial length. CONCLUSIONS: This analysis confirms that the changes in ocular refraction were mostly associated with variations in axial length, lens and corneal power. The relative contributions of the latter two varied, depending on the particular population.

Allowable movement of wavefront-guided contact lens corrections in normal and keratoconic eyes.

PURPOSE: The goal was to use SyntEyes modelling to estimate the allowable alignment error of wavefront-guided rigid contact lens corrections for a range of normal and keratoconic eye aberration structures to keep objectively measured visual image quality at or above average levels of well-corrected normal eyes. Secondary purposes included determining the required radial order of correction, whether increased radial order of the corrections further constrained the allowable alignment error and how alignment constraints vary with keratoconus severity. METHODS: Building on previous work, 20 normal SyntEyes and 20 keratoconic SyntEyes were fitted with optimised wavefront-guided rigid contact lens corrections targeting between three and eight radial orders that drove visual image quality, as measured objectively by the visual Strehl ratio, to near 1 (best possible) over a 5-mm pupil for the aligned position. The resulting wavefront-guided contact lens was then allowed to translate up to ±1 mm in the x- and y-directions and rotate up ±15°. RESULTS: Allowable alignment error changed as a function of the magnitude of aberration structure to be corrected, which depends on keratoconus severity. This alignment error varied only slightly with the radial order of correction above the fourth radial order. To return the keratoconic SyntEyes to average levels of visual image quality depended on maximum anterior corneal curvature (Kmax). Acceptable tolerances for misalignment that returned keratoconic visual image quality to average normal levels varied between 0.29 and 0.63 mm for translation and approximately ±6.5° for rotation, depending on the magnitude of the aberration structure being corrected. CONCLUSIONS: Allowable alignment errors vary as a function of the aberration structure being corrected, the desired goal for visual image quality and as a function of keratoconus severity.

Retinal shadows produced by myopia control spectacles.

PURPOSE: To analyse ocular coherence tomography (OCT) images of the retinal shadows caused by defocus and diffusion optics spectacles. METHODS: One eye was fitted successively with the Hoya Defocus Incorporated Multiple Segments (DIMS) spectacle lens, two variations of the +3.50 D peripheral add spectacle (DEFOCUS) and the low-contrast dot lens (Diffusion Optics Multiple Segments, DOMS); each at a vertex distance of 12 mm. Simultaneously, a retinal image of the macular region with central fixation was obtained using infrared OCT. The corneal power and intraocular distances were determined using an optical biometer. RESULTS: The retinal images for the DIMS and DOMS lenses showed patterns of obvious retinal shadows in the periphery, while the central 10-11° remained clear. The DEFOCUS lens produced a darkened peripheral area. Dividing the size of the retinal pattern, measured with the calliper of the OCT software, by the actual size on the spectacle lens gave a magnification of -0.57 times. This is consistent with the incoming OCT beam being imaged to a position approximately 31 mm beyond the front of the eye. [Correction added on 26 October 2023 after first online publication: The preceding paragraph was corrected.] CONCLUSION: With device-specific correction, retinal OCT images can help visualise the regions affected by the defocus or lowered contrast induced by myopia control spectacles. This is of potential value for improving myopia therapies.

Definitions for Keratoconus Progression and Their Impact on Clinical Practice.

PURPOSE: There is currently no consensus on which keratoconus need cross-linking nor on how to establish progression. This study assessed the performance of diverse progression criteria and compared them with our clinical knowledge of keratoconus evolution. METHODS: This was a retrospective, longitudinal, observational study. Habitual progression criteria, based on (combinations of) keratometry (K MAX ), front astigmatism (A F ), pachymetry (P MIN ), or ABCD progression display, from 906 keratoconus patients were analyzed. For each criterion and cutoff, we calculated %eyes flagged progressive at some point (R PROG ), individual consistency C IND (%examinations after progression detection still considered progressive), and population consistency C POP (% eyes with CIND >66%). Finally, other monotonic and consistent variables, such as front steep keratometry (K 2F ), mean radius of the back surface (R mB ), and the like, were evaluated for the overall sample and subgroups. RESULTS: Using a single criterion (e.g., ∆K MAX >1D) led to high values of R PROG . When combining two, (K MAX and A F ) led to worse C POP and higher variability than (K MAX and P MIN ); alternative criteria such as (K 2F and R mB ) obtained the best C POP and the lowest variability ( P <0.0001). ABC, as defined by its authors, obtained R PROG of 74.2%. Using wider 95% confidence intervals (95% CIs) and requiring two parameters over 95CI reduced R PROG to 27.9%. CONCLUSION: Previous clinical studies suggest that 20% to 30% of keratoconus cases are progressive. This clinical R PROG value should be considered when defining KC progression to avoid overtreatment. Using combinations of variables or wider margins for ABC brings R PROG closer to these clinical observations while obtaining better population consistency than current definitions.

Bi-exponential description for different forms of refractive development.

It was recently established that the axial power, the refractive power required by the eye for a sharp retinal image in an eye of a certain axial length, and the total refractive power of the eye may both be described by a bi-exponential function as a function of age (Rozema, 2023). Inspired by this result, this work explores whether these bi-exponential functions are able to simulate the various known courses of refractive development described in the literature, such as instant emmetropization, persistent hypermetropia, developing hypermetropia, myopia, instant homeostasis, modulated development, or emmetropizing hypermetropes. Moreover, the equations can be adjusted to match the refractive development of school-age myopia and pseudophakia up to the age of 20 years. All of these courses closely resemble those reported in the previous literature while simultaneously providing estimates for the underlying changes in axial and whole eye power.

Developing a model describing voluntary residency attrition: a qualitative study.

BACKGROUND: Many factors influencing residency attrition are identified in the literature, but what role these factors play and how they influence each other remains unclear. Understanding more about the interaction between these factors can provide background to put the available evidence into perspective and provide tools to reduce attrition. The aim of this study was therefore to develop a model that describes voluntary residency attrition. METHODS: Semi-structured interviews were held with a convenient sample of orthopaedic surgery residents in the Netherlands who dropped out of training between 2000 and 2018. Transcripts were analysed using a constructivist grounded theory approach. Concepts and themes were identified by iterative constant comparison. RESULTS: Seventeen interviews with former residents were analysed and showed that reasons for voluntary attrition were different for each individual and often a result of a cumulative effect. Individual expectations and needs determine residents' experiences with the content of the profession, the professional culture and the learning climate. Personal factors like previous clinical experiences, personal circumstances and personal characteristics influence expectations and needs. Specific aspects of the residency programme contributing to attrition were type of patient care, required skills for the profession, work-life balance and interpersonal interaction. CONCLUSIONS: This study provides a model for voluntary resident attrition showing the factors involved and how they interact. This model places previous research into perspective, gives implications for practice on the (im)possibilities of preventing attrition and opens possibilities for further research into resident attrition.

Particle Tracing Based on 4D Flow Magnetic Resonance Imaging: A Systematic Review into Methods, Applications, and Current Developments.

BACKGROUND: Particle tracing based on 4D Flow MRI has been applied as a quantitative and qualitative postprocessing technique to study temporally evolving blood flow patterns. PURPOSE: To systematically review the various methods to perform 4D Flow MRI-based particle tracing, as well as the clinical value, clinical applications, and current developments of the technique. STUDY TYPE: The study type is systematic review. SUBJECTS: Patients with cardiovascular disease (such as Marfan, Fontan, Tetralogy of Fallot), healthy controls, and cardiovascular phantoms that received 4D Flow MRI with particle tracing. FIELD STRENGTH/SEQUENCE: Three-dimensional three-directional cine phase-contrast MRI, at 1.5 T and 3 T. ASSESSMENT: Two systematic searches were performed on the PubMed database using Boolean operators and the relevant key terms covering 4D Flow MRI and particle tracing. One systematic search was focused on particle tracing methods, whereas the other on applications. Additional articles from other sources were sought out and included after a similar inspection. Particle tracing methods, clinical applications, clinical value, and current developments were extracted. STATISTICAL TESTS: The main results of the included studies are summarized, without additional statistical analysis. RESULTS: Of 127 unique articles retrieved from the initial search, 56 were included (28 for methods and 54 for applications). Most articles that described particle tracing methods used an adaptive timestep, a fourth order Runge-Kutta integration method, and linear interpolation in the time dimension. Particle tracing was applied in heart chambers, aorta, venae cavae, Fontan circulation, pulmonary arteries, abdominal vasculature, peripheral arteries, carotid arteries, and cerebral vasculature. Applications were grouped as intravascular, intracardiac, flow stasis, and research. DATA CONCLUSIONS: Particle tracing based on 4D Flow MRI gives unique insight into blood flow in several cardiovascular diseases, but the quality depends heavily on the MRI data quality. Further studies are required to evaluate the clinical value of the technique for different cardiovascular diseases. EVIDENCE LEVEL: 5. TECHNICAL EFFICACY: Stage 1.

Age- and sex-specific reference values of biventricular flow components and kinetic energy by 4D flow cardiovascular magnetic resonance in healthy subjects.

BACKGROUND: Advances in four-dimensional flow cardiovascular magnetic resonance (4D flow CMR) have allowed quantification of left ventricular (LV) and right ventricular (RV) blood flow. We aimed to (1) investigate age and sex differences of 4D flow CMR-derived LV and RV relative flow components and kinetic energy (KE) parameters indexed to end-diastolic volume (KEiEDV) in healthy subjects; and (2) assess the effects of age and sex on these parameters. METHODS: We performed 4D flow analysis in 163 healthy participants (42% female; mean age 43 ± 13 years) of a prospective registry study (NCT03217240) who were free of cardiovascular diseases. Relative flow components (direct flow, retained inflow, delayed ejection flow, residual volume) and multiple phasic KEiEDV (global, peak systolic, average systolic, average diastolic, peak E-wave, peak A-wave) for both LV and RV were analysed. RESULTS: Compared with men, women had lower median LV and RV residual volume, and LV peak and average systolic KEiEDV, and higher median values of RV direct flow, RV global KEiEDV, RV average diastolic KEiEDV, and RV peak E-wave KEiEDV. ANOVA analysis found there were no differences in flow components, peak and average systolic, average diastolic and global KEiEDV for both LV and RV across age groups. Peak A-wave KEiEDV increased significantly (r = 0.458 for LV and 0.341 for RV), whereas peak E-wave KEiEDV (r = - 0.355 for LV and - 0.318 for RV), and KEiEDV E/A ratio (r = - 0.475 for LV and - 0.504 for RV) decreased significantly, with age. CONCLUSION: These data using state-of-the-art 4D flow CMR show that biventricular flow components and kinetic energy parameters vary significantly by age and sex. Age and sex trends should be considered in the interpretation of quantitative measures of biventricular flow. Clinical trial registration  https://www. CLINICALTRIALS: gov . Unique identifier: NCT03217240.

"What matters to you?": The relevance of patient priorities in dialysis care for assessment and clinical practice.

BACKGROUND: Dialysis patients are confronted with numerous, complex problems, which make it difficult to identify individual patient's most prominent problems. The objectives of this study were to (1) identify dialysis patients' most prominent problems from a patient perspective and (2) to calculate disease-specific norms for questionnaires measuring these problems. METHODS: One hundred seventy-five patients treated with hemodialysis or peritoneal dialysis completed a priority list on several domains of functioning (e.g., physical health, mental health, social functioning, and daily activities) and a set of matching questionnaires assessing patient functioning on these domains. Patient priorities were assessed by calculating the importance ranking of each domain on the priority list. Subsequently, disease-specific norm scores were calculated for all questionnaires, both for the overall sample and stratified by patient characteristics. RESULTS: Fatigue was listed as patients' most prominent problem. Priorities differed between male and female patients, younger and older patients, and home and center dialysis patients, which was also reflected in their scores on the corresponding domains of functioning. Therefore, next to general norm scores, we calculated corrections to the general norms to take account of patient characteristics (i.e., sex, age, and dialysis type). CONCLUSIONS: Results highlight the importance of having attention for the specific priorities and needs of each individual patient. Adequate disease-specific, norm-based assessment is not only necessary for diagnostic procedures but is an essential element of patient-centered care: It will help to better understand and respect individual patient needs and tailor treatment accordingly.

Effects of the egg protein hydrolysate NWT-03 on cognitive function in men and women with the metabolic syndrome: a randomized, double-blind, placebo-controlled study.

Objectives: The metabolic syndrome is associated with cardiovascular diseases and cognitive decline. The egg protein hydrolysate NWT-03 has shown to improve cardiovascular risk factors in humans. This study investigated whether NWT-03 also has an effect on cognitive function.Methods: Men and women with the metabolic syndrome (n = 76) with a mean age of 60 ± 10 years participated in this randomized, double-blind, placebo-controlled, cross-over trial with an intervention (5 g/day NWT-03) and control period (5 g/day maltodextrin) of 4 weeks separated by a wash-out period of 2-8 weeks. Cognitive function was assessed with the anti-cue reaction time test (impulse control) and psychomotor vigilance test (sustained attention) at day 0, 2, and 27 of both periods. Serum brain-derived neurotrophic factor (BDNF) concentrations were measured at the start and end of both periods.Results: NWT-03 consumption significantly improved the change (day 27 - day 0) in response times of the anti-cue reaction time test compared with the control period (P < 0.001), but not of the psychomotor vigilance test (P = 0.487). Serum BDNF concentrations of all subjects did not significantly change (P = 0.241).Conclusion: NWT-03 has the ability to improve cognitive function within the executive function domain. The underlying mechanism warrants further research and could either be indirect via inhibition of dipeptidyl peptidase 4 (DPP4) or direct via passage of small peptides over the blood-brain barrier inducing local effects.Trial registration: ClinicalTrials.gov identifier: NCT02561663.

Cardiorespiratory Fitness in Individuals Post-stroke: Reference Values and Determinants.

OBJECTIVE: To provide reference values of cardiorespiratory fitness for individuals post-stroke in clinical rehabilitation and to gain insight in characteristics related to cardiorespiratory fitness post stroke. DESIGN: A retrospective cohort study. Reference equations of cardiopulmonary fitness corrected for age and sex for the fifth, 25th, 50th, 75th, and 95th percentile were constructed with quantile regression analysis. The relation between patient characteristics and cardiorespiratory fitness was determined by linear regression analyses adjusted for sex and age. Multivariate regression models of cardiorespiratory fitness were constructed. SETTING: Clinical rehabilitation center. PARTICIPANTS: Individuals post-stroke who performed a cardiopulmonary exercise test as part of clinical rehabilitation between July 2015 and May 2021 (N=405). MAIN OUTCOME MEASURES: Cardiorespiratory fitness in terms of peak oxygen uptake (V˙O2peak) and oxygen uptake at ventilatory threshold (V˙O2-VT). RESULTS: References equations for cardiorespiratory fitness stratified by sex and age were provided based on 405 individuals post-stroke. Median V˙O2peak was 17.8[range 8.4-39.6] mL/kg/min and median V˙O2-VT was 9.7[range 5.9-26.6] mL/kg/min. Cardiorespiratory fitness was lower in individuals who were older, women, using beta-blocker medication, and in individuals with a higher body mass index and lower motor ability. CONCLUSIONS: Population specific reference values of cardiorespiratory fitness for individuals post-stroke corrected for age and sex were presented. These can give individuals post-stroke and health care providers insight in their cardiorespiratory fitness compared with their peers. Furthermore, they can be used to determine the potential necessity for cardiorespiratory fitness training as part of the rehabilitation program for an individual post-stroke to enhance their fitness, functioning and health. Especially, individuals post-stroke with more mobility limitations and beta-blocker use are at a higher risk of low cardiorespiratory fitness.