Intraindividual Reproducibility Research Articles

Intra-individual radiomic analysis of pericoronary adipose tissue: Photon-counting detector vs energy-integrating detector CT angiography.

The impact of novel photon-counting detector (PCD)-CT technology on in-vivo radiomics is not fully understood. This study aimed to compare the intra-individual stability and reproducibility of pericoronary adipose tissue (PCAT) radiomic features between PCD-CT and energy-integrating detector (EID)-CT in patients undergoing coronary CT angiography (CCTA) on both systems. Patients undergoing clinically indicated CCTA on an EID-CT were prospectively enrolled for research PCD-CCTA within 30 days. Image acquisition parameters were standardized; PCD-CT datasets were reconstructed both down-sampled to 0.6 mm to match the clinical scan (PCD-CTDS) and at 0.2 mm ultrahigh-resolution mode (PCD-CTUHR). Automatic PCAT segmentation was performed; a total of 110 radiomic feature classes were extracted and compared across the three datasets (EID-CT, PCD-CTDS, and PCD-CDUHR). Feature stability was assessed using paired t-test filtered for false discoveries using Benjamini-Hochberg method, and reproducibility using intraclass correlation coefficient (ICC). A total of 42 patients (34 male [81.0 %]; 67.9 ± 7.6 years) were included. Feature stability was 91 % for EID-CT vs. PCD-CTDS, but decreased for UHR datasets (EID-CT vs. PCD-CTUHR: 55 %; PCD-CTDS vs. PCD-CTUHR: 51 %). However, inter-scanner reproducibility was poor in both comparisons (EID-CT vs. PCD-CTDS median ICC: 0.43 [0.03-0.69]; EID-CT vs. PCD-CTUHR: 0.29 [0.01-0.51]). Nevertheless, reproducibility improved within PCD-CT datasets (PCD-CTDS vs. PCD-CTUHR: 0.72 [0.48-0.83]), regardless of the difference in slice thickness. Most PCAT radiomic features remained stable between EID-CT and PCD-CTDS, although inter-scanner reproducibility was poor, emphasizing the significant impact of detector technology. Conversely, reproducibility of features within PCD-CT datasets showed more consistent results, even when comparing standard to UHR.

Intra-Individual Reproducibility of Automated Abdominal Organ Segmentation-Performance of TotalSegmentator Compared to Human Readers and an Independent nnU-Net Model.

The purpose of this study is to assess segmentation reproducibility of artificial intelligence-based algorithm, TotalSegmentator, across 34 anatomical structures using multiphasic abdominal CT scans comparing unenhanced, arterial, and portal venous phases in the same patients. A total of 1252 multiphasic abdominal CT scans acquired at our institution between January 1, 2012, and December 31, 2022, were retrospectively included. TotalSegmentator was used to derive volumetric measurements of 34 abdominal organs and structures from the total of 3756 CT series. Reproducibility was evaluated across three contrast phases per CT and compared to two human readers and an independent nnU-Net trained on the BTCV dataset. Relative deviation in segmented volumes and absolute volume deviations (AVD) were reported. Volume deviation within 5% was considered reproducible. Thus, non-inferiority testing was conducted using a 5% margin. Twenty-nine out of 34 structures had volume deviations within 5% and were considered reproducible. Volume deviations for the adrenal glands, gallbladder, spleen, and duodenum were above 5%. Highest reproducibility was observed for bones (- 0.58% [95% CI: - 0.58, - 0.57]) and muscles (- 0.33% [- 0.35, - 0.32]). Among abdominal organs, volume deviation was 1.67% (1.60, 1.74). TotalSegmentator outperformed the reproducibility of the nnU-Net trained on the BTCV dataset with an AVD of 6.50% (6.41, 6.59) vs. 10.03% (9.86, 10.20; p < 0.0001), most notably in cases with pathologic findings. Similarly, TotalSegmentator's AVD between different contrast phases was superior compared to the interreader AVD for the same contrast phase (p = 0.036). TotalSegmentator demonstrated high intra-individual reproducibility for most abdominal structures in multiphasic abdominal CT scans. Although reproducibility was lower in pathologic cases, it outperforms both human readers and a nnU-Net trained on the BTCV dataset.

Intraindividual reproducibility of myocardial radiomic features between energy-integrating detector and photon-counting detector CT angiography

BackgroundRadiomics is not yet used in clinical practice due to concerns regarding its susceptibility to technical factors. We aimed to assess the stability and interscan and interreader reproducibility of myocardial radiomic features between energy-integrating detector computed tomography (EID-CT) and photon-counting detector CT (PCD-CT) in patients undergoing coronary CT angiography (CCTA) on both systems.MethodsConsecutive patients undergoing clinically indicated CCTA on an EID-CT were prospectively enrolled for a PCD-CT CCTA within 30 days. Virtual monoenergetic images (VMI) at various keV levels and polychromatic images (T3D) were generated for PCD-CT, with image reconstruction parameters standardized between scans. Two readers performed myocardial segmentation and 110 radiomic features were compared intraindividually between EID-CT and PDC-CT series. The agreement of parameters was assessed using the intraclass correlation coefficient and paired t-test for the stability of the parameters.ResultsEighteen patients (15 males) aged 67.6 ± 9.7 years (mean ± standard deviation) were included. Besides polychromatic PCD-CT reconstructions, 60- and 70-keV VMIs showed the highest feature stability compared to EID-CT (96%, 90%, and 92%, respectively). The interscan reproducibility of features was moderate even in the most favorable comparisons (median ICC 0.50 [interquartile range 0.20–0.60] for T3D; 0.56 [0.33–0.74] for 60 keV; 0.50 [0.36–0.62] for 70 keV). Interreader reproducibility was excellent for the PCD-CT series and good for EID-CT segmentations.ConclusionMost myocardial radiomic features remain stable between EID-CT and PCD-CT. While features demonstrated moderate reproducibility between scanners, technological advances associated with PCD-CT may lead to greater reproducibility, potentially expediting future standardization efforts.Relevance statementWhile the use of PCD-CT may facilitate reduced interreader variability in radiomics analysis, the observed interscanner variations in comparison to EID-CT should be taken into account in future research, with efforts being made to minimize their impact in future radiomics studies.Key PointsMost myocardial radiomic features resulted in being stable between EID-CT and PCD-CT on certain VMIs.The reproducibility of parameters between detector technologies was limited.PCD-CT improved interreader reproducibility of myocardial radiomic features.Graphical

Short- and long-term reproducibility of body surface gastric mapping using the Gastric Alimetry® system.

Many diagnostic tests for gastroduodenal symptoms, such as gastric emptying scintigraphy (GES), gastric emptying breath tests (GEBT), and electrogastrography (EGG) show variable intra-individual reproducibility over time. This study investigated the short- and long-term reproducibility of body surface gastric mapping (BSGM), a non-invasive test for assessing gastric function, in controls and patients with chronic gastroduodenal disorders. Participants completed three standardized BSGM tests using Gastric Alimetry® (Alimetry, New Zealand). The test encompassed a fasting baseline (30 min), a 482 kCal standard meal, and a 4 h postprandial recording. The first two tests were >6 months apart and the last occurred ~1 week after the second test, to evaluate long and short-term reproducibility. Fourteen patients with upper gastrointestinal symptoms and 14 healthy controls were recruited. There were no significant differences in any BSGM metrics between the tests at short and long term (all p > 0.180). Lin's concordance correlation coefficients (CCC) for the primary metrics were high, ranging from 0.58 to 0.96, with intra-individual coefficients of variance (CVintra) ranging from 0.2% to 1.9%. Reproducibility was higher, and intra-individual variation lower, than in previous studies of GES (CCC = 0.54-0.83, CVintra = 3%-77%), GEBT (CVintra = 8%-11%), and EGG (CVintra = 3%-78%). BSGM spectral metrics demonstrate high reproducibility and low intra-individual variation at both short and long term, with superior results to comparable tests. The high reproducibility of Gastric Alimetry supports its role as a diagnostic aid for gastric dysfunction and a reliable tool for evaluating treatment outcomes and disease progression over time.

Quantifying Exhaled Particles in Healthy Humans During Various Respiratory Activities Under Realistic Conditions.

Background: Quantitatively collecting and characterizing exhaled aerosols is vital for infection risk assessment, but the entire droplet size spectrum has often been neglected. We analyzed particle number and size distribution of healthy participants in various respiratory activities, considering inter-individual variability, and deployed a simplified far-field model to inform on infection risks. Methods: Participants repeated the same respiratory activities on two visits. Particles were collected using an airtight extraction helmet supplied with High Efficiency Particulate Air (HEPA) filtered air. The sampling volume flow was transported to two particle counters covering the small and large particle spectrum. The applied simple mass balance model included respiratory activity, viral load, room size, and air exchange rates. Results: Thirty participants completed the study. The major fraction of the number-based size distribution was <5 μm in all respiratory activities. In contrast, the major fraction of the volume-based size distribution was 2-12 μm in tidal breathing, but >60 μm in all other activities. Aerosol volume flow was lowest in tidal breathing, 10-fold higher in quiet/normal speaking, deep breathing, coughing, and 100-fold higher in loud speaking/singing. Intra-individual reproducibility was high. Between participants, aerosol volume flow varied by two orders of magnitude in droplets <80 μm, and three orders of magnitude in droplets >80 μm. Simple model calculations not accounting for potential particle size-dependent differences in viral load and infection-related differences were used to model airborne pathogen concentrations. Conclusions: Quantitative analysis of exhaled aerosols for the entire droplet size spectrum as well as the variability in aerosol emission between individuals provides information that can support infection research. Clinical Trial Registration number: NCT04771585.

Reproducibility of non-contrast enhanced multi breath-hold ultrashort echo time functional lung MRI

PurposeTo evaluate the intraindividual reproducibility of functional lung imaging using non-contrast enhanced multi breath-hold 3D-UTE MRI. MethodsTen healthy volunteers underwent non-contrast enhanced 3D-UTE MRI at three time points for same-day and different-day measurements employing a stack-of-spirals trajectory at 3 T. At each time point, inspiratory and expiratory breathing states were acquired for tidal and deep breathing, each within a single breath-hold. For functional image analysis, fractional ventilation (FV) was calculated pixelwise after image registration from the MR signal change. To decouple FV from breathing depth, the individual lung volume was used for volume adjustment (rFV). Reproducibility evaluation was performed in eight lung segments. Statistical analyses included two way mixed intraclass correlation (ICC), sign-test, Friedman-test and modified Bland-Altman analyses. ResultsFV from tidal breathing showed an ICC of 0.81, a bias of 1.3% and an interval of confidence (CI) ranging from −67.1 to 69.6%. FV from deep breathing was higher reproducible with an ICC of 0.92 (bias, −0.2%; CI, −34.2 to 33.7%). Following volume adjustment, reproducibility of rFV for tidal breathing improved (ICC, 0,86; bias, 2.0%; CI, −34.3 to 38.3%), whereas it did not bear significant benefits for deep breathing (ICC, 0.89; bias, 2.8%; CI, −24.9 to 30.5%). Reproducibility was independent from the examination day. ConclusionNon-contrast-enhanced multi breath-hold 3D-UTE MRI allows for highly reproducible ventilation imaging.

A Reproducible Bioimpedance Transducer for Insulin Noninvasive Measurement

A bioimpedance transducer is proposed for non-invasive monitoring of insulin bioavailability after subcutaneous injection. The insulin bioavailability is assessed indirectly by measuring the local impedance variation due to the drug disappearance from the injection volume. The instrument allows to manage the extreme variability in insulin response by diabetic patients due to skin conditions and/or alterations such as lipodystrophy. In this way, the transducer can also be considered as a key component for new generation of artificial pancreas. The instrument achieves state of art accuracy and uncertainty. Intra-individual reproducibility also resulted improved with respect to previous studies. Moreover, the feasibility of an absorption measurement is proved. After presenting the concept design and the prototype, the metrological characterization during (i) laboratory (on passive electrical components), (ii) in-vitro (on eggplants), and (iii) in-vivo (on an human subject) experiments is reported. In laboratory tests, typical percentage deterministic errors of 1 % on magnitude and phase were obtained. The mean 1-σ repeatability of 0.05 % was obtained for both impedance magnitude and phase. The in-vitro tests were aimed to improve the reproducibility by comparing the electrical behavior of insulin and vehicle in eggplants. During the in-vivo tests, a decrease in percentage 1-σ intra-individual reproducibility was reported with respect to the state of art (from more than 200 % to 36 %), as the impedance magnitude is concerned. In a clinical application framework, an accuracy of 9 μl was obtained by means of a second-order polynomial model. The uncertainty resulted 4.2 μl, well below the typical volume of one insulin unit (10.0 μl).

ADDING OBJECTIVITY TO SUBMAXIMAL EXERCISE TESTING BY ASSESSMENT OF HEART RATE RECOVERY – A HEALTHY VOLUNTEER STUDY III (SEARCH-III)

<h3>Objective</h3> Risk prediction is a fundamental component of perioperative medicine. Submaximal exercise tests (SET) are a better-tolerated modality for functional capacity estimation versus maximal tests; but their results are easily influenced by patient motivation and effort. Heart rate recovery (HRR) may be an alternative, objective, modality for cardiopulmonary fitness determination. HRR1 and HRR2 (difference between HR at peak exercise and one/two minutes after exercise cessation) are validated methods for quantifying HRR after maximal testing. Previous work suggests however that HRR1/2 after submaximal exercise may be effort dependent.[1,2] Our group has devised two novel HRR quantification parameters, area under the curve (AUC) and effort correction, both demonstrating good reproducibility in the submaximal setting;[3,4] however, the minimum effort required for reliable HRR quantification during SET remains unknown. We therefore assessed the reproducibility of both existing and novel HRR quantification techniques across different submaximal effort levels. <h3>Design and methods</h3> Following R&D approval and with informed consent, 36 healthy adult volunteers underwent two SETs using a modified Astrand-Rhyming cycle ergometer protocol in a randomised order. Participants exercised briefly to 60% of predicted maximum heart rate (HRmax) and 70% HRmax, with one hour rest between SETs. HR was recorded at 30-second intervals during the recovery period for six minutes. HRR was quantified using HRR1, HRR2, and AUC. Effort-corrected (EC) equivalents of HRR1, HRR2 and AUC were computed by dividing absolute parameters by the effort ratio (HR on exercise cessation divided by HRmax). Intra-individual reproducibility was assessed between SETs using intraclass correlation coefficient (ICC), Spearman's correlation (rs) and Bland-Altman analysis. <h3>Results</h3> Effort-corrected HRR1 proved the best parameter displaying moderate reproducibility (ICC=0.58, 95%CI 0.32-0.76), moderate positive correlation (rs=0.64, p<0.001) and smallest bias (5.2bpm, LoA=-27.0-37.3) between SETs (fig. 1). Similarly, AUC reproducibility improved from poor (ICC=0.46) to moderate (ICC=0.56) after effort-correction. ICC remained poor in HRR2 after effort correction (HRR2 ICC=0.32 vs. EC-HRR2 ICC=0.44). Despite improvement in all parameters following effort correction, reproducibility and correlation were poor-moderate and Bland-Altman analysis demonstrated marked variability of differences across mean values with wide limits of agreement. <h3>Conclusion</h3> Unsatisfactory reproducibility was demonstrated across all HRR parameters at 60% HRmax versus the previously used target of 70% HRmax. Sensitivity analyses revealed a proportion of participants with elevated baseline HR such that minimal effort was required to reach the less demanding 60% HRmax target, producing no HRR as a result. Excluding these "non-responders" improved reproducibility of parameters between SETs. Using "personalised" HR targets based on each participant's resting HR may therefore better standardise effort exerted during testing. Further work should explore the applicability of submaximal HRR in the surgical population.

PSMA-1007 Uptake in Ganglia of the Sympathetic Trunk and Its Intra-individual Reproducibility

Aim/Purpose18F-labeled PSMA ligands offer various advantages as PET tracers over 68Ga-labeled PSMA counterparts. Especially, an improved spatial resolution leads to improved detection rates of smaller prostate cancer (PCa) lesions. However, physiological PSMA uptake of ganglia of the sympathetic trunk can be quickly misinterpreted as possible PSMA-positive lymph node metastases. The aim of this retrospective study is to investigate [18F]PSMA-1007 uptake and its intra-individual reproducibility in ganglia of the sympathetic trunk.MethodsWe retrospectively included 28 consecutive patients (median age 69 ± 9 with a range of 49–90) with biochemical recurrence of PCa who underwent [18F]PSMA-1007 PET/CT scan and, accordingly, a follow-up examination between August 2018 and August 2021. Cervical, coeliac, and sacral ganglia were identified on the iterative PET reconstructions and correlated with CT component. Tracer uptake of ganglia was determined by measuring SUVmax and SUVmean values. Anatomical position of the ganglia in relation to adjacent vertebral bodies were noted. Statistical analyses were conducted using two-way repeated measures ANOVA and descriptive statistics.ResultsThe highest [18F]PSMA-1007 uptake was found in coeliac ganglia followed by cervical and sacral ganglia. The SUVmax in coeliac ganglia was 3.13 ± 0.85 (follow-up scan 3.11 ± 0.93), in cervical ganglia 2.73 ± 0.69 (follow-up scan 2.67 ± 0.74), and in sacral ganglia 1.67 ± 0.50 (follow-up scan 1.64 ± 0.52). The SUVmean in coeliac ganglia was 2.28 ± 0.64 (follow-up scan 2.28 ± 0.66), in cervical ganglia 1.62 ± 0.43 (follow-up scan 1.61 ± 0.43) and in sacral ganglia 1.15 ± 0.33 (follow-up scan 1.12 ± 0.34). In a given ganglion station, there was no statistically significant difference of SUVmax or SUVmean values between baseline and follow-up scans.ConclusionsThe first systematically described physiological [18F]PSMA-1007 uptake in ganglia of the sympathetic trunk showed a low variability of SUVmax or SUVmean and a good intra-individual reproducibility of [18F]PSMA-1007 uptake in follow-up scans. These findings might improve and guide the differentiation of ganglia from possible malignant lesions.

Inflammatory Tumor Microenvironment in Cranial Meningiomas: Clinical Implications and Intraindividual Reproducibility.

The MIB-1 index was demonstrated to be significantly correlated to meningioma recurrence. However, to date, the relationship of the intraindividual course of the MIB-1 index and the growth fraction, respectively, to clinical tumor recurrence has not been demonstrated in cranial WHO grade 1 and 2 meningiomas. In the present paper, we compare the MIB-1 indices of 16 solely surgically treated primary meningiomas and their recurrent tumors regarding the course of the MIB-1 indices, time to recurrence, reproducibility and factors influencing the intraindividual MIB-1 indices. Regression analyses revealed (1) a strong intra-lab reproducibility (r = 0.88) of the MIB-1 index at the second versus the first operation, corresponding to a constant intrinsic growth activity of an individual meningioma, (2) a significant inverse correlation of both primary (r = −0.51) and secondary (r = −0.70) MIB-1 indices to time to recurrence, and (3) male sex, low plasma fibrinogen and diffuse CD68+ macrophage infiltrates contribute to an increase in the MIB-1 index. A strong intraindividual reproducibility of the MIB-1 index and a direct relationship of the MIB-1 index to the time to recurrence were observed. Individual MIB-1 indices might be used for tailored follow-up imaging intervals. Further research on the role of macrophages and inflammatory burden in the regrowth potential of meningiomas are needed.

Assessment of Smartphone-Based Spiral Tracing in Multiple Sclerosis Reveals Intra-Individual Reproducibility as a Major Determinant of the Clinical Utility of the Digital Test.

Technological advances, lack of medical professionals, high cost of face-to-face encounters, and disasters such as the COVID-19 pandemic fuel the telemedicine revolution. Numerous smartphone apps have been developed to measure neurological functions. However, their psychometric properties are seldom determined. It is unclear which designs underlie the eventual clinical utility of the smartphone tests. We have developed the smartphone Neurological Function Tests Suite (NeuFun-TS) and are systematically evaluating their psychometric properties against the gold standard of complete neurological examination digitalized into the NeurExTM app. This article examines the fifth and the most complex NeuFun-TS test, the “Spiral tracing.” We generated 40 features in the training cohort (22 healthy donors [HD] and 89 patients with multiple sclerosis [MS]) and compared their intraclass correlation coefficient, fold change between HD and MS, and correlations with relevant clinical and imaging outcomes. We assembled the best features into machine-learning models and examined their performance in the independent validation cohort (45 patients with MS). We show that by involving multiple neurological functions, complex tests such as spiral tracing are susceptible to intra-individual variations, decreasing their reproducibility and clinical utility. Simple tests, reproducibly measuring single function(s) that can be aggregated to increase sensitivity, are preferable in app design.

Intraindividual Long-term Immune Marker Stability in Plasma Samples Collected in Median 9.4 Years Apart in 304 Adult Cancer-free Individuals.

Changes in immune marker levels in the blood could be used to improve the early detection of tumor-associated inflammatory processes. To increase predictiveness and utility in cancer detection, intraindividual long-term stability in cancer-free individuals is critical for biomarker candidates as to facilitate the detection of deviation from the norm. We assessed intraindividual long-term stability for 19 immune markers (IL10, IL13, TNFα, CXCL13, MCP-3, MIP-1α, MIP-1β, fractalkine, VEGF, FGF-2, TGFα, sIL2Rα, sIL6R, sVEGF-R2, sTNF-R1, sTNF-R2, sCD23, sCD27, and sCD30) in 304 cancer-free individuals. Repeated blood samples were collected up to 20 years apart. Intraindividual reproducibility was assessed by calculating intraclass correlation coefficients (ICC) using a linear mixed model. ICCs indicated fair to good reproducibility (ICCs ≥ 0.40 and < 0.75) for 17 of 19 investigated immune markers, including IL10, IL13, TNFα, CXCL13, MCP-3, MIP-1α, MIP-1β, fractalkine, VEGF, FGF-2, TGFα, sIL2Rα, sIL6R, sTNF-R1, sTNF-R2, sCD27, and sCD30. Reproducibility was strong (ICC ≥ 0.75) for sCD23, while reproducibility was poor (ICC < 0.40) for sVEGF-R2. Using a more stringent criterion for reproducibility (ICC ≥ 0.55), we observed either acceptable or better reproducibility for IL10, IL13, CXCL13, MCP-3, MIP-1α, MIP-1β, VEGF, FGF-2, sTNF-R1, sCD23, sCD27, and sCD30. IL10, IL13, CXCL13, MCP-3, MIP-1α, MIP-1β, VEGF, FGF-2, sTNF-R1, sCD23, sCD27, and sCD30 displayed ICCs consistent with intraindividual long-term stability in cancer-free individuals. Our data support using these markers in prospective longitudinal studies seeking early cancer detection biomarkers.

Enhanced Access to the Health-Related Skin Metabolome by Fast, Reproducible and Non-Invasive WET PREP Sampling.

Our skin influences our physical and mental health, and its chemical composition can reflect environmental and disease conditions. Therefore, through sampling the skin metabolome, we can provide a promising window into the mechanisms of the body. However, the broad application of skin metabolomics has recently been hampered by a lack of easy and widely applicable sampling methods. Here, we present a novel rapid, simple, and, most importantly, painless and non-invasive sampling technique suitable for clinical studies of fragile or weakened skin. The method is called WET PREP and is simply a lavage of the skin which focuses on capturing the metabolome. We systematically evaluate WET PREPs in comparison with the non-invasive method of choice in skin metabolomics, swab collection, using ultra-performance liquid chromatography coupled to mass spectrometry (UPLC-MS2) on two complementary chromatographic columns (C18 reversed phase and hydrophilic interaction chromatography). We also integrate targeted analyses of key metabolites of skin relevance. Overall, WET PREP provides a strikingly more stable shared metabolome across sampled individuals, while also being able to capture unique individual metabolites with a high consistency in intra-individual reproducibility. With the exception of (phospho-)lipidomic studies, we recommend WET PREPs as the preferred skin metabolome sampling technique due to the quick preparation time, low cost, and gentleness for the patient.

An improved method to estimate absolute blood volume based on dialysate dilution.

Online hemodiafiltration machines equipped with a blood volume monitor and the possibility to rapidly infuse exact amounts of ultrapure dialysate into the extracorporeal circulation can be used to determine absolute blood volume in clinical practice. The aim of the present study was to evaluate the reproducibility of such measurements. Intra-individual reproducibility was evaluated in four measurements taken in hourly intervals within the same dialysis treatment. Ten patients were studied. Absolute blood volumes measured at the beginning and after 1hour of dialysis were significantly different (80.6±14.5 and 63.9±14.3mL/kg, P<.001) and highly reproducible between the last three measurements (63.9±14.3, 61.4±13.8, and 60.9±13.9mL/kg, P=n.s.). Measurement of absolute blood volume after 1hour of treatment is more precise than earlier measurements and might be better suited for guidance of ultrafiltration.

Individual variation of follicular phase changes in endothelial function across two menstrual cycles.

What is the central question of this study? The purpose of this study was to determine intra-individual reproducibility of follicular phase changes in endothelial function (flow-mediated dilatation) over two menstrual cycles in healthy, premenopausal women. What is the main finding and its importance? Phase changes in endothelial function were not consistent at the individual level across two menstrual cycles, which challenges the utility of interpreting individual responses over one cycle. Evidence regarding the impact of menstrual phase on endothelial function is conflicting, and studies to date have examined responses only over a single cycle. It is unknown whether the observed inter-individual variability of phase changes in endothelial function reflects stable, inter-individual differences in responses to oestrogen (E2 ; a primary female sex hormone). The purpose of this study was to examine changes in endothelial function from the early follicular (EF; low-E2 ) phase to the late follicular (LF; high-E2 ) phase over two consecutive cycles. Fourteen healthy, regularly menstruating women [22±3years of age (mean±SD)] participated in four visits (EFVisit1 , LFVisit2 , EFVisit3 and LFVisit4 ) over two cycles. Ovulation testing was used to determine the time between the LF visit and ovulation. During each visit, endothelial function [brachial artery flow-mediated dilatation (FMD)], E2 and progesterone were assessed. At the group level, there was no impact of phase or cycle on FMD (P=0.48 and P=0.65, respectively). The phase change in FMD in cycle1 did not predict the phase change in cycle2 (r=0.03, P=0.92). Using threshold-based classification (2×typical error threshold), four of 14 participants (29%) exhibited directionally consistent phase changes in FMD across cycles. Oestrogen was not correlated between cycles, and this might have contributed to variability in the FMD response. The intra-individual variability in follicular fluctuation in FMD between menstrual cycles challenges the utility of interpreting individual responses to phase over a single menstrual cycle.

Personalized connectivity-guided DLPFC-TMS for depression: Advancing computational feasibility, precision and reproducibility.

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) is an established treatment for refractory depression, however, therapeutic outcomes vary. Mounting evidence suggests that clinical response relates to functional connectivity with the subgenual cingulate cortex (SGC) at the precise DLPFC stimulation site. Critically, SGC‐related network architecture shows considerable interindividual variation across the spatial extent of the DLPFC, indicating that connectivity‐based target personalization could potentially be necessary to improve treatment outcomes. However, to date accurate personalization has not appeared feasible, with recent work indicating that the intraindividual reproducibility of optimal targets is limited to 3.5 cm. Here we developed reliable and accurate methodologies to compute individualized connectivity‐guided stimulation targets. In resting‐state functional MRI scans acquired across 1,000 healthy adults, we demonstrate that, using this approach, personalized targets can be reliably and robustly pinpointed, with a median accuracy of ~2 mm between scans repeated across separate days. These targets remained highly stable, even after 1 year, with a median intraindividual distance between coordinates of only 2.7 mm. Interindividual spatial variation in personalized targets exceeded intraindividual variation by a factor of up to 6.85, suggesting that personalized targets did not trivially converge to a group‐average site. Moreover, personalized targets were heritable, suggesting that connectivity‐guided rTMS personalization is stable over time and under genetic control. This computational framework provides capacity for personalized connectivity‐guided TMS targets to be robustly computed with high precision and has the flexibly to advance research in other basic research and clinical applications.

IntraIndividual Variability in Serum Alpha-1 Antitrypsin Levels.

Measuring alpha-1 antitrypsin (AAT) serum levels is often the first step when investigating for alpha-1 antitrypsin deficiency (AATD). The purpose of this study was to determine the test-retest reproducibility of AAT serum levels and to determine if between-measurements variability was associated with acute phase markers of inflammation. We retrospectively analyzed a sample of 255 patients from a community respirology practice with chronic obstructive pulmonary disease (COPD) in whom AAT serum levels were measured twice, on separate visits. White blood cell count and fibrinogen were also measured at the time of the second blood sampling as markers of acute phase inflammation. Intraclass correlation coefficient (ICC), Pearson correlation coefficient, and Bland-Altman analysis were used to document test-retest reproducibility. Regression analyses were used to identify potential correlates of test-retest AAT level differences. Although the 2 AAT serum levels were significantly correlated, the between-measurement agreement was weak (ICC of 0.38 [95% confidence interval (CI), 0.27 to 0.48]; Pearson correlation coefficient of 0.34 [95% CI, 0.23 to 0.44]) and Bland-Altman analysis revealed wide 95% limits of agreement. Considering that an AAT serum level below 1.13g/L should trigger further investigations to confirm the AAT status, discrepancies between the test-retest AAT levels resulted in reconsidering requirement for further investigation in 22% of patients. A significant correlation between the fibrinogen value and the second AAT level was found (r=0.21, p=0.004 [n=173]). Serum AAT levels showed weak intra-individual reproducibility which could lead to AATD status misclassification and potentially a missed diagnosis of AATD.

Reproducible improvement in endothelial function following two separate periods of high-intensity interval training in young men.

High-intensity interval training (HIIT) can improve vascular function, as assessed by brachial artery flow-mediated dilation (FMD). However, when separated by a period of detraining, the reproducibility of FMD responses to repeated periods of HIIT is unknown. The purpose of this study was to determine the group mean and intraindividual reproducibility of FMD responses to two 4-wk periods of HIIT, separated by 3 mo of detraining. Thirteen healthy, recreationally active men (21 ± 2 yr) completed the study. Each 4-wk HIIT period included 40 min of treadmill training four times/week. Each training session included four 7-min intervals: 4 min at 90%-95% heart rate maximum (HRmax) and 3 min at 70%-75% HRmax. Vascular (FMD) and cardiorespiratory fitness (maximal oxygen consumption [V̇o2max]) assessments were conducted before and following each 4-wk training period. Training resulted in significant improvements in V̇o2max (P < 0.001). Training also improved FMD (P < 0.001), with no differences between periods (P = 0.394), even after controlling for changes in baseline diameter and the shear rate stimulus. There was a significant, moderate relationship between the change in FMD in HIIT period 1 versus period 2 [R2 = 0.493, P = 0.011, intraclass correlation coefficient: 0.600, coefficient of variation: 17.3%]. Consecutive periods of HIIT separated by detraining resulted in similar improvements in FMD at the group level, and individual FMD changes in period 1 of HIIT predicted FMD changes in response to period 2. Considered alongside substantial between-participant variability in magnitude of FMD improvement, this suggests that there are reproducible, interindividual differences in the potential to improve vascular function with HIIT.NEW & NOTEWORTHY This is the first study examining endothelial function [flow-mediated dilation (FMD)] following repeated periods of high-intensity interval training (HIIT). Two periods of HIIT separated by detraining resulted in reproducible group-level improvements in FMD. Despite considerable between-subject variability in FMD adaptation, individual FMD changes with the first HIIT period predicted FMD changes in the second period. This indicates the existence of reproducible between-subject differences in susceptibility to FMD improvement with HIIT.

A micro-bioimpedance meter for monitoring insulin bioavailability in personalized diabetes therapy

An on-chip transducer, for monitoring noninvasively the insulin bio-availability in real time after administration in clinical diabetology, is proposed. The bioavailability is assessed as insulin decrease in situ after administration by means of local impedance measurement. Inter-and-intra individual reproducibility is enhanced by a personalized model, specific for the subject, identified and validated during each insulin administration. Such a real-time noninvasive bioavailability measurement allows to increase the accuracy of insulin bolus administration, by attenuating drawbacks of glycemic swings significantly. In the first part of this paper, the concept, the architecture, and the operation of the transducer, as well as details about its prototype, are illustrated. Then, the metrological characterization and validation are reported in laboratory, in vitro on eggplants, ex vivo on pig abdominal non-perfused muscle, and in vivo on a human subject, using injection as a reference subcutaneous delivery of insulin. Results of significant intra-individual reproducibility in vitro and ex vivo point out noteworthy scenarios for assessing insulin bioavailability in clinical diabetology.

Analysis of bioMARKer Distribution and Individual Reproducibility Under Rivaroxaban Treatment in Japanese Patients with Non-Valvular Atrial Fibrillation (R-MARK Study, CVI ARO2).

The "on-therapy range" of direct oral anticoagulants is the 90% interval of drug concentration. Previously, we reported the on-therapy range of rivaroxaban in a single-center cohort. The present study aimed to confirm the range and intraindividual reproducibility in a multicenter cohort.Eligible patients with non-valvular atrial fibrillation under rivaroxaban treatment for prevention of ischemic stroke were enrolled from nine institutes in Tokyo, Japan, between June 2016 and May 2017 (n = 324). The first and second (three months later) blood samples both taken within 1-5 hours after rivaroxaban intake were analyzed (n = 219). Plasma concentration of rivaroxaban (PC-Riv) and prothrombin time (PT) with five reagents were measured.The 90% interval of PC-Riv was 47.3-532.9 ng/mL. The 90% interval of PT measured with RecombiPlasTin 2G was 11.8-22.3 seconds, the widest range among the five reagents examined. PC-Riv reproducibility within a 90% interval was evaluated bidirectionally (first-to-second and second-to-first), and 92.4% of samples were reproducible. The change rate (CR) of PC-Riv between two samplings ranged widely, and high CR (≥54.3%, cutoff for predicting non-reproducibility) was predicted by concomitant drugs (non-dihydropyridine calcium antagonist and thiazide) and mitral regurgitation.We reported the on-therapy range of rivaroxaban in a multicenter cohort. This range was consistent with that of a single-center cohort and was highly reproducible within three months in daily clinical practice. However, caution is necessary regarding several factors that may affect the intraindividual variation of PC-Riv.