Intra-individual Differences Research Articles

Monitoring of blood immunosuppressant concentrations and lymphocyte activation for predicting viral infections following kidney transplantation: A pilot study.

The current standard pharmacokinetic monitoring of immunosuppressive therapy does not consider inter- and intra-individual differences in the biological response to multidrug immunosuppressive therapy. The authors evaluated the blood levels of the immunosuppressive drugs IL-2 and IFN-γ in circulating lymphocytes as surrogate indicators of the development of viral infections after living kidney transplantation. This single-center prospective study included 20 kidney transplant recipients who underwent living-donor transplantation at the Mie University Hospital. All the study participants received tacrolimus, mycophenolic acid, methylprednisolone, and basiliximab. The area under the concentration curves (AUCs) of blood tacrolimus and serum mycophenolic acid were measured 1 day prior to transplantation and on post-transplantation days (PTD) for up to 5 months. IL-2 and IFN-γ levels in circulating lymphocytes were measured simultaneously. One recipient experienced an acute graft rejection. Although the AUC of tacrolimus at PTD 7 was significantly higher in the virus-infected group than that in the non-infected group, the AUC of mycophenolic acid did not differ significantly between the 2 groups. The expression levels of IFN-γ+ NK, IFN-γ+ CD4+ T, and CD8+ T cells in the infected group also tended to be higher than those in the noninfected group. During the study period, there was a clear difference in the expression of IFN-γ+ CD8+ T cells, which increased significantly during or after infection. Circulating IFN-γ+ CD8+ T cell counts may serve as promising biomarkers for predicting opportunistic viral infections early after kidney transplantation.

Examining whether affectively-charged motivations predict subsequent affective response during physical activity: An ecological momentary assessment study.

Evidence suggests positive affective response during physical activity increases the likelihood of engaging in and maintaining regular activity exercise in the future. Elucidating antecedents for a positive affective response may help identify intervention strategies to increase activity. Affectively-charged motivations (e.g., desires, urges, dreading) have been posited as proximal antecedents to physical activity but have yet to be examined in terms of their influence on affective response in real-world settings. The current study used ecological momentary assessment (EMA) to examine within-subject effects of pre-physical activity affectively-charged motivation on subsequent affective response during physical activity. Participants included 56 adults (M = 39.18 years, SD = 11.98; 67.86% female) who completed a 14-day smartphone-based EMA study. Prior to starting physical activity (time t), participants self-initiated an event-contingent EMA survey that assessed affectively-charged motivation for physical activity (i.e., rating scale from "dreading it" to "excited to do it"). EMA surveys prompted during subsequent physical activity (time t + 15 min) assessed affective response (i.e., feeling good-bad, energized-exhausted, thrilled-miserable, interested-bored, and relaxed-nervous). Multi-level linear regression models examined within-subject effects of pre- physical activity affectively-charged motivations on subsequent affective response during physical activity controlling for between-subjects effects of affectively-charged motivation, age, biological sex, time of day, and day of the week. Overall, there were N = 304 physical activity occasions in the analysis (M = 5.43, SD = 3.97). When individuals reported more positive affectively-charged motivation for physical activity than usual before physical activity occasions, they reported feeling more energized (Estimate = 0.22, p < 0.001), good (Estimate = 0.25, p < 0.001), thrilled (Estimate = 0.12, p = 0.02), and interested (Estimate = 0.24, p < 0.001) during subsequent physical activity. Affectively-charged motivation was not associated with feeling more relaxed (Estimate = 0.11, p = 0.13) during subsequent physical activity. Momentary affectively-charged motivations predicted more positive affective response during subsequent physical activity among active adults. Future research can explore potential sources of intraindividual differences in affectively-charged motivations and further examine these associations with future physical activity behavior. To improve positive affective responses, interventions may boost affectively-charged motivations through real-time mobile prompting in naturalistic settings.

Percutaneous Bioelectric Current Stimulation in the Treatment of Chronic Achilles Tendinopathy: Protocol for a Double-Blind, Placebo-Controlled Randomized Multicenter Trial.

The consensus for the optimal treatment strategy for chronic Achilles tendinopathy (AT) is still debated and treatment options are limited. This results in a significant medical need for more effective treatment options. The aim of this study is to investigate the therapeutic effects of percutaneous bioelectric current stimulation (PBCS) on AT. A multicenter, randomized, double-blind, placebo-controlled clinical trial will be conducted. A total of 72 participants with chronic (ie, >3 months) midpoint AT will be randomized and receive four PBCS sessions-either verum or placebo-over 3 weeks. Both groups will complete daily Achilles tendon loading exercises in addition to the intervention. Evaluation sessions will be completed at baseline and during the intervention (weeks 0-3). Self-reported outcome measures will be completed at follow-up at weeks 4, 12, 26, and 52. The primary outcomes are the Victorian Institute of Sports Assessment-Achilles questionnaire scores and statistical evaluation of intraindividual differences between baseline and 12-week evaluations after initial treatment of verum therapy compared to control. Secondary outcomes will assess Pain Disability Index scores; average pain, using the 11-point Numeric Rating Scale; return to sports; and use of emergency medication. The study began in May 2021. As of October 2022, we randomized 66 out of 72 participants. We anticipate completing recruitment by the end of 2022 and completing primary data analysis by March 2023. The study will evaluate the effects of PBCS on pain, physical function, and clinical outcomes. German Clinical Trials Register DRKS00017293; https://tinyurl.com/mvz7s98k. DERR1-10.2196/40894.

Abstract 13537: The Difference Between Cystatin C- and Creatinine-Based Kidney Function Assessment is Associated With Clinical Outcomes, Quality of Life and Frailty in Patients With Heart Failure and Reduced Ejection Fraction: Insights From PARADIGM-HF

Introduction: Discrepancies between cystatin C (CysC)- and serum creatinine (sCr)- estimated glomerular filtration rate (eGFR) may reflect sarcopenia and malnutrition. Among pts with heart failure and reduced ejection fraction (HFrEF) enrolled in PARADIGM-HF (Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting-Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in HF), we investigated the difference between eGFRCysC and eGFRsCr and its association with clinical outcomes, quality of life (QoL) and frailty. Methods: Intra-individual differences between eGFRCysC and eGFRsCr (eGFRdiff) were calculated at randomization (n=1,970) and 8-month follow-up (n=1,631). Study outcomes included a composite of cardiovascular (CV) mortality or HF admission, and, separately, CV and all-cause mortality, worsening kidney function, poor QoL and frailty. Worsening HF was defined as outpatient intensification of HF therapy, emergency department visit or HF admission between randomization and 8-month follow-up. Results: At randomization, eGFRdiff was &gt;10 and &lt;-10 ml/min/1.73 m 2 in 25 and 36% of the pts, respectively. More negative values of eGFRdiff were associated with worse outcomes (adjusted hazard ratio per 1-standard deviation [SD]: CV mortality or HF admission 1.20, p=.003; CV mortality 1.37, p&lt;.001; all-cause mortality 1.42, p&lt;.001; worsening kidney function 1.30, p=.066). For each 1-SD decrease in eGFRdiff, the prevalence of poor QoL and frailty increased by 28% and 19%, respectively (p ≤.003). Pts with worsening HF had more marked decline in eGFRCysC than eGFRsCr. As a result, worsening HF was associated with a change in 8-month eGFRdiff by -4.7 ml/min/1.73 m 2 ( Figure ). Conclusions: In HFrEF pts, discrepancies between eGFRCysC and eGFRsCr are common and are associated with clinical outcomes, QoL and frailty. In pts with worsening HF, sCr may underestimate decline in kidney function due to changes in muscle mass and diet.

Adaptive behaviour in adolescents and adults with Dravet syndrome.

To explore the feasibility of using an adaptive behaviour profile (ABP) assessment generated from a well-known measure-the Vineland Adaptive Behavior Scales, Second Edition (VABS-II)-as an instrument for outcome measures in adolescents and adults with Dravet syndrome. We administered the VABS-II to 35 adolescents and adults with Dravet syndrome (15 males; mean age 24 years, SD 8 years, range: 12-46 years) and collected epilepsy history and neurological features at the time of assessment. We conducted a cross-sectional analysis of VABS-II raw scores and performed cluster analysis to identify different subgroups. We then explored possible relationships between clinical and epilepsy features, ABPs, and age. Most participants obtained the minimum standard scores in the various VABS-II subdomains, while the raw score analysis outlined interindividual and intraindividual differences among skills. We found two subpopulations: one with a 'lower' ABP and one with a 'higher' ABP, corresponding respectively to individuals in whom myoclonic seizures or generalized spike-and-wave activity were present ('complete phenotype') or absent ('incomplete phenotype') on electroencephalography. This study further delineates the natural history of Dravet syndrome. The assessment of an ABP through the VABS-II raw score analysis provides a means by which to illustrate profiles of adaptive behaviour in adolescents and adults with Dravet syndrome but shows limitations related to poor sensitivity in measuring fine clinical details. There is a need for new and more specific tools to monitor patients with developmental and epileptic encephalopathies. Most adults with Dravet syndrome obtained the minimum standard scores in the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) subdomains. The VABS-II raw score analysis showed interindividual and intraindividual variability. Individuals with myoclonic seizures and/or generalized spike-and-wave activity on electroencephalography showed a worse adaptive behaviour profile.

Autologous or bovine pericardium for aortic cusp replacement? Histomorphological and biomechanical properties as decision making tools

Abstract Background/Introduction Aortic valve cusp replacement using autologous pericardium is a promising technique. Expected advantages are reduced immune response, proper biomechanics and lower treatment expenses. During surgery decision for preferred pericardium segment is based on visual criteria. Autologous pericardium can be affected by patient's condition and age. Bovine pericardium, also the basic material for aortic valve prostheses, is easy available and carefully pre-examined. In this study, the homogeneity of tissue thickness, elastic modulus, vessel density and ECM components of GA-treated residual pericardia after surgery is compared with bovine pericardia equivalently treated. Purpose Aim of the study is the comparison of homogeneity of remaining autologous pericardium after surgical aortic valve replacement with bovine pericardia to evaluate and classify the individual applicability. Methods Up to 12 samples of human (n=7) or bovine (n=3) pericardia were analysed. Tissues were treated with 0.6% glutaraldehyde according to surgical protocol. Picrosiriusred- and HE-staining were performed (three edges per separated leaflet). Vessel or collagen content was determined with Zen Blue resp. Fiji software (colour deconvolution plugin, user threshold values). Sample thickness was measured via thickness gauge FD50 before uniaxial tensile testing. Hydroxyproline content was determined and related to dry weight. T-Test or ANOVA were used to test inter-species or intra-individual differences, respectively. Results Human pericardia contain with 64.66±3.85% less collagenous fibres compared to bovine pericardia (86.01±1.713%); their vessel density is with 29.46±3.73 mm–2 significantly higher than in bovine samples (12.34±1.636 mm–2). In addition, human pericardia are with 367.7±59.2 μm significantly thinner than bovine (524.4±96.8 μm). Tensile testing (human: 36.00±15.17 MPa; bovine: 41.30±7.767 MPa) also revealed significant differences. With 77.80±11.76 mg/g merely a trend was observed for a lower hydroxyproline content in human samples (bovine 93.16±5.130 mg/g). ANOVA analyses of human pericardia illustrate significant differences for all properties, thus thickness, elastic modulus and hydroxyproline and collagen content between the individual human pericardium samples. In contrast, bovine pericardia showed an intra-individual difference only for the parameter of tissue thickness. Conclusion Human and bovine pericardia differ in histological and biomechanical parameters. In contrast to bovine pericardia, individual human pericardia were significantly different in most parameters investigated, leading to the conclusion that autologous materials are critically more heterogeneous than xenogeneic tissues. Vessel density in human pericardium was twofold higher than in bovine pericardia and can result in a higher risk for calcification. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): TU Dresden

Implications of Escherichia coli community diversity in free-ranging Australian pinniped pups.

Escherichia coli is a widely studied bacterium, commonly used as an indicator of faecal contamination. Investigations into the structure and diversity of E. coli in free-ranging wildlife species has been limited. The objective of this study was to characterise intra-individual and inter-species E. coli phylotype and B2 sub-type diversity in free-ranging Australian pinniped pups, to determine whether a single E. coli colony is representative of the phylotype and B2 sub-type diversity in these hosts. Faecal samples were collected from free-ranging Australian fur seal (Arctocephalus pusillus doriferus), Australian sea lion (Neophoca cinerea) and long-nosed fur seal (Arctocephalus forsteri) pups from three breeding colonies between 2018 and 2021. Faecal swabs from thirty randomly selected pups (n=10 from each species) were cultured and ten E. coli colonies were selected from each culture based on morphology and separation between colonies on agar plates. Molecular screening techniques were utilised to assign isolates to phylotypes and B2 sub-types. There was no significant difference (p>0.05) in either intra-individual or inter-species E. coli phylotype and B2 sub-type diversity. The B2 phylotype was the most dominant, with 78% of isolates (n=234) assigned to this phylotype. Host factors (species, weight [kg] and standard length [cm]) did not significantly affect phylotype diversity. The absence of intra-individual and inter-species differences in E. coli diversity at a phylotype level suggests that a single E. coli colony could be used as an indicator of overall diversity of E. coli at a phylotype level in A. p. doriferus, N. cinerea and A. forsteri pups. These findings can be used to simplify and improve the efficiency of sampling protocols for ongoing monitoring of human-associated E. coli phylotypes in free-ranging pinniped populations.

Changes in Coagulation and Platelet Reactivity in People with HIV-1 Switching Between Abacavir and Tenofovir

Background: Several studies have shown an association between abacavir (ABC) and increased risk of myocardial infarction (MI), but the causative mechanism has not been established. Both vascular endothelial inflammation and platelet activation have been proposed as contributing factors. Objective: The study aims to investigate the effects of ABC relative to tenofovir disoproxil (TDF) on functional assays of primary and secondary hemostasis and a comprehensible range of relevant biomarkers. Methods: In an investigator-initiated, open-labeled, crossover trial, we included HIV-infected males receiving either ABC or TDF and switched treatment to the alternate drug. At inclusion and after three months on the new regimen, we performed Multiplate® and thromboelastography (TEG®) and measured biomarkers of coagulation, inflammation, platelet reactivity, endothelial disruption and activation, and fibrinolysis, lipids, HIV RNA, CD4, CD8, and creatinine. Treatment effects were assessed by comparing intraindividual differences between the two treatment orders by the Wilcoxon Rank Sum test. Results: In total, 43 individuals completed the study. No intraindividual differences were observed for Multiplate® or TEG® when switching between regimens. We observed a significant treatment effect on coagulation factors II-VII-X (p&lt;0.0001), sCD40L (a biomarker of platelet reactivity, p=0.04), thrombomodulin (biomarker of endothelial damage, p=0.04), lipids, and CD8 cell counts (p=0.04), with higher values during ABC treatment compared to TDF. Conclusion: Compared to TDF, ABC treatment affected several outcome measures in a pro-coagulant direction. Suggesting that the risk of MI associated with ABC may be caused by the sum of multiple, discrete disturbances in the hemostatic system and endothelium. Study Registration: The trial was registered at clinicaltrials.gov (NCT02093585).

Psychosocial Factors Associated With Accelerated GrimAge in Male U.S. Military Veterans

ObjectiveVeterans are at high risk for health morbidities linked to premature mortality. Recently developed “epigenetic clock” algorithms, which compute intra-individual differences between biological and chronological aging, can help inform prediction of accelerated biological aging and mortality risk. To date, however, scarce research has examined potentially modifiable correlates of GrimAge, a novel epigenetic clock comprised of DNA methylation surrogates of plasma proteins and smoking pack-years associated with various morbidities and time-to-death. The objective of the study was to examine psychosocial correlates of this novel epigenetic clock. DesignCross-sectional study. SettingU.S. veteran population. ParticipantsParticipants were male, European American (EA), and derived from a nationally representative sample of U.S. veterans (N = 1,135, mean age = 63.3, standard deviation [SD] = 13.0). MeasurementsWe examined the prevalence of accelerated GrimAge and its association with a broad range of health, lifestyle, and psychosocial variables. ResultsA total 18.3% of veterans had accelerated GrimAge (≥5 years greater GrimAge than chronological age; mean = 8.4 years acceleration, SD = 2.2). Fewer days of weekly physical exercise (relative variance explained [RVE] = 27%), history of lifetime substance use disorder (RVE = 21%), greater number of lifetime traumas (RVE = 19%), lower gratitude (RVE = 13%), reduced sleep quality (RVE = 7%), lower openness to experience (RVE = 7%), and unmarried/partnered status (RVE = 6%) were independently associated with increased odds of accelerated GrimAge. Increasing numbers of these risk factors were associated with greater odds of accelerated GrimAge, with greatest likelihood of acceleration for veterans with ≥3 risk factors (weighted 21.5%). ConclusionsThese results suggest that nearly 1-of-5 EA male U.S. veterans have accelerated GrimAge, and highlight a broad range of health, lifestyle, and psychosocial variables associated with accelerated GrimAge. Given that many of these factors are modifiable, these findings provide promising leads for risk stratification models of accelerated biological aging and precision medicine-based targets for interventions to mitigate risk for premature mortality in this population.

Comparison of gastrointestinal landmarks using the gas-sensing capsule and wireless motility capsule.

Accurate definition of the gastroduodenal and ileocaecal junctions (GDJ, ICJ) is essential for the measurement of regional transit times. To compare the assessment of these landmarks using the novel gas-sensing capsule and validated wireless motility capsule (WMC), and to evaluate intra-subject variance in transit times METHODS: Healthy subjects ingested the gas-sensing capsule and WMC tandemly in random order. Inter-observer agreement was evaluated by intra-class correlation coefficient (ICC). Agreement between the paired devices' transit times was assessed using Bland-Altman analysis; coefficient of variation was performed to express intra-individual variance in transit times. Similar analyses were completed with tandemly ingested gas-sensing capsules. The inter-observer agreement for landmarks for both capsules was excellent (mean ICC ≥0.97) in 50 studies. The GDJ was identifiable in 92% of the gas-sensing capsule studies versus 82% of the WMC studies (p= 0.27); the ICJ in 96% versus 84%, respectively (p= 0.11). In the primary cohort (n= 26), median regional transit times differed by less than 6min between paired capsules. Bland-Altman revealed a bias of -0.12 (95% limits of agreement, -0.94 to 0.70) hours for GDJ and -0.446 (-2.86 to 2.0) hours for ICJ. Similar results were found in a demographically distinct validation cohort (n= 24). For tandemly ingested gas-sensing capsules, coefficients of variation of transit times were 11%-35%, which were similar to variance between the paired gas-sensing capsule and WMC, as were the biases. The capsules were well tolerated. Key anatomical landmarks are accurately identified with the gas-sensing capsule in healthy individuals. Intra-individual differences in transit times between capsules are probablydue to physiological factors. Studies in populations with gastrointestinal diseases are now required.

Inter- and Intraindividual Differences in the Capacity of the Human Intestinal Microbiome in Fecal Slurries to Metabolize Fructoselysine and Carboxymethyllysine.

The advanced glycation endproduct carboxymethyllysine and its precursor fructoselysine are present in heated, processed food products and are considered potentially hazardous for human health. Upon dietary exposure, they can be degraded by human colonic gut microbiota, reducing internal exposure. Pronounced interindividual and intraindividual differences in these metabolic degradations were found in anaerobic incubations with human fecal slurries in vitro. The average capacity to degrade fructoselysine was 27.7-fold higher than that for carboxymethyllysine, and degradation capacities for these two compounds were not correlated (R2 = 0.08). Analysis of the bacterial composition revealed that interindividual differences outweighed intraindividual differences, and multiple genera were correlated with the individuals’ carboxymethyllysine and fructoselysine degradation capacities (e.g., Akkermansia, Alistipes).

Midfrontal Theta Activity Is Sensitive to Approach-Avoidance Conflict.

Midfrontal theta (FMθ) in the human EEG is commonly viewed as a generic and homogeneous mechanism of cognitive control in general and conflict processing in particular. However, the role of FMθ in approach-avoidance conflicts and its cross-task relationship to simpler stimulus-response conflicts remain to be examined more closely. Therefore, we recorded EEG data while 59 healthy participants (49 female, 10 male) completed both an approach-avoidance task and a flanker task. Participants showed significant increases in FMθ power in response to conflicts in both tasks. To our knowledge, this is the first study to show a direct relationship between FMθ and approach-avoidance conflicts. Crucially, FMθ activity was task dependent and showed no cross-task correlation. To assess the possibility of multiple FMθ sources, we applied source separation [generalized eigendecomposition (GED)] to distinguish independent FMθ generators. The activity of the components showed a similar pattern and was again task specific. However, our results did not yield a clear differentiation between task-specific FMθ sources for each of the participants. Overall, our results show FMθ increases in approach-avoidance conflicts, as has been established only for more simple response conflict paradigms so far. The independence of task-specific FMθ increases suggests differential sensitivity of FMθ to different forms of behavioral conflict.SIGNIFICANCE STATEMENT FMθ is well established as an indicator for cognitive conflict in tasks involving simple stimulus-response conflicts. However, we do not yet know about its role in more complex forms of goal ambivalence, such as approach-avoidance conflicts. Thus, we implemented an approach-avoidance task and a flanker task to investigate FMθ in response to simple as well as more complex response conflicts. To our knowledge, this is the first study to show a direct relationship between FMθ and approach-avoidance conflicts. Although the transient FMθ increase is similar to that induced in a simple response conflict task, individual FMθ responsiveness to these two forms of conflict were independent of each other, suggesting intraindividual differences in the sensitivity of FMθ to different forms of behavioral conflict.

Histological and stable isotope analysis of archeological bones from St. Rombout's cemetery (Mechelen, Belgium): Intrasite, intraindividual, and intrabone variability

AbstractThis study compares histological preservation in archeological bones from different burial types to unravel the histotaphonomy‐to‐funerary practices relationship. Αn intraskeletal approach is also adopted to explore intraindividual (inner ear part of the petrous bone vs. upper/lower limb long bones) and intrabone (proximal vs. distal diaphysis) variability in bone collagen preservation, δ13C, and δ15N. The aim is to (a) target bones that likely retain higher amounts of collagen, (b) better understand the inner ear bone collagen isotopic signature and remodeling, and (c) assess intrabone isotopic and histological homogeneity. For the histological analysis, the data have been collected from 61 specimens (20 individuals) from the medieval/postmedieval cemetery of St. Rombout, Belgium. Thin sections have been studied using optical and scanning electron microscopy. For the collagen and isotopic data, 101 samples have been collected from 21 individuals. Distinct histological patterns are observed only in bones from single coffin burials; however, bone histology can display intraindividual and intrabone variability, which are important to account for interpretations. Collagen wt.%, δ13C, and δ15N show significant intraindividual differences but insignificant intrabone variability. This study also confirms the extraordinary nature of the petrous bone, as the inner ear bone collagen δ13C and δ15N values reflect the dietary input of the first approximately 2–3 years of life.

Interplay between peer experiences and classroom behavioral engagement throughout early childhood: Intraindividual and interindividual differences

Developmental theorists emphasize the existence of reciprocal influences between children's peer experiences and their early classroom behavioral engagement. For school practitioners who must identify relevant intervention targets to design educational activities, estimating precisely how aspects of peer experiences and behavioral engagement jointly unfold over time is of key interest. In addition, it is important to differentiate between intraindividual and interindividual effects. Nevertheless, evidence of these reciprocal links or intra- and interindividual effects during the early stages of schooling is scarce. This study (N = 638 children) used a Latent Curve Model with Structured Residuals (LCM-SR) to disentangle interindividual differences (stable trait-like) from intraindividual changes (dynamic state-like) in the associations between peer experiences (social acceptance and friendship involvement) and children's classroom behavioral engagement from the beginning of kindergarten through Grade 2. Results indicated that the links between children's peer experiences and their behavioral engagement reflect their steady tendency to be well adjusted in the classroom as well as with peers, rather than highlighting reciprocal associations between these factors over time. However, results also underscored that children who showed high engagement tended to be concurrently more accepted by peers in the same school year in Grade 1 or Grade 2, beyond stable aspects of engagement and social acceptance. These findings support the need to develop educational practices to improve social acceptance as a way to foster behavioral engagement. They also indicate that behavioral engagement should be considered a concrete intervention target for school practitioners seeking to improve children's social acceptance during the school year.

Association of Intra-individual Differences in Estimated GFR by Creatinine Versus Cystatin C With Incident Heart Failure

Lower estimated glomerular filtration rate (eGFR) is associated with heart failure (HF) risk. However, eGFR based on cystatin C (eGFRcys) and creatinine (eGFRcr) may differ substantially within an individual. The clinical implications of these differences for risk of HF among persons with chronic kidney disease (CKD) are unknown. Prospective cohort study. 4,512 adults with CKD and without prevalent HF who enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Difference in GFR estimates (eGFRdiff; ie, eGFRcys minus eGFRcr). Incident HF hospitalization. Fine-Gray proportional subhazards regression was used to investigate the associations of baseline, time-updated, and slope of eGFRdiff with incident HF. Of 4,512 participants, one-third had eGFRcys and eGFRcr values that differed by over 15 mL/min/1.73 m2. In multivariable-adjusted models, each 15 mL/min/1.73 m2 lower baseline eGFRdiff was associated with higher risk of incident HF hospitalization (hazard ratio [HR], 1.20 [95% CI, 1.07-1.34]). In time-updated analyses, those with eGFRdiff less than-15 mL/min/1.73 m2 had higher risk of incident HF hospitalization (HR, 1.99 [95% CI, 1.39-2.86]), and those with eGFRdiff≥15 mL/min/1.73 m2 had lower risk of incident HF hospitalization (HR, 0.67 [95% CI, 0.49-0.91]) compared with participants with similar eGFRcys and eGFRcr. Participants with faster declines in eGFRcys relative to eGFRcr had higher risk of incident HF (HR, 1.49 [95% CI, 1.19-1.85]) compared with those in whom eGFRcys and eGFRcr declined in parallel. Entry into the CRIC Study was determined by eGFRcr, which constrained the range of baseline eGFRcr-but not eGFRcys-values. Among persons with CKD who have large differences between eGFRcys and eGFRcr, risk for incident HF is more strongly associated with eGFRcys. Diverging slopes between eGFRcys and eGFRcr over time are also independently associated with risk of incident HF.

Reinforcement Learning-Based Adaptive Biofeedback Engine for Overground Walking Speed Training

Wearable biofeedback systems (WBS) have been proposed to aid physical rehabilitation of individuals with motor impairments. Due to significant inter- and intra-individual differences, the effectiveness of a given biofeedback strategy may vary for different users and across therapeutic sessions, as a patient’s functional recovery progresses. To date, only a paucity of research has investigated the use of biofeedback strategies that can self-adapt based on the user’s response. This letter introduces a novel reinforcement learning with fuzzy logic biofeedback engine (RLFLE) for personalized overground walking speed training. The method leverages reinforcement learning and a fuzzy inference strategy to continuously modulate underfoot vibrotactile stimuli that encourage users to achieve a target walking speed. This stimulation strategy also enables the determination of a user’s maximum steady-state walking speed during a gait training session overground. The RLFLE was implemented in a custom-engineered WBS and validated against two simpler biofeedback strategies during walking tests with healthy adults. Participants showed lower walking speed errors when training with the RLFLE. Additionally, results indicate that the new method is more effective in determining an individual’s maximum steady-state walking speed. Given the importance of walking speed as an indicator of health status and as an essential outcome of exercise-based interventions, these results show promise for implementation in future technology-enhanced gait rehabilitation protocols.

Intra- and Inter-individual Differences in the Human Intestinal Microbial Conversion of (-)-Epicatechin and Bioactivity of Its Major Colonic Metabolite 5-(3',4'-Dihydroxy-Phenyl)-γ-Valerolactone in Regulating Nrf2-Mediated Gene Expression.

(-)-Epicatechin (EC) is one of the most popular polyphenols present in various food products in daily life. Upon intake, it is intensively metabolized by microbiota in the large intestine. In the present study, intra- and inter-individual variations in this gut microbial conversion of EC and the concomitant formation of its major metabolites, including 5-(3′,4′-dihydroxy phenyl)-γ-valerolactone (3,4-diHPV), were identified and quantified via liquid chromatography triple quadrupole mass spectrometry (LC-TQ-MS) in anaerobic fecal incubations. In addition, the bioactivity of EC and 3,4-diHPV in activating Nrf2-mediated gene expression was tested quantifying their effects in the U2OS Nrf2 CALUX assay (a reporter gene assay that is used to test the potency of chemicals in activation of Nrf2 signaling), and on the expression levels of Nrf2-related proteins in Hepa1c1c7 and Caco-2 cells via nanoLC-MSMS. A quantitative real-time polymerase chain reaction (RT-qPCR) was carried out to confirm selected Nrf2-regulated gene expressions at the mRNA level. Results obtained show that both intra- and inter-individual differences exist in human gut microbial EC degradation and 3,4-diHPV formation, with inter-individual differences being more distinct than intra-individual differences. The metabolite, 3,4-diHPV, showed higher potency in the U2OS Nrf2 CALUX assay than EC itself. Among the obviously altered Nrf2-related proteins, 14 and 10 Nrf2-associated proteins were upregulated to a higher extent upon 3,4-diHPV treatment than in the EC treated group for Hepa1c1c7 and Caco-2 cells, respectively. While only three and four of these Nrf2-associated proteins were induced at a higher level upon EC than upon 3,4-diHPV treatment for Hepa1c1c7 and Caco-2 cells, respectively. RT-qPCR results showed that indeed Nrf2-mediated genes (e.g., Nqo1 and Ugt1a) were only induced significantly in 3,4-diHPV treated and not in EC treated Hepa1c1c7 cells. Taken together, the results suggest that the major colonic EC metabolite, 3,4-diHPV, was more capable of inducing Nrf2-mediated gene expression than its parent compound EC. This implies that the evident inter- and intra-individual differences in the microbial conversion of EC to this major metabolite 3,4-diHPV may affect the overall health-promoting effects of EC consumption related to the Nrf2 pathway activation.

Effects of immersive virtual reality on upper limb function in subjects with multiple sclerosis: A cross-over study

BackgroundUpper limb dysfunctions are common in people with multiple sclerosis (PwMS) and lead to limitations in activities of daily living. In this study, we investigated the feasibility and effects of an immersive commercial virtual reality system for upper limb bilateral rehabilitation. MethodsA total of 20 participants were included in a cross over study with two arm sequences: Treatment-Waiting List (T-WL; N = 9) and Waiting List-Treatment (WT-T; N = 11). T-WL sequence performed 12 sessions of bilateral UL rehabilitation over a 4-week period, based on the use of a commercially VR immersive platform (Oculus Rift), followed by a 4-week wash-out period and a 4-week waiting list period. WL-T sequence followed the protocol in the reverse order.Participants were tested at baseline (T0), after the end of the first 4-week period (T1), at the end of the wash-out period and finally at the end of the third 4-week period (T2). The primary outcome was the Box and Blocks test (BBT). Secondary outcome measures were: Nine Hole Peg Test (NHPT), Maximal isometric handgrip strength, Manual Ability Measure-36 (MAM-36), Modified Fatigue Impact Scale (MFIS), and the System Usability Scale (SUS).In absence of carryover effects, we analyzed primary and secondary outcome measures with mixed linear effect models. Treatment efficacy was assessed on the within-subject differences. Specifically, we used the intra-individual differences at the end of treatment and waiting-list periods (T1 and T2) as dependent variables and sequences (T-WL or WL-T) as independent variable. In presence of carryover effects (p-value <0.05), we assessed between sequence differences by an unpaired t-test considering T0 and T1 as time points, and sequence as group factor. ResultsWe observed clinical and statistical improvements for BBT, with an overall between-sequence difference of 8.6 ± 2.6 blocks (p < 0.01) favoring treatment period in the less affected side, and a not significant change of 3.0 ± 2.6 blocks (p = 0.28) in the most affected side. Small and not significant between-sequence differences were found for 9HPT, and handgrip strength in both sides. Similarly, no differences were found for patient reported outcomes, MFIS and MAM-36. Finally, mean SUS score was 45.9 ± 11.1 points, representing a moderate usability of the system. ConclusionAn immersive VR-based approach resulted useful to improve gross manual dexterity in the less affected limb in PwMS. However, such improvement did not translate into modifications in terms of self-reported ability to carry out activities of daily living nor went along with improvement in fine hand dexterity, strength or fatigue. Finally, usability of this technology was overall judged moderate, with lower scores assigned to items representing user-friendliness.

The difference between cystatin C- and creatinine-based assessment of kidney function in acute heart failure.

Acute heart failure (HF) is associated with muscle mass loss, potentially leading to overestimation of kidney function using serum creatinine-based estimated glomerular filtration rate (eGFRsCr ). Cystatin C-based eGFR (eGFRCysC ) is less muscle mass dependent. Changes in the difference between eGFRCysC and eGFRsCr may reflect muscle mass loss. We investigated the difference between eGFRCysC and eGFRsCr and its association with clinical outcomes in acute HF patients. A post hoc analysis was performed in 841 patients enrolled in three trials: Diuretic Optimization Strategy Evaluation (DOSE), Renal Optimization Strategies Evaluation (ROSE), and Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF). Intra-individual differences between eGFRs (eGFRdiff ) were calculated as eGFRCysC -eGFRsCr at serial time points during HF admission. We investigated associations of (i) change in eGFRdiff between baseline and day 3 or 4 with readmission-free survival up to day 60; (ii) index hospitalization length of stay (LOS) and readmission with eGFRdiff at day 60. eGFRCysC reclassified 40% of samples to more advanced kidney dysfunction. Median eGFRdiff was -4 [-11 to 1.5] mL/min/1.73m2 at baseline, became more negative during admission and remained significantly different at day 60. The change in eGFRdiff between baseline and day 3 or 4 was associated with readmission-free survival (adjusted hazard ratio per standard deviation decrease in eGFRdiff : 1.14, P=0.035). Longer index hospitalization LOS and readmission were associated with more negative eGFRdiff at day 60 (both P≤0.026 in adjusted models). In acute HF, a marked difference between eGFRCysC and eGFRsCr is present at baseline, becomes more pronounced during hospitalization, and is sustained at 60day follow-up. The change in eGFRdiff during HF admission and eGFRdiff at day 60 areassociated with clinical outcomes.

Characterizing the longitudinal course of symptoms and functioning in bipolar disorder.

The course of Bipolar Disorder (BD) is highly variable, with marked inter and intra-individual differences in symptoms and functioning. In this study, we identified illness trajectories across major clinical domains that could have etiological, prognostic, and therapeutic relevance. Using the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, we performed univariate and multivariate trajectory modeling of depressive symptoms, manic symptoms, and psychosocial functioning. Multinomial regression was performed to identify baseline variables associated with poor outcome trajectories. Depressive symptoms predominated, with most subjects being found in trajectories characterized by various degrees of depressive symptoms and 13% of subjects being classified in a poor outcome 'persistently depressed' trajectory. Most subjects experienced few manic symptoms, although approximately 10% of subjects followed a trajectory of persistently manic symptoms. Trajectory analysis of psychosocial functioning showed impairment in most of the sample, with little improvement during follow up. Multi-trajectory analyses highlighted significant impairment in subjects with persistently mixed and persistently depressed trajectories of illness. In general, poor outcome trajectories were marked by lower educational attainment, higher unemployment and disability, and a greater likelihood of adverse clinical features (rapid cycling and suicide attempts) and comorbid diagnoses (anxiety disorders, PTSD, and substance abuse/dependence disorders). Subjects with BD can be classified into several trajectories of clinically relevant domains that are prognostically relevant and show differing degrees of associations with a broad range of negative clinical risk factors. The highest level of psychosocial disability was found in subjects with chronic mixed and depressive symptoms, who show limited improvement despite guideline-based treatment.