High Intra-individual Variability Research Articles

Exploring the thermally-controlled fentanyl transdermal therapy to provide constant drug delivery by physics-based digital twins

Transdermal drug delivery is suitable for low-molecular-weight drugs with specific lipophilicity, like fentanyl, which is widely used for cancer-induced pain management. However, fentanyl's transdermal therapy displays high intra-individual variability. Factors like skin characteristics at application sites and ambient temperature contribute to this variation. In this study, we developed a physics-based digital twin of the human body to cope with this variability and propose better adapted setups. This twin includes an in-silico skin model for drug penetration, a pharmacokinetic model, and a pharmacodynamic model. Based on the results of our simulations, applying the patch on the flank (side abdominal area) showed a 15.3% higher maximum fentanyl concentration in the plasma than on the chest. Additionally, the time to reach this maximum concentration when delivered through the flank was 19.8 h, which was 10.3 h earlier than via the upper arm. Finally, this variation led to an 18% lower minimum pain intensity for delivery via the flank than the chest. Moreover, the impact of seasonal changes on ambient temperature and skin temperature by considering the activity level was investigated. Based on our result, the fentanyl uptake flux by capillaries increased by up to 11.8% from an inactive state in winter to an active state in summer. We also evaluated the effect of controlling fentanyl delivery by adjusting the temperature of the patch to alleviate the pain to reach a mild pain intensity (rated three on the VAS scale). By implementing this strategy, the average pain intensity decreased by 1.1 points, and the standard deviation for fentanyl concentration in plasma and average pain intensity reduced by 37.5% and 33.3%, respectively. Therefore, our digital twin demonstrated the efficacy of controlled drug release through temperature regulation, ensuring the therapy toward the intended target outcome and reducing therapy outcome variability. This holds promise as a potentially useful tool for physicians.

Exploring the thermally-controlled fentanyl transdermal therapy to provide constant drug delivery by physics-based digital twins

Transdermal drug delivery is suitable for low-molecular-weight drugs with specific lipophilicity, like fentanyl, which is widely used for cancer-induced pain management. However, fentanyl's transdermal therapy displays high intra-individual variability. Factors like skin characteristics at application sites and ambient temperature contribute to this variation. In this study, we developed a physics-based digital twin of the human body to cope with this variability and propose better adapted setups. This twin includes an in-silico skin model for drug penetration, a pharmacokinetic model, and a pharmacodynamic model. Based on the results of our simulations, applying the patch on the flank (side abdominal area) showed a 15.3% higher maximum fentanyl concentration in the plasma than on the chest. Additionally, the time to reach this maximum concentration when delivered through the flank was 19.8 h, which was 10.3 h earlier than via the upper arm. Finally, this variation led to an 18% lower minimum pain intensity for delivery via the flank than the chest. Moreover, the impact of seasonal changes on ambient temperature and skin temperature by considering the activity level was investigated. Based on our result, the fentanyl uptake flux by capillaries increased by up to 11.8% from an inactive state in winter to an active state in summer. We also evaluated the effect of controlling fentanyl delivery by adjusting the temperature of the patch to alleviate the pain to reach a mild pain intensity (rated three on the VAS scale). By implementing this strategy, the average pain intensity decreased by 1.1 points, and the standard deviation for fentanyl concentration in plasma and average pain intensity reduced by 37.5% and 33.3%, respectively. Therefore, our digital twin demonstrated the efficacy of controlled drug release through temperature regulation, ensuring the therapy toward the intended target outcome and reducing therapy outcome variability. This holds promise as a potentially useful tool for physicians.

Relationship between foliar polycyclic aromatic hydrocarbons (PAHs) concentrations and plant traits: Intracanopy variability for a broadleaf species in an urban environment

The emission of potentially harmful compounds, including polycyclic aromatic hydrocarbons (PAHs), and the resulting air pollution is a serious problem in modern cities. It is therefore important to develop mitigation strategies, such as “smart” planting of trees that act as sinks for PAHs. However, the intra-individual (within-tree) variability in leaf PAH concentrations remains unknown. In this paper, we studied 15 ornamental apple trees (Malus × moerlandsii ‘Profusion’) growing on a main street in a medium-sized city in Galicia (NW Spain). We determined the PAH concentrations at 12 canopy positions in each tree (2 orientations and 2 distances from the trunk at 3 heights), measured various ecological traits (specific leaf area [SLA], δ13C, stomatal density, fatty acid contents and leaf hairiness) and analyzed the variability in traits within the canopy in relation to PAH concentrations. We observed high intra-individual variability in the PAH concentrations and the leaf traits. Statistical analyses revealed that leaf height was the main source of variability both in the PAH concentrations and in the traits, mainly due to the leaf morphology, particularly to the SLA. Therefore, the ideal vegetation to remove PAHs would be high leaf biomass trees, not too tall and with a high proportion of shade leaves.

Variability of fibrinolytic activity in pregnant patients exposed to tissue plasminogen activator: an in vitro study utilizing rotational thromboelastometry

BackgroundThe investigation into the variability of fibrinolysis in obstetric patients is notably limited despite its relevance to postpartum hemorrhage. We investigate an in vitro model of fibrinolysis measured by rotational thromboelastrometry (ROTEM) in maternal blood samples with lysis stimulated by tissue plasminogen activator (tPA). MethodsWritten informed consent was obtained from 19 patients at term pregnancy during admission to the labor and delivery unit. Patients who were taking medication affecting coagulation were excluded. Tissue plasminogen activator was added to whole blood samples to a final concentration of 100 or 220 ng/mL prior to ROTEM testing. ResultsThe addition of tPA produced high intra-individual fibrinolytic variability for clot firmness and lysis parameters. Patients responded differently to each tPA dose ranging from clot lysis within the range of 0 ng/mL tPA group to complete clot lysis. The coefficient of variation (CV) values for the 220 ng/mL tPA group were: EXTEM MCF 0.510, EXTEM LI30 1.601, FIBTEM MCF 0.349, FIBTEM LI30 2.097. CV values for the 100 ng/mL tPA group were: EXTEM MCF 0.144, EXTEM LI30 1.038, FIBTEM MCF 0.096, FIBTEM LI30 1.238. ConclusionWe demonstrate a wide range of fibrinolytic response in the obstetric population to exogeneous tPA. We found subgroups of patients that were very responsive to tPA and insensitive to tPA. This study represents a preliminary exploration into classifying the obstetric fibrinolytic phenotypes. Further research will integrate relevant coagulation factors to establish a predictive model for testing susceptibility to lysis that can be applied at the point of care.

The Clinical Impact of Sample Storage at -20 °C on Renin Reference Intervals and Aldosterone-Renin Ratio Calculations.

Cryoactivation is known to occur in whole blood and plasma samples when kept between +4 and -5 °C, leading to falsely high renin concentrations. In 2022 it has been clearly shown that cryoactivation can also occur in samples stored at -20 °C. Based on these new findings, here we discuss how this can influence the clinical diagnosis of patients. First, we show that storage of renin plasma samples can affect the renin measurements and thereby the aldosterone to renin ratio (ARR) calculation, which might explain the high intraindividual variability in ARR also recently demonstrated. Second, we discuss the existing studies on the establishment of renin reference intervals and note the lack of attention given to this recently revealed preanalytical condition. Our literature review of the reference intervals for renin suggest that cryoactivation might have influenced the published data.

INTRAINDIVIDUAL VARIABILITY IN SLEEP DURATION IS ASSOCIATED WITH HIPPOCAMPAL VOLUME IN MID LIFE

Abstract Sleep is associated with global cognition, consolidation of memories, and structural & functional integrity of areas of the brain that support healthy cognition. While there has been research on sleep in older adults that indicates associations between poor sleep, cognitive decline, memory performance, and changes in the brain, there has been comparatively little work assessing the impact of sleep on the structure of the brain during middle adulthood. Changes in the brain begin much earlier than older adulthood, with midlife seeing cortical thinning and a decrease in brain volume in areas that support healthy cognitive functioning and memory, such as the hippocampus. Understanding how sleep may contribute to hippocampal volume in midlife may help inform how changing poor sleep is important for supporting successful aging. The current study examines the associations between 7 days of actigraphy measured sleep and hippocampal volume (MRI) in 82 midlife adults (Mage = 49.13 years, SD = 11.74; 28-76 years old) who completed the Biomarker and Neuroscience projects in the Midlife in the United States Refresher study. Results indicated that bi-lateral hippocampal volume was negatively associated with high (vs low) intraindividual total sleep time variability (>= 60 min; mean average deviation), with a 280 and 252 mm3 (p’s = .006 & .035) volume reduction for left and right hemispheres respectively. This relationship was not seen for other measures of sleep quality and the analysis additionally controlled for age, sex, BMI, race, depression status, education, and subjective physical & mental/emotional health.

Evidence supporting the use of therapeutic drug monitoring of ganciclovir in transplantation.

This review describes current knowledge of ganciclovir (GCV) and valganciclovir (ValGCV) pharmacokinetic/pharmacodynamic characteristics, highlighting the likely contribution from host genetic factors to interpatient variability. The evidence and challenges surrounding optimization of drug dosing through therapeutic drug monitoring (TDM) are examined, with recommendations made. Pharmacokinetic studies of current dosing guidelines have shown high interindividual and intraindividual variability of GCV concentrations. This is sometimes associated with a slow decline in cytomegalovirus (CMV) viral load in some transplant recipients. A high incidence of GCV-associated myelosuppression has limited the use of this drug in the transplant setting. Patient groups identified to benefit from GCV TDM include pediatric patients, cystic fibrosis with lung transplantation, obese with kidney transplantation, and patients with fluctuating renal function or on hemodialysis. The emergence of refractory resistant CMV, particularly in immune compromised patients, highlights the importance of appropriate dosing of these antivirals. Host genetic factors need to be considered where recently, two host genes were shown to account for interpatient variation during ganciclovir therapy. Therapeutic Drug Monitoring has been shown to improve target antiviral-level attainment. The use of TDM may guide concentration-based dose adjustment, potentially improving virological and clinical outcomes. However, evidence supporting the use of TDM in clinical practice remains limited and further study is needed in the transplant cohort. Further studies examining novel biomarkers are needed to guide target concentrations in prophylaxis and treatment. The use of TDM in transplant recipients is likely to improve the clinical efficacy of current antivirals and optimize outcomes in transplant recipients.

Cognitive intraindividual variability, cognitive impairment and psychosocial functioning in first-episode psychosis patients

Cognitive intraindividual variability (IIV) refers to fluctuations in performance across tasks (i.e. dispersion) or in a single task on multiple occasions (i.e. inconsistency). Little is known about IIV in patients with first-episode psychosis (FEP). We aimed to explore the association between IIV and both global cognitive performance and psychosocial functioning in a sample of 103 FEP patients.Patients were recruited at discharge from the PEPsNa program, a FEP follow-up intervention program lasting 24 months. The Social and Occupational Functioning Scale (SOFAS) and the Cognitive Assessment Interview (CAI-Sp) were employed for assessing psychosocial functioning. Cognitive assessments were performed using the MATRICS Cognitive Assessment Battery (MCCB), and the variability in the cognitive functions assessed with the MCCB was used to calculate the IIV.Significant correlations were obtained between IIV and global MCCB scores, the CAI-Sp and the SOFAS. We found significant differences in psychosocial functioning and cognitive performance between patients with high and low IIV. A higher IIV in FEP patients was related both to worse psychosocial functioning and worse global cognitive performance. Unlike global cognitive performance, IIV was not related to clinical characteristics, suggesting that it could be an indicator of cognitive impairment even in the absence of global impairment.

PEG 400 Ion Suppression in Busulfan Detection by High-Performance Liquid Chromatography-Tandem Mass Spectrometry.

Busulfan (Bu), an alkylating agent commonly used in chemotherapy and transplantation, exhibits high intraindividual pharmacokinetic variability and possible time-dependent variations in clearance, which complicate therapeutic drug monitoring. Numerous analytical methods have been developed to reduce analysis time and facilitate timely decision-making regarding treatment changes; however, the validation procedures rarely involve analysis of potentially interfering excipients. Macrogol 400 (PEG 400) should be considered as a possible interfering agent in the detection of plasma Bu levels, especially as an ionization suppressor. Six intravenous formulations of Bu were compared with identify at least 1 common excipient (PEG 400). During the 176 therapeutic drug monitoring analyses of Bu, one of the PEG 400 specific mass-to-charge ratio transitions was determined using an instrumental method. After coelution with Bu and its internal standard (Bu-d8) was confirmed, all analyses were repeated using a different experimental setup free of ion suppression induced by PEG. The concentration-time profile of PEG 400 was also analyzed. The area under the curve obtained from the 2 data sets was compared and analyzed using Lin concordance correlation coefficient and Bland-Altman plot analysis. The results from the 2 analytical methods were comparable: PEG 400 negatively affected the Bu-d8 coefficient of variation but not the Bu/Bu-d8 ratio. The possible interference of PEG 400 should be thoroughly investigated, especially with respect to analytical methods that cannot be supported by correction of the stable isotopically labeled internal standard analog.

P-528 Intra-individual variability of serum progesterone level on the day of frozen blastocyst transfers in hormonal replacement therapy cycles

Abstract Study question Is there a significant intra-individual variability of serum progesterone level on the day of theHormone Replacement Therapy Frozen Embryo Transfer(HRT-FET) between two consecutive cycles? Summary answer No significant intra-individual variability of progesterone level measured the day of transfer was shown between two consecutive HRT-FET cycles. What is known already In frozen embryo transfer under HRT, a minimum P level around the day of embryo transfers necessary to optimize reproductive outcomes. Indeed, in a previous study, we have found that women with a serum P level ≤9.8ng/ml on the day of the single autologous blastocyst transfer had lower live birth rate. Moreover, some clinical factors have been described as influencing the P level on the day of the embryo transfer (i.e weight, gravidity, Ethnic origin,tobacco consumption…). Variations between patients raise the question of intra-individual variation in P measurement, in addition to the existence of inter-individual variation. Study design, size, duration We conducted an observational cohort study at the university-based reproductive medicine centre of our institution that focusing on women who underwent at least two consecutive single autologous HRT-FET of blastocyst, between January 2019 and March 2020. Participants/materials, setting, methods Patients undergoing two consecutive single autologous blastocyst HRT-FET using exogenous estradiol and vaginal micronized progesterone for endometrial preparation were included.The serum progesterone level was measured in the morning of the FET, in a single laboratory. The two progesterone measurements performed the day of the first (FET1) and the second FET (FET2) were compared to evaluate the intra-individual variability of serum P.Paired statistical analyses were performed, as appropriate. Main results and the role of chance Two hundred and sixty-four patients undergoing two consecutive single autologous blastocyst HRT-FET were included. The mean age of the included women was 35.0 ±4.2 years old. No significant intra-individual variability was observed between FET 1 and FET2 (Mean progesterone level after FET1: 13.4±5.1ng/ml versus after FET 2: 13.9±5.0; p = 0.08).Characteristics of embryo transfers were similar between the first and the second FET. Forty-nine patients (18.6%) had discordant progesterone levels (defined as one progesterone measurement > and one ≤ to the threshold of 9.8ng/ml) between FET1 and FET2. 37/264(14%) women had a high intra-individual variability (defined as a difference in serum progesterone values >75 e percentile (6.0ng/ml)) between FET1 and FET2. No specific clinical parameter was associated with a high intra-individual variability nor a discordant P measurements. Limitations, reasons for caution This study is limited by its retrospective design. Likewise, only women who underwent autologous blastocyst HRT-FET with micronized vaginal P were included. Wider implications of the findings No significant intra-individual variability was showed and the serum progesterone level seems to be reproducible in more than 80% of case. This study suggests that the serum progesterone level measured the day of the first transfer could be used to individualize luteal phase support on subsequent cycles. Trial registration number not applicable

Searching for biomarkers in the fluidity of mental ill-health.

Searching for biomarkers in the fluidity of mental ill-health.

Recall bias of students' affective experiences in adolescence: The role of personality and internalizing behavior.

Adolescence is characterized by multiple biopsychosocial changes, associated with a high intraindividual variability of emotional experiences. Previous findings suggest that this intraindividual variability is reflected in a recall bias of adolescents' emotion reports. However, corresponding findings are scarce and inconclusive. Studies on predictors of recall bias in adulthood indicate that personality traits, especially neuroticism and extraversion, as well as specific internalizing disorders might affect recall bias of emotion reports. The sample consists of 118 Swiss adolescent students in grade 8 and 9 (Mage = 15.15, SDage = 0.89). The students' momentary affective experience was recorded using smartphones over seven consecutive days in situ at 42 randomly generated occasions (six per day), with a total of 1059 protocols on current events. At the end of the experience-sampling phase, students filled out an online questionnaire, providing information about their personality and typical behavior as well as their retrospective affective experience. In addition, the students' behavior was evaluated by their teachers. We applied two-level structural equation modeling with latent difference variables. Adolescents high in extraversion showed retrospective overestimation of positive affective experiences and underestimation of negative affective experiences. Adolescents with high neuroticism tended to overestimate negative affect retrospectively, showing no significant effects for positive affect. However, internalizing behavior did not predict a negative recall bias in adolescents' affective experience. Retrospective self-reports about adolescents' affective experience are biased by relatively stable individual factors, whereas less stable individual factors did not seem to have any influence.

Plasma procalcitonin kinetics in healthy dogs and dogs undergoing tibial plateau leveling osteotomy.

Procalcitonin (PCT) is a well-established biomarker for bacterial infection in human patients. We aimed to analyze the kinetics of plasma PCT (pPCT) in healthy dogs and dogs with canine cranial cruciate ligament (CCL) rupture undergoing tibial plateau leveling osteotomy (TPLO). This prospective, longitudinal study included 15 healthy dogs and 25 dogs undergoing TPLO. Hematology, pPCT, and C-reactive protein (CRP) were assessed on 3 consecutive days in healthy dogs and 1 day preoperatively and days 1, 2, 10, and 56 postoperatively. Inter- and intraindividual variability of pPCT were assessed in healthy dogs. Median pPCT concentrations of dogs with CCL rupture preoperatively were compared with healthy controls, and median pPCT concentrations, as well as percentage change postanesthesia, arthroscopy, and TPLO, were compared with baseline. For the correlation analysis, the Spearman rank correlation test was used. Inter- and intraindividual variabilities of pPCT in healthy dogs were 36% and 15%, respectively. Median baseline pPCT concentrations were not significantly different between healthy dogs (118.9pg/mL; IQR: 75.3-157.3pg/mL) and dogs undergoing TPLO (95.9pg/mL; IQR: 63.8-117.0pg/mL). Plasma PCT concentrations were significantly lower immediately post- than preoperatively (P < 0.001). CRP, WBC, and neutrophil concentrations increased significantly on post-OP day 2 and had normalized by day 10. These results indicate that CCL rupture, as well as anesthesia, arthroscopy, and TPLO combined, are not associated with increased pPCT concentrations in dogs with uncomplicated recovery. Considering the high intraindividual variability, individual serial measurements rather than a population-based reference interval should be considered.

Sex and reproductive status affect sheltering and exploratory behaviours with high intra-individual variability in crayfish

Abstract The contexts in which individuals demonstrate behavioural consistency or variability have been the subject of research focus. We studied exploratory and sheltering behaviour in the crayfish F. virilis to understand how these behaviours vary by sex and reproductive readiness and to quantify the repeatability of these behaviours. Crayfish were tested in two sets of three rounds, one in the summer non-reproductive season and another in the autumn reproductive season. Reproductive crayfish spent more time outside the shelter and were more likely to accept a food item than non-reproductive crayfish. In the non-reproductive season, females spent more time outside the shelter than males, and over both seasons, females were more likely to seek and accept a food item. Repeatability estimates were low, indicating high intra-individual variability in these behaviours. Sheltering and exploratory behaviours were not correlated. This indicates sex or reproductive readiness have strong effects on both sheltering and exploratory behaviours.

Sex comparisons in physiological and cognitive performance during hypoxic challenge.

Within the tactical aviation community, human performance research lags in considering potential psychophysiological differences between male and female aviators due to little inclusion of females during the design and development of aircraft systems. A poor understanding of how male and female aviators differ with respect to human performance results in unknown potential sex differences on aeromedically relevant environmental stressors, perchance leading to suboptimal performance, safety, and health guidelines. For example, previous hypoxia studies have excluded female participants or lacked a sizeable sample to examine sex comparisons. As such, progress toward sensor development and improving hypoxia familiarization training are stunted due to limited knowledge of how individual differences, including sex, may or may not underlie hypoxia symptoms and performance impairment. Investigating sex differences bridges the gap between aerospace medicine and operational health, and addressing hypoxia is one of many facets yet to be studied. In the current study, we retrospectively examined N = 6 hypoxia studies with male-female participant samples (total, N = 189; male, n = 118; female, n = 71). We explored sex as a predictor of physiological response, sensory deficits, the severity of cognitive performance declines, and symptom manifestation via linear and binary logistic regression models. We found that the female sex predicted lower peripheral oxygen saturation and the likelihood of headache reporting in response to hypoxic challenge, yet explained little variance when combined with age and body mass index. The sensory and cognitive performance models did not converge, suggesting high intra-individual variability. Together, sex, age, and body mass index were not the most robust predictors in responses to hypoxic challenge; we cannot infer this for sensory deficits and cognitive performance within an experimentally induced hypoxic environment. The findings have implications for improving hypoxia familiarization training, monitoring sensor development, and emergency response and recovery protocols in case of a hypoxia occurrence suitable for all aircrew. We recommend continuing to elucidate the impact of sex and intrapersonal differences in hypoxia and other aeromedically relevant stressors in tactical aviation.

Effectiveness of KarXT (xanomeline-trospium) for cognitive impairment in schizophrenia: post hoc analyses from a randomised, double-blind, placebo-controlled phase 2 study

The muscarinic receptor agonist xanomeline improved cognition in phase 2 trials in Alzheimer’s disease and schizophrenia. We present data on the effect of KarXT (xanomeline–trospium) on cognition in schizophrenia from the 5-week, randomised, double-blind, placebo-controlled EMERGENT-1 trial (NCT03697252). Analyses included 125 patients with computerised Cogstate Brief Battery (CBB) subtest scores at baseline and endpoint. A post hoc subgroup analysis evaluated the effects of KarXT on cognitive performance in patients with or without clinically meaningful cognitive impairment at baseline, and a separate outlier analysis excluded patients with excessive intraindividual variability (IIV) across cognitive subdomains. ANCOVA models assessed treatment effects for completers and impairment subgroups, with or without removal of outliers. Sample-wide, cognitive improvement was numerically but not statistically greater with KarXT (n = 60) than placebo (n = 65), p = 0.16. However, post hoc analyses showed 65 patients did not exhibit clinically meaningful cognitive impairment at baseline, while eight patients had implausibly high IIV at one or both timepoints. Significant treatment effects were observed after removing outliers (KarXT n = 54, placebo n = 63; p = 0.04). Despite the small sample size, a robust (d = 0.50) and significant effect was observed among patients with cognitive impairment (KarXT n = 23, placebo n = 37; p = 0.03). These effects did not appear to be related to improvement in PANSS total scores (linear regression, R2 = 0.03). Collectively, these findings suggest that KarXT may have a separable and meaningful impact on cognition, particularly among patients with cognitive impairment.

Controversial Interactions of Tacrolimus with Dietary Supplements, Herbs and Food

Tacrolimus is an immunosuppressive calcineurin inhibitor used to prevent rejection in allogeneic organ transplant recipients, such as kidney, liver, heart or lung. It is metabolized in the liver, involving the cytochrome P450 (CYP3A4) isoform CYP3A4, and is characterized by a narrow therapeutic window, dose-dependent toxicity and high inter-individual and intra-individual variability. In view of the abovementioned facts, the aim of the study is to present selected interactions between tacrolimus and the commonly used dietary supplements, herbs and food. The review was based on the available scientific literature found in the PubMed, Scopus and Cochrane databases. An increase in the serum concentration of tacrolimus can be caused by CYP3A4 inhibitors, such as grapefruit, pomelo, clementine, pomegranate, ginger and turmeric, revealing the side effects of this drug, particularly nephrotoxicity. In contrast, CYP3A4 inducers, such as St. John’s Wort, may result in a lack of therapeutic effect by reducing the drug concentration. Additionally, the use of Panax ginseng, green tea, Schisandra sphenanthera and melatonin in patients receiving tacrolimus is highly controversial. Therefore, since alternative medicine constitutes an attractive treatment option for patients, modern healthcare should emphasize the potential interactions between herbal medicines and synthetic drugs. In fact, each drug or herbal supplement should be reported by the patient to the physician (concordance) if it is taken in the course of immunosuppressive therapy, since it may affect the pharmacokinetic and pharmacodynamic parameters of other preparations.

Global slowness and increased intra-individual variability are key features of attentional deficits and cognitive fluctuations in post COVID-19 patients

Fatigue, attentional deficits and cognitive fluctuations are the most characterizing symptoms of neurological involvement in Post COVID-19 syndrome (PCS). As the intraindividual variability (IIV) in cognitive performances has been recognized as a hallmark of brain-related disorders associated with cognitive deficits, it could be an interesting measure to elucidate the mechanisms subtending both the attentive impairment and the cognitive fluctuations in these patients. By referring to IIV analysis of Reaction Times (RTs), the present study aims to define the attentive impairment and its relation to fluctuations and fatigue, in patients suffering from Post COVID-19 neurological symptoms. 74 patients were enrolled. They underwent an extensive clinical and neuropsychological assessments, as well as computerized Sustained Attention and Stroop tasks. For studying IIV, RTs distributions of performances in computerized tasks were fitted with ex-Gaussian distribution, for obtaining the τ values. Finally, the Resting Motor Threshold (RMT) was also collected to estimate cortical excitability. 29 healthy volunteers served as controls. Patients showed poorer scores in Montreal Cognitive Assessment and higher RMT, in comparison with controls. In Sustained Attention Task, Mean, µ, σ and τ values were significantly higher in PCS patients (p value = < 0.0001; 0.001; 0.018 and < 0.0001, respectively). Repeated measures ANOVA comparing the RTs mean in Stroop task within-subject and between-subjects revealed significant condition and group effect (p < 0.0001 both) and significant interaction (p = 0.005), indicating worst performances in patients. The mean of the derived interference value was significantly higher in PCS patients than in controls (p = 0.036). Patients suffering from PCS show deficits in attention, both in the sustained and executive components. Both high RTs means and high IIV subtend these deficits and could explain the often-complained cognitive fluctuations in this population.

Attention impairment in motor functional neurological disorders: a neuropsychological study

Our objective was to assess cognitive functioning across multiple cognitive domains using a standardised neuropsychological battery in patients with motor functional neurological disorders (mFND). Thirty patients with clinically established mFND and 30 age-, sex- and education-matched control subjects underwent a thorough neuropsychological assessment evaluating (1) attention including processing speed, (2) executive functions including working memory, (3) short-term memory, (4) speech and language and (5) visuospatial functions. Performance validity tests (PVT) and self-report measures of depression, anxiety and cognitive complaints were included in the assessment. Only patients with valid test performance were included in the analysis. Three patients scored below the cut-off scores in PVT. Patients performed significantly worse than controls in the following areas: (1) the attention domain which included a slow processing speed (p = 0.005, Cohen's d = 0.89), (2) executive functions (p = 0.01, Cohen's d = 0.88) and (3) speech and language domains (p = 0.025, Cohen's d = 0.77). Patients with mFND showed greater intra-individual variability in cognitive performance (p = 0.005, Cohen's d = 0.94). Cognitive impairments were independent of depressive symptoms, which were higher in mFND patients. This study revealed both subjective and objective cognitive impairment in patients with mFND. The neuropsychological profile in mFND was characterised primarily by attentional impairment including a slow processing speed and a high intra-individual variability in cognitive performance. Cognitive impairment was associated with a valid test performance, highlighting that the deficits observed were not likely to be explained by a lack of effort in the patient group. Attention is considered to play a key role in mFND pathophysiology, and the results suggest that such impairments are objectively measurable.

CD86 occupancy in belatacept-treated kidney transplant patients is not associated with clinical and infectious outcomes

The CD86 occupancy assay has been developed to measure the number of CD86molecules unbound to belatacept, but its association with clinical outcomes has not been assessed yet. All kidney transplant patients switched to belatacept in our center between 2016 and 2018 were included. Blood samples were collected before each infusion for 1year to assess CD86 occupancy by CD86 antibody cytometry staining on the surface of CD14+ monocytes. Results were expressed as the median fluorescence intensity (MFI) value of CD86staining. At each infusion, the MFIDay of infusion /MFIDay 0 ratio was calculated. Forty-one patients were consecutively included. After every 2-week infusion period, CD86MFI ratio dropped from 1.00 to 0.73 [0.57-0.98], p=.07. However, this ratio progressively increased to 0.78 [0.53-1.13] at 1year, which was not statistically different from pre-switch ratio, p=.4. Over the first year, the MFI ratio coefficient of variation was 31.58% [23.75-38.31]. MFI ratio was not different between patients with or without opportunistic infections: 0.73 [0.60-0.88] versus 0.80 [0.71-1.00], p=.2, or between patients with or without EBV DNAemia, p=.2. Despite previous in vitro results, the CD86 occupancy assay suffers from a high intra-individual variability and does not appear to be relevant to clinical outcomes.