Immunosuppression, eotaxin and the diagnostic changes in eosinophils that precede early acute heart allograft rejection.

Peripheral blood eosinophil counts (EOS) are undetectable in 40% blood samples sent for routine haematology at Papworth Hospital during the first 3 months after heart transplantation (HTx). Increases in EOS usually precede the development of allograft rejection by a median of 4 days. We compared the effects of cyclosporin (dose and total blood concentration), prednisolone (dose and both total and unbound plasma concentrations) and azathioprine, as well as plasma concentrations of the CCR-3 chemokines, eotaxin and RANTES, on changes in EOS in 47 consecutive HTx recipients, with a median follow-up of 90 (IQR 85-95) days. Multivariate analysis confirmed the independent association between both prednisolone dose (P<0.0001) and eotaxin (P<0.0001) and changes in EOS. The plasma eotaxin concentration was, in turn, most closely associated with the cyclosporin dose (P<0.001) and plasma prednisolone concentration (P=0.022). The blood cyclosporin concentration (P=0.028), EOS (P=0.012) and prednisolone dose (P=0.015) were all independently associated with the risk of treated acute rejection. When prednisolone pharmacokinetic parameters were substituted for the prednisolone dose in this multivariate model, only the pharmacokinetic parameter retained a significant association with the risk of rejection. Changes in EOS preceding cardiac allograft rejection are directly associated with plasma eotaxin concentrations and indirectly with prednisolone dosage. Cyclosporin may also indirectly influence these changes by inhibiting eotaxin production. EOS, prednisolone dose and blood cyclosporin concentrations were independently associated with the risk of acute rejection. The total and unbound fractions of prednisolone in plasma appear to be even more closely related to rejection but are difficult to measure. Monitoring EOS, as a surrogate measure of prednisolone immunosuppression, may be more cost-effective for controlling rejection than conventional cyclosporin monitoring in the first 6 weeks after HTx

Genome-wide analyses for personality traits identify six genomic loci and show correlations with psychiatric disorders

Personality is influenced by genetic and environmental factors1 and associated with mental health. However, the underlying genetic determinants are largely unknown. We identified six genetic loci, including five novel loci2,3, significantly associated with personality traits in a meta-analysis of genome-wide association studies (N = 123,132–260,861). Of these genomewide significant loci, extraversion was associated with variants in WSCD2 and near PCDH15, and neuroticism with variants on chromosome 8p23.1 and in L3MBTL2. We performed a principal component analysis to extract major dimensions underlying genetic variations among five personality traits and six psychiatric disorders (N = 5,422–18,759). The first genetic dimension separated personality traits and psychiatric disorders, except that neuroticism and openness to experience were clustered with the disorders. High genetic correlations were found between extraversion and attention-deficit– hyperactivity disorder (ADHD) and between openness and schizophrenia and bipolar disorder. The second genetic dimension was closely aligned with extraversion–introversion and grouped neuroticism with internalizing psychopathology (e.g., depression or anxiety)

Early Onset Alcohol Use and Self-Harm: A Discordant Twin Analysis

Background Self-harm has considerable societal and economic costs and has been extensively studied in relation to alcohol involvement. Whereas early onset alcohol use (EAU) has been causally linked to maladaptive clinical outcomes, its association with self-harm is less well characterized. The current study aimed to further examine the link between EAU and both non-suicidal self-injury (NSSI) and suicide attempt (SA), and elucidate shared familial and causal/individual-specific pathways that explain this co-occurrence. Methods Using data from 6,082 Australian same-sex twin pairs (1,732 MZ and 1,309 DZ), ages 23-40, we examined prevalence rates of NSSI and SA among twin pairs concordant and discordant for EAU. Conditional logistic regression, controlling for early clinical covariates and the influence of zygosity on EAU, was used to examine the odds ratio (OR) of self-harm within twin pairs discordant for EAU. Results Prevalence rates of both NSSI and SA were highest among twin pairs concordant for EAU and for twins who reported EAU within discordant twin pairs. Results from discordant twin analyses revealed nearly four-fold increased odds of SA for the twin who endorsed EAU, and this OR was equal across monozygotic (MZ) and dizygotic (DZ) twins. EAU also was associated with elevated odds of NSSI (OR=7.62), although this was only the case for DZ twins in discordant pairs. Conclusions The equivalent increase in odds of SA for both MZ and DZ twins suggests that causal or individual-specific influences explain the link between EAU and SA. For NSSI, elevated odds for DZ twins and nonsignificant findings for MZ twins implicate correlated genetic factors in the association between EAU and NSSI. Future studies should test mechanisms through which EAU may causally influence SA, as well as examine whether genetic risk for third variables (e.g., negative urgency, stress reactivity) may explain the genetic overlap between EAU and NSSI.Psycholog

Best practice data standards for discrete chemical oceanographic observations

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Jiang, L.-Q., Pierrot, D., Wanninkhof, R., Feely, R. A., Tilbrook, B., Alin, S., Barbero, L., Byrne, R. H., Carter, B. R., Dickson, A. G., Gattuso, J.-P., Greeley, D., Hoppema, M., Humphreys, M. P., Karstensen, J., Lange, N., Lauvset, S. K., Lewis, E. R., Olsen, A., Pérez, F. F., Sabine, C., Sharp, J. D., Tanhua, T., Trull, T. W., Velo, A., Allegra, A. J., Barker, P., Burger, E., Cai, W-J., Chen, C-T. A., Cross, J., Garcia, H., Hernandez-Ayon J. M., Hu, X., Kozyr, A., Langdon, C., Lee., K, Salisbury, J., Wang, Z. A., & Xue, L. Best practice data standards for discrete chemical oceanographic observations. Frontiers in Marine Science, 8, (2022): 705638, https://doi.org/10.3389/fmars.2021.705638.Effective data management plays a key role in oceanographic research as cruise-based data, collected from different laboratories and expeditions, are commonly compiled to investigate regional to global oceanographic processes. Here we describe new and updated best practice data standards for discrete chemical oceanographic observations, specifically those dealing with column header abbreviations, quality control flags, missing value indicators, and standardized calculation of certain properties. These data standards have been developed with the goals of improving the current practices of the scientific community and promoting their international usage. These guidelines are intended to standardize data files for data sharing and submission into permanent archives. They will facilitate future quality control and synthesis efforts and lead to better data interpretation. In turn, this will promote research in ocean biogeochemistry, such as studies of carbon cycling and ocean acidification, on regional to global scales. These best practice standards are not mandatory. Agencies, institutes, universities, or research vessels can continue using different data standards if it is important for them to maintain historical consistency. However, it is hoped that they will be adopted as widely as possible to facilitate consistency and to achieve the goals stated above.Funding for L-QJ and AK was from NOAA Ocean Acidification Program (OAP, Project ID: 21047) and NOAA National Centers for Environmental Information (NCEI) through NOAA grant NA19NES4320002 [Cooperative Institute for Satellite Earth System Studies (CISESS)] at the University of Maryland/ESSIC. BT was in part supported by the Australia’s Integrated Marine Observing System (IMOS), enabled through the National Collaborative Research Infrastructure Strategy (NCRIS). AD was supported in part by the United States National Science Foundation. AV and FP were supported by BOCATS2 Project (PID2019-104279GB-C21/AEI/10.13039/501100011033) funded by the Spanish Research Agency and contributing to WATER:iOS CSIC interdisciplinary thematic platform. MH was partly funded by the European Union’s Horizon 2020 Research and Innovation Program under grant agreement N°821001 (SO-CHIC)

Distribution of cyclosporin in organ transplant recipients

Cyclosporin is an immunosuppressive agent with a narrow therapeutic index. The total concentration of cyclosporin in blood is usually monitored to guide dosage adjustment and to compensate for substantial interindividual and intra-individual variability in cyclosporin pharmacokinetics. Cyclosporin is a highly lipophilic molecule and widely distributes into blood, plasma and tissue components. It mainly accumulates in fat-rich organs, including adipose tissue and liver. In blood, it binds to erythrocytes in a saturable fashion that is dependent on haematocrit, temperature and the concentration of plasma proteins. In plasma, it binds primarily to lipoproteins, including high-density, low-density and very-low-density lipoprotein, and, to a lesser extent, albumin. The unbound fraction of cyclosporin in plasma (CsAfu) expressed as a percentage is approximately 2%. It has been shown that both the pharmacokinetic and pharmacodynamic properties of cyclosporin are related to its binding characteristics in plasma. Furthermore, there is some evidence to indicate that the unbound concentration of cyclosporin (CsAU) has a closer association with both kidney and heart allograft rejection than the total (bound + unbound) concentration. However, the measurement of CsAfu is inherently complex and cannot easily be performed in a clinical setting. Mathematical models that calculate CsAfu, and hence CsAU, from the concentration of plasma lipoproteins may be a more practical option, and should provide a more accurate correlate of effectiveness and toxicity of this drug in transplant recipients than do conventional monitoring procedures. In conclusion, the distribution characteristics of cyclosporin in blood, plasma and various tissues are clinically important. Further investigations are needed to verify whether determination of CsAU improves the clinical management of transplant recipients

Association between cyclosporine concentrations at 2 hours post-dose and clinical outcomes in de novo lung transplant recipients

Background: The objective of this study was to investigate the relationship between cyclosporine (CsA) pharmacokinetic parameters and clinical outcomes after lung transplantation. Methods: Data from 48 lung or heart/lung transplant recipients originally recruited to a randomized, prospective clinical trial of Sandimmune vs Neoral and followed for 12 months were included in this study. CsA dosing was based on the trough concentration. CsA concentrations at 0 (C0), 2 (C2), and 6 (C6) hours post-dosing were obtained at 1, 2, 3, 4, 13, 26, 39, and 52 post-operative weeks. Based on their average C2 levels in the first post-transplant month, patients were stratified retrospectively into Low C2 (\u3c1,000 μg/liter, n = 18), Intermediate C2 (1,000-1,500 μg/liter, n = 16) and High C2 (\u3e1,500 μg/liter, n = 14) Groups. Results: Cyclosporine C2 was the best single-point determinant (r2 = 0.934) for area-under-the-concentration-time curve (AUC0-6 hours) compared with C0 (r2 = 0.267) or C6 (r2 = 0.304). The mean ± SD values of CsA C2 and AUC0 to 6 hours in the first year post-transplant were significantly lower in patients with \u3e2 rejection episodes compared with those with ≤2 rejection episodes (C2: 875 ± 546 μg/liter vs 1,114 ± 633 μg/liter, p = 0.01; AUC 0-6 hours: 4,036 ± 1,904 μg × hour/liter vs 4,870 ± 2,182 μg × hour/liter; p = 0.01) whereas C0 and C6 did not differ. Patients in the Intermediate C2 Group were free from rejection episodes for a significantly longer duration (p \u3c 0.001) and had significantly higher predicted forced expiratory volume in 1 second (%) values (p \u3c 0.001) compared with the Low and High C2 Groups. The percentage of increase in serum creatinine concentration by the end of first month post-transplant was significantly higher in the Intermediate C2 Group (p \u3c 0.003). Conclusions: CsA C2 concentrations correlated better with the incidence of multiple rejections after lung transplantation than did C0 or C6. C2 concentrations between 1,000 and 1,500 μg/liter within the first post-operative month may be associated with better graft outcomes and improved pulmonary function and worsened renal function. Copyright © 2005 by the International Society for Heart and Lung Transplantation

Evaluation of an Enzyme-Immunometric Assay for Serum α-Glutathione S-Transferase

A commercially available enzyme-immunometric assay for serum α-glutathione S-transferase (GST) was evaluated. Endogenous serum α-GST diluted linearly within the calibration range. However, we recommend that the sample and second antibody reagent are always added sequentially in the assay to avoid hook effect. Between-assay variability was below 7% across the calibration range and the upper limit of the reference range in adults (n = 219) was 11 · 4 μg/L. Within-individual variability in serum α-GST concentrations measured over a 4–6 week period in 4 healthy adults was small. Serum α-GST concentrations did not change significantly 6 h after a therapeutic dose of paracetamol. Studies in two patients after liver transplantation showed that serum α-GST is a better discriminant of acute changes in liver function than conventional tests. Serum α-GST concentrations were unaffected by gross muscle damage, extra-hepatic inflammation, or haemolysis and thus appear to be more liver specific than transaminase activities. The effect of renal impairment on serum α-GST concentrations requires further investigation

Population pharmacokinetics of cyclosporine in cardiopulmonary transplant recipients

A population pharmacokinetic analysis of cyclosporine (CsA) was performed, and the influence of covariates on CsA oral clearance and relative bioavailability was investigated. Data from 48 recipients of heart-lung (n = 21) or single (n = 18) or double (n = 9) lung transplant were included in the study. Patients received oral CsA as either a conventional formulation (Sandimmune™) or a micro-emulsion (Neoral™). Steady-state CsA concentrations were measured before and at approximately 2 and 6 hours after the morning dose of CsA at the end of weeks 1, 2, 3, 4, 13, 26, 39, and 52 posttransplantation. A total of 1004 CsA concentration observations were analyzed using mixed effects-modeling (NONMEM). A 1-compartment pharmacokinetic model and first-order oral absorption were used to fit the data. The absorption rate constants were fixed at 0.25 L/h for Sandimmune and 1.35 L/h for Neoral formulations. Oral clearance (CL/F) was estimated to be 22.1 L/h (95% confidence intervals [CI] 19.5-24.7 L/h). Itraconazole (ITRA), cystic fibrosis (CF), and weight (WT) were identified as significant covariates for CL/F according to the final model: CL/F = 22.1 - 11.3 × ITRA + 23.5 × CF + 0.129 × (WT - 58.7) L/h; where ITRA = 1 if the patient was taking concomitant itraconazole, otherwise 0; CF = 1 if the patient had cystic fibrosis, otherwise CF = 0; and WT is patient weight in kilograms. The relative oral bioavailability of Sandimmune to Neoral was 0.82. The bioavailability of both preparations increased during the first month posttransplantation. Age, gender, and type of transplant (single, double, or heart-lung) were not identified as significant covariates for CsA clearance. The population pharmacokinetic model developed identified some sources of variability in CsA pharmacokinetics; however, an appreciable degree of variability is still present in this patient population. Copyright © 2005 by Lippincott Williams & Wilkins