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ISAC-TRIUMF operates targets under proton irradiation in the high-power regime of 50 kW (100 μA, 500 MeV) to produce radioactive isotope beams using the isotope separation on-line technique. The targets irradiated at ISAC have a total stopping power significantly lower than 500 MeV resulting in a residual high-power proton beam downstream of the target. The coupling of a supplementary target in a downstream position allows for additional scientific output. Irradiation conditions have been analyzed with the fluka code and relevant achievable research within operational limitations explored. Prominently, the study of material degradation under high radiation fields is of increasing interest due to the steady demand for high-performance materials for new-generation nuclear applications and beam-intercepting components at high-power particle accelerator facilities. Successive irradiations at ISAC yield relevant radiation damage of bulk material samples which can then be characterized using already existing facilities at TRIUMF and partner facilities. Additionally, a variety of isotopes produced by transmutation with research applicability can be harvested from these irradiations. With the purpose of unlocking this complementary research at ISAC-TRIUMF, a secondary target, attached to the primary ISAC target system, has been designed and commissioned.

Given a non-zero polynomial f in a polynomial ring R with coefficients in a finite field of prime characteristic p, we present an algorithm to compute a differential operator δ which raises 1/ f to its pth power. For some specific families of polynomials, we also study the level of such a differential operator δ , i.e., the least integer e such that δ is R^{p^e} -linear. In particular, we obtain a characterization of supersingular elliptic curves in terms of the level of the associated differential operator.

Haploidentical haematopoietic stem cell transplantation (haplo-HSCT) is one of the most effective therapies for treating malignant haematological disorders. However, HLA disparities are significant barriers to the success of this process since they increase the risk of graft versus host disease (GvHD). HLA disparities quantification could help to anticipate the probability and degree of GvHD, but the best tool for such quantification remains a challenge. The aim of this study was to quantify the degree of HLA epitope incompatibilities using PIRCHE (Predicted Indirectly Recognisable HLA Epitopes) algorithm for immunogenicity prediction and their potential relationship with GvHD degree and clinical outcome. We studied 145 patients who underwent a haplo-HSCT with post-transplant cyclophosphamide (PTCy) from a related donor between 2013 and 2020 at our centre evaluating molecular HLA mismatches by PIRCHE-algorithm. Patients with PIRCHE Score (PS) I + II > 38 in GvH direction, developed acute GvHD grade II-IV earlier than their counterparts (HR: 1.71, 95% CI: 1.02-2.87, p = 0.032). In addition, PS-B > 1 in GvH direction was an independent risk factor for chronic GvHD, (HR: 2.51, 95% CI 1.17-5.36, p = 0.017). A higher incidence of relapse was found for patients with PS-II > 28 HvG (HR: 9.16, 95% CI: 2.47-33.92, p < 0.001) which also favoured a worse GvHD/relapse-free survival in patients with PS-II > 27 in HvG direction (HR: 1.88, 95% CI: 1.11-3.18, p = 0.017). These findings indicate that the alloreactivity inferred by epitope HLA disparities is associated with post-transplant outcomes. Thus, analysing PS could benefit the selection of the most suitable donors allowing patient stratification based on HLA mismatches in the context of haplo-HSCT with PTCy., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The pathogenesis of COVID-19 warrants unravelling. Genetic polymorphism analysis may help answer the variability in disease outcome. To determine the role of KIR and HLA polymorphisms in susceptibility, progression, and severity of SARS-CoV-2 infection, 458 patients and 667 controls enrolled in this retrospective observational study from April to December 2020. Mild/moderate and severe/death study groups were established. HLA-A, -B, -C, and KIR genotyping were performed using the Lifecodes® HLA-SSO and KIR-SSO kits on the Luminex® 200™ xMAP fluoroanalyser. A probability score using multivariate binary logistic regression analysis was calculated to estimate the likelihood of severe COVID-19. ROC analysis was used to calculate the best cut-off point for predicting a worse clinical outcome with high sensitivity and specificity. A p ≤ 0.05 was considered statistically significant. KIR AA genotype protected positively against severity/death from COVID-19. Furthermore, KIR3DL1, KIR2DL3 and KIR2DS4 genes protected patients from severe forms of COVID-19. KIR Bx genotype, as well as KIR2DL2, KIR2DS2, KIR2DS3 and KIR3DS1 were identified as biomarkers of severe COVID-19. Our logistic regression model, which included clinical and KIR/HLA variables, categorised our cohort of patients as high/low risk for severe COVID-19 disease with high sensitivity and specificity (Se = 94.29%, 95% CI [80.84-99.30]; Sp = 84.55%, 95% CI [79.26-88.94]; OR = 47.58, 95%CI [11.73-193.12], p < 0.0001). These results illustrate an association between KIR/HLA ligand polymorphism and different COVID-19 outcomes and remarks the possibility of use them as a surrogate biomarkers to detect severe patients in possible future infectious outbreaks., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Information on the pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered cannabis-based medicine (CBM) in capsule formulation in patient populations is sparse. In this exploratory study, we aimed to evaluate the PK and PD in a probable steady state of CBM in neuropathic pain and spasticity in a population of patients with multiple sclerosis (MS). Of 134 patients participating in a randomized, double-blinded, placebo-controlled, trial, 23 patients with MS (17 female) mean age 52 years (range 21-67) were enrolled in this substudy. They received oral capsules containing Δ 9 -tetrahydrocannabinol (THC, n = 4), cannabidiol (CBD, n = 6), a combination (THC&CBD, n = 4), or placebo (n = 9). Maximum doses were 22.5 mg (THC) and 45 mg (CBD) a day divided into three administrations. PD parameters were evaluated for pain and spasticity. Blood samples were analyzed using an ultra-high-performance liquid chromatography-tandem mass spectrometer after protein precipitation and phospholipid removal. PK parameters were estimated using computerized modeling. The variation in daily dose and PK between individuals was considerable in a steady state, yet comparable with previous reports from healthy controls. Based on a simulation of the best model, the estimated PK parameters (mean) for THC (5 mg) were C max 1.21 ng/mL, T max 2.68 h, and half-life 2.75 h, and for CBD (10 mg) were C max 2.67 ng/mL, T max 0.10 h, and half-life 4.95 h, respectively. No effect was found on the PD parameters, but the placebo response was considerable. More immediate adverse events were registered in the active treatment groups compared with the placebo group., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The use and/or misuse of opioids by pregnant women would expose the fetuses to these drugs during critical stages of development with serious effects for the newborn, like the neonatal abstinence syndrome (NAS). We have revisited an established chicken model for NAS to describe the distribution of morphine and methadone to the brain and explore its validity as a valuable alternative to rodent models. For this purpose, chicken eggs were injected with a single dose of 10 mg/kg or 20 mg/kg morphine or 20 mg/kg methadone onto the chorioallantoic membrane (CAM) on embryonal day 13. Whole brains and lungs were harvested and the concentrations of morphine, methadone and their subsequent metabolites (morphine-3-glucuronide and EDDP, respectively) determined in the brain and lungs at different time points using LC-MS/MS. Morphine and methadone, as well as their metabolites, were detected both in the brain and lungs, with significantly higher concentrations in the lungs. Pharmacokinetic modelling showed that the distribution of morphine to the brain followed a first-order absorption with transit compartments and linear elimination, with concentrations linearly dependent on dose. Moreover, methadone, but not morphine, reduced μ receptor (the main morphine receptor) binding, which can be of relevance for opioid tolerance. The present study is the first to report the brain distribution of morphine, which can be described by standard pharmacokinetic processes, and methadone in the developing chicken embryo. The present findings supplement the already established model and support the use of this chicken model to study NAS., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ragnhild Elisabeth Paulsen reports financial support was provided by Anders Jahre's Foundation., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Immunotherapeutic interventions that block drug effects by binding drug molecules to specific antibodies in the bloodstream have shown promising effects in animal studies. For heroin, which effects are mainly mediated by the metabolites 6-acetylmorphine (6-AM; also known as 6-monoacetylmorphine or 6-MAM) and morphine, the optimal antibody specificity has been discussed. In rodents, 6-AM specific antibodies have been recommended based on the rapid metabolism of heroin to 6-AM in the bloodstream. Since the metabolic rate of heroin in blood is unsettled in humans, we examined heroin metabolism with state-of-the-art analytical methodology (UHPLC-MS/MS) in freshly drawn human whole blood incubated with a wide range of heroin concentrations (1-500 μM). The half-life of heroin was highly concentration dependent, ranging from 1.2-1.7 min for concentrations at or above 25 μM, and gradually increasing to approximately 20 min for 1 μM heroin. At concentrations that can be attained in the bloodstream shortly after an i.v. injection, approximately 70% was transformed into 6-AM within 3 min, similar to previous observations in vivo. Our results indicate that blood enzymes play a more important role for the rapid metabolism of heroin in humans than previously assumed. This points to 6-AM as an important target for an efficient immunotherapeutic approach to block heroin effects in humans., (© 2023 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Acute kidney injury (AKI) is a leading cause of early post-transplant kidney damage. Furthermore, acute tubular necrosis (ATN) is appointed as the most prevalent form of AKI, a frequent multifactorial process associated with high morbidity and mortality, yet giving rise to delayed graft function (DGF) and, ultimately, allograft dysfunction. Common factors such as prolonged cold ischemia time, advanced donor age, cadaveric versus living donor, donor history of hypertension, as well as donation after cardiac death have all been deemed risk factors for ATN. With the increasing number of older cadaveric and cardiac donors in the donation process, ATN could have a detrimental impact on patient welfare. Therefore understanding the underlying process would benefit the transplant outcome. We aimed to prospectively monitor several T cell subsets in a cohort of kidney transplant recipients (KTrs) to investigate whether there is an adaptive immune-mediated involvement in the ATN process., Methods: Peripheral blood was collected from 31 KTrs at different time points within the first-year post-transplantation for in vitro stimulation with Concanavalin-A (Con-A) in a humidified 5% CO2 incubator at 37 °C for 72 hours. Upon cell stimulation, flow cytometry was applied to quantify the surface expression through the median fluorescence intensity (MFI) of CD4+CD25+, CD8+CD25+, CD4+CD38+, CD8+CD38+, CD4+CD154+, CD8+CD154+, CD4+CD69+, CD8+CD69+, CD4+CD95+, and CD8+CD95+ T cells. Statistical analysis was carried out with SPSS Statistics IBM v.25 (IBM Corp, Armonk, NY, USA). MFIs values were compared using a univariate analysis by a nonparametric U-Mann Whitney test. ROC analysis was applied to define cut-off values most capable of stratifying patients at high risk of ATN. Spearman's rank-order coefficient test was applied to correlate biomarkers with allograft function. Multivariate regression independently validated CD8+ T lymphocytes as surrogate biomarkers of ATN. A p -value < 0.05 was considered statistically significant., Results: KTrs who developed ATN upon transplantation had significantly higher expression of CD25, CD69, and CD95 on CD8+ and lower expression of CD95 on CD4+ T lymphocytes than patients with stable graft function. ROC curve analysis showed that MFIs ≥1015.20 for CD8+CD25+, ≥2489.05 for CD8+CD69+, ≥4257.28 for CD8+CD95+, and ≤1581.98 for CD4+CD95+ were capable of stratifying KTrs at high risk of ATN. Furthermore, patients with an MFI below any cut-off were significantly less likely to develop ATN than those with other values. The allograft function was correlated with the CD4+CD95+/CD8+CD95+ ratio in KTrs who developed ATN. The multivariate analysis confirmed that, within the first-month post-transplant, MFI values of CD8+CD25+, CD4+CD95+, and CD8+CD95+ T lymphocytes, along with donor age, serum creatinine, and GFR were independent risk factors to ATN. Moreover, we were also able to corroborate previous immune factors of importance in immune-mediated response to the allograft, such as the patient's maximum panel reactive antibody (PRA) or the maintenance immunosuppression therapy., Conclusions: Our results demonstrate evidence for the implication of CD8+ T lymphocytes in the development of ATN early in the post-transplant phase. Post-transplant monitoring of activated CD8+ T lymphocytes may help identify which patients require further clinical intervention to prevent graft damage., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

Background: Donor-specific antibodies (DSAs) are IgG allo-antibodies against mismatched donor HLA molecules and can cause graft failure (GF) in the setting of haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Our aim was to report the experience of the Spanish Group of Hematopoietic Transplant (GETH-TC) in DSA-positive patients who had undergone haplo-HSCT., Methods: We conducted a survey of patients who underwent haplo-HSCT in GETH-TC centers between 2012 and 2021. Data were collected on the DSA assay used, monitoring strategy, complement fixation, criteria for desensitization, desensitization strategies and transplant outcomes., Results: Fifteen centers from the GETH-TC responded to the survey. During the study period, 1,454 patients underwent haplo-HSCT. Seventy of the transplants were performed in 69 DSA-positive patients, all of whom lacked a suitable alternative donor; 61 (88%) patients were female (90% with prior pregnancies). All patients received post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis. Regarding baseline DSA intensity, 46 (67%) patients presented mean fluorescence intensity (MFI) >5,000, including 21 (30%) with MFI >10,000 and three (4%) with MFI >20,000. Six patients did not receive desensitization treatment, four of them with MFI <5,000. Of 63 patients receiving desensitization treatment, 48 (76%) were tested after desensitization therapy, and a reduction in intensity was confirmed in 45 (71%). Three patients (5%) experienced an increase in MFI after desensitization, two of whom experienced primary GF. Cumulative incidence of neutrophil engraftment at day 28 was 74% in a median of 18 days (IQR, 15─20); six patients died before engraftment due to toxicity or infection and eight patients had primary GF despite desensitization in seven of them. After a median follow-up of 30 months, two-year overall and event-free survival were 46.5% and 39%, respectively. The two-year cumulative incidence of relapse was 16% and non-relapse mortality (NRM) was 43%. Infection was the most frequent cause of NRM, followed by endothelial toxicity. Multivariate analysis identified baseline MFI >20,000 as an independent risk factor for survival and an increase in titers after infusion as an independent risk factor for GF., Conclusions: Haplo-HSCT is feasible in DSA-positive patients, with high rates of engraftment after desensitization guided by DSA intensity. Baseline MFI >20,000 and increased intensity after infusion are risk factors for survival and GF., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bailén, Alenda, Herruzo-Delgado, Acosta-Fleitas, Vallés, Esquirol, Fonseca, Solán, Sánchez-Vadillo, Bautista, Bento, López-Godino, Pérez-Martínez, Torrent, Zanabili, Calbacho, Moreno, Pascual-Cascón, Guerra-Domínguez, Chinea, García-Cadenas, López-Corral, Boix-Giner, López Lorenzo, Humala, Duarte, Sampol, Heras, Vicario, Balas, Oarbeascoa, Fernández-Caldas, Anguita and Kwon.)

Background and Purpose: Studies using intermittent-access drug self-administration show increased motivation to take and seek cocaine and fentanyl, relative to continuous access. In this study, we examined the effects of intermittent- and continuous-access self-administration on heroin intake, patterns of self-administration and cue-induced heroin-seeking, after forced or voluntary abstinence, in male and female rats. We also modelled brain levels of heroin and its active metabolites., Experimental Approach: Rats were trained to self-administer a palatable solution and then heroin (0.075 mg·kg -1 per inf) either continuously (6 h·day -1 ; 10 days) or intermittently (6 h·day -1 ; 5-min access every 30-min; 10 days). Brain levels of heroin and its metabolites were modelled using a pharmacokinetic software. Next, heroin-seeking was assessed after 1 or 21 abstinence days. Between tests, rats underwent either forced or voluntary abstinence. The oestrous cycle was measured using a vaginal smear test., Key Results: Intermittent access exacerbated heroin self-administration and was characterized by a burst-like intake, yielding higher brain peaks of heroin and 6-monoacetylmorphine concentrations. Moreover, intermittent access increased cue-induced heroin-seeking during early, but not late abstinence. Heroin-seeking was higher in females after intermittent, but not continuous access, and this effect was independent of the oestrous cycle., Conclusions and Implications: Intermittent heroin access in rats resembles critical features of heroin use disorder: a self-administration pattern characterized by repeated large doses of heroin and higher relapse vulnerability during early abstinence. This has significant implications for refining animal models of substance use disorder and for better understanding of the neuroadaptations responsible for this disorder., Linked Articles: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc., (© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The process and evolution of an organ transplant procedure has evolved in terms of the prevention of immunological rejection with the improvement in the determination of immune response genes. These techniques include considering more important genes, more polymorphism detection, more refinement of the response motifs, as well as the analysis of epitopes and eplets, its capacity to fix complement, the PIRCHE algorithm and post-transplant monitoring with promising new biomarkers that surpass the classic serum markers such as creatine and other similar parameters of renal function. Among these new biomarkers, we analyze new serological, urine, cellular, genomic and transcriptomic biomarkers and computational prediction, with particular attention to the analysis of donor free circulating DNA as an optimal marker of kidney damage.

A single nucleotide polymorphism in intron 1 determines the new HLA-A*23:01:01:27 allele., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Persistent organic pollutants (POPs) can reach the fetal brain and contribute to developmental neurotoxicity. To explore the distribution of POPs to the fetal brain, we exposed chicken embryos to a POP mixture, containing 29 different compounds with concentrations based on blood levels measured in the Scandinavian human population. The mixture was injected into the allantois at embryonic day 13 (E13), aiming at a theoretical concentration of 10 times human blood levels. POPs concentrations in the brain were measured at 0.5, 1, 2, 4, 6, 24, 48, and 72 h after administration. Twenty-seven of the individual compounds were detected during at least one of the time-points analyzed. Generally, the concentrations of most of the measured compounds were within the order of magnitude of those reported in human brain samples. Differences in the speed of distribution to the brain were observed between the per- and polyfluoroalkyl substances (PFASs), which have protein binding potential, and the lipophilic polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and brominated flame retardants (BFRs). Based on pharmacokinetic modeling, PFASs were best described by a one compartment model. PFASs displayed relatively slow elimination (Kel) and persisted at high levels in the brain. Lipophilic OCPs and PCBs could be fitted to a 2-compartment model. These showed high levels in the brain relative to the dose administrated as calculated by area under the curve (AUC)/Dose. Altogether, our study showed that chicken is a suitable model to explore the distribution of POPs into the developing brain at concentrations which are relevant for humans., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: To study whether the preparation procedure, and its acidic and heating conditions, used by heroin users to prepare heroin for intravenous administration affects the final composition of the fluid to be injected., Methods: Samples from different seizures of illegal heroin provided by the Norwegian police were prepared by adding water and ascorbic acid before heating under controlled conditions in the laboratory. Further, three seizures were prepared with different amounts of ascorbic or citric acid relative to their diacetylmorphine content. Pure diacetylmorphine base or salt was also submitted to the procedure applying two different heating intensities. The seizures and the final product after preparation were analysed for diacetylmorphine, 6-acetylmorphine and morphine using liquid chromatography with tandem mass spectrometry (LC-MS-MS)., Results: After preparation, a decrease of 19.8% (25th and 75th percentiles = -29.2 and -15.3) in the initial diacetylmorphine content was observed. Both the 6-acetylmorphine and morphine content increased but, due to their low content in the initial product, diacetylmorphine still represented 83.9% (25th and 75th percentiles = 77.3 and 88.0) of the sum of these three opioids in the final solution. The loss of water during preparation caused an increase in the concentration of diacetylmorphine, 6-acetylmorphine and morphine, depending on the heating intensity applied. The content of these opioids was affected by the quantity and type of acid added in relation to the heroin purity and the level of diacetylmorphine dissolved being proportional to the amount of ascorbic acid, but not citric acid, in the sample with high heroin purity., Conclusions: Preparation of heroin for intravenous injection appears to change the amount or concentration of diacetylmorphine and its active metabolites, 6-acetylmorphine and morphine in the final product, depending on heroin purity, amount and type of acid used or heating conditions. These circumstances can contribute to unintentional variations in the potency of the final injected solution, and therefore affect the outcome after injection., (© 2021 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

A single nucleotide substitution in exon 3 of HLA-DQB1*06:03:01 results in a new allele, HLA-DQB1*06:03:27., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mixed acute rejection is a clinicopathological entity that is difficult to accurately diagnose, and so may be under-reported. Allografts are lost more often than in either humoral or cellular rejection. The diagnosis requires both histological and immunological studies on renal biopsy and blood specimens from the transplant recipient to provide the required rescue therapy to abolish the allogeneic response against the graft. We present a clinical case report of an active mixed acute rejection driven by a de novo donor-specific complement-binding anti-DQB1*03:01 antibody and intraepithelial CD8 T-cells in a patient with a kidney transplant. The patient was diagnosed, treated, and followed up as per the local institution's procedure with a full recovery of graft function. Our case emphasises the challenge of a mixed acute rejection and supports the need to improve the post-transplant outcome of recipients and their grafts.

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

A single nucleotide substitution in exon 3 of HLA-DPB1*105:01 results in a new allele, HLA-DPB1*571:01., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The kidney allograft biopsy is considered the gold standard for rejection diagnosis but is invasive and could be indeterminate. Several publications point to the role of miRNA expression in suggesting its involvement in the acceptance or rejection of organ transplantation. This study aimed to analyze microRNAs involved in the differentiation and activation of B and T lymphocytes from kidney transplant (KT) patients' peripheral blood leukocytes to be used as biomarkers of acute renal rejection (AR)., Methods: A total of 15 KT patients with and without acute rejection (AR/NAR) were analyzed and quantified by miRNA PCR array. A total of 84 miRNAs related to lymphocyte differentiation and activation B and T were studied. The functions and biological pathways were analyzed to predict the potential targets of differential expressed miRNAs., Results: Six miRNA were increased in the AR group (miR-191-5p, miR-223-3p, miR-346, miR-423-5p, miR-574-3p, and miR-181d) and miR-150-5p was increased in the NAR group. In silico studies showed a total of 2603 target genes for the increased miRNAs in AR, while for the decrease miRNA, a total of 1107 target-potential genes were found., Conclusions: Our results show that KT with AR shows a decrease in miR-150-5p expression compared to NAR, suggesting that the decrease in miR-150-5p could be related to an increased MBD6 whose deregulation could have clinical consequences.