Previous results from our group and others have shown that urinary pellet expression of miR155-5p and urinary CXCL-10 production could play a key role in the prognosis and diagnosis of acute ...rejection (AR) in kidney transplantation patients. Here, a logistic regression model was developed using NONMEM to quantify the relationships of miR155-5p urinary expression, CXCL-10 urinary concentration and tacrolimus and mycophenolic acid (MPA) exposure with the probability of AR in adult kidney transplant patients during the early post-transplant period. Owing to the contribution of therapeutic drug monitoring to achieving target exposure, neither tacrolimus nor MPA cumulative exposure was identified as a predictor of AR in the studied population. Even though CXCL-10 urinary concentration showed a trend, its effect on AR was not significant. In contrast, urinary miR155-5p expression was prognostic of clinical outcome. Monitoring miR155-5p urinary pellet expression together with immunosuppressive drug exposure could be very useful during routine clinical practice to identify patients with a potential high risk of rejection at the early stages of the post-transplant period. This early risk assessment would allow for the optimization of treatment and improved prevention of AR.
Analysis of the genotype that predicts the phenotypic characteristics of a cohort of glaucoma and ocular hypertension patients, and the correlation with their personal pharmacological response to ...beta-blockers (BB) and prostaglandin analogues (PGA). Prospective study that included 139 eyes from 72 patients under BB and/or PGA treatment, and in some cases other types of ocular hypotensive treatments. Five single-nucleotide polymorphisms were genotyped by real-time PCR assays: prostaglandin-F2α receptor (rs3766355, rs3753380); cytochrome-P450 2D6 (rs16947, rs769258); and beta-2-adrenergic receptor (rs1042714). Other studied variables were mean deviation (MD) of visual field, previous ocular interventions, medical treatment, baseline (bIOP), and treated intraocular pressure (tIOP). From a total of 139 eyes, 71 (51.1%) were left eyes. The main diagnosis was primary open angle glaucoma (66.2%). A total of 57 (41%) eyes were under three or more medications (PGA + BB + other) and, additionally, 57 eyes (41%) had had some kind of glaucoma surgery. The mean bIOP and tIOP were 26.55 ± 8.19 and 21.01 ± 5.54 mmHg, respectively. Significant differences in tIOP were found between heterozygous (HT) (21.07 ± 0.607 mmHg) and homozygous (HM) (20.98 ± 0.639 mmHg) rs3766355 with respect to wildtype individuals (16 ± 1.08 mmHg) (
= 0.031). The MD values presented significant differences between wildtype rs3766355 (-2 ± 2.2 dB), HT (-3.87 ± 4 dB), and HM carriers (-9.37 ± 9.51 dB) (
= 0.009). Significant differences were also observed between the MD in wildtype rs3753380 (-6.1 ± 8.67 dB), HT (-9.02 ± 8.63 dB), and HM carriers (-9.51 ± 7.44 dB) (
= 0.017). Patients carrying the variant rs3766355 in HM or HT presented clinically-significantly higher tIOP than wildtype patients. Additionally, some differences in MD were found in rs3766355 and rs3753380 carriers, and the more alleles that were affected, the worse the MD value, meaning greater severity of the glaucoma. Poor response to treatment and more visual field damage may be associated with being a carrier of these mutated alleles.
News strategies for the accurate assessment of the state of immunosuppression (IS) in liver transplant recipients are needed to prevent rejection and minimize drug-related side effects. miRNAs can ...potentially be used as diagnostic or prognostic biomarkers in transplant patients. This study evaluated the capacity of a plasmatic miRNA panel (miR-155-5p, miR-122-5p, miR-181a-5p, and miR148-3p) as an early non-invasive prognostic and diagnostic biomarker for T cell-mediated acute rejection (TCMAR) and subclinical rejection (SCR) in adult liver recipients.
A total of 145 liver recipients were included. All patients received a calcineurin inhibitor with or without mycophenolate mofetil and methylprednisolone. Plasmatic miRNA expression was assessed by qPCR before and at different time-points after liver transplantation.
Seventeen patients experienced TCMAR, and eight were diagnosed with SCR during the protocol biopsy at the 3rd month post-transplantation. Pre-transplantation, miR-155-5p expression was significantly higher in TCMAR patients and in SCR patients than in non-rejectors, and miR-181a-5p expression was also significantly higher in SCR patients than in non-rejectors. Post-transplantation, before transaminase-level modification, significantly increased miR-181a-5p, miR-155-5p, and miR-122-5p expression was observed in TCMAR and SCR patients. Binary logistic regression analyses showed, post-transplantation, that TCMAR risk was better predicted by individual expression of miR-181a-5p (LOGIT = -6.35 + 3.87
miR-181a-5p), and SCR risk was better predicted by the combination of miR-181a-5p and miR-155-5p expression (LOGIT = -5.18 + 2.27
miR-181a-5p+1.74
miR-155-5p).
Pre-transplantation plasmatic miR-155-5p expression may be useful for stratifying low-immunologic-risk patients, and post-transplantation miR-181a-5p and miR-155-5p may be candidates for inclusion in early, non-invasive prognostic biomarker panels to prevent TCMAR or SCR and better identify patient candidates for IS minimization. Large prospective randomized multicenter trials are needed to refine the cut-off values and algorithms and validate the clinical usefulness of these biomarkers.
Tacrolimus (Tac) is pivotal in preventing acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). It has been reported that genetic factors, ...including
*
and
22 polymorphisms, have an impact on Tac metabolism, dose requirement, and response to Tac. There is limited information regarding this topic in alloHSCT. The
genotype and a low Tac trough concentration/dose ratio (Tac C
/D ratio) can be used to identify fast metabolizers and predict the required Tac dose to achieve target concentrations earlier. We examined 62 Caucasian alloHSCT recipients with a fast metabolizer phenotype (C
/dose ratio ≤ 1.5 ng/mL/mg), assessing
genotypes and acute GVHD incidence. Forty-nine patients (79%) were poor metabolizers (2 copies of the variant *3 allele) and 13 (21%) were CYP3A5 expressers (
or
genotypes). CYP3A5 expressers had lower C
at 48 h (3.7 vs. 6.2 ng/mL,
= 0.03) and at 7 days (8.6 vs. 11.4 ng/mL,
= 0.04) after Tac initiation, tended to take longer to reach Tac therapeutic range (11.8 vs. 8.9 days,
= 0.16), and had higher incidence of both global (92.3% vs. 38.8%,
< 0.001) and grade II-IV acute GVHD (61.5% vs. 24.5%,
= 0.008). These results support the adoption of preemptive pharmacogenetic testing to better predict individual Tac initial dose, helping to achieve the therapeutic range and reducing the risk of acute GVHD earlier.
Background & Aims
Nuclear factor of activated T cell‐regulated gene expression (NFAT‐RGE) has been proposed as a pharmacodynamic biomarker for tacrolimus (Tac) and cyclosporine (CsA). Our aim was to ...evaluate the role of NFAT‐RGE in modulating intralymphocytary IL‐2 and IFN‐γ expression and its clinical utility as an early non‐invasive predictive biomarker for the risk of acute rejection (AR) and infection in de novo liver transplant (LT) recipients.
Methods
Fifty‐six LT recipients treated with Tac or CsA with and without mycophenolate mofetil (MMF) were included: 30 free of rejection or infection, 11 rejectors (T cell‐mediated acute rejection), 5 with subclinical rejection (SCR) and 10 with cytomegalovirus (CMV) infection. Within the first 3 months after transplantation, NFAT‐RGE of IL‐2, IFN‐γ and GM‐CSF and intralymphocytary synthesis of IL‐2 and IFN‐γ were evaluated by real‐time PCR and flow cytometry respectively.
Results
A significant increase in NFAT‐RGE was observed in patients who experienced TCMAR (75% 42–100%) or SCR (41% 18–78%) compared with patients without rejection or infection (14% 2–23%). Positive correlations between the %NFAT‐RGE‐IFN and both the %CD8CD69IFN‐γ and %CD4CD69IFN‐γ and between the %NFAT‐RGE‐IL2 and the %CD8CD69IL2 were observed. NFAT‐RGE was significantly lower in CMV+ patients than in non‐infected patients. Finally, an inverse correlation between the Tac or CsA concentration and inhibition of NFAT‐RGE were observed.
Conclusions
Sequential post‐transplantation NFAT‐RGE monitoring combined with intralymphocytary IL‐2 and IFN‐γ before transplantation and at the first and third month post‐transplantation may be key predictive and diagnostic biomarkers for the risk of TCMAR and SCR and better guide CNi therapy in LT patients.
Abstract
Objectives
Physiopathological changes in advanced cirrhosis could alter tigecycline pharmacokinetics (PK), thus affecting serum drug concentrations and compromising target attainment. We ...aimed to describe tigecycline PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target.
Methods
Serum concentrations and covariates were obtained from patients with severe infections under tigecycline treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate tigecycline exposure to assess the PTA.
Results
Twenty critically ill patients were enrolled in the study. Data were best described by a two-compartment linear model. Mean ± SD parameter estimates for clearance (CL), intercompartmental clearance (Q), central and peripheral volumes of distribution (V1 and V2) were 14.8 ± 11 L/h, 38.4 ± 24 L/h, 63.7 ± 14 L and 233 ± 30 L, respectively. MELD score significantly influenced tigecycline CL, and total serum proteins significantly affected V1. Monte Carlo simulations showed that tigecycline elimination is hampered as MELD score values increase, consequently requiring lower drug doses. Patients with hypoproteinaemia would have lower peak tigecycline concentrations but similar steady-state concentrations compared with patients with normoproteinaemia.
Conclusions
Our study confirms that tigecycline dose adjustment is needed in severe hepatic dysfunction and suggests using the MELD score for dose optimization since it is identified as a covariate that significantly influences tigecycline CL. Dosing regimens are recommended to reach several PK/PD targets considering this clinical variable and any MIC within the susceptibility range.
Tacrolimus (Tac) is pivotal in preventing acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (alloHSCT). It has been reported that genetic factors, ...including CYP3A5 *3 and CYP3A4* 22 polymorphisms, have an impact on Tac metabolism, dose requirement, and response to Tac. There is limited information regarding this topic in alloHSCT. The CYP3A5 genotype and a low Tac trough concentration/dose ratio (Tac Csub.0 /D ratio) can be used to identify fast metabolizers and predict the required Tac dose to achieve target concentrations earlier. We examined 62 Caucasian alloHSCT recipients with a fast metabolizer phenotype (Csub.0 /dose ratio ≤ 1.5 ng/mL/mg), assessing CYP3A5 genotypes and acute GVHD incidence. Forty-nine patients (79%) were poor metabolizers (2 copies of the variant *3 allele) and 13 (21%) were CYP3A5 expressers (CYP3A5*1/*1 or CYP3A5*1/*3 genotypes). CYP3A5 expressers had lower Csub.0 at 48 h (3.7 vs. 6.2 ng/mL, p = 0.03) and at 7 days (8.6 vs. 11.4 ng/mL, p = 0.04) after Tac initiation, tended to take longer to reach Tac therapeutic range (11.8 vs. 8.9 days, p = 0.16), and had higher incidence of both global (92.3% vs. 38.8%, p < 0.001) and grade II-IV acute GVHD (61.5% vs. 24.5%, p = 0.008). These results support the adoption of preemptive pharmacogenetic testing to better predict individual Tac initial dose, helping to achieve the therapeutic range and reducing the risk of acute GVHD earlier.
Meropenem is a β-lactam antibiotic frequently used to treat serious infections in intensive care unit patients. The main objective was to develop and validate a sensitive and specific ultra high ...performance liquid chromatography method with photodiode array detection for the quantitation of meropenem in human plasma. The applicability of the method for meropenem monitoring was also examined.
The validation of the method was performed following the FDA's guidelines for bioanalytical methods. In parallel, the method was applied for monitoring meropenem in forty plasma samples from ten critically ill patients treated intravenously at a total dose of 1g. Drug levels were measured in each patient at 0h, 2h, 4h and 8h after meropenem infusion.
With this method, intraday and day-to-day variation was below 10%; intraday and day-to-day accuracy was between 94% and 114%; the limit of quantification was 0.5μg/mL and recovery was above 70%. The method was successfully applied to quantitate meropenem concentrations and the results showed significant pharmacokinetic interindividual variability. Of special interest is that 50% of treated patients had meropenem plasma levels below the minimum inhibitory concentration at 8h after the start of infusion, which was strongly related to creatinine clearance >60mL/min.
The method meets the requirements to be applied for meropenem concentration measurements in pharmacokinetics studies and clinical routine. The results suggest the need for therapeutic drug monitoring of meropenem in treated critically-ill patients.
•We report a UHPLC method for the determination of meropenem levels in human plasma.•The method is precise, accurate and sensitive despite using a low volume of sample.•May be an acceptable alternative to mass spectrometry in clinical laboratories•A high proportion of critically ill patients present low meropenem exposure.•Monitoring meropenem plasma concentrations may be considered in critical patients.
Abstract The mayor goal still outstanding into the solid organ transplantation field involves the search of surrogate biomarkers able to predict several clinical events, such as acute rejection (AR) ...or opportunistic infection. In the present multicenter study, a series of interesting surface antigens with important activator or inhibitory immune functions on cultured peripheral T cells were monitored in liver transplant recipients drawn at baseline and up to one year after transplantation. Sixty-four patients were included in the multicenter study during 3 years. Pre- and post-transplantation surface antigens levels displayed significant differences between AR and non acute rejection (NAR) groups, and also this differential expression was used to construct a risk predictive model based on a composite panel of outcome biomarkers (CD38, CD69, CD95 and CD154). The model was able to stratify these patients at high risk of AR. These preliminary results could provide basic information to improve the immunosuppressive treatment and it might better help to predict AR episodes.
Abstrak
Indonesia dikenal sebagai masyarakat beragam dari aspek budaya, suku bangsa, ras dan agama. Keberagaman menjadi aset bangsa namun bisa menimbulkan friksi dan berakhir dengan konflik yang ...mengganggu integrasi bangsa. Hasil beberapa penelitian menunjukkan guru belum optimal dalam memberikan pemahaman tentang makna toleransi kepada siswa. Tujuan PkM meningkatkan kompetensi guru agama untuk meminimalkan sikap intoleran dengan pendekatan pendidikan multikultural. Jumlah peserta 50 orang, mengajar agama Islam, Kristen, Katolik, Buddha, dan Hindu. Metode pelatihan: pembahasan konsep, pemutaran video, diskusi kelompok, diskusi kelas dan membuat rencana tindak lanjut. Hasil PkM menunjukkan adanya peningkatan pemahaman peserta tentang pendidikan multikultural. Ini berdampak pada kesadaran guru bahwa peran guru dan materi ini sangat dibutuhkan dalam kehidupan bermasyarakat, bangsa dan negara. Peserta merancang kegiatan pembelajaran dengan pendekatan multikultural yang didampingi oleh tim PkM.
Kata kunci: guru, pendidikan multikultural, strategi pembelajaran
Abstract
Indonesian society is known as a diverse society both in terms of culture, ethnicity, race and religion. Diversity is an asset of the nation, but it can cause friction and end in conflicts that disrupt national integration. The results of several studies show that teachers are not optimal in providing an understanding of the meaning of tolerance to students. The aim of this community service (PkM) is to increase the competence of religious teachers to minimize intolerant attitudes with a multicultural education approach in the classroom. The number of participants was 50 people teach Islam, Christianity, Catholicism, Buddhism, and Hinduism. The training methods include discussing concepts, watching videos, group discussions, class discussions and making follow-up plans. The results of the PkM showed an increase in participants' understanding of multicultural education. This has an impact on teachers' awareness that the role of teachers and materials is very important and needed in the life of society, nation and state. Participants designed learning activities with a multicultural approach assisted by the PkM team.
Keywords : teacher, multicultural education, learning strategies
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