Therapie. 2022 Jan 23:S0040-5957(22)00014-2. doi: 10.1016/j.therap.2022.01.012. Online ahead of print.

NO ABSTRACT

PMID:35148894 | DOI:10.1016/j.therap.2022.01.012

Pharmacogenomics. 2022 Feb 11. doi: 10.2217/pgs-2021-0144. Online ahead of print.

ABSTRACT

Background: The aim of this study was to evaluate the association between well-defined genetic risk variants in SLC28A3, RARG and UGT1A6 and anthracycline-induced cardiotoxicity in Mexican pediatric patients. Methods: We tested a cohort of 79 children treated with anthracyclines for the presence of SLC28A3-rs7853758, RARG-rs2229774 and UGT1A6-rs17863783. Results: The SLC28A3-rs7853758 variant was more frequent in this cohort, while the UGT1A6-rs17863783 and RARG-rs2229774 variants were present at lower frequencies. A clinically important decrease of fractional shortening was associated with SLC28A3-rs7853758 variant. Conclusion: In this cohort, 39.2% of patients carried the protective SLC28A3 variant. A small number of tested patients have the risk variants of UGT1A6 and RARG. None of the patients shared the two risk variants.

PMID:35147047 | DOI:10.2217/pgs-2021-0144

Pharmacogenomics. 2022 Feb 11. doi: 10.2217/pgs-2022-0008. Online ahead of print.

NO ABSTRACT

PMID:35147039 | DOI:10.2217/pgs-2022-0008

Br J Clin Pharmacol. 2022 Feb 10. doi: 10.1111/bcp.15270. Online ahead of print.

ABSTRACT

CLOVES syndrome is a rare congenital overgrowth disorder caused by mutations in the phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) gene. It is part of the PIK3CA-related overgrowth syndrome (PROS) spectrum and its treatment is challenging. PROS malformations have traditionally been treated by surgery, but research into pharmacological treatments capable of blocking the PIK/AKT/mTOR pathway has increased over the past decade. The results have been promising and suggest that compassionate use of these treatments in patients with PROS disorders could have clinical benefits. Another promising drug is alpelisib (BYL719), which is a selective inhibitor that competitively binds to the p110a subunit of PIK3 in the intracellular PI3K/AKT signaling pathway. Compassionate use of low-dose alpelisib had striking effects in an uncontrolled case series of 19 PROS patients, several with life-threatening complications. Moreover, there were few adverse effects and the treatment did not impair linear growth, despite the young age of many of the patients. We present the case of a patient with CLOVES syndrome who was started on compassionate treatment with alpelisib after surgical debulking of a cystic lymphangioma and treatment with sirolimus. This promising drug significantly reduced the size of the lymphangioma and prevented progression of the tissue overgrowth in the gluteal region. This case suggests that low-dose PI3K inhibition may provide collateral benefits that extend beyond mitigation of disease-specific features of PROS.

PMID:35146800 | DOI:10.1111/bcp.15270

Mol Genet Genomics. 2022 Feb 11. doi: 10.1007/s00438-022-01855-9. Online ahead of print.

ABSTRACT

Previous studies have shown that the frequency of very important pharmacogenomic (VIP) genes varies in different populations which leads to the diversities in drug efficacy, safety, and the risk associated with adverse drug reactions (ADRs). The purpose of this study was to identify the distribution differences of VIP variants between the Li population and the other 13 populations. Based on the Pharmacogenomics Knowledgebase database (PhamGKB), we successfully genotyped 52 VIP variants within 27 genes in 200 unrelated Li population. χ2 test was used to evaluate the significant differences of genotype and allele frequencies between the Li and the other 13 populations from 1000 Genomes Project. Our study showed that the genotype frequencies of single nucleotide polymorphisms (SNPs) on KCNH2, ACE, CYP4F2, and CYP2E1 were considerably different between Li and the other 13 populations, especially in rs1805123 (KCNH2), rs4291 (ACE), rs3093105 (CYP4F2), and rs6413432 (CYP2E1) loci. Meanwhile, we found several VIP variants that might alter the drug metabolism of cisplatin-cyclophosphamide (CYP2E1), vitamin E (CYP4F2), asthma amlodipine, chlorthalidone, and lisinopril (ACE) through PharmGKB. We also identified other variants which were associated with adverse effects in isoniazid and rifampicin (CYP2E1; hepatotoxicity). The four loci rs1805123 (KCNH2), rs4291 (ACE), rs3093105 (CYP4F2), and rs6413432 (CYP2E1) provided a reliable basis for the prediction of the efficacy of certain drugs. The study complemented the existed pharmacogenomics information, which could provide theoretical basis for predicting the efficacy of certain drugs in the Li population.

PMID:35146537 | DOI:10.1007/s00438-022-01855-9

Cureus. 2022 Feb 2;14(2):e21834. doi: 10.7759/cureus.21834. eCollection 2022 Feb.

ABSTRACT

Clinical manifestations of biological aging can be remarkably similar to the side effects of frequently used medications. Fatigue, muscle pain, and confusion are common and often not shared as part of proper geriatric patient history. When patients report them, a root cause is usually confounding. These symptoms not only negatively impact health and wellness outcomes, patient quality of life, and increase costs to the healthcare system, but also may be a limitation on provider best practices. The patient, a 71-year-old female of European descent, enrolled in pharmacogenomics-enriched comprehensive medication management (PGx+CMM) program through her retirement benefit. At the time of testing, she was approximately 18 months post cerebrovascular accident and was being observed by her primary care provider for common chronic conditions. Of interest, she had been manifesting unreported clinical symptoms of fatigue, hypotension, and myalgia. Addressing these patient concerns and specifically focusing on an individual's goals, fears, and basic needs, rather than concentrating merely on the absence of disease, is the crux of personalized medicine and programs that address the notion of healthy aging. The patient's therapeutic regimen was adjusted based on PGx+CMM pharmacist review, use of a clinical decision support system (CDSS), and communication of recommendations to the prescribing physician. The patient saw rapid improvements in symptoms, suggesting they were caused by medication side effects. Her blood pressure and cholesterol levels remained controlled while noticeable side effects were eliminated. This case study demonstrates the positive impacts of personalized medicine and shows how pharmacists can be empowered with a CDSS to positively impact healthcare.

PMID:35145831 | PMC:PMC8809208 | DOI:10.7759/cureus.21834

Am J Cancer Res. 2022 Jan 15;12(1):337-354. eCollection 2022.

ABSTRACT

Acquired resistance and clonal heterogeneity are critical challenges in cancer treatment, and the lack of effective computational tools hampers the discovery of new treatments to overcome resistance. Using high-throughput transcriptomic databases of compound perturbation profiles, we have developed a bioinformatic strategy for identifying candidate drugs to overcome resistance with combinatorial therapy. We devised this strategy during an investigation into the acquired resistance against PARP inhibitors (PARPi) in a triple-negative inflammatory breast cancer cell line. In this study, we derived multiple PARPi-resistant clones and characterized their transcriptomic adaptations compared to the parental clone. The transcriptomes of the resistant clones showed substantial heterogeneity, highlighting the importance of characterizing multiple clones from the same tumour. Surprisingly, we found that these transcriptomic changes may not actually confer PARPi resistance, but they may nevertheless induce a shared secondary vulnerability. By modeling our data in relation to transcriptomic perturbation profiles of compounds, we uncovered deficiencies in Ras signaling that resulted from transcriptional adaptation to long-term PARPi treatment across multiple resistant clones. Due to these induced deficiencies, we predicted that the resistant clones would be sensitive to pharmacological reinforcement of PARPi-induced transcriptional adaptation. We then experimentally validated this predicted vulnerability that is shared by multiple resistant clones. Our results thus provide a promising paradigm for integrating transcriptomic data with compound perturbation profiles in order to identify drugs that can exploit an induced vulnerability and overcome therapeutic resistance, thus providing another strategy towards precision oncology.

PMID:35141022 | PMC:PMC8822293

Front Pharmacol. 2022 Jan 24;12:834129. doi: 10.3389/fphar.2021.834129. eCollection 2021.

ABSTRACT

Tardive dyskinesia is a severe motor adverse event of antipsychotic medication, characterized by involuntary athetoid movements of the trunk, limbs, and/or orofacial areas. It affects two to ten patients under long-term administration of antipsychotics that do not subside for years even after the drug is stopped. Dopamine, serotonin, cannabinoid receptors, oxidative stress, plasticity factors, signaling cascades, as well as CYP isoenzymes and transporters have been associated with tardive dyskinesia (TD) occurrence in terms of genetic variability and metabolic capacity. Besides the factors related to the drug and the dose and patients' clinical characteristics, a very crucial variable of TD development is individual susceptibility and genetic predisposition. This review summarizes the studies in experimental animal models and clinical studies focusing on the impact of genetic variations on TD occurrence. We identified eight genes emerging from preclinical findings that also reached statistical significance in at least one clinical study. The results of clinical studies are often conflicting and non-conclusive enough to support implementation in clinical practice.

PMID:35140610 | PMC:PMC8819690 | DOI:10.3389/fphar.2021.834129

Pharmgenomics Pers Med. 2022 Feb 2;15:81-89. doi: 10.2147/PGPM.S335860. eCollection 2022.

ABSTRACT

PURPOSE: Clopidogrel is widely used in coronary artery, peripheral arterial, and cerebrovascular disease. We aimed to study the association of the CYP2C19 phenotype with cardiovascular outcomes and interventional procedures in a hospital-based population.

PATIENTS AND METHODS: This cross-sectional, retrospective study enrolled patients with prior exposure to clopidogrel at the Taichung Veterans General Hospital (TCVGH) using data extracted from the Taiwan Precision Medicine Initiative (TPMI). Data on the CYP2C19 phenotype, drug-prescription profile, comorbidities, vascular intervention procedures, and hospitalization due to acute myocardial infarction (AMI) or stroke of clopidogrel users were analyzed.

RESULTS: From the 32,728 patients in the TCVGH-TPMI cohort, we selected 2687 clopidogrel users. A total of 400 (14.9%) clopidogrel poor metabolizers (PMs), 1235 (46.0%) intermediate metabolizers (IMs), and 1052 (39.2%) extensive metabolizers (EMs) were identified. The predominant loss-of-function allele is *2. In 2687 patients with clopidogrel exposure, the CYP2C19 PM phenotype was unassociated with hospitalization due to AMI or stroke after adjusting for comorbidities and carotid angiographies. Among the 1554 clopidogrel users who underwent cardiovascular intervention, 193 (12.4%) received two or more types of interventional procedures. Compared with non-PMs, patients with the PM phenotype had a higher risk of multiple carotid interventions (OR: 3.13, 95% CI: 1.19-8.22).

CONCLUSION: In this hospital-wide cohort, 8.2% were clopidogrel users, of which 14.9% were CYP2C19 PMs. The result of this study does not support universal genotyping of CYP2C19 in all clopidogrel users to identify risks for stroke and AMI. CYP2C19 PMs are more likely to undergo multiple carotid interventions than non-PMs. Prospective studies to investigate the association of the CYP2C19 genotype and carotid interventions and outcomes are needed to validate our results.

PMID:35140503 | PMC:PMC8819696 | DOI:10.2147/PGPM.S335860

J Child Adolesc Psychopharmacol. 2022 Feb 9. doi: 10.1089/cap.2021.0027. Online ahead of print.

ABSTRACT

Objectives: The decision to prescribe a medication and the choice of which one are often complex, particularly in the field of child and adolescent psychiatry where evidence is scarce. The aim of this review is to provide a synthesis of psychotropic drugs approved in children and adolescents for psychiatric indications in several countries. Methods: All psychopharmacological treatments used in child and adolescent psychiatry, approved by at least one regulatory agency from Switzerland, the United Kingdom, France, the European Union, or the United States, were considered. A comprehensive review of the summaries of product characteristics was performed. Results: A total of 143 psychotropic drugs were included: 47 anxiolytics/hypnotics, 45 antidepressants, 37 antipsychotics, 10 medications for attention-deficit/hyperactivity disorder (ADHD), and 4 mood stabilizers. Only a few of these drugs were approved for use in children or adolescents (38%) at least for a single psychiatric diagnosis in at least one country. The therapeutic class with the lowest rate of approved status was antidepressants (20%), followed by mood stabilizers (25%), anxiolytics/hypnotics (28%), antipsychotics (57%), and medications for ADHD (100%). Important differences in approved diagnoses, ages, and doses were observed between regulatory agencies. Tables presenting drugs for approved diagnoses based on age and regulatory agencies are presented in this article. Drugs classified by regulatory agencies, with complete data on diagnoses, ages, doses, pharmaceutical forms, and particular restrictions, are presented as Supplementary Material. Conclusion: This article provides an overview to prescribers with respect to the approved medications in children and adolescents in selected European countries and the United States.

PMID:35138922 | DOI:10.1089/cap.2021.0027

Ned Tijdschr Geneeskd. 2022 Jan 24;166:D6172.

ABSTRACT

Although current literature indicates both a clinical and a cost-effective benefit of routine genotype-guided treatment of patients treated with clopidogrel, this strategy is not recommended in guidelines. In cardiology, but also in neurology and vascular surgery, the current scientific evidence for this is still insufficient. Nevertheless, the role of pharmacogenetics will gain importance in today's medical world, where the demand for personalised medicine is on the rise. The implementation of genotyping in the clinic will nonetheless be a practical challenge due to a lack of clarity about who will bear the associated costs. In patients with coronary artery disease and a higher bleeding risk, it is valuable to determine the CYP2C19 genotype prior to treatment with clopidogrel. Pending further studies, we recommend that specialists prescribing clopidogrel should determine the CYP2C19 genotype in patients at high risk of recurrent ischemic events.

PMID:35138719

J Oncol Pharm Pract. 2022 Feb 9:10781552221076456. doi: 10.1177/10781552221076456. Online ahead of print.

ABSTRACT

INTRODUCTION: high dose methotrexate (HD-MTX) regimen is used in osteosarcoma, leukemia and lymphoma treatment. Osteosarcoma is mostly diagnosed in children and adolescents. Most frequent methotrexate toxicities are mucositis, myelosuppression, renal failure, hepatitis and necrotizing encephalopathy. Toxicities increase with renal impairment, denutrition, in older patients, with some pharmacogenetics factors or with drug interactions.

CASE REPORT: We report a 16th years old woman diagnosed with osteosarcoma and experienced an unexpected severe hepatic and skin toxicities as toxic epidermal necrolys, Steven Johnson syndrome.

MANAGEMENT AND OUTCOME: This toxicity occurred despite acid folinic rescue performed as good practice recommendation. Fourteen hours after methotrexate administration, renal failure was observed and after 72 h an erythematous rash and epidermal detachment with toxic epidermal necrolys. Seven days after methotrexate administration, hepatic failure began until grade IV cytolysis. High dose of folinic acid were administered during all severe toxicities. Methotrexate were not longer administered to this young patient and chemotherapy with ifosfamide (IFO), doxorubicine and cisplatin were performed in this patient and complete histologic response were observed in the surgical bone resection.

DISCUSSION: No classical toxicities risk factors were identified in this patient but a homozygote mutation of MTHFR gene and homozygote SLCO1B1 gene mutation were found. MTHFR and SLCO1B1 are both implicated in methotrexate metabolism.

PMID:35138194 | DOI:10.1177/10781552221076456

Hum Reprod. 2022 Feb 8:deac021. doi: 10.1093/humrep/deac021. Online ahead of print.

ABSTRACT

STUDY QUESTION: Does oxidative stress (OS) activate autophagy in human sperm?

SUMMARY ANSWER: Human spermatozoa subjected to OS activate an autophagic response.

WHAT IS KNOWN ALREADY: Autophagy is a regulated pathway of lysosomal degradation which helps eukaryotic cells to maintain or restore homeostasis, being a cellular stress response mechanism. OS is a main cause of impaired sperm function and is linked to male infertility; however, whether OS activates autophagy in human spermatozoa is unknown.

STUDY DESIGN, SIZE, DURATION: Human spermatozoa were exposed separately to ionomycin and hydrogen peroxide in order to induce OS. An untreated control group was included. Sperm cells under OS were then exposed to chloroquine in order to block autophagy. An untreated control and a control incubated only with the OS inducer were included in each experimental setting.

PARTICIPANTS/MATERIALS, SETTING, METHODS: For this study, semen samples from normozoospermic donors were used and motile sperm cells were selected by the swim up technique. First, the generation of OS under our experimental conditions was demonstrated by analyzing sperm parameters including viability, reactive oxygen species (ROS) production, mitochondrial membrane potential (ΔΨm) motility and thiol oxidation. Then, proteins involved in autophagy, including the microtubule-associated protein light chain 3 (LC3), particularly LC3-I and LC3-II, autophagy-related 5 (ATG5) and autophagy-related 16 (ATG16) proteins as well as the phosphorylated form of AMP-activated protein kinase (pAMPK) were evaluated in spermatozoa exposed to OS and compared to the untreated control. Finally, the impact of autophagy blocking by chloroquine treatment on sperm quality, metabolic parameters, including glycolysis and oxidative phosphorylation, as well as the cell death markers phosphatidylserine externalization and caspase activation was analyzed. Sperm quality parameters, cell death markers and autophagy-related proteins were analyzed by flow cytometry. Motility was evaluated by the computer-assisted sperm analysis system and metabolic parameters were analyzed using an extracellular flux analyzer.

MAIN RESULTS AND THE ROLE OF CHANCE: Exposure to ionomycin and hydrogen peroxide promotes OS resulting in increased ROS production and decreased viability, ΔΨm and motility, while increasing thiol oxidation. These alterations were accompanied by a decrease in LC3-I, indicating that autophagy was activated upon OS exposure. Ionomycin also caused an increase in LC3-II, ATG5, ATG16 and pAMPK content. Autophagy blocking of sperm exposed to OS caused deterioration in sperm quality and metabolic parameters as well as an increase in cell death markers.

LARGE SCALE DATA: N/A.

LIMITATIONS, REASONS FOR CAUTION: The study was carried out in vitro using motile sperm from normozoospermic donors; tests on sperm from infertile patients were not carried out. The autophagy blocking plus OS might generate a non-specific response to a highly stressful situation leading to the induction of cell death.

WIDER IMPLICATIONS OF THE FINDINGS: Human spermatozoa subjected to OS activate an autophagic response and its blockage results in increased oxidative damage and commits spermatozoa to cell death. These results suggest a crucial role of autophagy as a stress response by male gametes, which contributes to maintaining the functionality and lifespan of ejaculated sperm cells. Detection of autophagy activation in sperm cells ex vivo could be included in semen analysis as a marker of OS, especially in men displaying high levels of seminal ROS. Novel strategies that aim to activate this cellular stress response could improve sperm quality/functionality under natural ejaculate conditions in which increased ROS levels are expected.

STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Fondo Nacional de Investigación Científica y Tecnológica, Chile (ANID/FONDECYT, Grant number 11170758 to P.U.); the Comisión Nacional de Investigación Científica y Tecnológica, Chile (ANID/CONICYT, Grant number PAI79160030 to P.U.) and the Dirección de Investigación, Universidad de La Frontera. The authors disclose no potential conflicts of interest.

PMID:35137097 | DOI:10.1093/humrep/deac021

F1000Res. 2021 Mar 30;10:259. doi: 10.12688/f1000research.26828.1. eCollection 2021.

ABSTRACT

Background: Genetic testing in clinical trials introduces several ethical and logistical issues to discuss with potential participants when taking informed consent. The aim of this study was to explore the attitudes of healthy volunteers in phase 1 studies to the topics of genetic security, genetic privacy and incidental genetic findings. Methods: Healthy volunteers presenting for screening appointments at a phase 1 clinical trial unit (CMAX Clinical Research, Adelaide, Australia) took an anonymous paper survey about genetic testing. Results: There were 275 respondents to the survey. The mean age was 27 years (range 18-73); 54% were male and 53% were of North/Western European ethnicity. Just over half the healthy volunteers thought genetic security (56%) and genetic privacy (57%) were "important" or "very important". However, the security of their genetic information was ranked less important than other personal information, including mobile phone number, internet browser search history and email address. Two-thirds of respondents would trade genetic privacy for re-identifiability if information relevant to their health were discovered by genetic testing. Healthy volunteers favoured the return of incidental genetic findings (90% indicated this was "important" or "very important"). A level of risk (10 to 90%) for developing a serious medical condition that would "trigger" the return of incidental genetic findings to participants was not identified. Conclusions: Healthy volunteers screening for phase 1 clinical trials have mixed views about the importance of genetic security and genetic privacy, but they strongly favour the return of incidental genetic findings that could affect their health. These issues should be discussed with potential participants during informed consent for phase 1 clinical trials with genetic testing.

PMID:35136570 | PMC:PMC8787555 | DOI:10.12688/f1000research.26828.1

Clin Infect Dis. 2022 Feb 4:ciac001. doi: 10.1093/cid/ciac001. Online ahead of print.

ABSTRACT

BACKGROUND: Isoniazid (INH) metabolism depends on the N-acetyl transferase 2 (NAT2) enzyme, whose maturation process remains unknown in low birth weight (LBW) and preterm infants. We aimed to assess INH exposure and safety in infants receiving oral tuberculosis prevention.

METHODS: This population pharmacokinetics (PK) analysis used INH and N-acetyl-isoniazid (ACL) concentrations in infants (BW ≤ 4 kg), including preterm, with follow-up for 6 months. PK parameters were described using nonlinear mixed effects modeling. Simulations were performed to assess INH exposure and optimal dosing regimens, using two targets: Cmax at 3-6 mg/L and AUC ≥ 10.52 mg.h/L.

RESULTS: We included 57 infants (79% preterm, 84% LBW) in the PK analysis, with a median (range) gestational age of 34 (28.7-39.4) weeks. At the time of sampling, postnatal age was 2.3 (0.2-7.3) months and weight (WT) was 3.7 (0.9-9.3) kg. NAT2 genotype was available in 43 (75.4%) patients (10 slow, 26 intermediate, and 7 fast metabolizers). Ninety percent of NAT2 maturation was attained by 4.4 post-natal months. WT, postmenstrual age and NAT2 genotype significantly influenced INH exposure, with a 5-fold difference in AUC between slow and fast metabolizers for the same dose. INH appeared safe across the broad range of exposure for 61 infants included in the safety analysis.

CONCLUSIONS: In LBW/preterm infants, INH dosing needs frequent adjustment to account for growth and maturation. Pharmacogenetics-based dosing regimens is the most powerful approach to deliver safe and equalized exposures for all infants, since NAT2 genotype highly impacts INH pharmacokinetic variability.

PMID:35134861 | DOI:10.1093/cid/ciac001

Elife. 2022 Feb 8;11:e70518. doi: 10.7554/eLife.70518. Online ahead of print.

ABSTRACT

Adenylosuccinate Lyase (ADSL) functions in de novo purine biosynthesis (DNPS) and the purine nucleotide cycle. ADSL deficiency (ADSLD) causes numerous neurodevelopmental pathologies, including microcephaly and autism spectrum disorder. ADSLD patients have normal serum purine nucleotide levels but exhibit accumulation of dephosphorylated ADSL substrates, S-Ado and SAICAr, the latter being implicated in neurotoxic effects through unknown mechanisms. We examined the phenotypic effects of ADSL depletion in human cells and their relation to phenotypic outcomes. Using specific interventions to compensate for reduced purine levels or modulate SAICAr accumulation, we found that diminished AMP levels resulted in increased DNA damage signaling and cell cycle delays, while primary ciliogenesis was impaired specifically by loss of ADSL or administration of SAICAr. ADSL deficient chicken and zebrafish embryos displayed impaired neurogenesis and microcephaly. Neuroprogenitor attrition in zebrafish embryos was rescued by pharmacological inhibition of DNPS, but not increased nucleotide concentration. Zebrafish also displayed phenotypes commonly linked to ciliopathies. Our results suggest that both reduced purine levels and impaired DNPS contribute to neurodevelopmental pathology in ADSLD and that defective ciliogenesis may influence the ADSLD phenotypic spectrum.

PMID:35133277 | DOI:10.7554/eLife.70518

J Korean Med Sci. 2022 Feb 7;37(5):e33. doi: 10.3346/jkms.2022.37.e33.

ABSTRACT

BACKGROUND: Tacrolimus is the most commonly used immunosuppressive drug in solid organ transplantation. After administering a conventional twice-daily dose of tacrolimus, peak levels were achieved within the first 1.5 to 2 hours. A group of patients showed different early absorption phase of tacrolimus after kidney transplantation.

METHODS: Trough(C0) and 1.5-hour blood levels (C1.5) of tacrolimus were measured in 95 kidney transplantation recipients. Patients with a C1.5/C0 < 1.5 and > 1.5 were defined as those having flat pattern peaks and as controls, respectively. Transplantation outcomes were compared between the groups. Whole exome sequencing was performed to investigate the genetic susceptibility to flat pattern peaks.

RESULTS: Twenty-eight patients showed flat pattern peaks. The mean C1.5/C0 values were 1.13 ± 0.22 and 3.78 ± 1.25 in the flat pattern peak and control groups, respectively. In multivariate analysis, flat pattern peak was an independent risk factor for biopsy-proven acute rejection (BPAR) and/or borderline change (P = 0.014). Patients having flat pattern peaks showed significantly lower post-transplant 36-month estimated glomerular filtration rate (P = 0.001). Two single nucleotide variants in ABCB1 genes, rs1922242 and rs2235035, were associated with flat pattern peaks (P = 0.019 and P = 0.027, respectively).

CONCLUSION: Both of C1.5 and C0 should be measured to distinguish the patients showing unique initial absorption. A C1.5/C0 ratio lower than 1.5 was associated with an increased risk of BPAR and/or borderline change. Single nucleotide variants s in ABCB1 gene might influence the flat pattern peaks of tacrolimus absorption.

PMID:35132839 | DOI:10.3346/jkms.2022.37.e33

Ann Rheum Dis. 2022 Feb 7:annrheumdis-2021-222007. doi: 10.1136/annrheumdis-2021-222007. Online ahead of print.

NO ABSTRACT

PMID:35131763 | DOI:10.1136/annrheumdis-2021-222007

ESMO Open. 2022 Feb 4;7(1):100381. doi: 10.1016/j.esmoop.2022.100381. Online ahead of print.

NO ABSTRACT

PMID:35131649 | DOI:10.1016/j.esmoop.2022.100381

Expert Rev Mol Diagn. 2022 Feb 7. doi: 10.1080/14737159.2022.2037425. Online ahead of print.

ABSTRACT

INTRODUCTION: The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease has had a catastrophic impact on the world resulting in several deaths. Since World Health Organization declared the pandemic status of the disease, several molecular diagnostic kits have been developed to help the tracking of viruses spread.

AREAS COVERED: This review aims to describe and evaluate the currently reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) diagnosis kit. Several processes used in COVID-19 diagnostic procedures are detailed in further depth to demonstrate optimal practices. Therefore, we debate the main factors that influence the viral detection of SARS-COV-2 and how they can affect the diagnosis of patients.

EXPERT OPINION: Here is highlighted and discussed several factors that can interfere in the RT-PCR analysis, such as the viral load of the sample, collection site, collection methodology, sample storage, transport, primer, and probe mismatch/dimerization in different brand kits. This is a pioneer study to discuss the factor that could lead to the wrong interpretation of RT-qPCR diagnosis of SARS-CoV-2. This study aimed to help the readers to understand what very likely is behind a bad result of SARS-CoV-2 detection by RT-PCR and what could be done to reach a reliable diagnosis.

PMID:35130461 | DOI:10.1080/14737159.2022.2037425