Neuroimage. 2021 Jul 8:118378. doi: 10.1016/j.neuroimage.2021.118378. Online ahead of print.

ABSTRACT

Humans are highly attuned to patterns in the environment. This ability to detect environmental patterns, referred to as statistical learning, plays a key role in many diverse aspects of cognition. However, the spatiotemporal neural mechanisms underlying implicit statistical learning, and how these mechanisms may relate or give rise to explicit learning, remain poorly understood. In the present study, we investigated these different aspects of statistical learning by using an auditory nonlinguistic statistical learning paradigm combined with magnetoencephalography. Twenty-four healthy volunteers were exposed to structured and random tone sequences, and statistical learning was quantified by neural entrainment. Already early during exposure, participants showed strong entrainment to the embedded tone patterns. A significant increase in entrainment over exposure was detected only in the structured condition, reflecting the trajectory of learning. While source reconstruction revealed a wide range of brain areas involved in this process, entrainment in areas around the left pre-central gyrus as well as right temporo-frontal areas significantly predicted behavioral performance. Sensor level results confirmed this relationship between neural entrainment and subsequent explicit knowledge. These results give insights into the dynamic relation between neural entrainment and explicit learning of triplet structures, suggesting that these two aspects are systematically related yet dissociable. Neural entrainment reflects robust, implicit learning of underlying patterns, whereas the emergence of explicit knowledge, likely built on the implicit encoding of structure, varies across individuals and may depend on factors such as sufficient exposure time and attention.

PMID:34246769 | DOI:10.1016/j.neuroimage.2021.118378

Am J Hum Genet. 2021 Jul 10:S0002-9297(21)00241-X. doi: 10.1016/j.ajhg.2021.06.017. Online ahead of print.

ABSTRACT

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a life-threatening food allergy triggered by wheat in combination with the second factor such as exercise. The identification of potential genetic risk factors for this allergy might help high-risk individuals before consuming wheat-containing food. We aimed to identify genetic variants associated with WDEIA. A genome-wide association study was conducted in a discovery set of 77 individuals with WDEIA and 924 control subjects via three genetic models. The associations were confirmed in a replication set of 91 affected individuals and 435 control individuals. Summary statistics from the combined set were analyzed by meta-analysis with a random-effect model. In the discovery set, a locus on chromosome 6, rs9277630, was associated with WDEIA in the dominant model (OR = 3.95 [95% CI, 2.31-6.73], p = 7.87 × 10-8). The HLA-DPB1∗02:01:02 allele displayed the most significant association with WDEIA (OR = 4.51 [95% CI, 2.66-7.63], p = 2.28 × 10-9), as determined via HLA imputation following targeted sequencing. The association of the allele with WDEIA was confirmed in replication samples (OR = 3.82 [95% CI, 2.33-6.26], p = 3.03 × 10-8). A meta-analysis performed in the combined set revealed that the HLA-DPB1∗02:01:02 allele was significantly associated with an increased risk of WDEIA (OR = 4.13 [95% CI, 2.89-5.93], p = 1.06 × 10-14). Individuals carrying the HLA-DPB1∗02:01:02 allele have a significantly increased risk of WDEIA. Further validation of these findings in independent multiethnic cohorts is needed.

PMID:34246321 | DOI:10.1016/j.ajhg.2021.06.017

Drug Metab Pers Ther. 2021 Jul 12. doi: 10.1515/dmdi-2021-0112. Online ahead of print.

ABSTRACT

OBJECTIVES: One of the key components of ERAS is adequate pain control in the postoperative period. There are no rational schemes for postoperative pain relief. At the same time, adequate postoperative pain relief promotes early activation and early rehabilitation of patients and shortens the duration of the postoperative stay, and does not cause postoperative complications associated with analgesia (weakness, intestinal paresis, nausea and vomiting). The aims of the present study are to assess the possible association of CYP2D6 and CYP2C9 polymorphisms with the efficacy and safety of tramadol and ketorolac in postoperative pain.

METHODS: A total of 107 patients were genotyped for CYP2D6 and CYP2C9 polymorphisms. All patients underwent laparoscopic cholecystectomy. Postoperative pain relief was carried out with ketorolac and tramadol. Postoperative pain syndrome was assessed using a visual analogue scale and McGill pain questionnaire. The profile of side effects was assessed by the dynamics of red blood counts as a possible trigger for the development of gastrointestinal bleeding according to the method of global assessment of triggers.

RESULTS: Pain was statistically significantly lower in CYP2C9*2 carriers, according to visual analogue scale (VAS): after 12 h - by 1.5 (p=0.002); after 24 h - by 1.1 (p=0.012); after 36 h - by 1.05 (p=0.004); after 48 h - by 0.7 (p=0.026). In CYP2C9*3 carriers the results were not statistically significant. In carriers of CYP2D6*4 pain syndromes were higher at all-time intervals, but statistically reliable results were obtained only after 2 h - by 1.01 (p=0.054) and after 24 h - by 0.8 (p=0.035). The profile of adverse reactions for NSAIDs was evaluated by the dynamics of hemoglobin and erythrocyte indices. A more pronounced decrease in the relative difference in hemoglobin levels was noted in CYP2C9*2 and CYP2C9*3 polymorphism carriers - by 1.7 (p=0.00268) and-by 2.2 (p=0.000143), respectively.

CONCLUSIONS: CYP2D6 and CYP2C9 can predict analgesic effectiveness of tramadol and ketorolac. CYP2C9 can predict the risk of gastrointestinal bleeding, including those hidden to ketorolac.

PMID:34246203 | DOI:10.1515/dmdi-2021-0112

Pediatr Blood Cancer. 2021 Jul 10:e29203. doi: 10.1002/pbc.29203. Online ahead of print.

ABSTRACT

BACKGROUND: In vitro data suggest that the growth of rhabdomyosarcoma (RMS) cells is suppressed in a concentration-dependent manner by 4-hydroxycyclophosphamide (4HCY), the principal precursor to the cytotoxic metabolite of cyclophosphamide (CY). Various retrospective studies on the relationship between genes encoding proteins involved in the formation and elimination of 4HCY (i.e., 4HCY pharmacokinetics) and cyclophosphamide (CY) efficacy and toxicity have been conflicting.

PROCEDURES: We evaluated germline pharmacogenetics in 262 patients with newly diagnosed intermediate-risk RMS who participated in one prospective Children's Oncology Group clinical trial, ARST0531. Patients were treated with either vincristine/actinomycin/cyclophosphamide (VAC) or VAC alternating with vincristine/irinotecan (VAC/VI). We analyzed the associations between event-free survival and 394 single-nucleotide polymorphisms (SNP) in 14 drug metabolizing enzymes or transporters involved in 4HCY pharmacokinetics.

RESULTS: Eight SNPs were associated (p-value < .05 by univariate analysis) with 3-year event-free survival; no SNPs survived a false discovery rate < 0.05.

CONCLUSIONS: Our data suggest that a pharmacogenomic approach to therapy personalization of cyclophosphamide in intermediate-risk rhabdomyosarcoma is not viable. Other methods to personalize therapy should be explored.

PMID:34245211 | DOI:10.1002/pbc.29203

Neuromuscul Disord. 2021 Jun 12:S0960-8966(21)00158-9. doi: 10.1016/j.nmd.2021.06.004. Online ahead of print.

ABSTRACT

Biallelic variants in PLEKHG5 have been reported so far associated with different clinical phenotypes including Lower motor neuron disease (LMND) [also known as distal hereditary motor neuropathies (dHMN or HMN) or distal spinal muscular atrophy (DSMA4)] and intermediate Charcot-Marie-Tooth disease (CMT). We report four patients from two families presenting with intermediate CMT and atypical clinical and para-clinical findings. Patients presented with predominant distal weakness with none or mild sensory involvement and remain ambulant at last examination (22-36 years). Nerve conduction studies revealed, in all patients, intermediate motor nerve conduction velocities, reduced sensory amplitudes and multiple conduction blocks in upper limbs, outside of typical nerve compression sites. CK levels were strikingly elevated (1611-3867 U/L). CSF protein content was mildly elevated in two patients. Diffuse bilateral white matter lesions were detected in one patient. Genetic analysis revealed three novel frameshift variants c.1835_1860del and c.2308del (family 1) and c.104del (family 2). PLEKHG5-associated disease ranges from pure motor phenotypes with predominantly proximal involvement to intermediate CMT with predominant distal motor involvement and mild sensory symptoms. Leukoencephalopathy, elevated CK levels and the presence of conduction blocks associated with intermediate velocities in NCS are part of the phenotype and may arise suspicion of the disease, thus avoiding misdiagnosis and unnecessary therapeutics in these patients.

PMID:34244018 | DOI:10.1016/j.nmd.2021.06.004

Transl Oncol. 2021 Jul 6;14(10):101174. doi: 10.1016/j.tranon.2021.101174. Online ahead of print.

ABSTRACT

As the third most common malignancy and the second most deadly cancer, colorectal cancer (CRC) induces estimated 1.9 million incidence cases and 0.9 million deaths worldwide in 2020. The incidence of CRC is higher in highly developed countries, and it is increasing in middle- and low-income countries due to westernization. Moreover, a rising incidence of early-onset CRC is also emerging. The large number of CRC cases poses a growing global public health challenge. Raising awareness of CRC is important to promote healthy lifestyle choices, novel strategies for CRC management, and implementation of global screening programs, which are critical to reducing CRC morbidity and mortality in the future. CRC is a heterogeneous disease, and its subtype affiliation influences prognosis and therapeutic response. An accurate CRC subtype classification system is of great significance for basic research and clinical outcome. Here, we present the global epidemiology of CRC in 2020 and projections for 2040, review the major CRC subtypes to better understand CRC molecular basis, and summarize current risk factors, prevention, and screening strategies for CRC.

PMID:34243011 | DOI:10.1016/j.tranon.2021.101174

Drug Metab Pharmacokinet. 2020 Oct 9;39:100362. doi: 10.1016/j.dmpk.2020.10.001. Online ahead of print.

ABSTRACT

Sorafenib was suggested to cause drug-drug interaction (DDI) with the common anticoagulant, warfarin based on published studies. The inhibition on CYP2C9 enzyme was thought to be the mechanism, but further studies are warranted. Thus, a mechanistic PBPK/PD model for warfarin enantiomers was developed to predict DDI potential with sorafenib, aiming at providing reference for the rational use of both drugs. PBPK models of warfarin enantiomers were constructed by Simcyp software. A mechanistic PK/PD model was built in NONMEM software. PBPK model of sorafenib was fitted via a top-down method. The final PBPK/PD model of warfarin enantiomers was verified and validated by different dosing regimens, ethnicities and genetic polymorphisms, and used to perform DDI simulations between warfarin racemate and sorafenib among general populations and sub-populations with various CYP2C9 and VKORC1 genotypes. Results suggested low DDI risk between warfarin and sorafenib for general populations. Potentially serious consequence was seen for those carrying both CYP2C9 ∗2 and ∗3 and VKORC1 A/A genotypes. This PBPK/PD modeling approach for warfarin enantiomers enabled DDI evaluation with sorafenib. Close monitoring and warfarin dosage adjustment were recommended for patients carrying mutant genotypes. The novel model could be applied to investigate other drugs that may interact with warfarin.

PMID:34242938 | DOI:10.1016/j.dmpk.2020.10.001

J Comput Biol. 2021 Jul 9. doi: 10.1089/cmb.2020.0356. Online ahead of print.

ABSTRACT

Repurposing of marketed drugs to find new indications has become an alternative to circumvent the risk of traditional drug development by its productivity quality. Despite many approaches, computational analysis has great potential to fuel the development of all-rounder drugs to find new classes of medicine for neglected and rare disease. The genes that can explain variations in drug response associated to disease are more important and significant in drug therapeutics necessitate elucidating the relationships of a gene, drug, and disease. The proposed computational analysis facilitates the discovery of knowledge on both target and disease-based relationships from large sources of biomedical literature spread over different platforms. It uses the utility of text mining for automatic extraction of valuable aggregated biomedical entities (disease, gene, and drug) from PubMed to serves as an input to the analysis of association prediction. The top-ranked associations considered for identification of repurposing drugs and also the hidden associations identified using concurrence principle to extrapolate the new relationships. Such findings are reported as novel and contribute to the knowledge base for pharmacogenomics, would immensely support the discovery and progress of novel therapeutic pathways and patient segment biomarkers.

PMID:34242526 | DOI:10.1089/cmb.2020.0356

Pharmacotherapy. 2021 Jul 9. doi: 10.1002/phar.2611. Online ahead of print.

ABSTRACT

INTRODUCTION: CYP2C19 genotype-guided selection of P2Y12 inhibitor therapy after percutaneous coronary intervention (PCI) is associated with improved clinical outcomes, but clinical utility in older patients in a real-world setting is unknown.

OBJECTIVES: To compare the clinical effectiveness of genotype-guided P2Y12 inhibitor selection following PCI in older patients (≥70 years) and younger patients (<70 years).

METHODS: A single-center, retrospective, cohort study was conducted in 1,469 patients who underwent PCI and had CYP2C19 genotype testing. Risk of major adverse cardiovascular or cerebrovascular events (MACCE), defined as stent thrombosis, ischemic stroke, transient ischemic attack, non-fatal acute coronary syndrome, or cardiovascular death during 12 months after PCI, was compared across genotype and antiplatelet therapy groups by proportional hazards regression in patients ≥70 years and <70 years.

RESULTS: The study population was comprised of 402 (27.4%) ≥70 years (older group) and 1067 (72.6%) <70 years (younger group). Alternative P2Y12 inhibitors (prasugrel or ticagrelor) were used less often in the older group than the younger group in patients with a CYP2C19 no function allele (55% vs. 67%; p=0.02) and in patients without a no function allele (10% vs. 35%, p<0.001). For patients treated with clopidogrel, MACCE was significantly higher in no function allele carriers compared to those without a no function allele in the older group (19.2% vs. 12.7%; adjusted HR 2.32; 95% CI 1.07-5.05; p=0.03) and the younger group (17.4% vs. 10.4%; adjusted HR 2.01; 95% CI 1.17-3.46; p=0.01). In patients without a no function allele, MACCE risk was similar with clopidogrel compared to prasugrel or ticagrelor in the older group (adjusted HR 0.99; 95% CI 0.44-2.21; p=0.98) and the younger group (adjusted HR 1.12; 95% CI 0.72-1.74; p=0.61).

CONCLUSION: This study suggests important clinical benefits of CYP2C19 genotype-guided antiplatelet therapy after PCI in both younger and older patients.

PMID:34242414 | DOI:10.1002/phar.2611

Transplantation. 2021 Jul 1. doi: 10.1097/TP.0000000000003871. Online ahead of print.

ABSTRACT

BACKGROUND: The single-nucleotide polymorphism CYP3A5 rs776746 is related to a reduction in the metabolizing activity of the CYP3A5 enzyme. Persons carrying at least one copy of the wild-type allele, defined as CYP3A5 expressers, exhibit higher clearance and lower trough concentrations of tacrolimus than homozygous nonexpressers, and this difference may affect alloimmunization and allograft function.

METHODS: We retrospectively studied 400 kidney transplant recipients treated with a tacrolimus-based immunosuppression regimen to detect CYP3A5 genotype, de novo formation of human leukocyte antigen (HLA) antibodies and donor-specific antibodies (DSA), and clinical outcome up to 5 years after transplant.

RESULTS: We found that 69 (17%) of the 400 patients were CYP3A5 expressers. During the first 3 years after transplant, CYP3A5 expressers tended to have lower tacrolimus trough levels than non-expressers, even though their tacrolimus dosage was as much as 80% higher. De novo DSAs were found more frequently in CYP3A5 expressers than in nonexpressers (13/69 [19%] vs. 33/331 [10%], p = 0.02). De novo DSA-free survival rates (p = 0.02) were significantly lower for expressers than for nonexpressers. CYP3A5 genotype had no effect on allograft failure, but CYP3A5 expressers exhibited a significantly higher frequency of antibody-mediated rejection. CYP3A5 expresser status was an independent risk factor for the development of de novo DSAs (relative risk, 2.34, p= 0.01).

CONCLUSIONS: Early detection of CYP3A5 expressers, enabling genotype-based dose adjustment of tacrolimus immediately after renal transplant, may be a useful strategy for reducing the risk of de novo DSA production and antibody-mediated rejection.

PMID:34241984 | DOI:10.1097/TP.0000000000003871

Clin Sci (Lond). 2021 Jul 16;135(13):1609-1625. doi: 10.1042/CS20200307.

ABSTRACT

Cardiovascular disease remains the primary cause of mortality globally, being responsible for an estimated 17 million deaths every year. Cancer is the second leading cause of death on a global level with roughly 9 million deaths per year being attributed to neoplasms. The two share multiple common risk factors such as obesity, poor physical exercise, older age, smoking and there exists rare monogenic hypertension syndromes. Hypertension is the most important risk factor for cardiovascular disease and affects more than a billion people worldwide and may also be a risk factor for the development of certain types of cancer (e.g. renal cell carcinoma (RCC)). The interaction space of the two conditions becomes more complicated when the well-described hypertensive effect of certain antineoplastic drugs is considered along with the extensive amount of literature on the association of different classes of antihypertensive drugs with cancer risk/prevention. The cardiovascular risks associated with antineoplastic treatment calls for efficient management of relative adverse events and the development of practical strategies for efficient decision-making in the clinic. Pharmacogenetic interactions between cancer treatment and hypertension-related genes is not to be ruled out, but the evidence is not still ample to be incorporated in clinical practice. Precision Medicine has the potential to bridge the gap of knowledge regarding the full spectrum of interactions between cancer and hypertension (and cardiovascular disease) and provide novel solutions through the emerging field of cardio-oncology. In this review, we aimed to examine the bidirectional associations between cancer and hypertension including pharmacotherapy.

PMID:34240734 | DOI:10.1042/CS20200307

Gastroenterol Res Pract. 2021 Jun 17;2021:5960821. doi: 10.1155/2021/5960821. eCollection 2021.

ABSTRACT

lncRNA is a key epigenetic regulator in biological processes. In the human cancer transcriptome library MiTranscriptome, we identified GAU1 as the top upregulated lncRNA in colorectal cancer (CRC) by sample set enrichment analysis (overexpression ranking percentile = 99.75%, P < 10-50), which is coexpressed with the potential oncogene GALNT8 (Spearman rho = 0.67, P = 2.44 × 10-23, TCGA dataset n = 184). Experimental data revealed that GAU1 regulates the expression of GALNT8. The overexpression of either GAU1 or GALNT8 significantly promotes the cell cycle and proliferation of CRC cell lines and correlates with poor prognosis in patients with CRC (P = 3.04 × 10-2), while silencing of GAU1 or GALNT8 suppressed the cancer cell proliferation and induced the CRC cell line resistance to oxaliplatin in vitro treatment. Our results suggested that the previously less studied GAU1 and GALNT8 may play as CRC prognosis markers and potential targets for chemotherapy treatment.

PMID:34239555 | PMC:PMC8233076 | DOI:10.1155/2021/5960821

Transl Psychiatry. 2021 Jul 8;11(1):381. doi: 10.1038/s41398-021-01488-3.

ABSTRACT

Major depressive disorder (MDD) is complex and multifactorial, posing a major challenge of tailoring the optimal medication for each patient. Current practice for MDD treatment mainly relies on trial and error, with an estimated 42-53% response rates for antidepressant use. Here, we sought to generate an accurate predictor of response to a panel of antidepressants and optimize treatment selection using a data-driven approach analyzing combinations of genetic, clinical, and demographic factors. We analyzed the response patterns of patients to three antidepressant medications in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, and employed state-of-the-art machine learning (ML) tools to generate a predictive algorithm. To validate our results, we assessed the algorithm's capacity to predict individualized antidepressant responses on a separate set of 530 patients in STAR*D, consisting of 271 patients in a validation set and 259 patients in the final test set. This assessment yielded an average balanced accuracy rate of 72.3% (SD 8.1) and 70.1% (SD 6.8) across the different medications in the validation and test set, respectively (p < 0.01 for all models). To further validate our design scheme, we obtained data from the Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) of patients treated with citalopram, and applied the algorithm's citalopram model. This external validation yielded highly similar results for STAR*D and PGRN-AMPS test sets, with a balanced accuracy of 60.5% and 61.3%, respectively (both p's < 0.01). These findings support the feasibility of using ML algorithms applied to large datasets with genetic, clinical, and demographic features to improve accuracy in antidepressant prescription.

PMID:34238923 | DOI:10.1038/s41398-021-01488-3

J Clin Oncol. 2021 Jun 2:JCO2002574. doi: 10.1200/JCO.20.02574. Online ahead of print.

ABSTRACT

PURPOSE: This meta-analysis aims to combine and analyze randomized clinical trials comparing computed tomography lung screening (CTLS) versus either no screening (NS) or chest x-ray (CXR) in subjects with cigarette smoking history, to provide a precise and reliable estimation of the benefits and harms associated with CTLS.

MATERIALS AND METHODS: Data from all published randomized trials comparing CTLS versus either NS or CXR in a highly tobacco-exposed population were collected, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Subgroup analyses by comparator (NS or CXR) were performed. Pooled risk ratio (RR) and relative 95% CIs were calculated for dichotomous outcomes. The certainty of the evidence was assessed using the GRADE approach.

RESULTS: Nine eligible trials (88,497 patients) were included. Pooled analysis showed that CTLS is associated with: a significant reduction of lung cancer-related mortality (overall RR, 0.87; 95% CI, 0.78 to 0.98; NS RR, 0.80; 95% CI, 0.69 to 0.92); a significant increase of early-stage tumors diagnosis (overall RR, 2.84; 95% CI 1.76 to 4.58; NS RR, 3.33; 95% CI, 2.27 to 4.89; CXR RR, 1.52; 95% CI, 1.04 to 2.23); a significant decrease of late-stage tumors diagnosis (overall RR, 0.75; 95% CI, 0.68 to 0.83; NS RR, 0.67; 95% CI, 0.56 to 0.80); a significant increase of resectability rate (NS RR, 2.57; 95% CI, 1.76 to 3.74); a nonsignificant reduction of all-cause mortality (overall RR, 0.99; 95% CI, 0.94 to 1.05); and a significant increase of overdiagnosis rate (NS, 38%; 95% CI, 14 to 63). The analysis of lung cancer-related mortality by sex revealed nonsignificant differences between men and women (P = .21; I-squared = 33.6%).

CONCLUSION: Despite there still being uncertainty about overdiagnosis estimate, this meta-analysis suggested that the CTLS benefits outweigh harms, in subjects with cigarette smoking history, ultimately supporting the systematic implementation of lung cancer screening worldwide.

PMID:34236916 | DOI:10.1200/JCO.20.02574

ACS Omega. 2021 Jun 17;6(25):16584-16591. doi: 10.1021/acsomega.1c01797. eCollection 2021 Jun 29.

ABSTRACT

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 3CL protease is a promising target for inhibition of viral replication by interaction with a cysteine residue (Cys145) at its catalytic site. Dalcetrapib exerts its lipid-modulating effect by binding covalently to cysteine 13 of a cholesteryl ester transfer protein. Because 12 free cysteine residues are present in the 3CL protease, we investigated the potential of dalcetrapib to inhibit 3CL protease activity and SARS-CoV-2 replication. Molecular docking investigations suggested that dalcetrapib-thiol binds to the catalytic site of the 3CL protease with a delta G value of -8.5 kcal/mol. Dalcetrapib inhibited both 3CL protease activity in vitro and viral replication in Vero E6 cells with IC50 values of 14.4 ± 3.3 μM and an EC50 of 17.5 ± 3.5 μM (mean ± SD). Near-complete inhibition of protease activity persisted despite 1000-fold dilution after ultrafiltration with a nominal dalcetrapib-thiol concentration of approximately 100 times below the IC50 of 14.4 μM, suggesting stable protease-drug interaction. The inhibitory effect of dalcetrapib on the SARS-CoV-2 3CL protease and viral replication warrants its clinical evaluation for the treatment of COVID-19.

PMID:34235330 | PMC:PMC8230949 | DOI:10.1021/acsomega.1c01797

Transl Clin Pharmacol. 2021 Jun;29(2):107-116. doi: 10.12793/tcp.2021.29.e10. Epub 2021 Jun 15.

ABSTRACT

A common cause of drug hypersensitivity reactions is iodinated contrast media (ICM). ICM-induced hypersensitivity had been considered to be a non-immunological reaction, but evidence for an immunological mechanism has increased recently. Thus, we evaluated whether HLA-A, -B, and -C alleles were associated with ICM-induced hypersensitivity. In total, 126 patients who underwent contrast-enhanced computed tomography studies through outpatient clinics at a tertiary referral hospital between 2008 and 2012 were assessed. Sixty-one patients experienced ICM-induced hypersensitivity and the remainder, 65, were ICM-tolerant patients (control). ICM-induced hypersensitivity patients showed 51 with immediate, 7 with non-immediate, 3 with both or mixed type. HLA-A, -B, and -C genotyping was performed using a PCR sequence-based typing method. Four kinds of ICM were used: iopromide, iohexol, iobitridol, and iodixanol. The most used ICM among the hypersensitivity patients was iopromide. Significant difference in the frequency of HLA-B*58:01 (odds ratios [OR], 3.90; p = 0.0200, 95% confidence interval [CI], 1.16-13.07) was observed between ICM-induced immediate hypersensitivity and control. There were statistically significant differences in the frequencies of the HLA-B*38:02 (OR, 10.24; p = 0.0145; 95% CI, 1.09-96.14) and HLA-B*58:01 (OR, 3.98; p = 0.0348; 95% CI, 1.03-15.39) between iopromide-induced immediate hypersensitivity and control. The mechanism of ICM-induced hypersensitivity remains unknown, but this study showed associations, although weak, with HLA-B*58:01 alleles for ICM-induced immediate hypersensitivity and HLA-B*38:02 and HLA-B*58:01 for iopromide-induced immediate hypersensitivity as risk predictors. Further studies are needed to validate the associations in larger samples and to identify the functional mechanism behind these results.

PMID:34235123 | PMC:PMC8255545 | DOI:10.12793/tcp.2021.29.e10

Front Psychiatry. 2021 Jun 21;12:669446. doi: 10.3389/fpsyt.2021.669446. eCollection 2021.

ABSTRACT

Despite its drastic efficacy in resistant psychiatric disorders, clozapine remains rarely used in youth due to its side effects. Clozapine plasma level is determined through its metabolism involving several isoforms of cytochromes 450 (CYP450) family. Isoform CYP1A2 appears as a limiting enzyme involved in the metabolism of clozapine, while isoforms 2C19, 2D6, 3A4, and 3A5 also contribute in a minor way. Clozapine efficacy is limited by a significant inter-patient variability in exposure according to CYP's polymorphisms. Clozapine plasma levels may be increased with CYP inhibitors such as fluvoxamine. This drug is a potent enzymatic inhibitor of CYP1A2 and, to a lesser extent, of CYP3A4 and CYP2D6. Hence, in case of CYP's polymorphisms in youth, the use of fluvoxamine as add-on to clozapine could help in reaching clinical and biological efficacy and allowing lower clozapine dosage and a better tolerance profile as it has already been described in adults. We report four pediatric cases with severe psychiatric disorders underlying our experience with CYP polymorphism explorations and the use of fluvoxamine as add-on to clozapine. Our four patients clinically improved after the introduction of fluvoxamine, enhancing clozapine metabolism and therefore the clozapine plasma level within therapeutic range. Despite the interesting results of fluvoxamine, we report a severe issue of tolerance for one patient, emphasizing the need for caution regarding possible drug interactions when fluvoxamine is considered. Hence, we propose a detailed step-by-step multidisciplinary protocol.

PMID:34234701 | PMC:PMC8255476 | DOI:10.3389/fpsyt.2021.669446

Front Pharmacol. 2021 Jun 21;12:684162. doi: 10.3389/fphar.2021.684162. eCollection 2021.

ABSTRACT

Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of drugs which are widely used globally for the treatment of pain and inflammation, and in the case of aspirin, for secondary prevention of cardiovascular disease. Chronic non-steroidal anti-inflammatory drug use is associated with potentially serious upper gastrointestinal adverse drug reactions (ADRs) including peptic ulcer disease and gastrointestinal bleeding. A few clinical and genetic predisposing factors have been identified; however, genetic data are contradictory. Further research is needed to identify clinically relevant genetic and non-genetic markers predisposing to NSAID-induced peptic ulceration.

PMID:34234675 | PMC:PMC8256335 | DOI:10.3389/fphar.2021.684162

J Hum Genet. 2021 Jul 8. doi: 10.1038/s10038-021-00952-8. Online ahead of print.

ABSTRACT

Certain large genome cohort studies attempt to return the individual genomic results to the participants; however, the implementation process and psychosocial impacts remain largely unknown. The Tohoku Medical Megabank Project has conducted large genome cohort studies of general residents. To implement the disclosure of individual genomic results, we extracted the potential challenges and obstacles. Major challenges include the determination of genes/disorders based on the current medical system in Japan, the storage of results, prevention of misunderstanding, and collaboration of medical professionals. To overcome these challenges, we plan to conduct multilayer pilot studies, which deal with different disorders/genes. We finally chose familial hypercholesterolemia (FH) as a target disease for the first pilot study. Of the 665 eligible candidates, 33.5% were interested in the pilot study and provided consent after an educational "genetics workshop" on the basic genetics and medical facts of FH. The genetics professionals disclosed the results to the participants. All positive participants were referred to medical care, and a serial questionnaire revealed no significant psychosocial distress after the disclosure. Return of genomic results to research participants was implemented using a well-prepared protocol. To further elucidate the impact of different disorders, we will perform multilayer pilot studies with different disorders, including actionable pharmacogenomics and hereditary tumor syndromes.

PMID:34234266 | DOI:10.1038/s10038-021-00952-8

Semin Liver Dis. 2021 Jul 7. doi: 10.1055/s-0041-1730927. Online ahead of print.

ABSTRACT

The acronym nonalcoholic fatty-liver disease (NAFLD) groups a heterogeneous patient population. Although in many patients the primary driver is metabolic dysfunction, a complex and dynamic interaction of different factors (i.e., sex, presence of one or more genetic variants, coexistence of different comorbidities, diverse microbiota composition, and various degrees of alcohol consumption among others) takes place to determine disease subphenotypes with distinct natural history and prognosis and, eventually, different response to therapy. This review aims to address this topic through the analysis of existing data on the differential contribution of known factors to the pathogenesis and clinical expression of NAFLD, thus determining the different clinical subphenotypes observed in practice. To improve our understanding of NAFLD heterogeneity and the dominant drivers of disease in patient subgroups would predictably impact on the development of more precision-targeted therapies for NAFLD.

PMID:34233370 | DOI:10.1055/s-0041-1730927