Am J Hum Genet. 2021 May 20:S0002-9297(21)00185-3. doi: 10.1016/j.ajhg.2021.05.001. Online ahead of print.

ABSTRACT

Identifying the molecular mechanisms by which genome-wide association study (GWAS) loci influence traits remains challenging. Chromatin accessibility quantitative trait loci (caQTLs) help identify GWAS loci that may alter GWAS traits by modulating chromatin structure, but caQTLs have been identified in a limited set of human tissues. Here we mapped caQTLs in human liver tissue in 20 liver samples and identified 3,123 caQTLs. The caQTL variants are enriched in liver tissue promoter and enhancer states and frequently disrupt binding motifs of transcription factors expressed in liver. We predicted target genes for 861 caQTL peaks using proximity, chromatin interactions, correlation with promoter accessibility or gene expression, and colocalization with expression QTLs. Using GWAS signals for 19 liver function and/or cardiometabolic traits, we identified 110 colocalized caQTLs and GWAS signals, 56 of which contained a predicted caPeak target gene. At the LITAF LDL-cholesterol GWAS locus, we validated that a caQTL variant showed allelic differences in protein binding and transcriptional activity. These caQTLs contribute to the epigenomic characterization of human liver and help identify molecular mechanisms and genes at GWAS loci.

PMID:34038741 | DOI:10.1016/j.ajhg.2021.05.001

Vet Surg. 2021 May 26. doi: 10.1111/vsu.13671. Online ahead of print.

ABSTRACT

OBJECTIVE: Evaluate center of mass (CoM) displacement values during four-limb and three-limb standing with limb suspension in dogs before and after applying sensory stimulation to a forelimb or hindlimb.

STUDY DESIGN: Experimental study.

ANIMALS: Six clinically normal beagles.

METHODS: A four force-plate apparatus was built to assess static weight distribution. Dogs stood on the device with one limb in contact with each force plate. We created a plastic device to induce sensory stimulation so that lameness could not be detected visually when stimulating the paw. Experimenters confirmed the degree of lameness by walking before and after measurement. Body-weight shifts were induced via suspension of each limb and transient sensory stimulation to the right forelimb or left hindlimb. CoMs of five postures were compared, with and without transient sensory stimulation.

RESULTS: The four-limb CoM was located cranial to the center of the X- and Y-axis coordinates (X: -0.82 ± 9.12, Y: 61.00 ± 5.82). During three-limb standing with suspension of either forelimb, CoM shifted backward toward the contralateral side compared to four-limb standing. During hindlimb suspension, CoM shifted to the contralateral side. With right forelimb sensory stimulation, there were large CoM changes for both four-limb and three-limb standing (X: -34.53 ± 9.09, Y: 52.21 ± 6.88). CoM changes were small with left hindlimb sensory stimulation (X: 6.47 ± 13.86, Y: 69.41 ± 5.55).

CONCLUSION: CoMs during four-limb and three-limb standing were influenced by sensory stimulation of a forelimb and, to a lesser extent, of a hindlimb.

CLINICAL SIGNIFICANCE: Static evaluation of CoM may aid clinicians in the diagnosis and recovery of forelimb lameness.

PMID:34038003 | DOI:10.1111/vsu.13671

JAMA Netw Open. 2021 May 3;4(5):e2110467. doi: 10.1001/jamanetworkopen.2021.10467.

NO ABSTRACT

PMID:34037737 | DOI:10.1001/jamanetworkopen.2021.10467

JAMA Netw Open. 2021 May 3;4(5):e2110446. doi: 10.1001/jamanetworkopen.2021.10446.

ABSTRACT

IMPORTANCE: Pharmacogenomic (PGx) testing provides preemptive pharmacotherapeutic guidance regarding the lack of therapeutic benefit or adverse drug reactions of PGx targeted drugs. Pharmacogenomic information is of particular value among children with complex medical conditions who receive multiple medications and are at higher risk of developing adverse drug reactions.

OBJECTIVES: To assess the implementation outcomes of a PGx testing program comprising both a point-of-care model that examined targeted drugs and a preemptive model informed by whole-genome sequencing that evaluated a broad range of drugs for potential therapy among children in a pediatric tertiary care setting.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study was conducted at The Hospital for Sick Children in Toronto, Ontario, from January 2017 to September 2020. Pharmacogenomic analyses were performed among 172 children who were categorized into 2 groups: a point-of-care cohort and a preemptive cohort. The point-of-care cohort comprised 57 patients referred to the consultation clinic for planned therapy with PGx targeted drugs and/or for adverse drug reactions, including lack of therapeutic benefit, after the receipt of current or past medications. The preemptive cohort comprised 115 patients who received exploratory whole-genome sequencing-guided PGx testing for their heart conditions from the cardiac genome clinic at the Ted Rogers Centre for Heart Research.

EXPOSURES: Patients received PGx analysis of whole-genome sequencing data and/or multiplex genotyping of 6 pharmacogenes (CYP2C19, CYP2C9, CYP2D6, CYP3A5, VKORC1, and TPMT) that have established PGx clinical guidelines.

MAIN OUTCOMES AND MEASURES: The number of patients for whom PGx test results warranted deviation from standard dosing regimens.

RESULTS: A total of 172 children (mean [SD] age, 8.5 [5.6] years; 108 boys [62.8%]) were enrolled in the study. In the point-of-care cohort, a median of 2 target genes (range, 1-5 genes) were investigated per individual, with CYP2C19 being the most frequently examined; genotypes in 21 of 57 children (36.8%) were incompatible with standard treatment regimens. As expected from population allelic frequencies, among the 115 children in the whole-genome sequencing-guided preemptive cohort, 92 children (80.0%) were recommended to receive nonstandard treatment regimens for potential drug therapies based on their 6-gene pharmacogenetic profile.

CONCLUSIONS AND RELEVANCE: In this cohort study, among both the point-of-care and preemptive cohorts, the multiplex PGx testing program provided dosing recommendations that deviated from standard regimens at an overall rate that was similar to the population frequencies of relevant variants.

PMID:34037732 | DOI:10.1001/jamanetworkopen.2021.10446

CNS Neurol Disord Drug Targets. 2021 May 24. doi: 10.2174/1871527320666210525090904. Online ahead of print.

ABSTRACT

BACKGROUND: A dimeric dipeptide mimetic of the BDNF loop 4, bis(N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide (GSB-106), which activates TrkB, PI3K/AKT, MAPK/ERK and PLC-γ1 was created at the V.V. Zakusov Research Institute of Pharmacology. GSB-106 showed neuroprotective activity in vitro and in vivo at systemic administration.

OBJECTIVE: In this work, we studied the GSB-106 effect on the cerebral infarct volume, as well as on neurogenesis and synaptogenesis under experimental ischemic stroke, induced by intravascular occlusion of the middle cerebral artery in rats.

METHODS: GSB-106 was administered i.p. in a dose of 0.1 mg/kg 24 h after surgery and then once a day, with the end of administration on the day 6 after surgery. On the day 7 brain samples were collected for morphometric and biochemical (Western-blot) analysis.

RESULTS: It was established that GSB-106 reduced the brain damage volume by 24%, restores impaired neurogenesis and/or gliogenesis (by Ki-67) in the hippocampus and in the striatum and completely restored the reduced immunoreactivity to synaptic markers synaptophysin and PSD-95 in the striatum.

CONCLUSIONS: Thus, the dimer dipeptide BDNF mimetic GSB-106 exhibits neuroregenerative properties at clinically relevant time window (24 h) in a model of ischemic stroke presumably due to stimulation of neurogenesis (and/or gliogenesis) and synaptogenesis.

PMID:34036924 | DOI:10.2174/1871527320666210525090904

Pharmacogenomics. 2021 May 26. doi: 10.2217/pgs-2020-0158. Online ahead of print.

ABSTRACT

Aim: The ERBB gene family plays an important role in cell proliferation and differentiation, and aberrant activations could result in tumorigenesis, which makes this gene family an attractive drug target in the area of precision oncology. Materials & methods: Functional divergence analysis and conservation analysis were performed using ClustalW, MEGA7 and DIVERGE3 software. Results: One hundred and forty five functional divergence residues sites, 94 totally conserved sites and averagely 345 conserved sites of individual gene member were obtained. Some have been reported to play role in drug binding, tumorigenesis and drug resistance. Conclusion: Functional divergence residues with high posterior probabilities and conserved residues may possess certain functions, and aberrant alterations may confer drug resistance or contribute to tumorigenesis.

PMID:34036795 | DOI:10.2217/pgs-2020-0158

Br J Clin Pharmacol. 2021 May 25. doi: 10.1111/bcp.14917. Online ahead of print.

NO ABSTRACT

PMID:34036624 | DOI:10.1111/bcp.14917

MicroPubl Biol. 2021 May 4;2021. doi: 10.17912/micropub.biology.000388.

ABSTRACT

The molecular chaperone Hsp90 is highly conserved from bacteria to mammals. In fission yeast, Hsp90 is essential in many cellular processes and its expression is known to be increased by heat stress (HS). Here, we describe the distinct spatiotemporal distribution of Hsp90 under high-heat stress (HHS: 45˚C) and mild-heat stress (MHS: 37˚C). Hsp90 is largely distributed in the cytoplasm under non-stressed conditions (27˚C). Under HHS, Hsp90 forms several cytoplasmic granules within 5 minutes, then the granules disappear within 60 minutes. Under MHS, Hsp90 forms fewer granules than under HHS within 5 minutes and strikingly the granules persist and grow in size. In addition, nuclear enrichment of Hsp90 was observed after 60 minutes under both HS conditions. Our data suggest that assembly/disassembly of Hsp90 granules is differentially regulated by temperatures.

PMID:34036246 | PMC:PMC8140757 | DOI:10.17912/micropub.biology.000388

J Oncol. 2021 May 6;2021:6697975. doi: 10.1155/2021/6697975. eCollection 2021.

ABSTRACT

Acute myeloid leukemia is a group of hematological neoplasms characterized by a heterogeneous course and high mortality. The important factor in the neoplastic process is metalloproteinases, proteolytic enzymes capable of degrading various components of the extracellular matrix, which take an active part in modifying the functioning of the cell, including transformation to cancer cell. They interact with numerous signaling pathways responsible for the process of cell growth, proliferation, or apoptosis. In the present study, changes in the expression of MMP2, MMP9, and MMP16 genes between patients with AML and people without cancer were examined. The impact of cytogenetic changes in neoplastic cells on the expression level of MMP2, MMP9, and MMP16 was also assessed, as well as the impact of the altered expression on the effectiveness of the first cycle of remission-inducing therapy. To evaluate the expression of all studied genes MMP2, MMP9, and MMP16, SYBR Green-based real-time PCR method was used; the reference gene was GAPDH. For two investigated genes MMP2 and MMP16, the lower expression level was observed in patients with AML when compared to healthy people. The MMP9 gene expression level did not differ between patients with AML and healthy individuals which may indicate a different regulation of gene expression in acute myeloid leukemia. However, no correlation was observed between the genes' expression of all tested metalloproteinases and the result of cytoreductive treatment or the presence of cytogenetic changes. The obtained results show that the expression of MMP2 and MMP16 genes is reduced while the expression of MMP9 is unchanged in patients with acute myeloid leukemia. This may indicate a different regulation of the expression of these genes, and possible disruptions in gene transcription or posttranscriptional mechanisms in the MMP2 and MMP16 genes, however, do not affect the level of MMP9 expression. Obtained results in AML patients are in contrary to various types of solid tumors where increased expression is usually observed.

PMID:34035811 | PMC:PMC8121570 | DOI:10.1155/2021/6697975

Sci Rep. 2021 May 25;11(1):10847. doi: 10.1038/s41598-021-90365-6.

ABSTRACT

We conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical trial. We found a significant association at 5p13.3 (rs1173773; P = 4.94 × 10-8) near the natriuretic peptide receptor 3 gene (NPR3). By day 15 of the study, 44%, 54% and 59% of participants with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. In 851 participants not treated with colchicine (placebo), there was a significant association at 9q33.1 (rs62575331; P = 2.95 × 10-8) in interaction with colchicine (P = 1.19 × 10-5) without impact on risk of hospitalisations, highlighting a possibly shared mechanistic pathway. By day 15 of the study, 46%, 62% and 64% of those with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. The findings need to be replicated and could contribute to the biological understanding of COVID-19 symptom remission.

PMID:34035401 | DOI:10.1038/s41598-021-90365-6

BMC Bioinformatics. 2021 May 25;22(1):269. doi: 10.1186/s12859-021-04146-z.

ABSTRACT

BACKGROUND: Predicting the drug response of a patient is important for precision oncology. In recent studies, multi-omics data have been used to improve the prediction accuracy of drug response. Although multi-omics data are good resources for drug response prediction, the large dimension of data tends to hinder performance improvement. In this study, we aimed to develop a new method, which can effectively reduce the large dimension of data, based on the supervised deep learning model for predicting drug response.

RESULTS: We proposed a novel method called Supervised Feature Extraction Learning using Triplet loss (Super.FELT) for drug response prediction. Super.FELT consists of three stages, namely, feature selection, feature encoding using a supervised method, and binary classification of drug response (sensitive or resistant). We used multi-omics data including mutation, copy number aberration, and gene expression, and these were obtained from cell lines [Genomics of Drug Sensitivity in Cancer (GDSC), Cancer Cell Line Encyclopedia (CCLE), and Cancer Therapeutics Response Portal (CTRP)], patient-derived tumor xenografts (PDX), and The Cancer Genome Atlas (TCGA). GDSC was used for training and cross-validation tests, and CCLE, CTRP, PDX, and TCGA were used for external validation. We performed ablation studies for the three stages and verified that the use of multi-omics data guarantees better performance of drug response prediction. Our results verified that Super.FELT outperformed the other methods at external validation on PDX and TCGA and was good at cross-validation on GDSC and external validation on CCLE and CTRP. In addition, through our experiments, we confirmed that using multi-omics data is useful for external non-cell line data.

CONCLUSION: By separating the three stages, Super.FELT achieved better performance than the other methods. Through our results, we found that it is important to train encoders and a classifier independently, especially for external test on PDX and TCGA. Moreover, although gene expression is the most powerful data on cell line data, multi-omics promises better performance for external validation on non-cell line data than gene expression data. Source codes of Super.FELT are available at https://github.com/DMCB-GIST/Super.FELT .

PMID:34034645 | DOI:10.1186/s12859-021-04146-z

JAMA Netw Open. 2021 May 3;4(5):e2111398. doi: 10.1001/jamanetworkopen.2021.11398.

ABSTRACT

IMPORTANCE: Male sex is a risk factor for developing severe COVID-19 illness. It is not known whether sex hormones contribute to this predisposition.

OBJECTIVE: To investigate the association of concentrations of serum testosterone, estradiol, and insulinlike growth factor 1 (IGF-1, concentrations of which are regulated by sex hormone signaling) with COVID-19 severity.

DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study was conducted using serum samples collected from consecutive patients who presented from March through May 2020 to the Barnes Jewish Hospital in St Louis, Missouri, with COVID-19 (diagnosed using nasopharyngeal swabs).

EXPOSURES: Testosterone, estradiol, and IGF-1 concentrations were measured at the time of presentation (ie, day 0) and at days 3, 7, 14, and 28 after admission (if the patient remained hospitalized).

MAIN OUTCOMES AND MEASURES: Baseline hormone concentrations were compared among patients who had severe COVID-19 vs those with milder COVID-19 illness. RNA sequencing was performed on circulating mononuclear cells to understand the mechanistic association of altered circulating hormone concentrations with cellular signaling pathways.

RESULTS: Among 152 patients (90 [59.2%] men; 62 [40.8%] women; mean [SD] age, 63 [16] years), 143 patients (94.1%) were hospitalized. Among 66 men with severe COVID-19, median [interquartile range] testosterone concentrations were lower at day 0 (53 [18 to 114] ng/dL vs 151 [95 to 217] ng/dL; P = .01) and day 3 (19 [6 to 68] ng/dL vs 111 [49 to 274] ng/dL; P = .006) compared with 24 men with milder disease. Testosterone concentrations were inversely associated with concentrations of interleukin 6 (β = -0.43; 95% CI, -0.52 to -0.17; P < .001), C-reactive protein (β = -0.38; 95% CI, -0.78 to -0.16; P = .004), interleukin 1 receptor antagonist (β = -0.29; 95% CI, -0.64 to -0.06; P = .02), hepatocyte growth factor (β = -0.46; 95% CI, -0.69 to -0.25; P < .001), and interferon γ-inducible protein 10 (β = -0.32; 95% CI, -0.62 to -0.10; P = .007). Estradiol and IGF-1 concentrations were not associated with COVID-19 severity in men. Testosterone, estradiol, and IGF-1 concentrations were similar in women with and without severe COVID-19. Gene set enrichment analysis revealed upregulated hormone signaling pathways in CD14+CD16- (ie, classical) monocytes and CD14-CD16+ (ie, nonclassical) monocytes in male patients with COVID-19 who needed intensive care unit treatment vs those who did not.

CONCLUSIONS AND RELEVANCE: In this single-center cohort study of patients with COVID-19, lower testosterone concentrations during hospitalization were associated with increased disease severity and inflammation in men. Hormone signaling pathways in monocytes did not parallel serum hormone concentrations, and further investigation is required to understand their pathophysiologic association with COVID-19.

PMID:34032853 | DOI:10.1001/jamanetworkopen.2021.11398

Pharmacogenomics. 2021 May 25. doi: 10.2217/pgs-2021-0049. Online ahead of print.

ABSTRACT

Tweetable abstract High-quality studies examining the influence of CYP2D6 on the exposure and tolerability of antipsychotics in youth are needed to mitigate the limitations of prior studies.

PMID:34032507 | DOI:10.2217/pgs-2021-0049

Pharmacogenomics. 2021 May 25. doi: 10.2217/pgs-2021-0016. Online ahead of print.

ABSTRACT

The Pharmacogenomics Access & Reimbursement Symposium, a landmark event presented by the Golden Helix Foundation and the Pharmacogenomics Access & Reimbursement Coalition, was a 1-day interactive meeting comprised of plenary keynotes from thought leaders across healthcare that focused on value-based strategies to improve patient access to personalized medicine. Stakeholders including patients, healthcare providers, industry, government agencies, payer organizations, health systems and health policy organizations convened to define opportunities to improve patient access to personalized medicine through best practices, successful reimbursement models, high quality economic evaluations and strategic alignment. Session topics included health technology assessment, health economics, health policy and value-based payment models and innovation.

PMID:34032472 | DOI:10.2217/pgs-2021-0016

Clin Pharmacol Ther. 2021 May 25. doi: 10.1002/cpt.2309. Online ahead of print.

ABSTRACT

Aminoglycosides are widely used antibiotics with notable side effects such as nephrotoxicity, vestibulotoxicity and sensorineural hearing loss (cochleotoxicity). MT-RNR1 is a gene that encodes the 12s rRNA subunit and is the mitochondrial homologue of the prokaryotic 16s rRNA. Some MT-RNR1 variants (i.e., m.1095T>C; m.1494C>T; m.1555A>G) more closely resemble the bacterial 16s rRNA subunit and result in increased risk of aminoglycoside-induced hearing loss. Use of aminoglycosides should be avoided in individuals with an MT-RNR1 variant associated with an increased risk of aminoglycoside-induced hearing loss unless the high risk of permanent hearing loss is outweighed by the severity of infection and safe or effective alternative therapies are not available. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of aminoglycosides based on MT-RNR1 genotype (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org).

PMID:34032273 | DOI:10.1002/cpt.2309

J Am Heart Assoc. 2021 May 25:e020633. doi: 10.1161/JAHA.120.020633. Online ahead of print.

ABSTRACT

Pulmonary hypertension (PH) attributable to left heart disease (LHD) is believed to be the most common form of PH and is strongly associated with increased mortality and morbidity in this patient population. Specific therapies for PH-LHD have not yet been identified and the use of pulmonary artery hypertension-targeted therapies in PH-LHD are not recommended. Endothelin receptor antagonists, phosphodiesterase-5 inhibitors, guanylate cyclase stimulators, and prostacyclins have all been studied in PH-LHD with conflicting results. Understanding the mechanisms underlying PH-LHD could potentially provide novel therapeutic targets. Fibrosis, oxidative stress, and metabolic syndrome have been proposed as pathophysiological components of PH-LHD. Genetic associations have also been identified, offering additional mechanisms with biological plausibility. This review summarizes the evidence and challenges for treatment of PH-LHD and focuses on underlying mechanisms on the horizon that could develop into potential therapeutic targets for this disease.

PMID:34032129 | DOI:10.1161/JAHA.120.020633

Mol Divers. 2021 May 24. doi: 10.1007/s11030-021-10225-3. Online ahead of print.

ABSTRACT

Convolutional neural networks (CNNs) have been used to extract information from various datasets of different dimensions. This approach has led to accurate interpretations in several subfields of biological research, like pharmacogenomics, addressing issues previously faced by other computational methods. With the rising attention for personalized and precision medicine, scientists and clinicians have now turned to artificial intelligence systems to provide them with solutions for therapeutics development. CNNs have already provided valuable insights into biological data transformation. Due to the rise of interest in precision and personalized medicine, in this review, we have provided a brief overview of the possibilities of implementing CNNs as an effective tool for analyzing one-dimensional biological data, such as nucleotide and protein sequences, as well as small molecular data, e.g., simplified molecular-input line-entry specification, InChI, binary fingerprints, etc., to categorize the models based on their objective and also highlight various challenges. The review is organized into specific research domains that participate in pharmacogenomics for a more comprehensive understanding. Furthermore, the future intentions of deep learning are outlined.

PMID:34031788 | DOI:10.1007/s11030-021-10225-3

Nat Commun. 2021 May 24;12(1):3046. doi: 10.1038/s41467-021-23379-3.

ABSTRACT

Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer type with high morbidity in Southeast Asia, however the pathogenic mechanism of this disease is poorly understood. Using integrative pharmacogenomics, we find that NPC subtypes maintain distinct molecular features, drug responsiveness, and graded radiation sensitivity. The epithelial carcinoma (EC) subtype is characterized by activations of microtubule polymerization and defective mitotic spindle checkpoint related genes, whereas sarcomatoid carcinoma (SC) and mixed sarcomatoid-epithelial carcinoma (MSEC) subtypes exhibit enriched epithelial-mesenchymal transition (EMT) and invasion promoting genes, which are well correlated with their morphological features. Furthermore, patient-derived organoid (PDO)-based drug test identifies potential subtype-specific treatment regimens, in that SC and MSEC subtypes are sensitive to microtubule inhibitors, whereas EC subtype is more responsive to EGFR inhibitors, which is synergistically enhanced by combining with radiotherapy. Through combinational chemoradiotherapy (CRT) screening, effective CRT regimens are also suggested for patients showing less sensitivity to radiation. Altogether, our study provides an example of applying integrative pharmacogenomics to establish a personalized precision oncology for NPC subtype-guided therapies.

PMID:34031426 | DOI:10.1038/s41467-021-23379-3

Psychol Med. 2021 May 25:1-13. doi: 10.1017/S0033291721001744. Online ahead of print.

ABSTRACT

BACKGROUND: Obsessive-compulsive disorder (OCD) is a psychiatric disorder with multiple symptom dimensions (e.g. contamination, symmetry). OCD clusters in families and decades of twin studies clearly demonstrate an important role for genetics in the etiology of the disorder.

METHODS: In this review, we summarize the genetic epidemiology and molecular genetic studies of OCD and obsessive-compulsive symptoms.

RESULTS: OCD is a heritable, polygenic disorder with contributions from both common and rare variants, including de novo deleterious variations. Multiple studies have provided reliable support for a large additive genetic contribution to liability to OCD, with discrete OCD symptom dimensions having both shared and unique genetic risks. Genome-wide association studies have not produced significant results yet, likely because of small sample sizes, but larger meta-analyses are forthcoming. Both twin and genome-wide studies show that OCD shares genetic risk with its comorbid conditions (e.g. Tourette syndrome and anorexia nervosa).

CONCLUSIONS: Despite significant efforts to uncover the genetic basis of OCD, the mechanistic understanding of how genetic and environmental risk factors interact and converge at the molecular level to result in OCD's heterogeneous phenotype is still mostly unknown. Future investigations should increase ancestral genetic diversity, explore age and/or sex differences in genetic risk for OCD and expand the study of pharmacogenetics, gene expression, gene × environment interactions and epigenetic mechanisms for OCD.

PMID:34030745 | DOI:10.1017/S0033291721001744

Int J Infect Dis. 2021 May 21:S1201-9712(21)00446-X. doi: 10.1016/j.ijid.2021.05.044. Online ahead of print.

ABSTRACT

OBJECTIVES: To be effective, piperacillin/tazobactam (PTZ) unbound plasma levels need to be above the minimum inhibitory concentration (MIC) at least 50% of the time between dosing intervals (50% fT>MIC). We aimed to compare the plasma piperacillin concentrations at the mid-dosing intervals (Cmid, 50% fT) and the proportion of patients achieving 50% fT>MIC between extended infusion (EI) and intermittent bolus (IB) methods in children.

METHODS: A prospective, randomized trial of EI versus IB of PTZ was conducted in children aged 1 month to 18 years. PTZ dosing was 100 mg/kg/dose of piperacillin intravenously every 8 hours. Patients were randomly assigned to receive EI (4-h infusion) or IB group (30-min infusion). Primary outcome measured was plasma piperacillin Cmid.

RESULTS: Ninety patients with a median age (IQR) of 48 months (16-127) were enrolled. The most common indication for PTZ use was pneumonia (32.2%). Geometric mean (95% CI) plasma piperacillin Cmid of EI versus IB were 51.9 mg/L (40.6-66.6) versus 6.0 mg/L (4.2-8.6), P < 0.01. The EI group had a trend of higher proportion of patients who achieved 50% fT>4xMIC (72.7% versus 30.0%, P = 0.06).

CONCLUSIONS: PTZ administration with EI resulted in a higher Cmid compared with IB method. In settings with increased piperacillin MICs, this approach should be implemented, particularly during the empirical treatment period.

PMID:34029707 | DOI:10.1016/j.ijid.2021.05.044