Population Pharmacokinetics and Dosing Optimization of Amoxicillin in Neonates and Young Infants.

Antimicrob Agents Chemother. 2018 Dec 03;:

Authors: Tang BH, Wu YE, Kou C, Qi YJ, Qi H, Xu HY, Leroux S, Huang X, Zhou Y, Zheng Y, Jacqz-Aigrain E, Shen AD, Zhao W

Abstract
Backgrounds: Amoxicillin is widely used to treat bacterial infections in neonates. However, considerable inter-center variability in dosage regimens of antibiotic exist in clinical practice. Pharmacokinetics of amoxicillin has been described in only a few preterm neonates. Thus, we aimed to evaluate population pharmacokinetics of amoxicillin through a large samples covered entire age range of neonates and young infants, and establish evidence-based dosage regimens based on developmental pharmacokinetics-pharmacodynamics.Methods: This is a prospective, multi-center, pharmacokinetic study using an opportunistic sampling design. Amoxicillin plasma concentrations were determined using high performance liquid chromatography. Population pharmacokinetic analysis was performed using NONMEM.Results: A total of 224 pharmacokinetic samples from 187 newborns (postmenstrual age range: 28.4 - 46.3 weeks) were available for analysis. A 2-compartment model with first-order elimination was used to describe population pharmacokinetics. Covariate analysis showed that current weight, postnatal age and gestational age were significant covariates. The final model was further validated for predictive performance in an independent cohort of patients. Monte Carlo simulation demonstrated that for early-onset sepsis, the currently used dosage regimen (25mg/kg BID) resulted in 99.0% of premature neonates and 87.3% of term neonates achieving the pharmacodynamic target (% time above MIC), using MIC breakpoint of 1 mg/L. For late-onset sepsis, 86.1% of premature neonates treated with 25mg/kg TID and 79.0% of term neonates receiving 25mg/kg QID reached the pharmacodynamic target, using MIC breakpoint of 2 mg/L.Conclusion: The population pharmacokinetics of amoxicillin was assessed in neonates and young infants. A dosage regimen was established based on developmental pharmacokinetics-pharmacodynamics.

PMID: 30509939 [PubMed - as supplied by publisher]

Association between exhaled carbon monoxide and asthma outcomes in Peruvian children.

Respir Med. 2018 Dec;145:212-216

Authors: Pereira AA, Pollard SL, Locke R, Romero K, Lima JJ, Hansel NN, Checkley W, GASP Study Investigators

Abstract
BACKGROUND: Asthma prevalence continues to increase in low and middle-income countries, presenting challenges in assessing asthma control in resource-poor settings. Previous studies suggest that exhaled carbon monoxide (eCO) is higher with asthma severity and lower with treatment. We hypothesized that eCO levels may be elevated in children with asthma, particularly in children with partially controlled or uncontrolled asthma in a low-resource setting in Lima, Peru.
METHODS: We compared average eCO levels between 248 children with asthma and 221 healthy controls as well as the odds of asthma by eCO quartiles (0-1, 2, 3, and ≥4 ppm) using multivariable linear and logistic regression. eCO quartiles were also used to compare the odds of partially controlled or uncontrolled asthma (score ≤19 on the Asthma Control Test) in a multivariable logistic regression model.
FINDINGS: Average adjusted eCO level was 0.56 ppm (95% CI 0.07-1.05) higher in children with asthma. The adjusted odds of asthma were 1.22 (95% CI 0.75-1.97), 1.46 (0.81-2.63), and 1.76 (0.96-3.23) in the second, third, and fourth eCO quartiles compared to the first eCO quartile, respectively. Among children with asthma, the adjusted odds of partially controlled or uncontrolled asthma in those in the second, third, and fourth eCO quartiles, compared to the first, were 1.61 (95% CI 0.74-3.48), 3.66 (95% CI 1.51-8.87), and 2.50 (95% CI 1.06-5.90), respectively.
INTERPRETATION: eCO may serve as an inexpensive biomarker for asthma control, particularly in low-resource settings.

PMID: 30509712 [PubMed - in process]

Fundamental Considerations for Genetically-Guided Pain Management with Opioids Based on CYP2D6 and OPRM1 Polymorphisms.

Pain Physician. 2018 Nov;21(6):E611-E621

Authors: Ruano G, Kost JA

Abstract
BACKGROUND: A major challenge for effective pharmacotherapy in pain management is to provide the drug best suited to the patient's innate characteristics.
OBJECTIVE: The article illustrates pharmacogenetic principles to optimize treatments for patients and increase the likelihood of pain relief without dependence. Genetic variances are particularly relevant to opioid drugs used in pain control, and can now be harvested for predictive clinical decision support.
STUDY DESIGN: Clinically actionable polymorphisms in CYP2D6 (cytochrome p450 2D6) and OPRM1 (mu 1 opioid receptor), the most important gene coding, respectively, for a metabolizing enzyme and receptor for opioids are reviewed, and functional effects described.
METHODS: Risk of dysfunction is calculated from the frequency of the alleles with null function for CYP2D6, and from the low function polymorphism for OPRM1. Integration of genetic variability was performed for 9 combinatorial scenarios for CYP2D6 and OPRM1. Each combination was quantified in frequency and classified for clinical impact. A rational and pharmacological basis for personalized pain management based on pharmacokinetic and pharmacodynamic modeling is extracted from the frequency of the combinations.
RESULTS: Patients can be classified in 3 broad risk categories for opioid side effects and dependence. Patients at high-risk with dysfunctional CYP2D6 or OPRM1 account for ~14% of the population and are best managed with non-opioids. Patients at medium risk with subnormal CYP2D6 or OPRM1 account for ~48% of the population and can be managed with dose monitoring. Patients at low risk with functional CYP2D6 and OPRM1 account for ~38% of the population and should be availed to opioid therapy.
LIMITATIONS: Heuristic clinical decision support considerations are not validated yet by deployment in large clinical practices. Environmental modifiers such as other drugs and dietary supplements interact with innate characteristics to modify the genetic predictions.
CONCLUSION: Through clinical decision support interpreting the genotyping data, drug choices and doses can then be tailored to provide safe and effective therapy for individual patients. This precision affords personalized medicine to be practiced in pain treatment. Genetic factors could help determine why some patients seem more vulnerable than others to opioid side effects and dependence.
KEY WORDS: Pain management, opioids, CYP2D6, OPRM1, clinical decision support, pharmacokinetics, pharmacodynamics, pharmacogenetics, combinatorial genotypes.

PMID: 30508992 [PubMed - in process]

Clinical Value of Pharmacogenomic Testing in a Patient Receiving FOLFIRINOX for Pancreatic Adenocarcinoma.

Front Pharmacol. 2018;9:1309

Authors: Velez-Velez LM, Hughes CL, Kasi PM

Abstract
Pharmacogenomic testing may have clinical value in the treatment of patients with gastrointestinal malignancies such as colorectal and pancreatic cancer. These types of cancer are often treated with combination chemotherapy regimens. These regimens can lead to severe adverse effects in patients with diminished drug tolerability potentially due to certain genetic variants in the enzymes involved in the metabolism of the chemotherapies. Genetic variants resulting in decreased enzymatic activity of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and dihydropyrimidine dehydrogenase (DPD) are known to increase irinotecan and 5-fluorouracil-related toxicity, respectively. We report a case of a patient with pancreatic adenocarcinoma who was found to be not only homozygous for the UGT1A1∗28 allele, but also heterozygous for a DPYD variant through pharmacogenomic testing. Potentially severe adverse effects were prevented in this patient's case by implementing preemptive dose reductions. On the basis of the significant implications of chemotherapy-related toxicity in this and other similar cases, we report on the clinical value of integrating pharmacogenomic testing into clinical practice to allow for preemptive and/or point-of-care dose reductions in patients potentially at risk for increased toxicity. This is even more important in an era where combinatorial triplet chemotherapies are increasingly being used.

PMID: 30498448 [PubMed]

Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for the use of potent volatile anesthetic agents and succinylcholine in the context of RYR1 or CACNA1S genotypes.

Clin Pharmacol Ther. 2018 Nov 30;:

Authors: Gonsalves SG, Dirksen RT, Sangkuhl K, Pulk R, Alvarellos M, Vo T, Hikino K, Roden D, Klein T, Mark Poler S, Patel S, Caudle KE, Gordon R, Brandom B, Biesecker LG

Abstract
The identification in a patient of one of the 50 variants in the RYR1 or CACNA1S genes reviewed here should lead to a presumption of malignant hyperthermia susceptibility. Malignant hyperthermia susceptibility can lead to life-threatening reactions to potent volatile anesthetic agents or succinylcholine. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of these agents in patients with these RYR1 or CACNA1S variants (updates at https://cpicpgx.org/guidelines/ and www.pharmgkb.org). This article is protected by copyright. All rights reserved.

PMID: 30499100 [PubMed - as supplied by publisher]

Effects of proton pump inhibitor on the human gut microbiome profile in multi-ethnic groups in Singapore.

Singapore Med J. 2018 Nov 29;:

Authors: Koo SH, Deng J, Ang DSW, Hsiang JC, Lee LS, Aazmi S, Mohamed EHM, Yang H, Yap SY, Teh LK, Salleh MZ, Lee EJD, Ang TL

Abstract
INTRODUCTION: The objectives of this study were to examine the effects of ethnicity, gender, and a proton pump inhibitor (PPI), omeprazole, on the human gut microbiome. PPIs are commonly used for the treatment of acid-related disorders. We hypothesised that PPI therapy might perturb microbial communities and alter the gut microbiome.
METHODS: Healthy subjects of Chinese (n = 12), Malay (n = 12) and Indian (n = 10) ancestry, aged 21-37 years, were enrolled. They provided a baseline stool sample (Day 1) and were then given a course of omeprazole at therapeutic dose (20 mg daily) for seven days. Stool samples were collected again on Day 7 and 14 (one week after stopping omeprazole). Microbial DNA was extracted from the stool samples, followed by polymerase chain reaction, library construction, 16S rRNA sequencing using Illumina MiSeq, and statistical and bioinformatics analyses.
RESULTS: The findings showed an increase in species richness (p = 0.018) after omeprazole consumption on Day 7, which reverted to baseline on Day 14. There were significant increases in the relative abundance of Streptococcus vestibularis (p = 0.0001) and Veillonella dispar (p = 0.0001) on Day 7, which diminished on Day 14. Faecalibacterium prausnitzii, Sutterella stercoricanis and Bacteroides denticanum were characteristic of Chinese, Malays and Indians, respectively. Lactobacillaceae and Bacteroides xylanisolvens were the signature taxa of male and female subjects, respectively.
CONCLUSION: The study demonstrated alterations in the gut microbiome following omeprazole treatment. This may explain the underlying pathology of increased risk of Clostridium difficile infections associated with omeprazole therapy.

PMID: 30488079 [PubMed - as supplied by publisher]

Polymorphisms in mTOR and Calcineurin Signaling Pathways Are Associated With Long-Term Clinical Outcomes in Kidney Transplant Recipients.

Front Pharmacol. 2018;9:1296

Authors: Campos-Salazar AB, Genvigir FDV, Felipe CR, Tedesco-Silva H, Medina-Pestana J, Monteiro GV, Basso RG, Cerda A, Hirata MH, Hirata RDC

Abstract
Monitoring of immunosuppressive drugs, such as calcineurin and mTOR inhibitors, is essential to avoid undesirable kidney transplant outcomes. Polymorphisms in pharmacokinetics-related genes have been associated with variability in blood levels of immunosuppressive drugs and adverse effects, but influence of pharmacodynamics-related genes remains to be elucidated. The influence of polymorphisms in genes of the mTOR and calcineurin signaling pathways on long-term clinical outcomes was investigated in Brazilian kidney transplant recipients within the 1-year post-transplant. Two-hundred and sixty-nine kidney transplant recipients were enrolled at a kidney transplant center in São Paulo city, Brazil, and treated with tacrolimus plus everolimus or mycophenolate sodium (clinical trial NCT01354301). Clinical and laboratory data, including renal function parameters and drug blood levels were recorded. Genomic DNA was extracted from blood samples. Polymorphisms in MTOR rs1057079 (c.4731G>A), rs1135172 (c.1437T>C), and rs1064261 (c.2997C>T); PPP3CA rs3730251 (c.249G>A); FKBP1A rs6033557 (n.259+24936T>C); FKBP2 rs2159370 (c.-2110G>T); and FOXP3 rs3761548 (c.-23+2882A>C) and rs2232365 (c.-22-902A>G) were analyzed by real-time PCR. Frequencies of gene polymorphisms did not differ among the treatment groups. Analysis of primary outcomes showed that patients carrying MTOR c.1437CC and FOXP3 c.-23+2882CC genotypes had higher serum creatinine than non-carriers (p < 0.05) at 1-year post-transplant. MTOR c.4731G allele (AG+GG genotype) was associated with increased risk for acute rejection (OR = 3.53, 95% CI = 1.09-11.48, p = 0.037). Moreover, 1-year cumulative incidence of rejection was higher in MTOR c.4731G allele carriers compared to AA genotype carriers (p = 0.027). Individually, analysis of secondary outcomes revealed that FKBP2 c.-2110GG genotype carriers had higher risk of leukopenia, FKBP1A n.259+24936C allele carriers had increased risk of constipation, and FOXP3 c.-22-902A or c.-23+2882A allele had higher risk of gastrointestinal disorders (p < 0.05). However, these results were not maintained in the multivariable analysis after p-value adjustment. In conclusion, variants in genes of mTOR and calcineurin pathways are associated with long-term impaired renal function, increased risk of acute rejection, and, individually, with adverse events in Brazilian kidney transplant recipients.

PMID: 30487748 [PubMed]

Diagnostic and Therapeutic Strategies for Fluoropyrimidine Treatment of Patients Carrying Multiple DPYD Variants.

Genes (Basel). 2018 Nov 28;9(12):

Authors: Lunenburg CATC, Henricks LM, van Kuilenburg ABP, Mathijssen RHJ, Schellens JHM, Gelderblom H, Guchelaar HJ, Swen JJ

Abstract
DPYD genotyping prior to fluoropyrimidine treatment is increasingly implemented in clinical care. Without phasing information (i.e., allelic location of variants), current genotype-based dosing guidelines cannot be applied to patients carrying multiple DPYD variants. The primary aim of this study is to examine diagnostic and therapeutic strategies for fluoropyrimidine treatment of patients carrying multiple DPYD variants. A case series of patients carrying multiple DPYD variants is presented. Different genotyping techniques were used to determine phasing information. Phenotyping was performed by dihydropyrimidine dehydrogenase (DPD) enzyme activity measurements. Publicly available databases were queried to explore the frequency and phasing of variants of patients carrying multiple DPYD variants. Four out of seven patients carrying multiple DPYD variants received a full dose of fluoropyrimidines and experienced severe toxicity. Phasing information could be retrieved for four patients. In three patients, variants were located on two different alleles, i.e., in trans. Recommended dose reductions based on the phased genotype differed from the phenotype-derived dose reductions in three out of four cases. Data from publicly available databases show that the frequency of patients carrying multiple DPYD variants is low (< 0.2%), but higher than the frequency of the commonly tested DPYD*13 variant (0.1%). Patients carrying multiple DPYD variants are at high risk of developing severe toxicity. Additional analyses are required to determine the correct dose of fluoropyrimidine treatment. In patients carrying multiple DPYD variants, we recommend that a DPD phenotyping assay be carried out to determine a safe starting dose.

PMID: 30487465 [PubMed]

Multiethnic Genome-wide Association Study of Diabetic Retinopathy using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.

Diabetes. 2018 Nov 28;:

Authors: Pollack S, Igo RP, Jensen RA, Christiansen M, Li X, Cheng CY, Ng MCY, Smith AV, Rossin EJ, Segrè AV, Davoudi S, Tan GS, Ida Chen YD, Kuo JZ, Dimitrov LM, Stanwyck LK, Meng W, Hosseini SM, Imamura M, Nousome D, Kim J, Hai Y, Jia Y, Ahn J, Leong A, Shah K, Park KH, Guo X, Ipp E, Taylor KD, Adler SG, Sedor JR, Freedman BI, Family Investigation of Nephropathy and Diabetes-Eye Research Group, DCCT/EDIC Research Group, Lee IT, H-H Sheu W, Kubo M, Takahashi A, Hadjadj S, Marre M, Tregouet DA, Mckean-Cowdin R, Varma R, McCarthy MI, Groop L, Ahlqvist E, Lyssenko V, Agardh E, Morris A, Doney ASF, Colhoun HM, Toppila I, Sandholm N, Groop PH, Maeda S, Hanis CL, Penman A, Chen CJ, Hancock H, Mitchell P, Craig JE, Chew EY, Paterson AD, Grassi MA, Palmer C, Bowden DW, Yaspan BL, Siscovick D, Cotch MF, Wang JJ, Burdon KP, Wong TY, Klein BEK, Klein R, Rotter JI, Iyengar SK, Price A, Sobrin L

Abstract
To identify genetic variants associated with diabetic retinopathy (DR), we performed a large, multiethnic genome-wide association study (GWAS). Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value < 1 X 10-5 were investigated in replication cohorts that included 18,545 Europeans, 16,453 Asians and 2,710 Hispanics. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like (NVL) was associated with DR in European discovery cohorts (P = 2.1 x 10-9), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR (PDR) was found to have significant connectivity (P=0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in NVL, as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.

PMID: 30487263 [PubMed - as supplied by publisher]

Acute enlargement of a vascular plaque and gait changes in a young girl.

BMJ. 2018 Nov 28;363:k4679

Authors: Tedesco KT, Sarthy J, Pinto N, Boos MD

PMID: 30487229 [PubMed - in process]

Impact of CYP2C9 and VKORC1 Polymorphisms on Warfarin Sensitivity and Responsiveness in Jordanian Cardiovascular Patients during the Initiation Therapy.

Genes (Basel). 2018 Nov 27;9(12):

Authors: Al-Eitan LN, Almasri AY, Khasawneh RH

Abstract
Warfarin is an oral anticoagulant frequently used in the treatment of different cardiovascular diseases. Genetic polymorphisms in the CYP2C9 and VKORC1 genes have produced variants with altered catalytic properties. A total of 212 cardiovascular patients were genotyped for 17 Single Nucleotide Polymorphisms (SNPs) within the CYP2C9 and VKORC1 genes. This study confirmed a genetic association of the CYP2C9*3 and VKORC1 rs10871454, rs8050894, rs9934438, and rs17708472 SNPs with warfarin sensitivity. This study also found an association between CYP2C9 and VKORC1 genetic haplotype blocks and warfarin sensitivity. The initial warfarin dose was significantly related to the CYP2C9*3 polymorphism and the four VKORC1 SNPs (p < 0.001). There were significant associations between rs4086116 SNP and TAT haplotype within CYP2C9 gene and rs17708472 SNP and CCGG haplotype within VKORC1 gene and warfarin responsiveness. However, possessing a VKORC1 variant allele was found to affect the international normalized ratio (INR) outcomes during initiation of warfarin therapy. In contrast, there was a loose association between the CYP2C9 variant and INR measurements. These findings can enhance the current understanding of the great variability in response to warfarin treatment in Arabs.

PMID: 30486437 [PubMed]

Pericentromeric hypomethylation elicits an interferon response in an animal model of ICF syndrome.

Elife. 2018 11 28;7:

Authors: Rajshekar S, Yao J, Arnold PK, Payne SG, Zhang Y, Bowman TV, Schmitz RJ, Edwards JR, Goll M

Abstract
Pericentromeric satellite repeats are enriched in 5-methylcytosine (5mC). Loss of 5mC at these sequences is common in cancer and is a hallmark of Immunodeficiency, Centromere and Facial abnormalities (ICF) syndrome. While the general importance of 5mC is well-established, the specific functions of 5mC at pericentromeres are less clear. To address this deficiency, we generated a viable animal model of pericentromeric hypomethylation through mutation of the ICF-gene ZBTB24. Deletion of zebrafish zbtb24 caused a progressive loss of 5mC at pericentromeres and ICF-like phenotypes. Hypomethylation of these repeats triggered derepression of pericentromeric transcripts and activation of an interferon-based innate immune response. Injection of pericentromeric RNA is sufficient to elicit this response in wild-type embryos, and mutation of the MDA5-MAVS dsRNA-sensing machinery blocks the response in mutants. These findings identify activation of the innate immune system as an early consequence of pericentromeric hypomethylation, implicating derepression of pericentromeric transcripts as a trigger of autoimmunity.
Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

PMID: 30484769 [PubMed - in process]

Continuing war on pain: a personalized approach to the therapy with nonsteroidal anti-inflammatory drugs and opioids.

Per Med. 2018 Nov 28;:

Authors: Bach-Rojecky L, Vađunec D, Žunić K, Kurija J, Šipicki S, Gregg R, Mikula I, Primorac D

Abstract
Successful pain management requires the delivery of analgesia with minimal risk of adverse drug reactions. Nonsteroidal anti-inflammatory drugs and opioids remain the mainstay of treatment for the majority of patients. Unfortunately, almost 50% of all patients experience inadequate pain relief and serious side effects. Allelic variants in genes coding for target proteins, transporters and enzymes, which govern analgesic drugs action and their fate in the organism, might explain inter-individual variability in pain severity and in drug-induced pain relief and toxicities. Additionally, it seems that epigenetic changes contribute to the highly variable response to pain treatment. Therefore, pharmacogenomic testing might be a valuable tool for personalization of pain treatment, with a multidisciplinary team approach involved.

PMID: 30484741 [PubMed - as supplied by publisher]

Biological role of metabolic reprogramming of cancer cells during epithelial‑mesenchymal transition (Review).

Oncol Rep. 2018 Nov 23;:

Authors: Li M, Bu X, Cai B, Liang P, Li K, Qu X, Shen L

Abstract
Epithelial‑mesenchymal transition (EMT) is required for the distant metastasis of tumors. The degree of tumor malignancy increases as EMT progresses. Notably, the biology of tumor cells differs from that of normal cells, with regards to characteristics and energy metabolism mechanisms; abnormal glucose metabolism, excessive accumulation of fatty acids and other metabolic disorders occur in metastatic tumors. Previous studies have confirmed that the regulation of tumor cell metabolism can affect tumor metastasis and some findings have resulted in novel clinical applications. The present review aimed to provide a basis for treatments targeting the tumor EMT process and metabolic reprogramming.

PMID: 30483813 [PubMed - as supplied by publisher]

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders.

Nat Neurosci. 2018 Dec;21(12):1656-1669

Authors: Walters RK, Polimanti R, Johnson EC, McClintick JN, Adams MJ, Adkins AE, Aliev F, Bacanu SA, Batzler A, Bertelsen S, Biernacka JM, Bigdeli TB, Chen LS, Clarke TK, Chou YL, Degenhardt F, Docherty AR, Edwards AC, Fontanillas P, Foo JC, Fox L, Frank J, Giegling I, Gordon S, Hack LM, Hartmann AM, Hartz SM, Heilmann-Heimbach S, Herms S, Hodgkinson C, Hoffmann P, Jan Hottenga J, Kennedy MA, Alanne-Kinnunen M, Konte B, Lahti J, Lahti-Pulkkinen M, Lai D, Ligthart L, Loukola A, Maher BS, Mbarek H, McIntosh AM, McQueen MB, Meyers JL, Milaneschi Y, Palviainen T, Pearson JF, Peterson RE, Ripatti S, Ryu E, Saccone NL, Salvatore JE, Sanchez-Roige S, Schwandt M, Sherva R, Streit F, Strohmaier J, Thomas N, Wang JC, Webb BT, Wedow R, Wetherill L, Wills AG, 23andMe Research Team, Boardman JD, Chen D, Choi DS, Copeland WE, Culverhouse RC, Dahmen N, Degenhardt L, Domingue BW, Elson SL, Frye MA, Gäbel W, Hayward C, Ising M, Keyes M, Kiefer F, Kramer J, Kuperman S, Lucae S, Lynskey MT, Maier W, Mann K, Männistö S, Müller-Myhsok B, Murray AD, Nurnberger JI, Palotie A, Preuss U, Räikkönen K, Reynolds MD, Ridinger M, Scherbaum N, Schuckit MA, Soyka M, Treutlein J, Witt S, Wodarz N, Zill P, Adkins DE, Boden JM, Boomsma DI, Bierut LJ, Brown SA, Bucholz KK, Cichon S, Costello EJ, de Wit H, Diazgranados N, Dick DM, Eriksson JG, Farrer LA, Foroud TM, Gillespie NA, Goate AM, Goldman D, Grucza RA, Hancock DB, Harris KM, Heath AC, Hesselbrock V, Hewitt JK, Hopfer CJ, Horwood J, Iacono W, Johnson EO, Kaprio JA, Karpyak VM, Kendler KS, Kranzler HR, Krauter K, Lichtenstein P, Lind PA, McGue M, MacKillop J, Madden PAF, Maes HH, Magnusson P, Martin NG, Medland SE, Montgomery GW, Nelson EC, Nöthen MM, Palmer AA, Pedersen NL, Penninx BWJH, Porjesz B, Rice JP, Rietschel M, Riley BP, Rose R, Rujescu D, Shen PH, Silberg J, Stallings MC, Tarter RE, Vanyukov MM, Vrieze S, Wall TL, Whitfield JB, Zhao H, Neale BM, Gelernter J, Edenberg HJ, Agrawal A

Abstract
Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10-13) and African ancestries (rs2066702; P = 2.2 × 10-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

PMID: 30482948 [PubMed - in process]

Ophthalmic Insert versus Eye Drops for Mydriasis in Neonates: A Randomized Clinical Trial.

Neonatology. 2018 Nov 27;115(2):142-148

Authors: Bremond-Gignac D, Jacqz-Aigrain E, Abdoul H, Daruich A, Beresniak A, Baud O, Alberti C, on behalf of the CLAIR FO Study Group

Abstract
BACKGROUND: Eye drop treatment routinely used to obtain mydriasis prior to fundoscopy in neonates requires repeated instillations of mydriatic agents that can lead to systemic side effects.
OBJECTIVES: The aim of this study was to compare the mydriatic efficacy and tolerance of administration of phenylephrine and tropicamide via the ophthalmic insert Mydriasert® versus standard eye drop treatment in neonates.
METHODS: In this prospective, single-blinded, noninferiority study, 80 hospitalized neonates (age < 18 months) requiring bilateral fundus examination were randomized to receive eye drops (repeated instillations of 2.5% phenylephrine and 0.5% tropicamide) or the insert. The primary outcome was mydriasis suitable for fundoscopy 75 min after mydriatic agent introduction (T75).
RESULTS: Mydriasis was successfully achieved in both eyes at T75 in 97.5% (n = 39/40) of the insert group patients versus 90% (n = 36/40) receiving eye drops (between-group difference 7.5%, demonstrating noninferiority). Mydriasis remained stable in 60.0% of patients (n = 24/40) in the insert group versus 15% (n = 6/40) in the eye drop group (p < 0.0001). The insert group required fewer nursing interventions than the eye drop group (p = 0.0001). Mean blood pressure were significantly higher in the insert versus the eye drop group (p < 0.0001 and p = 0.0003, respectively); mean heart rate was not significantly different between the groups (p = 0.37). In the insert group, 2 patients reported an adverse event (bradycardia, n = 1, and gastroesophageal reflux, n = 1; both appeared to be related to neonate pathology).
CONCLUSIONS: The degree of mydriasis achieved with Mydriasert® was noninferior to that obtained with eye drops. The insert appears to be safe to use in neonates without a history of increased vagal tone or gastrointestinal reflux.

PMID: 30481790 [PubMed - as supplied by publisher]

Clinical Utility of Pharmacogenetic Testing and a Clinical Decision Support Tool to Enhance the Identification of Drug Therapy Problems Through Medication Therapy Management in Polypharmacy Patients.

J Manag Care Spec Pharm. 2018 Dec;24(12):1250-1259

Authors: Kim K, Magness JW, Nelson R, Baron V, Brixner DI

Abstract
BACKGROUND: In polypharmacy patients, medication therapy management (MTM) services provide a comprehensive review of current medications and future treatment goals. Pharmacogenetics (PGx) may further optimize the identification of potential drug therapy problems (DTPs); however, the clinical utility of PGx information with a clinical decision support tool (CDST) in an MTM setting in identifying DTPs has not been systematically assessed.
OBJECTIVE: To assess the clinical utility of an MTM service enhanced by pharmacogenetic test results and a clinical decision support tool.
METHODS: This study was a post hoc analysis of the data obtained from an open-label, randomized, observational trial. Polypharmacy patients eligible for MTM service were randomly assigned to 3 intervention arms: standard MTM (SMTM), MTM incorporating CDST (CMTM), and CMTM further enhanced by PGx test results of CYP450 and VKORC1 enzymes (PGxMTM). Allocation for this post hoc analysis was based on patient adherence to the research protocol and completion of a PGx test. The number of DTPs per patient was compared across the 3 arms using analysis of variance. In addition, the frequency of serious DTPs as a categorical variable (grade 3 or above vs. lower grade) was compared across the 3 arms between PGx driven and non-PGx driven DTP recommendations. Statistical significance was tested using the chi-square test. The level of agreement between the DTP seriousness and the acceptance made by prescribers was presented as Cohen's kappa coefficient.
RESULTS: Numbers of patients after cohort reallocation based on completion of PGx testing were 104, 180, and 58 for the SMTM, CMTM, and PGxMTM arms, respectively. On average, 3.08 DTPs were identified for each patient, which was nearly identical across all 3 arms. Blinded clinical pharmacists considered seriousness (grade 3 or 4) in 31% of the PGx-related DTPs in comparison with 4.9% of the non-PGx DTPs (P < 0.001). The more serious (i.e., grade 3 or above) DTP recommendations were more likely to be accepted by prescribers with the odds ratios of 1.95 (P = 0.05) and 2.39 (P = 0.15), when the analysis was performed for all DTPs and DTPs from the PGxMTM arm only, respectively.
CONCLUSIONS: MTM enhanced by PGx testing and the clinical decision support tool did not increase the number of DTPs identified. However, PGx testing and the decision support software helps pharmacists determine more serious DTPs, and resulting subsequent recommendations were more readily accepted by a prescriber. Future study of the patient safety outcomes and overall health care costs associated with the utility of the decision support is warranted.
DISCLOSURES: No funding was received for conducting the post hoc analysis presented in this study. Magness is employed by Magellan Health, which received funding from Genelex for costs to administrate the medication management program. The open-label randomized trial was sponsored by Genelex (Clinicaltrials.gov ID number NCT02428660). PGx tests were provided and laboratory analysis was performed by Genelex. Valerie Baron is an employee of YouScript, which created the clinical decision support tool used in this study and formerly was part of Genelex. The other authors have nothing to disclose.

PMID: 30479202 [PubMed - in process]

Involvement of miRNA polymorphism in mucositis development in childhood acute lymphoblastic leukemia treatment.

Pharmacogenomics. 2018 Dec;19(18):1403-1412

Authors: Gutierrez-Camino Á, Umerez M, Lopez-Lopez E, Santos-Zorrozua B, Martin-Guerrero I, de Andoin NG, Ana S, Navajas A, Astigarraga I, Garcia-Orad A

Abstract
AIM: Mucositis, linked to methotrexate, daunorubicin or cyclophosphamide, is a frequent childhood acute lymphoblastic leukemia (ALL) therapy side effect. miRNAs regulate the expression of pharmacokinetic/pharmacodynamic pathway genes. SNPs in miRNAs could affect their levels or function, and affect their pharmacokinetic/pharmacodynamic pathway target genes. Our aim was to determine the association between miRNA genetic variants targeting mucositis-related genes and mucositis-developing risk.
PATIENTS & METHODS: We analyzed 160 SNPs in 179 Spanish children with B-cell precursor ALL homogeneously treated with LAL/SHOP protocols.
RESULTS: We identified three SNPs in miR-4268, miR-4751 and miR-3117 associated with mucositis, diarrhea and vomiting, respectively.
CONCLUSION: The effect of these SNPs on genes related to drug pharmacokinetics/pharmacodynamics could explain mucositis, diarrhea and vomiting development during ALL therapy.

PMID: 30479191 [PubMed - in process]

Autonomic dysfunction and HPV immunization: an overview.

Immunol Res. 2018 Nov 27;:

Authors: Blitshetyn S, Brinth L, Hendrickson JE, Martinez-Lavin M

Abstract
This article reviews the case series reported from several countries describing patients with suspected severe side effects to the HPV vaccines. The described symptom clusters are remarkably similar and include disabling fatigue, headache, widespread pain, fainting, gastrointestinal dysmotility, limb weakness, memory impairment episodes of altered awareness, and abnormal movements. This constellation of symptoms and signs has been labeled with different diagnoses such as complex regional pain syndrome (CRPS), postural orthostatic tachycardia syndrome (POTS), small fiber neuropathy (SFN), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), or fibromyalgia. It is known that autoimmunity and autoantibodies are present in a subset of patients with CRPS, POTS, SFN, ME/CFS, and fibromyalgia. This article proposes that vaccine-triggered, immune-mediated autonomic dysfunction could lead to the development of de novo post-HPV vaccination syndrome possibly in genetically susceptible individuals. Being cognizant that a temporal relationship between vaccination and symptom onset does not necessarily equate to causality, mounting evidence of case series calls for well-designed case-control studies to determine the prevalence and possible causation between these symptom clusters and HPV vaccines. Since personalized medicine is gaining momentum, the use of adversomics and pharmacogenetics may eventually help identify individuals who are predisposed to HPV vaccine adverse events.

PMID: 30478703 [PubMed - as supplied by publisher]

Being Overweight or Obese and the Development of Asthma.

Pediatrics. 2018 Nov 26;:

Authors: Lang JE, Bunnell HT, Hossain MJ, Wysocki T, Lima JJ, Finkel TH, Bacharier L, Dempsey A, Sarzynski L, Test M, Forrest CB

Abstract
OBJECTIVES: Adult obesity is linked to asthma cases and is estimated to lead to 250 000 new cases yearly. Similar incidence and attributable risk (AR) estimates have not been developed for children. We sought to describe the relationship between overweight and obesity and incident asthma in childhood and quantify AR statistics in the United States for overweight and obesity on pediatric asthma.
METHODS: The PEDSnet clinical data research network was used to conduct a retrospective cohort study (January 2009-December 2015) to compare asthma incidence among overweight and/or obese versus healthy weight 2- to 17-year-old children. Asthma incidence was defined as ≥2 encounters with a diagnosis of asthma and ≥1 asthma controller prescription. Stricter diagnostic criteria involved confirmation by spirometry. We used multivariable Poisson regression analyses to estimate incident asthma rates and risk ratios and accepted formulas for ARs.
RESULTS: Data from 507 496 children and 19 581 972 encounters were included. The mean participant observation period was 4 years. The adjusted risk for incident asthma was increased among children who were overweight (relative risk [RR]: 1.17; 95% confidence interval [CI]: 1.10-1.25) and obese (RR: 1.26; 95% CI: 1.18-1.34). The adjusted risk for spirometry-confirmed asthma was increased among children with obesity (RR: 1.29; 95% CI: 1.16-1.42). An estimated 23% to 27% of new asthma cases in children with obesity is directly attributable to obesity. In the absence of overweight and obesity, 10% of all cases of asthma would be avoided.
CONCLUSIONS: Obesity is a major preventable risk factor for pediatric asthma.

PMID: 30478238 [PubMed - as supplied by publisher]