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Background: Cisplatin-induced ototoxicity remains a significant concern in pediatric cancer treatment due to its permanent impact on quality of life. Previously, genetic association analyses have been performed to detect genetic variants associated with this adverse reaction., Methods: In this study, a combination of interpretable neural networks and Generative Adversarial Networks (GANs) was employed to identify genetic markers associated with cisplatin-induced ototoxicity. The applied method, BRI-Net, incorporates biological domain knowledge to define the network structure and employs adversarial training to learn an unbiased representation of the data, which is robust to known confounders. Leveraging genomic data from a cohort of 362 cisplatin-treated pediatric cancer patients recruited by the CPNDS (Canadian Pharmacogenomics Network for Drug Safety), this model revealed two statistically significant single nucleotide polymorphisms to be associated with cisplatin-induced ototoxicity., Results: Two markers within the CERS6 (rs13022792, p-value: 3 × 10 -4 ) and TLR4 (rs10759932, p-value: 7 × 10 -4 ) genes were associated with this cisplatin-induced adverse reaction. CERS6, a ceramide synthase, contributes to elevated ceramide levels, a known initiator of apoptotic signals in mouse models of inner ear hair cells. TLR4, a pattern-recognition protein, initiates inflammation in response to cisplatin, and reduced TLR4 expression has been shown in murine hair cells to confer protection from ototoxicity., Conclusion: Overall, these findings provide a foundation for understanding the genetic landscape of cisplatin-induced ototoxicity, with implications for improving patient care and treatment outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Vincristine-induced peripheral neuropathy is a common and highly debilitating toxicity from vincristine treatment that affects quality of life and often requires dose reduction, potentially affecting survival. Although previous studies demonstrated genetic factors are associated with vincristine neuropathy risk, the clinical relevance of most identified variants is limited by small sample sizes and unclear clinical phenotypes. A genome-wide association study was conducted in 1100 cases and controls matched by vincristine dose and genetic ancestry, uncovering a statistically significant (p < 5.0 × 10 -8 ) variant in MCM3AP gene that substantially increases the risk of neuropathy and 12 variants protective against neuropathy within/near SPDYA, METTL8, PDE4D, FBN2, ZFAND3, NFIB, PAPPA, LRRTM3, NRG3, VTI1A, ARHGAP5, and ACTN1. A follow-up pathway analysis reveals the involvement of four key pathways, including nerve structure and development, myelination, neuronal transmission, and cytoskeleton/microfibril function pathways. These findings present potential actionable genomic markers of vincristine neuropathy and offer opportunities for tailored interventions to improve vincristine safety in children with cancer. This study is registered with ClinicalTrials.gov under the title National Active Surveillance Network and Pharmacogenomics of Adverse Drug Reactions in Children (ID NCT00414115, registered on December 21, 2006)., (© 2024. The Author(s).)

Background: Pharmacogenetic testing in clinical settings has improved the safety and efficacy of drug treatment. There is a growing number of studies evaluating pharmacogenetic implementation and identifying barriers and facilitators. However, no review has focused on bridging the gap between identifying barriers and facilitators of testing and the clinical strategies adopted in response. This review was conducted to understand the implementation and evaluation strategies of pharmacogenetic testing programs., Methods: A PRISMA-compliant scoping review was conducted. The included studies discussed pharmacogenetic testing programs implemented in a hospital setting. Quantitative, qualitative, and mixed design methods were included., Results: A total of 232 of the 7043 articles that described clinical pharmacogenetic programs were included. The most common specialties that described pharmacogenetic implementation were psychiatry (26%) and oncology (16%), although many studies described institutional programs implemented across multiple specialties (19%). Different specialties reported different clinical outcomes, but all reported similar program performance indicators, such as test uptake and the number of times the test recommendations were followed. There were benefits and drawbacks to delivering test results through research personnel, pharmacists, and electronic alerts, but active engagement of physicians was necessary for the incorporation of pharmacogenetic results into clinical decision making., Conclusions: Further research is required on the maintenance and sustainability of pharmacogenetic testing initiatives. These findings provide an overview of the implementation and evaluation strategies of different specialties that can be used to improve pharmacogenetic testing., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Rare diseases have become an increasingly important public health priority due to their collective prevalence and often life-threatening nature. Incentive programs, such as the Orphan Drug Act have been introduced to increase the development of rare disease therapeutics. While the approval of these therapeutics requires supportive data from stringent pre-market studies, these data lack the ability to describe the causes of treatment response heterogeneity, leading to medications often being more harmful or less effective than predicted. If a Goal Line were to be used to describe the multifactorial continuum of phenotypic variations occurring in response to a medication, the 'Goal Posts', or the two defining points of this continuum, would be (1) Super-Response, or an extraordinary therapeutic effect; and (2) Serious Harm. Investigation of the pharmacogenomics behind these two extreme phenotypes can potentially lead to the development of new therapeutics, help inform rational use criteria in drug policy, and improve the understanding of underlying disease pathophysiology. In the context of rare diseases where cohort sizes are smaller than ideal, 'small data' and 'big data' approaches to data collection and analysis should be combined to produce the most robust results. This paper presents the importance of studying drug response in parallel to other research initiatives in rare diseases, as well as the need for international collaboration in the area of rare disease pharmacogenomics., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Cisplatin is associated with acute kidney injury (AKI) and electrolyte abnormalities. Urine tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP-7) may be early cisplatin-AKI biomarkers., Methods: We conducted a 12-site prospective cohort study with pediatric patients treated with cisplatin (May 2013-December 2017). Blood and urine (measured for TIMP-2, IGFBP-7) were collected pre-cisplatin, 24-h post-cisplatin, and near hospital discharge during the first or second cisplatin cycle (early visit (EV)) and during second-to-last or last cisplatin cycle (late visit (LV))., Primary Outcome: serum creatinine (SCr)-defined AKI (≥ stage 1)., Results: At EV (median (interquartile (IQR)) age: 6 (2-12) years; 78 (50%) female), 46/156 (29%) developed AKI; at LV, 22/127 (17%) experienced AKI. At EV, TIMP-2, IGFBP-7, and TIMP-2*IGFBP-7 pre-cisplatin infusion concentrations were significantly higher in participants with vs. those without AKI. At EV and LV, biomarker concentrations were significantly lower in participants with vs. those without AKI at post-infusion and near-hospital discharge. Biomarker values normalized to urine creatinine were higher in patients with AKI compared to without (LV post-infusion, median (IQR): TIMP-2*IGFBP-7: 0.28 (0.08-0.56) vs. 0.04 (0.02-0.12) (ng/mg creatinine) 2 /1000; P < .001). At EV, pre-infusion biomarker concentrations had the highest area under the curves (AUC) (range: 0.61-0.62) for AKI diagnosis; at LV, biomarkers measured post-infusion and near discharge yielded the highest AUCs (range: 0.64-0.70)., Conclusions: TIMP-2*IGFBP-7 were poor to modest at detecting AKI post-cisplatin. Additional studies are needed to determine whether raw biomarker values or biomarker values normalized to urinary creatinine are more strongly associated with patient outcomes. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: Cisplatin is commonly used to treat solid tumors; however, its use can be complicated by drug-induced hearing loss (ie, ototoxicity). The presence of certain genetic variants has been associated with the development/occurrence of cisplatin-induced ototoxicity, suggesting that genetic factors may be able to predict patients who are more likely to develop ototoxicity. The authors aimed to review genetic associations with cisplatin-induced ototoxicity and discuss their clinical relevance., Methods: An updated systematic review was conducted on behalf of the Canadian Pharmacogenomics Network for Drug Safety, based on the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 statement. Pharmacogenomic studies that reported associations between genetic variation and cisplatin-induced ototoxicity were included. The evidence on genetic associations was summarized and evaluated, and knowledge gaps that can be used to inform future pharmacogenomic studies identified., Results: Overall, 40 evaluated reports, considering 47 independent patient populations, captured associations involving 24 genes. Considering GRADE criteria, genetic variants in 2 genes were strongly (ie, odds ratios ≥3) and consistently (ie, replication in ≥3 independent populations) predictive of cisplatin-induced ototoxicity. Specifically, an ACYP2 variant has been associated with ototoxicity in both children and adults, whereas TPMT variants are relevant in children. Encouraging evidence for associations involving several other genes also exists; however, further research is necessary to determine potential clinical relevance., Conclusions: Genetic variation in ACYP2 and TPMT may be helpful in predicting patients at the highest risk of developing cisplatin-induced ototoxicity. Further research (including replication studies considering diverse pediatric and adult patient populations) is required to determine whether genetic variation in additional genes may help further identify patients most at risk., Competing Interests: Several authors on this article (B. Brooks, S.R. Rassekh, C. J. D. Ross, and B. C. Carleton) were authors on published studies discussed in this systematic review; however, transparent grading criteria were employed to limit bias. All authors declare no other conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a predominantly drug-induced disease, with a mortality rate of 15-20%, that engages the expertise of multiple disciplines: dermatology, allergy, immunology, clinical pharmacology, burn surgery, ophthalmology, urogynecology, and psychiatry. SJS/TEN has an incidence of 1-5/million persons per year in the United States, with even higher rates globally. One of the challenges of SJS/TEN has been developing the research infrastructure and coordination to answer questions capable of transforming clinical care and leading to improved patient outcomes. SJS/TEN 2021, the third research meeting of its kind, was held as a virtual meeting on August 28-29, 2021. The meeting brought together 428 international scientists, in addition to a community of 140 SJS/TEN survivors and family members. The goal of the meeting was to brainstorm strategies to support the continued growth of an international SJS/TEN research network, bridging science and the community. The community workshop section of the meeting focused on eight primary themes: mental health, eye care, SJS/TEN in children, non-drug induced SJS/TEN, long-term health complications, new advances in mechanisms and basic science, managing long-term scarring, considerations for skin of color, and COVID-19 vaccines. The meeting featured several important updates and identified areas of unmet research and clinical need that will be highlighted in this white paper., Competing Interests: KM was employed by Stevens-Johnson Syndrome Foundation. EJP reports grants from National Institutes of Health (R01HG010863, R01AI152183, U01AI154659) and from the National Health and Medical Research Council of Australia. She receives Royalties and consulting fees from UpToDate and has received consulting fees from Janssen, Verve, Biocryst, Regeneron, AstraZeneca and Novavax. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer OI declared a shared affiliation with the author AS to the handling editor at the time of review., (Copyright © 2023 Marks, Botta, Abe, Beachkofsky, Boothman, Carleton, Chung, Cibotti, Dodiuk-Gad, Grimstein, Hasegawa, Hoofnagle, Hung, Kaffenberger, Kroshinsky, Lehloenya, Martin-Pozo, Micheletti, Mockenhaupt, Nagao, Pakala, Palubinsky, Pasieka, Peter, Pirmohamed, Reyes, Saeed, Shupp, Sukasem, Syu, Ueta, Zhou, Chang, Becker, Bellon, Bonnet, Cavalleri, Chodosh, Dewan, Dominguez, Dong, Ezhkova, Fuchs, Goldman, Himed, Mallal, Markova, McCawley, Norton, Ostrov, Phan, Sanford, Schlundt, Schneider, Shear, Shinkai, Tkaczyk, Trubiano, Volpi, Bouchard, Divito and Phillips.)

Background: Fluoropyrimidine toxicity is often due to variations in the gene ( DPYD ) encoding dihydropyrimidine dehydrogenase (DPD). DPYD genotyping can be used to adjust doses to reduce the likelihood of fluoropyrimidine toxicity while maintaining therapeutically effective drug levels. Methods: A multiplex QPCR assay was locally developed to allow genotyping for six DPYD variants. The test was offered prospectively for all patients starting on fluoropyrimidines at the BC Cancer Centre in Vancouver and then across B.C., Canada as well as retrospectively for patients suspected to have had an adverse reaction to therapy. Dose adjustments were made for variant carriers. The incidence of toxicity in the first three cycles was compared between DPYD variant allele carriers and non-variant carriers. Subsequent to an initial implementation phase, this test was made available province-wide. Results: In 9 months, 186 patients were tested and 14 were found to be heterozygous variant carriers. Fluoropyrimidine-related toxicity was higher in DPYD variant carriers. Of 127 non-variant carriers who have completed chemotherapy, 18 (14%) experienced severe (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Of note, 22% (3 patients) of the variant carriers experienced severe toxicity even after DPYD -guided dose reductions. For one of these carriers who experienced severe thrombocytopenia within the first week, DPYD testing likely prevented lethal toxicity. In DPYD variant carriers who tolerate reduced doses, a later 25% increase led to chemotherapy discontinuation. As a result, a recommendation was made to clinicians based on available literature and expert opinion specifying that variant carriers who tolerated two cycles without toxicity can have a dose escalation of only 10%. Conclusion: DPYD -guided dose reductions were a feasible and acceptable method of preventing severe toxicity in DPYD variant carriers. Even with dose reductions, there were variant carriers who still experienced severe fluoropyrimidine toxicity, highlighting the importance of adhering to guideline-recommended dose reductions. Following the completion of the pilot phase of this study, DPYD genotyping was made available province-wide in British Columbia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Anderson, Hughesman, Young, Lohrisch, Ross and Carleton.)

Background: Cisplatin, widely used in the treatment of solid tumors, causes permanent hearing loss in more than 60% of treated children. Previous studies have implicated several clinical factors in the development of ototoxicity, including cumulative cisplatin dose. However, the role of cisplatin dose intensity in the development of hearing loss in children remains unclear. Pharmacogenetic studies have also identified genetic variants in TPMT that increase the risk of cisplatin-induced hearing loss. This study aims to determine whether cisplatin dose intensity contributes to the risk of hearing loss in children and whether genetic variations in TPMT further modifies the risk of cisplatin-induced hearing loss., Methods: The authors genotyped 371 cisplatin-treated children for the presence of any 3 TPMT -risk variants. Patients were categorized into high-, moderate-, and low-intensity cisplatin dosing groups according to the cisplatin dose administered per unit time. Kaplan-Meier curves were plotted to compare the cumulative incidence of hearing loss between the genotype and dose intensity groups., Results: Patients receiving cisplatin at high dose intensity experienced significantly higher incidences of ototoxicity than those receiving cisplatin at low dose intensity ( P = 9 × 10 -7 ). Further stratification by TPMT genotype revealed that carriers of ≥1 TPMT variants receiving high-intensity cisplatin developed ototoxicity sooner and more often than their wild-type counterparts (93.8% vs. 56.6% at 12 months; P = 5 × 10 -5 ) and noncarriers receiving low-intensity cisplatin (21.2% at 12 months)., Conclusions: Cisplatin dose intensity is strongly associated with ototoxicity development in children, and this risk is further increased by the presence of TPMT -risk alleles., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Anthracyclines, which are effective chemotherapeutic agents, cause cardiac dysfunction in up to 57% of patients. The cumulative anthracycline dose is a crucial predictor of cardiotoxicity; however, the cumulative dose alone cannot explain all cardiotoxic events. Strongly associated genetic variants in SLC28A3 , UGT1A6 , and RARG contribute to anthracycline-induced cardiotoxicity in pediatric patients and may help identify those most susceptible. This study aimed to examine how these pharmacogenetic effects are modulated by cumulative anthracycline doses in the development of cardiotoxicity., Methods: A total of 595 anthracycline-treated children were genotyped and cardiotoxicity cases were identified. A dose-stratified analysis was performed to compare the contributions of SLC28A3 rs7853758, UGT1A6 rs17863783, and RARG rs2229774 variants to the development of cardiotoxicity in low-dose (<150 mg/m 2 cumulative dose) and high-dose (>250 mg/m 2 cumulative dose) patient groups. Logistic regression was used to model the relationships between the cumulative anthracycline dose, genetic variants, and cardiotoxicity in the full cohort., Results: At < 150 mg/m 2 cumulative anthracycline dose, the SLC28A3 protective variant did not reach statistical significance [odds ratio (OR) 0.46 (95% confidence interval (CI) 0.10-1.45), P = 0.23], but it was statistically significant at doses >250 mg/m 2 [OR 0.43 (95% CI 0.22-0.78), P = 0.0093]. Conversely, the UGT1A6 and RARG risk variants were either statistically significant or approaching significance at doses <150 mg/m 2 [OR 7.18 (95% CI 1.78-28.4), P = 0.0045 for UGT1A6 and OR 2.76 (95% CI 0.89-7.63), P = 0.057 for RARG ], but not at doses >250 mg/m 2 [OR 2.91 (95% CI 0.80-11.0), P = 0.10; OR 1.56 (95% CI 0.89-2.75), P = 0.12]., Conclusions: These findings suggest that the SLC28A3 variant imparts more significant protection for patients receiving higher anthracycline doses, whereas the UGT1A6 and RARG risk variants significantly increased the risk of cardiotoxicity at low anthracycline doses., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Studies of myocarditis/pericarditis following mRNA COVID-19 vaccines in Hong Kong have been published. Data are consistent with data from other active surveillance or healthcare databases. The mRNA COVID-19 vaccines have been shown to rarely increase risk of myocarditis, with the highest risk among males aged 12-17 after the second dose. An increased risk of pericarditis has also been shown after the second dose, though less common than myocarditis and more evenly distributed among different sex and age groups. Because of the increased risk of post-vaccine myocarditis, Hong Kong implemented a single dose mRNA COVID-19 vaccine policy on September 15, 2021 for adolescents (age 12-17 years). Post-policy, there were no cases of carditis. 40,167 first dose patients did not receive a second dose. This policy was highly successful in the reduction of carditis, but the trade-off is the potential risk of disease and cost to population-level immunity. This commentary brings forward some important global policy considerations., Competing Interests: Bruce C. Carleton receives federal grant funds from the Canadian Institutes of Health Research, Genome Canada, Genome BC, and the Global Vaccine Data Network with additional support provided by the British Columbia Provincial Health Services Authority, BC Children's Hospital Foundation, and Health Canada. In the past three years he has also had research funding from Dynacare Next Specialized Diagnostics as part of a Genome Canada federal grant, and provided consultation services to the Canadian Agency for Drugs and Technologies in Health, and UnitedHealth Group. He is also a Board member of the Rare Disease Foundation (unpaid position). Ian Wong reports research funding from the Health and Medical Research Fund to investigate the safety of COVID-19 vaccines. He also reports research funding outside the submitted work from Amgen, Bristol-Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, the Hong Kong Research Grants Council, the Hong Kong Health and Medical Research Fund, National Institute for Health Research in England, European Commission, National Health and Medical Research Council in Australia. He is also a non-executive director of Jacobson Medical in Hong Kong. He has received consulting fees from the World Health Organization and IQVIA. He is a member of the Expert Committee on Clinical Events Assessment Following COVID-19 Immunization, Department of Health, The Government of the Hong Kong Special Administrative Region, Hong Kong Special Administrative Region, China. Patrick Ip reports research funding from the University Grant Council (UGC) on study of long term impact of COVID-19 pandemic on health and well-being of children and families in Hong Kong, the Health and Medical Research Fund on Vitamin D Deficiency and Insufficiency among Pregnancy Women and Children, and Hong Kong Jockey Club Charities Trust on Interventions to support health and development of disadvantaged children. Daniel Salmon has received research funding from the Centers for Disease Control and Prevention and advisory committee remuneration from Merck and remuneration as an advisor on policy boards for Janssen Pharmaceuticals, Sanofi and Moderna. He has reports payment for expert testimony on COVID vaccination among health workers. He also reports other research funding outside the submitted work from the Vaccine Confidence Project, National Institutes of Health, GAVI and WHO as well as support for attending meetings from the National Association of Country and City Health Officials Health Summit and World Vaccine Congress. Francisco Lai has been supported by the RGC Postdoctoral Fellowship under the Hong Kong Research Grants Council and has received research grants from the Health Bureau of the Government of the Hong Kong Special Administrative Region, outside the submitted work. He is also is partially supported by the Laboratory of Data Discovery for Health (D24H) funded by the by AIR@InnoHK administered by Innovation and Technology Commission., (© 2023 The Author(s).)

Background: Few studies describe acute kidney injury (AKI) burden during paediatric cisplatin therapy and post-cisplatin kidney outcomes. We determined risk factors for and rate of (1) AKI during cisplatin therapy, (2) chronic kidney disease (CKD) and hypertension 2-6 months post-cisplatin, and (3) whether AKI is associated with 2-6-month outcomes., Methods: This prospective cohort study enrolled children (aged < 18 years at cancer diagnosis) treated with cisplatin from twelve Canadian hospitals. AKI during cisplatin therapy (primary exposure) was defined based on Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria (≥ stage one). Severe electrolyte abnormalities (secondary exposure) included ≥ grade three hypophosphatemia, hypokalemia, or hypomagnesemia (National Cancer Institute Common Terminology Criteria for Adverse Events v4.0). CKD was albuminuria or decreased kidney function for age (KDIGO guidelines). Hypertension was defined based on the 2017 American Academy of Pediatrics guidelines., Results: Of 159 children (median [interquartile range [IQR]] age: 6 [2-12] years), 73/159 (46%) participants developed AKI and 55/159 (35%) experienced severe electrolyte abnormalities during cisplatin therapy. At median [IQR] 90 [76-110] days post-cisplatin, 53/119 (45%) had CKD and 18/128 (14%) developed hypertension. In multivariable analyses, AKI was not associated with 2-6-month CKD or hypertension. Severe electrolyte abnormalities during cisplatin were associated with having 2-6-month CKD or hypertension (adjusted odds ratio (AdjOR) [95% CI]: 2.65 [1.04-6.74]). Having both AKI and severe electrolyte abnormalities was associated with 2-6-month hypertension (AdjOR [95% CI]: 3.64 [1.05-12.62])., Conclusions: Severe electrolyte abnormalities were associated with kidney outcomes. Cisplatin dose optimization to reduce toxicity and clear post-cisplatin kidney follow-up guidelines are needed. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: This scoping review summarizes a key aspect of vaccinomics by collating known associations between heterogeneity in human genetics and vaccine immunogenicity and safety., Methods: We searched PubMed for articles in English using terms covering vaccines routinely recommended to the general US population, their effects, and genetics/genomics. Included studies were controlled and demonstrated statistically significant associations with vaccine immunogenicity or safety. Studies of Pandemrix®, an influenza vaccine previously used in Europe, were also included, due to its widely publicized genetically mediated association with narcolepsy., Findings: Of the 2,300 articles manually screened, 214 were included for data extraction. Six included articles examined genetic influences on vaccine safety; the rest examined vaccine immunogenicity. Hepatitis B vaccine immunogenicity was reported in 92 articles and associated with 277 genetic determinants across 117 genes. Thirty-three articles identified 291 genetic determinants across 118 genes associated with measles vaccine immunogenicity, 22 articles identified 311 genetic determinants across 110 genes associated with rubella vaccine immunogenicity, and 25 articles identified 48 genetic determinants across 34 genes associated with influenza vaccine immunogenicity. Other vaccines had fewer than 10 studies each identifying genetic determinants of their immunogenicity. Genetic associations were reported with 4 adverse events following influenza vaccination (narcolepsy, GBS, GCA/PMR, high temperature) and 2 adverse events following measles vaccination (fever, febrile seizure)., Conclusion: This scoping review identified numerous genetic associations with vaccine immunogenicity and several genetic associations with vaccine safety. Most associations were only reported in one study. This illustrates both the potential of and need for investment in vaccinomics. Current research in this field is focused on systems and genetic-based studies designed to identify risk signatures for serious vaccine reactions or diminished vaccine immunogenicity. Such research could bolster our ability to develop safer and more effective vaccines., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr. Dudley reports research support from Walgreens and Merck. Dr. Gerber reports support for manuscript revisions from RTI International. Dr. Salmon reports consulting and/or research support from Walgreens, Merck, and Janssen. Dr. Poland is the chair of a Safety Evaluation Committee for novel investigational vaccine trials being conducted by Merck Research Laboratories. Dr. Poland offers consultative advice on vaccine development to Merck & Co., Medicago, GlaxoSmithKline, Sanofi Pasteur, Emergent Biosolutions, Dynavax, Genentech, Eli Lilly and Company, Janssen Global Services LLC, Kentucky Bioprocessing, and Genevant Sciences, Inc. Dr. Poland holds patents related to vaccinia, influenza, and measles peptide vaccines. Dr. Poland has received grant funding from ICW Ventures for preclinical studies on a peptide-based COVID-19 vaccine. These activities have been reviewed by the Mayo Clinic Conflict of Interest Review Board and are conducted in compliance with Mayo Clinic Conflict of Interest policies. All other authors have no disclosures]., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Anthracycline chemotherapies cause heart failure in a subset of cancer patients. We previously reported that the anthracycline doxorubicin (DOX) induces cardiotoxicity through the activation of cyclin-dependent kinase 2 (CDK2)., Objectives: The aim of this study was to determine whether retinoblastoma-like 2 (RBL2/p130), an emerging CDK2 inhibitor, regulates anthracycline sensitivity in the heart., Methods: Rbl2 -/- mice and Rbl2 +/+ littermates received DOX (5 mg/kg/wk for 4 weeks intraperitoneally, 20 mg/kg cumulative). Heart function was monitored with echocardiography. The association of RBL2 genetic variants with anthracycline cardiomyopathy was evaluated in the SJLIFE (St. Jude Lifetime Cohort Study) and CPNDS (Canadian Pharmacogenomics Network for Drug Safety) studies., Results: The loss of endogenous Rbl2 increased basal CDK2 activity in the mouse heart. Mice lacking Rbl2 were more sensitive to DOX-induced cardiotoxicity, as evidenced by rapid deterioration of heart function and loss of heart mass. The disruption of Rbl2 exacerbated DOX-induced mitochondrial damage and cardiomyocyte apoptosis. Mechanistically, Rbl2 deficiency enhanced CDK2-dependent activation of forkhead box O1 (FOXO1), leading to up-regulation of the proapoptotic protein Bim. The inhibition of CDK2 desensitized Rbl2-depleted cardiomyocytes to DOX. In wild-type cardiomyocytes, DOX exposure induced Rbl2 expression in a FOXO1-dependent manner. Importantly, the rs17800727 G allele of the human RBL2 gene was associated with reduced anthracycline cardiotoxicity in childhood cancer survivors., Conclusions: Rbl2 is an endogenous CDK2 inhibitor in the heart and represses FOXO1-mediated proapoptotic gene expression. The loss of Rbl2 increases sensitivity to DOX-induced cardiotoxicity. Our findings suggest that RBL2 could be used as a biomarker to predict the risk of cardiotoxicity before the initiation of anthracycline-based chemotherapy., Competing Interests: This work was supported by the National Heart, Lung, and Blood Institute; National Institutes of Health (R00HL119605 and R56HL145034 to Dr Cheng; R01HL151472 to Dr Cheng and Dr Chow); National Cancer Institute, National Institutes of Health (R01CA211996 to Dr Chow); and WSU College of Pharmacy and Pharmaceutical Sciences. The SJLIFE study was supported by the National Cancer Institute, National Institutes of Health (CA195547, CA21765, and CA261898). The CPNDS work was supported by the Canadian Institutes of Health Research. Dr Xia was partially supported by T32HL007208 during manuscript preparation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr Chow has received research funds from Abbott Laboratories for work unrelated to this project. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background: Various definitions used to describe cisplatin nephrotoxicity potentially lead to differences in determination of risk factors. This study evaluated incidence of kidney injury according to commonly used and alternative definitions in two cohorts of children who received cisplatin., Methods: This retrospective cohort study included children from Vancouver, Canada (one center), and Mexico City, Mexico (two centers), treated with cisplatin for a variety of solid tumors. Serum creatinine-based definitions (KDIGO and Pediatric RIFLE (pRIFLE)), electrolyte abnormalities consisted of hypokalemia, hypophosphatemia and hypomagnesemia (based on NCI-CTCAE v5), and an alternative definition (Alt-AKI) were used to describe nephrotoxicity. Incidence with different definitions, definitional overlap, and inter-definition reliability was analyzed., Results: In total, 173 children (100 from Vancouver, 73 from Mexico) were included. In the combined cohort, Alt-AKI criteria detected more patients with cisplatin nephrotoxicity compared to pRIFLE and KDIGO criteria (82.7 vs. 63.6 vs. 44.5%, respectively). Nephrotoxicity and all electrolyte abnormalities were significantly more common in Vancouver cohort than in Mexico City cohort except when using KDIGO definition. The most common electrolyte abnormalities were hypomagnesemia (88.9%, Vancouver) and hypophosphatemia (24.2%, Mexico City). The KDIGO definition provided highest overlap of cases in Vancouver (100%), Mexico (98.6%), and the combined cohort (99.4%). Moderate overall agreement was found among Alt-AKI, KDIGO, and pRIFLE definitions (κ = 0.18, 95% CI 0.1-0.27) in which KDIGO and pRIFLE showed moderate agreement (κ = 0.48, 95% CI 0.36-0.60)., Conclusions: Compared to pRIFLE and KDIGO criteria, Alt-AKI criteria detected more patients with cisplatin nephrotoxicity. pRIFLE is more sensitive to detect not only actual kidney injury but also patients at risk of cisplatin nephrotoxicity, while KDIGO seems more useful to detect clinically significant kidney injury. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

The effectiveness of anthracycline chemotherapeutics (e.g., doxorubicin) is limited by anthracycline-induced cardiotoxicity (ACT). A nonsynonymous variant (S427L) in the retinoic acid receptor-γ (RARG) gene has been associated with ACT. This variant causes reduced RARG activity, which is hypothesized to lead to increased susceptibility to ACT through reduced activation of the retinoic acid pathway. This study explored the effects of activating the retinoic acid pathway using a RAR-agonist, all-trans retinoic acid (ATRA), in human cardiomyocytes and mice treated with doxorubicin. In human cardiomyocytes, ATRA induced the gene expression of RARs (RARG, RARB) and repressed the expression of topoisomerase II enzyme genes (TOP2A, TOP2B), which encode for the molecular targets of anthracyclines and repressed downstream ACT response genes. Importantly, ATRA enhanced cell survival of human cardiomyocytes exposed to doxorubicin. The protective effect of ATRA was also observed in a mouse model (B6C3F1/J) of ACT, in which ATRA treatment improved heart function compared to doxorubicin-only treated mice. Histological analyses of the heart also indicated that ATRA treatment reduced the pathology associated with ACT. These findings provide additional evidence for the retinoic acid pathway's role in ACT and suggest that the RAR activator ATRA can modulate this pathway to reduce ACT., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Hasbullah et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Medication use in children represents 15-20% of total drug sales. More than 50% of children receive at least one prescription medication a year. Despite this, few drugs have a paediatric formulation available. Furthermore, 80% of paediatric prescriptions are considered off-label. Off-label use is defined as the use of products that differ in dose, indication or route of administration from the one established in the summary of product characteristics. Off-label use is associated with an increased risk of adverse drug reactions, including therapeutic failure. The US Food and Drug Administration and the European Medicines Agency have made changes to regulations to incentivize the development of paediatric formulations. Novel paediatric formulations can ease drug administration, reducing medication errors, increasing dosing acceptability, medication adherence and improve safety. Two routes for paediatric drug approval are available, the traditional, requiring clinical trials and the formulation bridging path, where these formulations need to demonstrate equivalence with the existing adult formulations. New formulations seeking regulatory approval require bioequivalence studies, but the regulatory framework, which states that bioequivalence data are obtained from adults and then extrapolated to children, may be disregarding important physiological differences between these two populations of patients. It is important to ensure that drugs for children have been appropriately studied and are properly manufactured for them. Adequately designed studies will provide data that will improve our understanding of how drug disposition differs between adults and children and will pave the way for children to get the best possible treatment., (© 2022 British Pharmacological Society.)

Pharmacogenomics (PGx) relates to the study of genetic factors determining variability in drug response. Implementing PGx testing in paediatric patients can enhance drug safety, helping to improve drug efficacy or reduce the risk of toxicity. Despite its clinical relevance, the implementation of PGx testing in paediatric practice to date has been variable and limited. As with most paediatric pharmacological studies, there are well-recognised barriers to obtaining high-quality PGx evidence, particularly when patient numbers may be small, and off-label or unlicensed prescribing remains widespread. Furthermore, trials enrolling small numbers of children can rarely, in isolation, provide sufficient PGx evidence to change clinical practice, so extrapolation from larger PGx studies in adult patients, where scientifically sound, is essential. This review paper discusses the relevance of PGx to paediatrics and considers implementation strategies from a child health perspective. Examples are provided from Canada, the Netherlands and the UK, with consideration of the different healthcare systems and their distinct approaches to implementation, followed by future recommendations based on these cumulative experiences. Improving the evidence base demonstrating the clinical utility and cost-effectiveness of paediatric PGx testing will be critical to drive implementation forwards. International, interdisciplinary collaborations will enhance paediatric data collation, interpretation and evidence curation, while also supporting dedicated paediatric PGx educational initiatives. PGx consortia and paediatric clinical research networks will continue to play a central role in the streamlined development of effective PGx implementation strategies to help optimise paediatric pharmacotherapy., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Polygenic models have emerged as promising prediction tools for the prediction of complex traits. Currently, the majority of polygenic models are developed in the context of predicting disease risk, but polygenic models may also prove useful in predicting drug outcomes. This study sought to understand how polygenic models incorporating pharmacogenetic variants are being used in the prediction of drug outcomes. A systematic review was conducted with the aim of gaining insights into the methods used to construct polygenic models, as well as their performance in drug outcome prediction. The search uncovered 89 papers that incorporated pharmacogenetic variants in the development of polygenic models. It was found that the most common polygenic models were constructed for drug dosing predictions in anticoagulant therapies ( n = 27). While nearly all studies found a significant association with their polygenic model and the investigated drug outcome (93.3%), less than half (47.2%) compared the performance of the polygenic model against clinical predictors, and even fewer (40.4%) sought to validate model predictions in an independent cohort. Additionally, the heterogeneity of reported performance measures makes the comparison of models across studies challenging. These findings highlight key considerations for future work in developing polygenic models in pharmacogenomic research.

Background & Aims: According to pivotal clinical trials, cure rates for sofosbuvir-based antiviral therapy exceed 96%. Treatment failure is usually assumed to be because of virological resistance-associated substitutions or clinical risk factors, yet the role of patient-specific genetic factors has not been well explored. We determined if patient-specific genetic factors help predict patients likely to fail sofosbuvir treatment in real-world treatment situations., Methods: We recruited sofosbuvir-treated patients with chronic hepatitis C from five Canadian treatment sites, and performed a case-control pharmacogenomics study assessing both previously published and novel genetic polymorphisms. Specifically studied were variants predicted to impair CES1-dependent production of sofosbuvir's active metabolite, interferon-λ signalling variants expected to impact a patient's immune response to the virus and an HLA variant associated with increased spontaneous and treatment-induced viral clearance., Results: Three hundred and fifty-nine sofosbuvir-treated patients were available for analyses after exclusions, with 34 (9.5%) failing treatment. We identified CES1 variants as novel predictors for treatment failure in European patients (rs115629050 or rs4513095; odds ratio (OR): 5.43; 95% confidence interval (CI): 1.64-18.01; P = .0057), replicated associations with IFNL4 variants predicted to increase interferon-λ signalling (eg rs12979860; OR: 2.25; 95% CI: 1.25-4.06; P = .0071) and discovered a novel association with a coding variant predicted to enhance the activity of IFNL4's receptor (rs2834167 in IL10RB; OR: 1.81; 95% CI: 1.01-3.24; P = .047)., Conclusions: Ultimately, this work demonstrates that patient-specific genetic factors could be used as a tool to identify patients at higher risk of treatment failure and allow for these patients to receive effective therapy sooner., (© 2022 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Background: Ondansetron is a highly effective antiemetic for the treatment of nausea and vomiting. However, this medication has also been associated with QT prolongation. Pharmacogenomic information on therapeutic response to ondansetron exists, but no investigation has been performed on genetic factors that influence the cardiac safety of this medication., Methods: Three patient groups receiving ondansetron were recruited and followed prospectively (pediatric post-surgical patients n = 101; pediatric oncology patients n = 98; pregnant women n = 62). Electrocardiograms were conducted at baseline, and 5- and 30-min post-ondansetron administration, to determine the effect of ondansetron treatment on QT interval. Pharmacogenomic associations were assessed via analyses of comprehensive CYP2D6 genotyping and genome-wide association study data., Results: In the entire cohort, 62 patients (24.1%) met the criteria for prolonged QT, with 1.2% of the cohort exhibiting unsafe QT prolongation. The most significant shift from baseline occurred at five minutes post-ondansetron administration (P = 9.8 × 10 -4 ). CYP2D6 activity score was not associated with prolonged QT. Genome-wide analyses identified novel associations with a missense variant in TLR3 (rs3775291; P = 2.00 × 10 -7 ) and a variant linked to the expression of SLC36A1 (rs34124313; P = 1.97 × 10 -7 )., Conclusions: This study has provided insight into the genomic basis of ondansetron-induced cardiac changes and has emphasized the importance of genes that have been implicated in serotonin-related traits. These biologically-relevant findings represent the first step towards understanding this adverse event with the overall goal to improve the safety of this commonly used antiemetic medication., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

We identified the first-generation antihistamine hydroxyzine as the earliest and most frequently prescribed drug affecting the central nervous system in children under the age of 5 years in the province of British Columbia, Canada (1. 1% prevalence). Whereas, the antagonism of H1-receptors exerts anti-pruritic effects in atopic dermatitis and diaper rash, animal studies suggest an adverse association between reduced neurotransmission of histamine and psychomotor behavior. In order to investigate hydroxyzine safety, we characterized the longitudinal patterns of hydroxyzine use in children under the age of 5 years and determined mental- and psychomotor disorders up to the age of 10 years. We found significantly higher rates of ICD-9 and ICD-10 codes for disorders such as tics (307), anxiety (300) and disturbance of conduct (312) in frequent users of hydroxyzine. Specifically, repeat prescriptions of hydroxyzine compared to a single prescription show an increase in tic disorder, anxiety and disturbance of conduct by odds ratios of: 1.55 (95%CI: 1.23-1.96); 1.34 (95%CI: 1.05-1.70); and 1.34 (95%CI: 1.08-1.66) respectively in children up to the age of 10 years. Furthermore, a non-significant increased trend was found for ADHD (314) and disturbance of emotions (313). This is the first study reporting an association between long-term neurodevelopmental adverse effects and early use of hydroxyzine. Controlled studies are required in order to prove a causal relationship and to confirm the safety of hydroxyzine in the pediatric population. For the time being, we suggest the shortest possible duration for hydroxyzine use in preschool-age children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gober, Li, Yan, Bailey and Carleton.)

Background: Multiple pharmacogenomic studies have identified the synonymous genomic variant rs7853758 (G > A, L461L) and the intronic variant rs885004 in SLC28A3 (solute carrier family 28 member 3) as statistically associated with a lower incidence of anthracycline-induced cardiotoxicity. However, the true causal variant(s), the cardioprotective mechanism of this locus, the role of SLC28A3 and other solute carrier (SLC) transporters in anthracycline-induced cardiotoxicity, and the suitability of SLC transporters as targets for cardioprotective drugs has not been investigated., Methods: Six well-phenotyped, doxorubicin-treated pediatric patients from the original association study cohort were recruited again, and human induced pluripotent stem cell-derived cardiomyocytes were generated. Patient-specific doxorubicin-induced cardiotoxicity (DIC) was then characterized using assays of cell viability, activated caspase 3/7, and doxorubicin uptake. The role of SLC28A3 in DIC was then queried using overexpression and knockout of SLC28A3 in isogenic human-induced pluripotent stem cell-derived cardiomyocytes using a CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9). Fine-mapping of the SLC28A3 locus was then completed after SLC28A3 resequencing and an extended in silico haplotype and functional analysis. Genome editing of the potential causal variant was done using cytosine base editor. SLC28A3-AS1 overexpression was done using a lentiviral plasmid-based transduction and was validated using stranded RNA-sequencing after ribosomal RNA depletion. Drug screening was done using the Prestwick Chemical Library (n = 1200), followed by in vivo validation in mice. The effect of desipramine on doxorubicin cytotoxicity was also investigated in 8 cancer cell lines., Results: Here, using the most commonly used anthracycline, doxorubicin, we demonstrate that patient-derived cardiomyocytes recapitulate the cardioprotective effect of the SLC28A3 locus and that SLC28A3 expression influences the severity of DIC. Using Nanopore-based fine-mapping and base editing, we identify a novel cardioprotective single nucleotide polymorphism, rs11140490, in the SLC28A3 locus; its effect is exerted via regulation of an antisense long noncoding RNA ( SLC28A3-AS1 ) that overlaps with SLC28A3. Using high-throughput drug screening in patient-derived cardiomyocytes and whole organism validation in mice, we identify the SLC competitive inhibitor desipramine as protective against DIC., Conclusions: This work demonstrates the power of the human induced pluripotent stem cell model to take a single nucleotide polymorphism from a statistical association through to drug discovery, providing human cell-tested data for clinical trials to attenuate DIC.

Anthracyclines are widely used as part of chemotherapeutic regimens in paediatric oncology patients. The most serious adverse drug reaction caused by anthracycline use is cardiotoxicity, a serious condition that can lead to cardiac dysfunction and subsequent heart failure. Both clinical and genetic factors contribute to a patient's risk of experiencing anthracycline-induced cardiotoxicity. In particular, genetic variants in RARG, UGT1A6 and SLC28A3 have been consistently shown to influence an individual's risk of experiencing this reaction. By combining clinical and genetic risks, decision-making can be improved to optimize treatment and prevent potentially serious adverse drug reactions. As part of a precision medicine initiative, we used pharmacogenetic testing, focused on RARG, UGT1A6 and SLC28A3 variants, to help predict an individual's risk of experiencing anthracycline-induced cardiotoxicity. Pharmacogenetic results are currently being used in clinical decision-making to inform treatment regimen choice, anthracycline dosing and decisions to initiate cardioprotective agents. In this case series, we demonstrate examples of the impact of genetic testing and discuss its potential to allow patients to be increasingly involved in their own treatment decisions., (© 2021 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Background: Ototoxicity is a common adverse event of cisplatin treatment. The authors investigated the development of cisplatin-induced hearing loss (CIHL) over time in children with cancer by age and examined the influence of other clinical characteristics on the course of CIHL., Methods: Data from Canadian patients with childhood cancer were retrospectively reviewed. Hearing loss was graded according to International Society of Pediatric Oncology criteria. The Kaplan-Meier method was applied to estimate the cumulative incidence of CIHL for the total cohort and according to age. Cox regression models were used to explore the effects of independent variables on CIHL development up to 3 years after the start of therapy., Results: In total, 368 patients with 2052 audiological assessments were included. Three years after initiating therapy, the cumulative incidence of CIHL was highest in patients aged ≤5 years (75%; 95% confidence interval [CI], 66%-84%), with a rapid increase observed to 27% (95% CI, 21%-35%) at 3 months and to 61% (95% CI, 53%-69%) at 1 year, compared with patients aged >5 years (48%; 95% CI, 37%-62%; P < .001). The total cumulative dose of cisplatin at 3 months (per 100 mg/m 2 increase: hazard ratio [HR], 1.20; 95% CI, 1.01-1.41) vincristine (HR, 2.87; 95% CI, 1.89-4.36) and the total duration of concomitantly administered antibiotics (>30 days: HR, 1.85; 95% CI, 1.17-2.95) further influenced CIHL development over time., Conclusions: In young children, the cumulative incidence of CIHL is higher compared with that in older children and develops early during therapy. The course of CIHL is further influenced by the total cumulative dose of cisplatin and other ototoxic (co-)medication. These results highlight the need for audiological monitoring at each cisplatin cycle., (© 2021 American Cancer Society.)

Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but its use is limited by dose-dependent cardiotoxicity. A recent genome-wide association study identified a SNP (rs2229774) in retinoic acid receptor-γ (RARG) as statistically associated with increased risk of anthracycline-induced cardiotoxicity. Here, we show that human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with rs2229774 and who suffered doxorubicin-induced cardiotoxicity (DIC) are more sensitive to doxorubicin. We determine that the mechanism of this RARG variant effect is mediated via suppression of topoisomerase 2β (TOP2B) expression and activation of the cardioprotective extracellular regulated kinase (ERK) pathway. We use patient-specific hiPSC-CMs as a drug discovery platform, determining that the RARG agonist CD1530 attenuates DIC, and we confirm this cardioprotective effect in an established in vivo mouse model of DIC. This study provides a rationale for clinical prechemotherapy genetic screening for rs2229774 and a foundation for the clinical use of RARG agonist treatment to protect cancer patients from DIC., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This study aims to evaluate genetic risk factors for cisplatin-induced nephrotoxicity by investigating not previously studied genetic risk variants and further examining previously reported genetic associations. A genome-wide study (GWAS) was conducted in genetically estimated Europeans in a discovery cohort of cisplatin-treated adults from Toronto, Canada, followed by a candidate gene approach in a validation cohort from the Netherlands. In addition, previously reported genetic associations were further examined in both the discovery and validation cohorts. The outcome, nephrotoxicity, was assessed in two ways: (i) decreased estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) and (ii) increased serum creatinine according to the Common Terminology Criteria for Adverse Events v4.03 for acute kidney injury (AKI-CTCAE). Four different Illumina arrays were used for genotyping. Standard quality control was applied for pre- and post-genotype imputation data. In the discovery cohort ( n = 608), five single-nucleotide polymorphisms (SNPs) reached genome-wide significance. The A allele in rs4388268 (minor allele frequency = 0.23), an intronic variant of the BACH2 gene, was consistently associated with increased risk of cisplatin-induced nephrotoxicity in both definitions, meeting genome-wide significance (β = -8.4, 95% CI -11.4--5.4, p = 3.9 × 10 -8 ) for decreased eGFR and reaching suggestive association (OR = 3.9, 95% CI 2.3-6.7, p = 7.4 × 10 -7 ) by AKI-CTCAE. In the validation cohort of 149 patients, this variant was identified with the same direction of effect (eGFR: β = -1.5, 95% CI -5.3-2.4, AKI-CTCAE: OR = 1.7, 95% CI 0.8-3.5). Findings of our previously published candidate gene study could not be confirmed after correction for multiple testing. Genetic predisposition of BACH2 (rs4388268) might be important in the development of cisplatin-induced nephrotoxicity, indicating opportunities for mechanistic understanding, tailored therapy and preventive strategies.

Background: Few studies have described associations between the AKI biomarkers urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) with AKI in cisplatin-treated children. We aimed to describe excretion patterns of urine NGAL and KIM-1 and associations with AKI in children receiving cisplatin., Methods: Participants ( n =159) were enrolled between 2013 and 2017 in a prospective cohort study conducted in 12 Canadian pediatric hospitals. Participants were evaluated at early cisplatin infusions (at first or second cisplatin cycle) and late cisplatin infusions (last or second-to-last cycle). Urine NGAL and KIM-1 were measured ( 1 ) pre-cisplatin infusion, ( 2 ) post-infusion (morning after), and ( 3 ) at hospital discharge at early and late cisplatin infusions. Primary outcome: AKI defined by serum creatinine rise within 10 days post-cisplatin, on the basis of Kidney Disease Improving Global Outcomes guidelines criteria (stage 1 or higher)., Results: Of 159 children, 156 (median [interquartile range (IQR)] age: 5.8 [2.4-12.0] years; 78 [50%] female) had biomarker data available at early cisplatin infusions and 127 had data at late infusions. Forty six of the 156 (29%) and 22 of the 127 (17%) children developed AKI within 10 days of cisplatin administration after early and late infusions, respectively. Urine NGAL and KIM-1 concentrations were significantly higher in patients with versus without AKI (near hospital discharge of late cisplatin infusion, median [IQR] NGAL levels were 76.1 [10.0-232.7] versus 14.9 [5.4-29.7] ng/mg creatinine; KIM-1 levels were 4415 [2083-9077] versus 1049 [358-3326] pg/mg creatinine; P <0.01). These markers modestly discriminated for AKI (area under receiver operating characteristic curve [AUC-ROC] range: NGAL, 0.56-0.72; KIM-1, 0.48-0.75). Biomarker concentrations were higher and better discriminated for AKI at late cisplatin infusions (AUC-ROC range, 0.54-0.75) versus early infusions (AUC-ROC range, 0.48-0.65)., Conclusions: Urine NGAL and KIM-1 were modest at discriminating for cisplatin-associated AKI. Further research is needed to determine clinical utility and applicability of these markers and associations with late kidney outcomes., Competing Interests: T.D. Blydt-Hansen reports having ownership interest in Apple, Hydrogenics, and Royal Bank of Canada; receiving honoraria from Astellas Canada; receiving research funding from Astellas Canada, Canadian Institutes of Health Research, Child and Family Research Institute, Children’s Hospital of Manitoba Research Institute, and Transplant Research Foundation of BC; having consultancy agreements with Astellas Canada, Horizon Canada, Novartis, and Ricordati; and serving as a scientific advisor for or member of BC Transplant, Canadian National Transplant Research Program, International Pediatric Transplant Association (council member), and North American Pediatric Transplant and Collaborative Studies. B.C. Carleton reports serving as a scientific advisor for or member of AEVI Genomic Medicine, United Health Group Pharmacogenomics (on the advisory committee); having consultancy agreements with Dynacare Specialized Diagnostics; receiving research funding from Dynacare Specialized Diagnostics (ended in June 2021) and grants from federal and provincial agencies; and having other interests/relationships with Rare Disease Society. P. Devarajan reports having consultancy agreements with Alnylam, Dicerna, Natera, and Reata; being a coinventor on patents for the use of NGAL as a biomarker of kidney injury; and serving on speakers bureaus for BioPorto Inc., Natera, and Reata. M. Pinsk reports having consultancy agreements with Canadian Agency for Drugs and Technologies in Health (as consultant); serving as an expert witness for legal consultations (multiple); and having other interests/relationships with Canadian Society of Nephrology, International Pediatric Nephrology Association, and Medical Council of Canada. K. R. Schultz reports having consultancy agreements with AVM Biotech, Celgene/Juno, Jazz, and Medpace; receiving honoraria from Bristol Myers Squibb (BMS), Celegene, and Jazz; serving on the data safety monitoring boards for BMS/Juno and Medpace; and serving as a scientific advisor or membership of Jazz. R.T. Tsuyuki reports receiving research funding from AstraZeneca, Merck Canada Inc., and Sanofi; serving as the editor-in-chief for Canadian Pharmacists Journal, and as president, chair, and on the board of directors for Hypertension Canada; receiving honoraria from Emergent Biosolutions and Merck Canada Inc.; and having consultancy agreements with Emergent Biosolutions and Shoppers Drug Mart. M. Zappitelli reports having consultancy agreements with BioPorto Inc., CytoPheryx Inc., and Eloxx Pharmaceuticals; receiving honoraria from Bioporto Inc. and Eloxx Pharmaceuticals; and having other interests/relationships with Canadian Pediatric Nephrologists Association, Canadian Society of Nephrology, and Kidney Foundation of Canada. All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Background: The current use of ribavirin in difficult-to-cure chronic hepatitis C patients (HCV) and patients with severe respiratory infections is constrained by the issue of ribavirin-induced hemolytic anemia that affects 30% of treated patients, requiring dosage modification or discontinuation. Though some genetic variants have been identified predicting this adverse effect, known clinical and genetic factors do not entirely explain the risk of ribavirin-induced anemia., Methods: We assessed the associations of previously identified variants in inosine triphosphatase (ITPA), solute carrier 28A2 (SLC28A2) and vitamin D receptor (VDR) genes with ribavirin-induced anemia defined as hemoglobin decline of ≥30 g/L on treatment, followed by a staged discovery (n = 114), replication (n = 74), and combined (n = 188) genome-wide association study to uncover potential new predictive variants., Results: We identified a novel association in the gene coding glycophorin C (rs6741425; OR:0.12, 95%CI:0.04-0.34, P = 2.94 × 10 -6 ) that predicts protection against ribavirin-induced anemia. We also replicated the associations of ITPA and VDR genetic variants with the development of ribavirin-induced anemia (rs1127354; OR:0.13, 95%CI:0.04-0.41, P = 8.66 ×10 -5 ; and rs1544410; OR:1.65, 95%CI:1.01-2.70, P = 0.0437)., Conclusions: GYPC variation affecting erythrocyte membrane strength is important in predicting risk for developing ribavirin-induced anemia. ITPA and VDR genetic variants are also important predictors of this adverse reaction., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Importance: Ototoxicity is an irreversible direct and late effect of certain childhood cancer treatments. Audiologic surveillance during therapy as part of the supportive care pathway enables early detection of hearing loss, decision-making about ongoing cancer treatment, and, when applicable, the timely use of audiologic interventions. Pediatric oncologic clinical practice and treatment trials have tended to be driven by tumor type and tumor-specific working groups. Internationally accepted standardized recommendations for monitoring hearing during treatment have not previously been agreed on., Objective: To provide standard recommendations on hearing loss monitoring during childhood cancer therapy for clinical practice., Methods: An Ototoxicity Task Force was formed under the umbrella of the International Society of Paediatric Oncology, consisting of international audiologists, otolaryngologists, and leaders in the field of relevant pediatric oncology tumor groups. Consensus meetings conducted by experts were organized, aimed at providing standardized recommendations on age-directed testing, timing, and frequency of monitoring during cancer treatment based on literature and consensus. Consensus statements were prepared by the core group, adapted following several videoconferences, and finally agreed on by the expert panel., Findings: The consensus reached was that children who receive ototoxic cancer treatment (platinum agents, cranial irradiation, and/or brain surgery) require a baseline case history, monitoring of their middle ear and inner ear function, and assessment of tinnitus at each audiologic follow-up. As a minimum, age-appropriate testing should be performed before and at the end of treatment. Ideally, audiometry with counseling before each cisplatin cycle should be considered in the context of the individual patient, specific disease, feasibility, and available resources., Conclusions and Relevance: This is an international multidisciplinary consensus report providing standardized supportive care recommendations on hearing monitoring in children undergoing potentially ototoxic cancer treatment. The recommendations are intended to improve the care of children with cancer and facilitate comparative research on the timing and development of hearing loss caused by different cancer treatment regimens.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10 -10 , OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity., (© 2021. The Author(s).)

Coronavirus disease 2019 (COVID-19) has resulted in the death of over 18 000 Canadians and has impacted the lives of all Canadians. Many Canadian research groups have expanded their research programs to include COVID-19. Over the past year, our knowledge of this novel disease has grown and has led to the initiation of a number of clinical vaccine and drug trials for the prevention and treatment of COVID-19. Here, we review SARS-CoV-2 (the coronavirus that causes COVID-19) and the natural history of COVID-19, including a timeline of disease progression after SARS-CoV-2 exposure. We also review the pathophysiological effects of COVID-19 on the organ systems that have been implicated in the disease, including the lungs, upper respiratory tract, immune system, central nervous system, cardiovascular system, gastrointestinal organs, the liver, and the kidneys. Then we review general therapeutics strategies that are being applied and investigated for the prevention or treatment of COVID-19, including vaccines, antivirals, immune system enhancers, pulmonary supportive agents, immunosuppressants and (or) anti-inflammatories, and cardiovascular system regulators. Finally, we provide an overview of all current Health Canada authorized clinical drug and vaccine trials for the prevention or treatment of COVID-19.

Anthracyclines are highly effective chemotherapeutic agents; however, their clinical utility is limited by severe anthracycline-induced cardiotoxicity (ACT). Genome-wide association studies (GWAS) have uncovered several genetic variants associated with ACT, but the impact of these findings requires further elucidation. We conducted a transcriptome-wide association study (TWAS) using our previous GWAS summary statistics (n = 280 patients) to identify gene expression-related associations with ACT. We identified a genetic association between decreased expression of GDF5 and ACT (Z-score = -4.30, P = 1.70 × 10 -5 ), which was replicated in an independent cohort (n = 845 patients, P = 3.54 × 10 -3 ). Additionally, cell viability of GDF5-silenced human cardiac myocytes was significantly decreased in response to anthracycline treatment. Subsequent gene set enrichment and pathway analyses of the TWAS data revealed that genes essential for survival, cardioprotection and response to anthracyclines, as well as genes involved in ribosomal, spliceosomal and cardiomyopathy pathways are important for the development of ACT.

Methotrexate (MTX), an important chemotherapeutic agent, is often accompanied with mucositis. The occurrence and severity are unpredictable and show large interindividual variability. In this study, we review and meta-analyze previously studied genetic variants in relation to MTX-induced mucositis. We conducted a systematic search in Medline and Embase. We included genetic association studies of MTX-induced mucositis in cancer patients. A meta-analysis was conducted for single nucleotide polymorphisms (SNPs) for which at least two studies found a statistically significant association. A total of 34 SNPs were associated with mucositis in at least one study of the 57 included studies. Two of the seven SNPs included in our meta-analysis were statistically significantly associated with mucositis: MTHFR c.677C > T (recessive, grade ≥3 vs grade 0-2, OR 2.53, 95 %CI [1.48-4.32], False Discovery Rate[FDR]-corrected p-value 0.011) and MTRR c.66A > G (overdominant, grade ≥1 vs grade 0, OR 2.08, 95 %CI [1.16-3.73], FDR-corrected p-value 0.042)., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aim: To improve the identification and interpretation of pharmacogenetic variants through the integration of disease and drug-related traits. Materials & methods: We hypothesized that integrating genome-wide disease and pharmacogenomic data may drive new insights into drug toxicity and response by identifying shared genetic architecture. Pleiotropic variants were identified using a methodological framework incorporating colocalization analysis. Results: Using genome-wide association studies summary statistics from the UK Biobank, European Bioinformatics Institute genome-wide association studies catalog and the Pharmacogenomics Research Network, we validated pleiotropy at the ABCG2 locus between allopurinol response and gout and identified novel pleiotropy between antihypertensive-induced new-onset diabetes, Crohn's disease and inflammatory bowel disease at the IL18RAP/SLC9A4 locus. Conclusion: New mechanistic insights and genetic loci can be uncovered by identifying pleiotropy between disease and drug-related traits.

Background: Cisplatin is used to treat a wide range of childhood cancers and cisplatin-induced hearing loss (CIHL) is a common and debilitating toxicity. We aimed to address persistent knowledge gaps in CIHL by establishing benchmarks for the prevalence of and risk factors for CIHL., Methods: In this multi-institutional cohort study, children (age 0-14 years), adolescents, and young adults (age 15-39 years) diagnosed with a cisplatin-treated tumour from paediatric cancer centres, who had available cisplatin dosing information, and primary audiology data for central review from consortia located in Canada and the USA were eligible for inclusion. Audiology was centrally reviewed and CIHL graded using the consensus International Society of Pediatric Oncology (SIOP) Boston Ototoxicity Scale. We assessed the prevalence of moderate or severe CIHL (SIOP grade ≥2) at latest follow-up and end of therapy, in each demographic, diagnosis, and treatment group and their relative contributions to risk for CIHL. Secondary endpoints explored associations of cisplatin dose reductions and CIHL with survival. We also examined whether cisplatin dose reductions and CIHL were associated with survival outcomes., Findings: We included 1481 patients who received cisplatin. Of the 1414 (95·5%) participants who had audiometry at latest follow-up (mean 3·9 years [SD 4·2] since diagnosis), 620 (43·8%) patients developed moderate or severe CIHL. The highest prevalence of CIHL was seen in the youngest patients (aged <5 years; 360 [59·4%] of 606 patients) and those with a CNS tumour (221 [50·9%] of 434 patients), hepatoblastoma (110 [65·9%] of 167 patients), or neuroblastoma (154 [62·1%] of 248 patients). After accounting for cumulative cisplatin dose, higher fractionated doses were associated with risk for CIHL (for each 10mg/m 2 increase per day, adjusted odds ratio [aOR] 1·15 [95% CI 1·07-1·25]; for each 50 mg/m 2 increase per cycle aOR 2·16 [1·37-3·51]). Vincristine exposure was newly identified as a risk factor for CIHL (aOR 3·55 [2·19-5·84]). Dose reductions and moderate or severe CIHL were not significantly associated with survival differences., Interpretation: Using this large, multicentre cohort, benchmarks were established for the prevalence of CIHL in patients treated with cisplatin. Variations in cisplatin dosing confer additive risk for developing CIHL and warrant investigation as a potential approach to decrease the burden of therapy., Funding: US National Institutes of Health and National Institute on Deafness and Other Communication Disorders, US National Institutes of Health and National Cancer institute, St Baldrick's Foundation, Genome Canada, Genome British Columbia, Canadian Institutes of Health Research, the Canada Foundation for Innovation, University of British Columbia, British Columbia Children's Hospital Research Institute, British Columbia Provincial Health Services Authority, Health Canada, and C17 Research Network., (Copyright © 2021 Elsevier Ltd. All rights reserved.)