Int J Infect Dis. 2021 Mar 23:S1201-9712(21)00278-2. doi: 10.1016/j.ijid.2021.03.059. Online ahead of print.

ABSTRACT

OBJECTIVES: Colistin loading dose is required to achieve adequate drug exposure for the treatment of multidrug-resistant Gram-negative bacteria. However, data on acute kidney injury (AKI) rate associated with this approach in children is unknown.We aimed to study the AKI rates in children who were prescribed a colistin loading dose.

METHODS: A retrospective study was conducted in patients aged 1 month to 18 years and receiving intravenous colistin for ≥48 hours. Loading dose (LD) was defined as colistin methanesulfonate of 4-5 mg of colistin base activity/kg/dose. AKI was defined regarding KDIGO serum creatinine (SCr) criteria: SCr ≥1.5 times of the baseline during 3-7 days interval after colistin initiation. Augmented renal clearance (ARC) was defined as estimated eGFR >150 mL/min/1.73 m2. The rates of AKI were compared between children receiving or not receiving an LD, and between different eGFR groups.

RESULTS: One hundred eighty-one children were enrolled. The mean age was 4.3 years (95% confidence interval (CI), 3.6-4.9 years). Ninety-five (52.5%) were male. There were 157 children with baseline eGFR of ≥80 mL/min/1.73 m2. The overall AKI rate within the first week in this group was 20.4% (95% CI, 14.4-27.6%): LD, 16.1% vs no LD, 23.2%, P = 0.29. Subgroup analysis excluding patients with ARC showed lower AKI rate of 12.8% (95% CI, 6.8-21.3%): LD, 9.7% vs no LD, 14.3%, P = 0.53.

CONCLUSIONS: AKI rate was not different among children who received an intravenous colistin loading dose. This approach should be implemented to ensuring drug exposure which is necessary for good treatment outcomes.

PMID:33771669 | DOI:10.1016/j.ijid.2021.03.059

Pharmacol Ther. 2021 Mar 23:107841. doi: 10.1016/j.pharmthera.2021.107841. Online ahead of print.

ABSTRACT

Ciliopathies are a family of rather diverse conditions, which have been grouped based on the finding of altered or dysfunctional cilia, potentially motile, small cellular antennae extending from the surface of postmitotic cells. Cilia-related disorders include embryonically arising conditions such as Joubert, Usher or Kartagener syndrome, but also afflictions with a postnatal or even adult onset phenotype, i.e. autosomal dominant polycystic kidney disease. The majority of ciliopathies are syndromic rather than affecting only a single organ due to cilia being found on almost any cell in the human body. Overall ciliopathies are considered rare diseases. Despite that, pharmacological research and the strive to help these patients has led to enormous therapeutic advances in the last decade. In this review we discuss new treatment options for certain ciliopathies, give an outlook on promising future therapeutic strategies, but also highlight the limitations in the development of therapeutic approaches of ciliopathies.

PMID:33771583 | DOI:10.1016/j.pharmthera.2021.107841

Ann Pharmacother. 2021 Mar 26:10600280211003875. doi: 10.1177/10600280211003875. Online ahead of print.

ABSTRACT

OBJECTIVE: To provide an overview of clinical recommendations regarding genomic medicine relating to pain management and opioid use disorder.

DATA SOURCES: A literature review was conducted using the search terms pain management, pharmacogenomics, pharmacogenetics, pharmacokinetics, pharmacodynamics, and opioids on PubMed (inception to February 1, 2021), CINAHL (2016 through February 1, 2021), and EMBASE (inception through February 1, 2021).

STUDY SELECTION AND DATA EXTRACTION: All relevant clinical trials, review articles, package inserts, and guidelines evaluating applicable pharmacogenotypes were considered for inclusion.

DATA SYNTHESIS: More than 300 Food and Drug Administration-approved medications contain pharmacogenomic information in their labeling. Genetic variability may alter the therapeutic effects of commonly prescribed pain medications. Pharmacogenomic-guided therapy continues to gain traction in clinical practice, but a multitude of barriers to widespread pharmacogenomic implementation exist.

RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Pain is notoriously difficult to treat given the need to balance safety and efficacy when selecting pharmacotherapy. Pharmacogenomic data can help optimize outcomes for patients with pain. With improved technological advances, more affordable testing, and a better understanding of genomic variants resulting in treatment disparities, pharmacogenomics continues to gain popularity. Unfortunately, despite these and other advancements, pharmacogenomic testing and implementation remain underutilized and misunderstood in clinical care, in part because of a lack of health care professionals trained in assessing and implementing test results.

CONCLUSIONS: A one-size-fits-all approach to pain management is inadequate and outdated. With increasing genomic data and pharmacogenomic understanding, patient-specific genomic testing offers a comprehensive and personalized treatment alternative worthy of additional research and consideration.

PMID:33771051 | DOI:10.1177/10600280211003875

Drug Metab Pers Ther. 2021 Mar 26. doi: 10.1515/dmdi-2020-0164. Online ahead of print.

ABSTRACT

OBJECTIVES: Hydroxychloroquine (HCQ) has been used as an off label for the management of coronavirus disease (Covid-19) infection with other drugs. However, different genetic variants can affect the metabolism of HCQ leading to inter-individual differences in its efficacy. In this study, we investigated the effects of variants in CYP2D6, CYP3A4 and CYP3A5 on the risk of Covid-19 infection among patients receiving HCQ for controlling rheumatoid arthritis (RA).

METHODS: A total of 60 patients were genotyped for CYP2D6*2XN, CYP2D6*4, CYP3A4*1B and CYP3A5*2. They were receiving HCQ for the treatment of RA. The patients were evaluated clinically for fever and dry cough, radiologically via chest computed tomography (CT) and immunologically via anti-Covid-19 IgG and IgM titers.

RESULTS: Variants in CYP2D6 significantly affected the grade of ground glass (CYP2D6*4 AA carriers showed the higher risk for grade 3) and the risk of positive anti-Covid-19 IgM (CYP2D6*2XN CC and CYP3A4*1B AA had the lowest risk), the duration of HCQ, the use of corticosteroids or gender did not affect the Covid-19 status significantly.

CONCLUSIONS: In general, the outcome of the studied patients receiving HCQ was good (no deaths, no intubation needed). CYP2D6 variants could affect the outcome of Covid-19 infection.

PMID:33770833 | DOI:10.1515/dmdi-2020-0164

Pharmacogenomics. 2021 Mar 26. doi: 10.2217/pgs-2020-0130. Online ahead of print.

ABSTRACT

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.

PMID:33769074 | DOI:10.2217/pgs-2020-0130

Pharmacogenomics. 2021 Mar 26. doi: 10.2217/pgs-2020-0148. Online ahead of print.

ABSTRACT

Common autoimmune, inflammatory rheumatic diseases including rheumatoid arthritis and ankylosing spondylitis can lead to structural and functional disability, an increase in mortality and a decrease in the quality of a patient's life. To date, the core of available therapy consists of nonsteroidal anti-inflammatory drugs, glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs, like methotrexate. Nowadays, biological therapy including anti-TNF, IL-6 and IL-1 inhibitors, as well as antibodies targeting IL-17 and Janus kinase inhibitors have been found to be helpful in the management of rheumatic conditions. The review provides a summary of the current therapy strategies with a focus on miRNA, which is considered to be a potential biomarker and possible answer to the challenges in the prediction of treatment outcome in patients with rheumatoid arthritis and ankylosing spondylitis.

PMID:33769067 | DOI:10.2217/pgs-2020-0148

Cell Prolif. 2021 Mar 25:e13029. doi: 10.1111/cpr.13029. Online ahead of print.

ABSTRACT

High-grade serous carcinoma (HGSC) is the most common and malignant histological type of epithelial ovarian cancer, the origin of which remains controversial. Currently, the secretory epithelial cells of the fallopian tube are regarded as the main origin and the ovarian surface epithelial cells as a minor origin. In tubal epithelium, these cells acquire TP53 mutations and expand to a morphologically normal 'p53 signature' lesion, transform to serous tubal intraepithelial carcinoma and metastasize to the ovaries and peritoneum where they develop into HGSC. This shifting paradigm of the main cell of origin has revolutionarily changed the focus of HGSC research. Various cell lines have been derived from the two cellular origins by acquiring immortalization via overexpression of hTERT plus disruption of TP53 and the CDK4/RB pathway. Malignant transformation was achieved by adding canonical driver mutations (such as gain of CCNE1) revealed by The Cancer Genome Atlas or by noncanonical gain of YAP and miR181a. Alternatively, because of the extreme chromosomal instability, spontaneous transformation can be achieved by long passage of murine immortalized cells, whereas in humans, it requires ovulatory follicular fluid, containing regenerating growth factors to facilitate spontaneous transformation. These artificially and spontaneously transformed cell systems in both humans and mice have been widely used to discover carcinogens, oncogenic pathways and malignant behaviours in the development of HGSC. Here, we review the origin, aetiology and carcinogenic mechanism of HGSC and comprehensively summarize the cell models used to study this fatal cancer having multiple cells of origin and overt genomic instability.

PMID:33768671 | DOI:10.1111/cpr.13029

J Clin Pharm Ther. 2021 Mar 25. doi: 10.1111/jcpt.13407. Online ahead of print.

ABSTRACT

WHAT IS KNOWN AND OBJECTIVES: Tacrolimus (TAC) is a first-line immunosuppressant which is used to prevent transplant rejection after solid organ transplantation (SOT). However, it has a narrow therapeutic index and high individual variability in pharmacokinetics (PK) and pharmacogenomics (PG). It has been reported that the metabolism of TAC can be affected by genetic factors, leading to different rates of metabolism in different subjects. Wuzhi Capsule (WZC) is a commonly used TAC-sparing agent in Chinese SOT to reduce TAC dosing due to its inhibitory effect on TAC metabolism by enzymes of the CYP3A subfamily. The aims of this study were to assess the effect of TAC+WZC co-administration and genetic polymorphism on the pharmacokinetics of TAC, by using a population pharmacokinetic (PPK) model. A dosing guideline for individualized TAC dosing is proposed based on the PPK study.

METHODS: The medical records of 165 adult patients with kidney transplant and their 824 TAC concentrations from two kidney transplantation centres were reviewed. The genotypes of four single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and ABCB1 (rs1128503, rs2032582 and rs1045642) were tested by MASSARRAY. A PPK model was constructed by nonlinear mixed effect model (NONMEM® , Version 7.3). Finally, Monte Carlo simulations were employed to design initial dosing regimens based on the final model.

RESULTS AND DISCUSSION: The one-compartmental PPK model with first-order absorption and elimination of TAC was established in kidney transplant recipients (KTRs). CYP3A5*3 had significant impact on the PPK model. The haematocrit (HCT), postoperative time (POD) and CYP3A5*3 genotypes had a significant influence on TAC clearance when combined with WZC. The model was expressed as 23.4 × (HCT/0.3)-0.729 × 0.837 (combination with WZC) × e-0.0875(POD/12.6) ×1.18 (CYP3A5 expressors). For patients carrying the CYP3A5*3/*3 allele and with 30% HCT, the required TAC dose to achieve target trough concentrations of 10-15 ng/ml was 4 mg twice daily (q12h). For patients with the CYP3A5*3/*3 allele, the required dose was 3 mg TAC q12h when combined with WZC, and for patients with the CYP3A5*1/*1 or *1/*3 allele, the required dose was 4 mg of TAC q12h when co-administered with WZC.

WHAT IS NEW AND CONCLUSION: Wuzhi Capsule co-administration and CYP3A5 variants affect the PK of TAC Dosing guidelines are made based on the PPK model to allow individualized administration of TAC, especially when co-administered with WZC.

PMID:33768546 | DOI:10.1111/jcpt.13407

Clin Pharmacol Ther. 2021 Mar 26. doi: 10.1002/cpt.2241. Online ahead of print.

ABSTRACT

We conducted the first HLA allele and genome wide association study to identify loci associated with hypersensitivity reactions exclusively to the PEGylated preparation of asparaginase (pegaspargase) in racially diverse cohorts of pediatric leukemia patients: St. Jude Children's Research Hospital's Total XVI (TXVI, n = 598), Children's Oncology Group AALL0232 (n = 2472) and AALL0434 (n = 1189). Germline DNA was genotyped using arrays. Genetic variants not genotyped directly were imputed. HLA alleles were imputed using SNP2HLA or inferred using BWAkit. Analyses between genetic variants and hypersensitivity were performed in each cohort first using cohort-specific covariates and then combined using meta-analyses. Nongenetic risk factors included fewer intrathecal injections (P = 2.7x10-5 in TXVI) and male sex (P = 0.025 in AALL0232). HLA alleles DQB1*02:02, DRB1*07:01, and DQA1*02:01 had the strongest associations with pegaspargase hypersensitivity (P < 5.0x10-5 ) in patients with primarily European ancestry (EA), with the three alleles associating in a single haplotype. The top allele HLA-DQB1*02:02 was tagged by HLA-DQB1 rs1694129 in EAs (r2 = 0.96) and less so in non-EAs. All single nucleotide polymorphisms associated with pegaspargase hypersensitivity reaching genome-wide significance in EAs were in class II HLA loci, and were partially replicated in non-EAs, as is true for other HLA associations. The rs9958628 variant, in ARHGAP28 (previously linked to immune response in children) had the strongest genetic association (P = 8.9x10-9 ) in non-EAs. The HLA-DQB1*02:02-DRB1*07:01-DQA1*02:01 associated with hypersensitivity reactions to pegaspargase is the same haplotype associated with reactions to non-PEGylated asparaginase, even though the antigens differ between the two preparations.

PMID:33768542 | DOI:10.1002/cpt.2241

Front Genet. 2021 Mar 9;12:626954. doi: 10.3389/fgene.2021.626954. eCollection 2021.

ABSTRACT

Cancer is a critical health burden in Africa, and mortality rates are rising rapidly. Treatments are expensive and often cause adverse drug reactions (ADRs). Fluoropyrimidine treatments can lead to severe toxicity events which have been linked to variants within the dihydropyrimidine dehydrogenase (DPYD) gene. There are clinical guidelines to improve safety outcomes of treatment, but these are primarily based on variants assessed in non-African populations. Whole genome sequencing data from the 1000 Genomes Project and the African Genome Variation Project were mined to assess variation in DPYD in eight sub-Saharan African populations. Variant functional annotation was performed with a series of bioinformatics tools to assess potential likelihood of deleterious impact. There were 29 DPYD coding variants identified in the datasets assessed, of which 25 are rare, and some of which are known to be deleterious. One African-specific variant (rs115232898-C), is common in sub-Saharan Africans (1-4%) and known to reduce the function of the dihydropyrimidine dehydrogenase enzyme (DPD), having been linked to cases of severe toxicity. This variant, once validated in clinical trials, should be considered for inclusion in clinical guidelines for use in sub-Saharan African populations. The rs2297595-C variant is less well-characterized in terms of effect, but shows significant allele frequency differences between sub-Saharan African populations (0.5-11.5%; p = 1.5 × 10-4), and is more common in East African populations. This study highlights the relevance of African-data informed guidelines for fluorouracil drug safety in sub-Saharan Africans, and the need for region-specific data to ensure that Africans may benefit optimally from a precision medicine approach.

PMID:33767731 | PMC:PMC7985174 | DOI:10.3389/fgene.2021.626954

Front Microbiol. 2021 Mar 3;12:562199. doi: 10.3389/fmicb.2021.562199. eCollection 2021.

ABSTRACT

Serological methods serve as a direct or indirect means of pathogen infection diagnosis in plant and animal species, including humans. Dot-ELISA (DE) is an inexpensive and sensitive, solid-state version of the microplate enzyme-linked immunosorbent assay, with a broad range of applications in epidemiology. Yet, its applicability is limited by uncertainties in the qualitative output of the assay due to overlapping dot colorations of positive and negative samples, stemming mainly from the inherent color discrimination thresholds of the human eye. Here, we report a novel approach for unambiguous DE output evaluation by applying machine learning-based pattern recognition of image pixels of the blot using an impartial predictive model rather than human judgment. Supervised machine learning was used to train a classifier algorithm through a built multivariate logistic regression model based on the RGB ("Red," "Green," "Blue") pixel attributes of a scanned DE output of samples of known infection status to a model pathogen (Lettuce big-vein associated virus). Based on the trained and cross-validated algorithm, pixel probabilities of unknown samples could be predicted in scanned DE output images, which would then be reconstituted by pixels having probabilities above a cutoff. The cutoff may be selected at will to yield desirable false positive and false negative rates depending on the question at hand, thus allowing for proper dot classification of positive and negative samples and, hence, accurate diagnosis. Potential improvements and diagnostic applications of the proposed versatile method that translates unique pathogen antigens to the universal basic color language are discussed.

PMID:33767673 | PMC:PMC7986560 | DOI:10.3389/fmicb.2021.562199

Sci Rep. 2021 Mar 25;11(1):6846. doi: 10.1038/s41598-021-86349-1.

ABSTRACT

CADASIL is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the EGF-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraine, psychiatric disturbances, recurrent strokes and dementia, being executive function characteristically impaired. The molecular pathways altered by this receptor aggregation need to be studied further. A genome-wide transcriptome study (four cases paired with three healthy siblings) was carried out, in addition to a qRT-PCR for validation purposes (ten new cases and eight new controls). To study the expression profile by cell type of the significant mRNAs found, we performed an in situ hybridization (ISH) (nine cases and eight controls) and a research in the Single-nuclei Brain RNA-seq expression browser (SNBREB). Pathway analysis enrichment was carried out with Gene Ontology and Reactome. Neuropsychological tests were performed in five of the qRT-PCR cases. The two most significant differentially expressed mRNAs (BANP, p-value = 7.23 × 10-4 and PDCD6IP, p-value = 8.36 × 10-4) were selected for the validation study by qRT-PCR. Additionally, we selected two more mRNAs (CAMK2G, p-value = 4.52 × 10-3 and E2F4, p-value = 4.77 × 10-3) due to their association with ischemic neuronal death. E2F4 showed differential expression in the genome-wide transcriptome study and in the qRT-PCR (p = 1.23 × 10-3), and it was upregulated in CADASIL cases. Furthermore, higher E2F4 expression was associated with worse executive function (p = 2.04 × 10-2) and attention and information processing speed (IPS) (p = 8.73 × 10-2). In situ hibridization showed E2F4 expression in endothelial and vascular smooth vessel cells. In silico studies indicated that E2F4 is also expressed in brain endothelial cells. Among the most significant pathways analyzed, there was an enrichment of vascular development, cell adhesion and vesicular machinery terms and autophagy process. E2F4 is more highly expressed in the skin biopsy of CADASIL patients compared to controls, and its expression is present in endothelial cells and VSMCs. Further studies are needed to understand whether E2F4 could be useful as a biomarker, to monitor the disease or be used as a therapeutic target.

PMID:33767277 | DOI:10.1038/s41598-021-86349-1

Sci Rep. 2021 Mar 25;11(1):6850. doi: 10.1038/s41598-021-86267-2.

ABSTRACT

The formula of a standardized extract of Centella asiatica (ECa 233) was modified to improve its dissolution, with implications for pharmacokinetics and metabolomic profile. This study aimed to understand the resultant changes in disposition kinetics of ECa 233 and alterations to human metabolome after oral administration. This study was a two-sequence of dosages (250 and 500 mg), with an open-label phase I clinical trial. The modified formula was administered in single and multiple doses to twelve healthy Thai volunteers. The major parent compounds, madecassoside and asiaticoside, were rarely absorbed, instead undergoing biotransformation into active metabolites, madecassic acid and asiatic acid with possibility to be eliminated via fecal route. Increasing the dose of ECa 233 resulted in significantly greater plasma levels of those active metabolites, with accumulation of asiatic acid after multiple oral administration for seven days. Examining the impacts of accumulation behavior on metabolomics, the study traced changes in levels pre- and post-dose of five relevant human metabolites. Administration of ECa 233 was found to be significantly associated with an increase of choline, an endogenous metabolite with documented benefits for learning and memory. Therefore, ECa 233 may be useful in mitigating cognitive impairment, through its role in modulating human metabolites.

PMID:33767223 | DOI:10.1038/s41598-021-86267-2

Gene. 2021 Mar 22:145592. doi: 10.1016/j.gene.2021.145592. Online ahead of print.

ABSTRACT

PURPOSE: CYP2C19 metabolizes the antiplatelet and antiepileptic drugs. Any alteration in CYP2C19 activity might influence the therapeutic efficacy. The objective of this study was to identify CYP2C19 variants prevalent in Indians and perform their in silico characterization.

METHODS: Infinium global screening array (GSA) was used for CYP2C19 genotyping in 2000 healthy Indians. In addition, we performed in silico characterization of the identified variants.

RESULTS: Out of the 11 variants covered (*2, *3, *4,*5,*6, *7,*8, *9,*10,*11, and *17), five were identified in Indians (*2, *3, *6,*8 and *17). The *2 and *17 were the most prevalent alleles (minor allele frequencies, MAF: 32.0% and 13.95%). The *3, *6 and *8 were rare (MAFs: 0.425%, 0.025% and 0.05%). The *2 variant is shown to affect the splicing at the fifth exon-intron boundary. The *3 variant is a non-sense variant that is predicted to be deleterious. On the otherhand, the *17 variant showed more binding affinity for GATA binding protein 1 (GATA1), myocyte enhancer factor 2 (MEF2) and ectotropic viral integration site 1 (EVI1). The *6 and *8 variants predicted to be deleterious. The *2, *3 and *7 variants showed lesser probability of exon skipping, while *17 showed more probability. The genotype distribution of Indian subjects is comparable with that of South Asians (SAS) (1000 genome project, phase 3).

CONCLUSION: The *2, *3 and *17 variants are the key pharmacogenetic determinants in Indians. The *2 and *3 are loss-of-function variants. The *17 is a gain-of-function variant with increased binding of transcriptional factors.

PMID:33766706 | DOI:10.1016/j.gene.2021.145592

Semin Ophthalmol. 2021 Mar 25:1-12. doi: 10.1080/08820538.2021.1893764. Online ahead of print.

ABSTRACT

BACKGROUND: The Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) spectrum of diseases are devastating blistering disorders involving mucosal surfaces with ocular sequelae that manifest particularly profound long-term morbidity. Advances in deoxyribonucleic acid (DNA) sequencing, genome-wide association studies, and both molecular and pharmacogenetics have helped clarify genetic susceptibility and characterize the iatrogenic risk of SJS for a given patient.

METHODS: A review of peer reviewed publications featured on PubMed pertaining to the clinical, pathologic, pharmacogenetic and molecular genetic features of SJS/TEN was conducted. Propose: To provide an in-depth clinicopathologic description of the ocular, ocular adnexal, and cutaneous findings in SJS/TEN, summarize pathogenesis and related conditions, and provide an update on the molecular genetic modifications that contribute to the phenotypic variations and genetic susceptibilities of SJS.

CONCLUSIONS: HLA subtyping and other genetic testing may eventually be valuable in the appropriate context to prevent the debilitating ocular sequelae of SJS, particularly as it relates to medication use.

PMID:33764253 | DOI:10.1080/08820538.2021.1893764

Basic Clin Pharmacol Toxicol. 2021 Mar 24. doi: 10.1111/bcpt.13583. Online ahead of print.

ABSTRACT

In China, pharmacists have started to manage cancer pain at outpatient clinics. This retrospective study performed at a tertiary teaching hospital was aimed to evaluate the effects of a physician-pharmacist joint clinic for cancer pain management. The study was performed between December 2016 and August 2019 and included 113 outpatients with moderate to severe cancer-related pain. Patients were divided into two groups according to the clinic each patient visited: the physician-pharmacist joint clinic (joint group, n=59) or physician-only clinic (usual group, n=54). Brief Pain Inventory (BPI) and Morisky Medication Adherence Measure (MMAM) were used to collect data on pain intensity, interference, and medication adherence. Pain Management Index (PMI) was also calculated. BPI, MMAM, and PMI were assessed at baseline (patients' first visit, week 0) and week-4 follow-up. The Chinese version of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) was used to assess patients' Health-Related Quality of Life (HRQoL) at week 4. The primary outcomes were the improvement in pain intensity, adequacy of pain management, and medication adherence. The secondary outcome was the improvement in HRQoL. At week 4, compared to the usual group, the BPI pain intensity categories except the pain right now were significantly lower in the joint group: worst pain, 4 (3 - 7) versus 6 (4 - 8), P = 0.020; least pain, 1 (0 - 2) versus 2 (1 - 3), P = 0.010; average pain, 3 (2 - 4) versus 4 (2 - 5), P = 0.023; pain right now, 2 (1 - 3) versus 2 (0 - 4), P = 0.796. For the seven pain interference categories, there were no significant improvements in the joint group (P > 0.05). Significantly more patients achieved adequate pain control in the joint group than the usual group ((P = 0.002). There was also a significant difference in medication adherence between the two groups (P = 0.001). There were no significant differences in HRQoL between the two groups. The study suggests that pharmacist participation in outpatient cancer pain management is associated with improvement of patients' pain control and medication adherence.

PMID:33763950 | DOI:10.1111/bcpt.13583

Front Genet. 2021 Mar 8;12:535123. doi: 10.3389/fgene.2021.535123. eCollection 2021.

ABSTRACT

Although best practices have emerged on how to analyse and interpret personal genomes, the utility of whole genome screening remains underdeveloped. A large amount of information can be gathered from various types of analyses via whole genome sequencing including pathogenicity screening, genetic risk scoring, fitness, nutrition, and pharmacogenomic analysis. We recognize different levels of confidence when assessing the validity of genetic markers and apply rigorous standards for evaluation of phenotype associations. We illustrate the application of this approach on a family of five. By applying analyses of whole genomes from different methodological perspectives, we are able to build a more comprehensive picture to assist decision making in preventative healthcare and well-being management. Our interpretation and reporting outputs provide input for a clinician to develop a healthcare plan for the individual, based on genetic and other healthcare data.

PMID:33763108 | PMC:PMC7982663 | DOI:10.3389/fgene.2021.535123

Front Pharmacol. 2021 Mar 8;12:624662. doi: 10.3389/fphar.2021.624662. eCollection 2021.

ABSTRACT

Background: The effectiveness of antibiotics for the treatment of severe bacterial infections in newborns in resource-limited settings has been determined by empirical evidence. However, such an approach does not warrant optimal exposure to antibiotic agents, which are known to show different disposition characteristics in this population. Here we evaluate the rationale for a simplified regimen of gentamicin taking into account the effect of body size and organ maturation on pharmacokinetics. The analysis is supported by efficacy data from a series of clinical trials in this population. Methods: A previously published pharmacokinetic model was used to simulate gentamicin concentration vs. time profiles in a virtual cohort of neonates. Model predictive performance was assessed by supplementary external validation procedures using therapeutic drug monitoring data collected in neonates and young infants with or without sepsis. Subsequently, clinical trial simulations were performed to characterize the exposure to intra-muscular gentamicin after a q.d. regimen. The selection of a simplified regimen was based on peak and trough drug levels during the course of treatment. Results: In contrast to current World Health Organization guidelines, which recommend gentamicin doses between 5 and 7.5 mg/kg, our analysis shows that gentamicin can be used as a fixed dose regimen according to three weight-bands: 10 mg for patients with body weight <2.5 kg, 16 mg for patients with body weight between 2.5 and 4 kg, and 30 mg for those with body weight >4 kg. Conclusion: The choice of the dose of an antibiotic must be supported by a strong scientific rationale, taking into account the differences in drug disposition in the target patient population. Our analysis reveals that a simplified regimen is feasible and could be used in resource-limited settings for the treatment of sepsis in neonates and young infants with sepsis aged 0-59 days.

PMID:33762945 | PMC:PMC7982486 | DOI:10.3389/fphar.2021.624662

medRxiv. 2021 Mar 12:2021.03.07.21252875. doi: 10.1101/2021.03.07.21252875. Preprint.

ABSTRACT

BACKGROUND: There is considerable variability in COVID-19 outcomes amongst younger adults-and some of this variation may be due to genetic predisposition. We characterized the clinical implications of the major genetic risk factor for COVID-19 severity, and its age-dependent effect, using individual-level data in a large international multi-centre consortium.

METHOD: The major common COVID-19 genetic risk factor is a chromosome 3 locus, tagged by the marker rs10490770. We combined individual level data for 13,424 COVID-19 positive patients (N=6,689 hospitalized) from 17 cohorts in nine countries to assess the association of this genetic marker with mortality, COVID-19-related complications and laboratory values. We next examined if the magnitude of these associations varied by age and were independent from known clinical COVID-19 risk factors.

FINDINGS: We found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (hazard ratio [HR] 1·4, 95% confidence interval [CI] 1·2-1·6) and COVID-19 related mortality (HR 1·5, 95%CI 1·3-1·8). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (odds ratio [OR] 2·0, 95%CI 1·6-2·6), venous thromboembolism (OR 1·7, 95%CI 1·2-2·4), and hepatic injury (OR 1·6, 95%CI 1·2-2·0). Risk allele carriers ≤ 60 years had higher odds of death or severe respiratory failure (OR 2·6, 95%CI 1·8-3·9) compared to those > 60 years OR 1·5 (95%CI 1·3-1·9, interaction p-value=0·04). Amongst individuals ≤ 60 years who died or experienced severe respiratory COVID-19 outcome, we found that 31·8% (95%CI 27·6-36·2) were risk variant carriers, compared to 13·9% (95%CI 12·6-15·2%) of those not experiencing these outcomes. Prediction of death or severe respiratory failure among those ≤ 60 years improved when including the risk allele (AUC 0·82 vs 0·84, p=0·016) and the prediction ability of rs10490770 risk allele was similar to, or better than, most established clinical risk factors.

INTERPRETATION: The major common COVID-19 risk locus on chromosome 3 is associated with increased risks of morbidity and mortality-and these are more pronounced amongst individuals ≤ 60 years. The effect on COVID-19 severity was similar to, or larger than most established risk factors, suggesting potential implications for clinical risk management.

FUNDING: Funding was obtained by each of the participating cohorts individually.

PMID:33758887 | PMC:PMC7987046 | DOI:10.1101/2021.03.07.21252875

PLoS One. 2021 Mar 24;16(3):e0247989. doi: 10.1371/journal.pone.0247989. eCollection 2021.

ABSTRACT

Letrozole, an aromatase inhibitor (AI), is the first-line adjuvant drug for treating hormone receptor-positive (HR+) breast cancer in postmenopausal women. However, harmful adverse events (AEs) and significant differences in drug response among individuals remain a significant problem in clinical application. Current evidence suggests that the observed individual variation in the treatment outcomes of AI is conferred by genetic variants. Hence, in this study, we examined the association of TCL1A gene polymorphisms with letrozole-induced AEs. The study subjects were postmenopausal HR+ breast cancer patients who were receiving adjuvant letrozole. Genomic DNA was isolated by a routine standard phenol-chloroform method. In total, 198 South Indian patients were genotyped for four single nucleotide polymorphisms (SNPs) in the TCL1A gene loci by the TaqMan allelic discrimination assay using the RT-PCR system. We used the odds ratio and 95% confidence interval to assess the genetic association. Musculoskeletal (MS) AEs and vasomotor symptoms (VMSs) are the most common side effects observed in the study cohort. Among 198 patients, 81 experienced musculoskeletal toxicity, reporting MS-AEs, 57 had VMSs, and 33 of them had both. The most frequently identified polymorphic variants in the patient series were rs11849538 (G), with an allele frequency of about 27.3%, followed by rs7158782-G (27.3%), rs7159713-G (25.8%), and rs2369049-G (22.5%). The genetic association analysis indicated no significant difference in the proportion of TCL1A gene variants between patients with and without AEs on either MS-AEs or VMSs. Though we observed high LD in all patient groups, the inferred haplotypes displayed a non-significant association with letrozole-induced specific AEs. However, the SNP functionality analysis by RegulomeDB provided a 2b rank score for rs7158782, suggesting a potential biological function. Our findings suggest that TCL1A gene polymorphisms may not play any role in the prediction of letrozole-induced AEs in South Indian HR+ breast cancer patients.

PMID:33760860 | DOI:10.1371/journal.pone.0247989