Framework for Implementing Individualised Dosing of Anti-Cancer Drugs in Routine Care: Overcoming the Logistical Challenges.

Precision medicine in oncology involves identifying the 'right drug', at the 'right dose', for the right person. Currently, many orally administered anti-cancer drugs, particularly kinase inhibitors (KIs), are prescribed at a standard fixed dose. Identifying the right dose remains one of the biggest challenges to optimal patient care.

Understanding the Risk of Drug Interactions Between Ritonavir-Containing COVID-19 Therapies and Small-Molecule Kinase Inhibitors in Patients With Cancer.

Purpose: The introduction of COVID-19 therapies containing ritonavir has markedly expanded the scope of use for this medicine. As a strong cytochrome P450 3A4 inhibitor, the use of ritonavir is associated with a high drug interaction risk. There are currently no data to inform clinician regarding the likely magnitude and duration of interaction between ritonavir-containing COVID-19 therapies and small-molecule kinase inhibitors (KIs) in patients with cancer.

Efficacy and Safety of NSAIDs in Infants: A Comprehensive Review of the Literature of the Past 20 Years.

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in infants, children, and adolescents worldwide; however, despite sufficient evidence of the beneficial effects of NSAIDs in children and adolescents, there is a lack of comprehensive data in infants. The present review summarizes the current knowledge on the safety and efficacy of various NSAIDs used in infants for which data are available, and includes ibuprofen, dexibuprofen, ketoprofen, flurbiprofen, naproxen, diclofenac, ketorolac, indomethacin, niflumic acid, meloxicam, celecoxib, parecoxib, rofecoxib, acetylsalicylic acid, and nimesulide. The efficacy of NSAIDs has been documented for a variety of conditions, such as fever and pain.

Detection of , an Olive Trunk Pathogen, on Olive Pruning Debris.

has recently been identified as a pathogen contributing to olive trunk diseases in South Africa. Little is known regarding the biology and epidemiology of this pathogen. The aim of this study was to investigate whether olive pruning debris act as an inoculum source of in established orchards.

Combining Therapeutic Drug Monitoring and Pharmacokinetic Modelling Deconvolutes Physiological and Environmental Sources of Variability in Clozapine Exposure.

Clozapine is a key antipsychotic drug for treatment-resistant schizophrenia but exhibits highly variable pharmacokinetics and a propensity for serious adverse effects. Currently, these challenges are addressed using therapeutic drug monitoring (TDM). This study primarily sought to (i) verify the importance of covariates identified in a prior clozapine population pharmacokinetic (popPK) model in the absence of environmental covariates using physiologically based pharmacokinetic (PBPK) modelling, and then to (ii) evaluate the performance of the popPK model as an adjunct or alternative to TDM-guided dosing in an active TDM population.

Plasma concentration guided dosing of drugs used for the treatment of childhood leukaemias: protocol for a systematic review.

Introduction: Childhood leukaemia is the most common type of cancer in children and represents among 25% of the diagnoses in children <15 years old. Childhood survival rates have significantly improved within the last 40 years due to a rapid advancement in therapeutic interventions. However, in high-risk groups, survival rates remain poor.

A giant NLR gene confers broad-spectrum resistance to Phytophthora sojae in soybean.

Phytophthora root and stem rot caused by P. sojae is a destructive soybean soil-borne disease found worldwide. Discovery of genes conferring broad-spectrum resistance to the pathogen is a need to prevent the outbreak of the disease.

Dieback and decline pathogens of olive trees in South Africa.

Trunk disease fungal pathogens reduce olive production globally by causing cankers, dieback, and other decline-related symptoms on olive trees. Very few fungi have been reported in association with olive dieback and decline in South Africa. Many of the fungal species reported from symptomatic olive trees in other countries have broad host ranges and are known to occur on other woody host plants in the Western Cape province, the main olive production region of South Africa.

Cost-effectiveness of oral anticancer drugs and associated individualised dosing approaches in patients with cancer: protocol for a systematic review.

Introduction: Oral anticancer drugs (OADs) have rapidly expanded with more than 70 OADs targeting several molecular targets. Many of the OADs exert an exposure-response relationship but still, a 'one-size fits-all' dose is used, ignoring interindividual variability. Several of these OADs share similar mechanisms of actions and thus target the same cancer and has resulted in a substantial research focus on comparing the health benefit of each.

Pathogenicity Testing of Fungal Isolates Associated with Olive Trunk Diseases in South Africa.

A recent olive trunk disease survey performed in the Western Cape Province, South Africa, identified several fungi associated with olive trunk disease symptoms, including species of Basidiomycota, Botryosphaeriaceae, Coniochaetaceae, Calosphaeriaceae, Diaporthaceae, Diatrypaceae, Phaeomoniellaceae, Phaeosphaeriaceae, Symbiotaphrinaceae, Togniniaceae, and Valsaceae. Many of the species recovered had not yet been reported from olive trees; therefore, the aim of this study was to determine their pathogenicity toward this host. Pathogenicity tests were first conducted on detached shoots to select virulent isolates, which were then used in field trials.

Computational Treatment Simulations to Assess the Need for Personalized Tamoxifen Dosing in Breast Cancer Patients of Different Biogeographical Groups.

Tamoxifen is used worldwide to treat estrogen receptor-positive breast cancer. It is extensively metabolized, and minimum steady-state concentrations of its metabolite endoxifen (C) >5.97 ng/mL have been associated with favorable outcome.

Saved by the pump: Two successful resuscitations utilising emergency department-initiated extracorporeal cardiopulmonary resuscitation in South Africa.

Extracorporeal life support is the utilisation of advanced techniques to sustain circulatory and/or ventilatory functions in critically ill patients when standard therapies fail. It is well established in developed countries. There is increasing literature supporting its application in refractory cardiac arrest with a potential reversible cause, a procedure also known as extracorporeal cardiopulmonary resuscitation (eCPR).

Occurrence of Canker and Wood Rot Pathogens on Stone Fruit Propagation Material and Nursery Trees in the Western Cape of South Africa.

Dieback and canker of young stone fruit trees can cause suboptimal growth and even death under severe conditions. One source of inoculum of canker pathogens could be through nursery trees harboring latent infections that would not be visible to inspections done according to the deciduous fruit scheme. The objectives of this study were to identify the canker and wood rot fungal pathogens present in nursery stone fruit trees as well as in propagation material and to evaluate their pathogenicity.

The Use of Translational Modelling and Simulation to Develop Immunomodulatory Therapy as an Adjunct to Antibiotic Treatment in the Context of Pneumonia.

The treatment of respiratory tract infections is threatened by the emergence of bacterial resistance. Immunomodulatory drugs, which enhance airway innate immune defenses, may improve therapeutic outcome. In this concept paper, we aim to highlight the utility of pharmacometrics and Bayesian inference in the development of immunomodulatory therapeutic agents as an adjunct to antibiotics in the context of pneumonia.

Exploring the Use of Serum-Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Hepatic Cytochromes P450 and Organic Anion Transporting Polypeptides.

Liver-derived small extracellular vesicles (sEVs), prepared from small sets of banked serum samples using a novel two-step protocol, were deployed as liquid biopsy to study the induction of cytochromes P450 (CYP3A4, CYP3A5, and CYP2D6) and organic anion transporting polypeptides (OATP1B1 and OATP1B3) during pregnancy (nonpregnant (T0), first, second, and third (T3) trimester women; N = 3 each) and after administration of rifampicin (RIF) to healthy male subjects. Proteomic analysis revealed induction (mean fold-increase, 90% confidence interval) of sEV CYP3A4 after RIF 300 mg × 7 days (3.5, 95% CI = 2.

Simulation-Based Assessment of the Impact of Non-Adherence on Endoxifen Target Attainment in Different Tamoxifen Dosing Strategies.

Tamoxifen is widely used in breast cancer treatment and minimum steady-state concentrations of its active metabolite endoxifen (C) above 5.97 ng/mL have been associated with favourable disease outcome. Yet, about 20% of patients do not reach target C applying conventional tamoxifen dosing.

Therapeutic drug monitoring of oral targeted antineoplastic drugs.

Purpose: This review provides an overview of the current challenges in oral targeted antineoplastic drug (OAD) dosing and outlines the unexploited value of therapeutic drug monitoring (TDM). Factors influencing the pharmacokinetic exposure in OAD therapy are depicted together with an overview of different TDM approaches. Finally, current evidence for TDM for all approved OADs is reviewed.

Survey of Trunk Pathogens in South African Olive Nurseries.

Several fungal trunk pathogens are associated with olive trunk diseases in South Africa. Little is known regarding the inoculum sources of these pathogens in the olive industry, and no specific management strategies are in place. The aim of this study was to investigate the status of olive nurseries in South Africa, with regard to the presence of trunk pathogens in olive plant material, to determine whether nursery material can be considered inoculum sources contributing to long-distance dispersal of these pathogens.

Validation of a 3-h Sampling Interval to Assess Variability in Cytochrome P450 3A Phenotype and the Impact of Induction and Mechanism-Based Inhibition Using Midazolam as a Probe Substrate.

Drug probe phenotyping is used extensively in academic and industry research to evaluate cytochrome P450 (CYP) phenotype in order to account for sources of between- and within- subject variability in metabolic clearance. In terms of application, CYP3A is the most important drug metabolizing enzyme the most frequently studied. Currently, phenotyping studies for CYP3A involve the administration of midazolam and collection of timed blood samples up to 24-48 hours in order to determine an area under the plasma concentration time curve (AUC).

Identification of the caffeine to trimethyluric acid ratio as a dietary biomarker to characterise variability in cytochrome P450 3A activity.

Purpose: Cytochrome P450 (CYP) 3A plays an important role in the metabolism of many clinically used drugs and exhibits substantial between-subject variability (BSV) in activity. Current methods to assess variability in CYP3A activity have limitations and there remains a need for a minimally invasive clinically translatable strategy to define CYP3A activity. The purpose of this study was to evaluate the potential for a caffeine metabolic ratio to describe variability in CYP3A activity.

Interactions between humidity and evaporative heat dissipation in a passerine bird.

Environmental humidity is thought to be a major determinant of evaporative cooling capacity at high air temperatures (T), but the technical challenges of experimentally manipulating humidity in respirometry chambers have resulted in far less being known about the effects of humidity compared to those of T. We tested the prediction that at T approaching and exceeding normothermic body temperature (T), high humidity would result in higher T, lower evaporative water loss (EWL) and/or higher resting metabolic rate (RMR) in a passerine bird, the white-browed sparrow-weaver (Plocepasser mahali). We used open-system flow-through respirometry to measure EWL, RMR and T in sparrow-weavers experiencing T = 36-44 °C and chamber humidities of 6, 13, 19 or 25 g m.

Effect of early adverse events on response and survival outcomes of advanced melanoma patients treated with vemurafenib or vemurafenib plus cobimetinib: A pooled analysis of clinical trial data.

This study aimed to evaluate the impact of early adverse events on overall survival (OS), progression-free survival (PFS) and objective response within a pooled secondary analysis of participants treated with first-line vemurafenib or vemurafenib plus cobimetinib in the clinical trials BRIM3 and coBRIM. The study included 583 participants who received vemurafenib monotherapy and 247 who received vemurafenib plus cobimetinib. Adverse events requiring vemurafenib/cobimetinib dose adjustment within the first 28 days of therapy were significantly associated with OS (hazard ratio (HR) [95% CI]: dose reduced/interrupted = 0.