[Pharmacological Effects of CDK4 & 6 Selective Inhibitor Abemaciclib in Hormone Receptor-Positive Breast Cancer].

Abemaciclib, a selective cyclin dependent kinases 4 and 6(CDK4 & 6)inhibitor, is under development for the treatment of hormone receptor(HR)-positive, HER2-negative breast cancer. CDK4 & 6 inhibitors attenuate Rb phosphorylation resulting in a G1 arrest and tumor growth inhibition. Abemaciclib potently inhibits both CDK4 and CDK6, with 14-fold higher potency for CDK4-cyclin D1 complexes than CDK6-cyclin D3 in enzymatic assays. Low frequency of severe neutropenia requiring drug holiday in clinical trials of abemaciclib in breast cancer patients enables continuous daily dosing. Abemaciclib's preclinical difference in selectivity for CDK4 vs CDK6 could help explain its safety profile and ability to be dosed on a continuous schedule. Continuous inhibition of CDK4 & 6 by abemaciclib results in irreversible growth inhibition through induction of senescence and apoptosis in breast cancer cell lines. Abemaciclib shows its growth inhibitory effect particularly in estrogen receptor(ER)- positive breast cancer, and sensitivity to abemaciclib is associated with high ER levels and Rb positivity. In animals bearing ERpositive breast cancer, significant tumor growth inhibition was shown by single-agent and combination with anti-estrogen agents. Abemaciclib penetrates the blood-brain barrier and showed antitumor activity in glioma models. As described above, there are some characteristics demonstrate differences of abemaciclib and other CDK4 & 6 inhibitors. In clinical studies, abemaciclib has demonstrated efficacy and generally tolerable safety profile in HR-positive, HER2-negative breast cancer patients.

Biochemistry and Biology of GDF11 and Myostatin: Similarities, Differences, and Questions for Future Investigation.

Growth differentiation factor 11 (GDF11) and myostatin (or GDF8) are closely related members of the transforming growth factor ß superfamily and are often perceived to serve similar or overlapping roles. Yet, despite commonalities in protein sequence, receptor utilization and signaling, accumulating evidence suggests that these 2 ligands can have distinct functions in many situations. GDF11 is essential for mammalian development and has been suggested to regulate aging of multiple tissues, whereas myostatin is a well-described negative regulator of postnatal skeletal and cardiac muscle mass and modulates metabolic processes. In this review, we discuss the biochemical regulation of GDF11 and myostatin and their functions in the heart, skeletal muscle, and brain. We also highlight recent clinical findings with respect to a potential role for GDF11 and/or myostatin in humans with heart disease. Finally, we address key outstanding questions related to GDF11 and myostatin dynamics and signaling during development, growth, and aging.

Mechanically Ventilating the Severe Asthmatic.

The management of the critically ill patients with asthma can be rather challenging. Potentially devastating complications relating to this presentation include hypoxemia, worsening bronchospasm, pulmonary aspiration, tension pneumothorax, dynamic hyperinflation, hypotension, dysrhythmias, and seizures. In contrast to various other pathologies requiring mechanical ventilation, acute asthma is generally associated with better outcomes. This review serves as a practical guide to the physician managing patients with severe acute asthma requiring mechanical ventilation. In addition to specifics relating to endotracheal intubation, we also discuss the interpretation of ventilator graphics, the recommended mode of ventilation, dynamic hyperinflation, permissive hypercapnia, as well as the role of extracorporeal membrane oxygenation and noninvasive mechanical ventilation.

Neuronal control of locomotor handedness in Drosophila.

Genetically identical individuals display variability in their physiology, morphology, and behaviors, even when reared in essentially identical environments, but there is little mechanistic understanding of the basis of such variation. Here, we investigated whether Drosophila melanogaster displays individual-to-individual variation in locomotor behaviors. We developed a new high-throughout platform capable of measuring the exploratory behavior of hundreds of individual flies simultaneously. With this approach, we find that, during exploratory walking, individual flies exhibit significant bias in their left vs. right locomotor choices, with some flies being strongly left biased or right biased. This idiosyncrasy was present in all genotypes examined, including wild-derived populations and inbred isogenic laboratory strains. The biases of individual flies persist for their lifetime and are nonheritable: i.e., mating two left-biased individuals does not yield left-biased progeny. This locomotor handedness is uncorrelated with other asymmetries, such as the handedness of gut twisting, leg-length asymmetry, and wing-folding preference. Using transgenics and mutants, we find that the magnitude of locomotor handedness is under the control of columnar neurons within the central complex, a brain region implicated in motor planning and execution. When these neurons are silenced, exploratory laterality increases, with more extreme leftiness and rightiness. This observation intriguingly implies that the brain may be able to dynamically regulate behavioral individuality.

Behavioral idiosyncrasy reveals genetic control of phenotypic variability.

Quantitative genetics has primarily focused on describing genetic effects on trait means and largely ignored the effect of alternative alleles on trait variability, potentially missing an important axis of genetic variation contributing to phenotypic differences among individuals. To study the genetic effects on individual-to-individual phenotypic variability (or intragenotypic variability), we used Drosophila inbred lines and measured the spontaneous locomotor behavior of flies walking individually in Y-shaped mazes, focusing on variability in locomotor handedness, an assay optimized to measure variability. We discovered that some lines had consistently high levels of intragenotypic variability among individuals, whereas lines with low variability behaved as although they tossed a coin at each left/right turn decision. We demonstrate that the degree of variability is itself heritable. Using a genome-wide association study (GWAS) for the degree of intragenotypic variability as the phenotype across lines, we identified several genes expressed in the brain that affect variability in handedness without affecting the mean. One of these genes, Ten-a, implicates a neuropil in the central complex of the fly brain as influencing the magnitude of behavioral variability, a brain region involved in sensory integration and locomotor coordination. We validated these results using genetic deficiencies, null alleles, and inducible RNAi transgenes. Our study reveals the constellation of phenotypes that can arise from a single genotype and shows that different genetic backgrounds differ dramatically in their propensity for phenotypic variabililty. Because traditional mean-focused GWASs ignore the contribution of variability to overall phenotypic variation, current methods may miss important links between genotype and phenotype.

The ultrasonographic "whirlpool sign" in testicular torsion: valuable tool or waste of valuable time? A systematic review and meta-analysis.

PURPOSE: A positive whirlpool sign (WS) is defined as the presence of a spiral-like pattern when the spermatic cord is assessed during ultrasonography (US), using standard, high-resolution ultrasonography (HRUS) and/or color Doppler sonography (CDS), in the presence of testicular torsion. The objective of this review was to assess the validity and accuracy of this sign by performing a comprehensive systematic literature review and meta-analysis. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, a comprehensive literature search was performed (August, 2017), using the following databases: BMJ Best Practice, Cochrane Library, Embase, PubMed, Scopus, and Web of Science. Selected studies were further assessed for relevance and quality using the Oxford 2010 Critical Appraisal Skills Program (CASP). RESULTS: Of the studies assessed, a total of 723 participants were included, with a mean of 72.3 (SD 71.9) participants. Of the participants, 226 (31.3%) were diagnosed with testicular torsion (TT). Meta-analysis of the studies that provided sufficient data resulted in a pooled sensitivity and specificity of the WS of 0.73 (95% CI, 0.65-0.79) and 0.99 (95% CI, 0.92-0.99), respectively. Removal of all neonates increased the pooled sensitivity to 0.92 (95% CI, 0.70-0.98) while the pooled specificity remained almost unchanged at 0.99 (95% CI, 0.95-1.00). The estimated summary effect of all studies with sufficient data was 4.34 (95% CI, 1.01-7.67; n = 394; p = 0.001). A large degree of heterogeneity was suggested by an I2 statistic of 88.27% (95% CI, 68.60-98.68%). Removal of neonatal subjects increased the estimated summary effect to 5.32 (95% CI, 1.59-9.05; n = 375; p = 0.001). CONCLUSION: The WS, when correctly diagnosed, may be viewed as a very definitive sign for TT in the pediatric and adult populations. However, its role in neonates is limited.

A review of hemodynamic monitoring techniques, methods and devices for the emergency physician.

The emergency department (ED) is frequently the doorway to the intensive care unit (ICU) for a significant number of critically ill patients presenting to the hospital. Hemodynamic monitoring (HDM) which is a key component in the effective management of the critically ill patient presenting to the ED, is primarily concerned with assessing the performance of the cardiovascular system and determining the correct therapeutic intervention to optimise end-organ oxygen delivery. The spectrum of hemodynamic monitoring ranges from simple clinical assessment and routine bedside monitoring to point of care ultrasonography and various invasive monitoring devices. The clinician must be aware of the range of available techniques, methods, interventions and technological advances as well as possess a sound approach to basic hemodynamic monitoring prior to selecting the optimal modality. This article comprises an in depth discussion of an approach to hemodynamic monitoring techniques and principles as well as methods of predicting fluid responsiveness as it applies to the ED clinician. We review the role, applicability and validity of various methods and techniques that include; clinical assessment, passive leg raising, blood pressure, finger based monitoring devices, the mini-fluid challenge, the end-expiratory occlusion test, central venous pressure monitoring, the pulmonary artery catheter, ultrasonography, bioreactance and other modern invasive hemodynamic monitoring devices.

Recovery of locomotion after injury in Drosophila melanogaster depends on proprioception.

Locomotion is necessary for survival in most animal species. However, injuries to the appendages mediating locomotion are common. We assess the recovery of walking in Drosophila melanogaster following leg amputation. Whereas flies pre-amputation explore open arenas in a symmetric fashion on average, foreleg amputation induces a strong turning bias away from the side of the amputation. However, we find that unbiased walking behavior returns over time in wild-type flies, while recovery is significantly impaired in proprioceptive mutants. To identify the biomechanical basis of this locomotor impairment and recovery, we then examine individual leg motion (gait) at a fine scale. A minimal mathematical model that links neurodynamics to body mechanics during walking shows that redistributing leg forces between the right and left side enables the observed recovery. Altogether, our study suggests that proprioceptive input from the intact limbs plays a crucial role in the behavioral plasticity associated with locomotor recovery after injury.

Organoid culture promotes dedifferentiation of mouse myoblasts into stem cells capable of complete muscle regeneration.

Experimental cell therapies for skeletal muscle conditions have shown little success, primarily because they use committed myogenic progenitors rather than true muscle stem cells, known as satellite cells. Here we present a method to generate in vitro-derived satellite cells (idSCs) from skeletal muscle tissue. When transplanted in small numbers into mouse muscle, mouse idSCs fuse into myofibers, repopulate the satellite cell niche, self-renew, support multiple rounds of muscle regeneration and improve force production on par with freshly isolated satellite cells in damaged skeletal muscle. We compared the epigenomic and transcriptional signatures between idSCs, myoblasts and satellite cells and used these signatures to identify core signaling pathways and genes that confer idSC functionality. Finally, from human muscle biopsies, we successfully generated satellite cell-like cells in vitro. After further development, idSCs may provide a scalable source of cells for the treatment of genetic muscle disorders, trauma-induced muscle damage and age-related muscle weakness.

Reactivation of mitogen-activated protein kinase (MAPK) pathway by FGF receptor 3 (FGFR3)/Ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma.

Oncogenic B-RAF V600E mutation is found in 50% of melanomas and drives MEK/ERK pathway and cancer progression. Recently, a selective B-RAF inhibitor, vemurafenib (PLX4032), received clinical approval for treatment of melanoma with B-RAF V600E mutation. However, patients on vemurafenib eventually develop resistance to the drug and demonstrate tumor progression within an average of 7 months. Recent reports indicated that multiple complex and context-dependent mechanisms may confer resistance to B-RAF inhibition. In the study described herein, we generated B-RAF V600E melanoma cell lines of acquired-resistance to vemurafenib, and investigated the underlying mechanism(s) of resistance. Biochemical analysis revealed that MEK/ERK reactivation through Ras is the key resistance mechanism in these cells. Further analysis of total gene expression by microarray confirmed a significant increase of Ras and RTK gene signatures in the vemurafenib-resistant cells. Mechanistically, we found that the enhanced activation of fibroblast growth factor receptor 3 (FGFR3) is linked to Ras and MAPK activation, therefore conferring vemurafenib resistance. Pharmacological or genetic inhibition of the FGFR3/Ras axis restored the sensitivity of vemurafenib-resistant cells to vemurafenib. Additionally, activation of FGFR3 sufficiently reactivated Ras/MAPK signaling and conferred resistance to vemurafenib in the parental B-RAF V600E melanoma cells. Finally, we demonstrated that vemurafenib-resistant cells maintain their addiction to the MAPK pathway, and inhibition of MEK or pan-RAF activities is an effective therapeutic strategy to overcome acquired-resistance to vemurafenib. Together, we describe a novel FGFR3/Ras mediated mechanism for acquired-resistance to B-RAF inhibition. Our results have implications for the development of new therapeutic strategies to improve the outcome of patients with B-RAF V600E melanoma.

LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models.

The HGF/MET signaling pathway regulates a wide variety of normal cellular functions that can be subverted to support neoplasia, including cell proliferation, survival, apoptosis, scattering and motility, invasion, and angiogenesis. MET over-expression (with or without gene amplification), aberrant autocrine or paracrine ligand production, and missense MET mutations are mechanisms that lead to activation of the MET pathway in tumors and are associated with poor prognostic outcome. We report here preclinical development of a potent, orally bioavailable, small-molecule inhibitor LY2801653 targeting MET kinase. LY2801653 is a type-II ATP competitive, slow-off inhibitor of MET tyrosine kinase with a dissociation constant (Ki) of 2 nM, a pharmacodynamic residence time (Koff) of 0.00132 min(-1) and t1/2 of 525 min. LY2801653 demonstrated in vitro effects on MET pathway-dependent cell scattering and cell proliferation; in vivo anti-tumor effects in MET amplified (MKN45), MET autocrine (U-87MG, and KP4) and MET over-expressed (H441) xenograft models; and in vivo vessel normalization effects. LY2801653 also maintained potency against 13 MET variants, each bearing a single-point mutation. In subsequent nonclinical characterization, LY2801653 was found to have potent activity against several other receptor tyrosine oncokinases including MST1R, FLT3, AXL, MERTK, TEK, ROS1, DDR1/2 and against the serine/threonine kinases MKNK1/2. The potential value of MET and other inhibited targets within a number of malignancies (such as colon, bile ducts, and lung) is discussed. LY2801653 is currently in phase 1 clinical testing in patients with advanced cancer (trial I3O-MC-JSBA, NCT01285037).

Proteolytic processing of protocadherin proteins requires endocytosis.

The α-, ß-, and γ-protocadherins (Pcdhα, Pcdhß, and Pcdhγ) comprise a large family of single-pass transmembrane proteins predominantly expressed in the nervous system. These proteins contain six cadherin-like extracellular domains, and proteolysis of Pcdhα and Pcdhγ by the γ-secretase complex releases their intracellular domains into the cytoplasm where they may function locally and/or enter the nucleus and affect gene expression. Thus, cleavage of Pcdhs may function to link intercellular contacts and intracellular signaling. Here we report that shedding of the Pcdhα extracellular domain and subsequent processing by γ-secretase require endocytosis and that Pcdhs interact with the regulator of vesicular sorting ESCRT-0 in undifferentiated cells. We also find that the accumulation of Pcdh cleavage products is regulated during development. Differentiation leads to an increase in the interactions between Pcdh proteins and a decrease in the accumulation of cleavage products. We conclude that Pcdh processing requires endocytosis and that the level of cleavage products is regulated during neuronal differentiation.

Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret.

The clustered protocadherins (Pcdhs) are a large family of cadherin-like transmembrane proteins expressed in the nervous system. Stochastic expression of Pcdh genes and alternative splicing of their pre-mRNAs have the potential to generate enormous protein diversity at the cell surface of neurons. At present, the regulation and function of Pcdh proteins are largely unknown. Here, we show that Pcdhs form a heteromeric signaling complex(es), consisting of multiple Pcdh isoforms, receptor tyrosine kinases, phosphatases, and cell adhesion molecules. In particular, we find that the receptor tyrosine kinase rearranged during transformation (Ret) binds to Pcdhs in differentiated neuroblastoma cells and is required for stabilization and differentiation-induced phosphorylation of Pcdh proteins. In addition, the Ret ligand glial cell line-derived neurotrophic factor induces phosphorylation of Pcdhgamma in motor neurons and phosphorylation of Pcdhalpha and Pcdhgamma in sympathetic neurons. Conversely, Pcdh proteins are also required for the stabilization of activated Ret in neuroblastoma cells and sympathetic ganglia. Thus, Pcdhs and Ret are functional components of a phosphorylation-dependent signaling complex.

Development of a Cloud-Based Clinical Decision Support System for Ophthalmology Triage Using Decision Tree Artificial Intelligence.

Purpose: Clinical decision support systems (CDSS) are an emerging frontier in teleophthalmology, drawing on heuristic decision making to augment processes such as triage and referral. We describe the development and implementation of a novel cloud-based decision tree CDSS for on-call ophthalmology consults. The objective was to standardize the triage and referral process while providing a more accurate provisional diagnosis and urgency. Design: Prospective comparative cohort study. Subjects: On-call referrals to a Canadian community ophthalmology clinic. Methods: A web-based decision tree algorithm was developed using current guidelines and expert opinion. The algorithm collected tailored information on the patient's ophthalmic concern, and outputted a provisional diagnosis and urgency before sending an electronic referral to the on-call ophthalmology clinic. Data were described using descriptive statistics. Spearman-rho correlations and Cohen's kappa coefficient were used to characterize the observed relationships. Post hoc analysis was conducted using analysis of contingency tables and adjusted residuals. Main Outcome Measures: Diagnostic category, provisional diagnosis, and urgency for the referring provider, CDSS, and ophthalmologist. Results: Ninety-six referrals were processed. Referring providers included medical doctors (76.0%, n = 73), optometrists (20.8%, n = 20), and nurse practitioners (3.1%, n = 3). The CDSS (κ = 0.5898; 95% confidence interval [CI], 0.4868-0.6928; P < 0.0001) performed equally well with 66.7% agreement in determining category when compared with referring providers (κ = 0.5880; 95% CI, 0.4798-0.6961; P < 0.0001). The CDSS (agreement = 53.1%; κ = 0.4999; 95% CI, 0.4021-0.5978; P < 0.0001) performed better than referring providers (agreement = 43.8%; κ = 0.4191; 95% CI, 0.3194-0.5188; P < 0.0001) in determining a diagnosis. The CDSS (ρ = 0.5014; 95% CI, 0.3092-0.6935; P < 0.0001) also performed better than referring providers (ρ = 0.4035; 95% CI, 0.2406-0.5665; P < 0.0001) in determining urgency. The CDSS assigned a lower level of urgency in 22 cases (22.9%) compared with referring providers in 6 cases (6.3%). Conclusions: To our knowledge, this is the first cloud-based CDSS in ophthalmology designed to augment the triage and referral process. The CDSS achieves a more accurate diagnosis and urgency, standardizes information collection, and overcomes antiquated paper-based consults. Future directions include developing a random forest model or integrating convolutional neural network-based machine learning to refine the speed and accuracy of triage and referral processes, with emphasis on increasing sensitivity of the CDSS.

Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types.

Aging is a complex process involving transcriptomic changes associated with deterioration across multiple tissues and organs, including the brain. Recent studies using heterochronic parabiosis have shown that various aspects of aging-associated decline are modifiable or even reversible. To better understand how this occurs, we performed single-cell transcriptomic profiling of young and old mouse brains after parabiosis. For each cell type, we cataloged alterations in gene expression, molecular pathways, transcriptional networks, ligand-receptor interactions and senescence status. Our analyses identified gene signatures, demonstrating that heterochronic parabiosis regulates several hallmarks of aging in a cell-type-specific manner. Brain endothelial cells were found to be especially malleable to this intervention, exhibiting dynamic transcriptional changes that affect vascular structure and function. These findings suggest new strategies for slowing deterioration and driving regeneration in the aging brain through approaches that do not rely on disease-specific mechanisms or actions of individual circulating factors.

Precise Quantification of Behavioral Individuality From 80 Million Decisions Across 183,000 Flies.

Individual animals behave differently from each other. This variability is a component of personality and arises even when genetics and environment are held constant. Discovering the biological mechanisms underlying behavioral variability depends on efficiently measuring individual behavioral bias, a requirement that is facilitated by automated, high-throughput experiments. We compiled a large data set of individual locomotor behavior measures, acquired from over 183,000 fruit flies walking in Y-shaped mazes. With this data set we first conducted a "computational ethology natural history" study to quantify the distribution of individual behavioral biases with unprecedented precision and examine correlations between behavioral measures with high power. We discovered a slight, but highly significant, left-bias in spontaneous locomotor decision-making. We then used the data to evaluate standing hypotheses about biological mechanisms affecting behavioral variability, specifically: the neuromodulator serotonin and its precursor transporter, heterogametic sex, and temperature. We found a variety of significant effects associated with each of these mechanisms that were behavior-dependent. This indicates that the relationship between biological mechanisms and behavioral variability may be highly context dependent. Going forward, automation of behavioral experiments will likely be essential in teasing out the complex causality of individuality.

SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib.

Imatinib inhibits Bcr-Abl, the oncogenic tyrosine kinase that causes chronic myeloid leukemia. The second-line inhibitors nilotinib and dasatinib are effective in patients with imatinib resistance resulting from Bcr-Abl kinase domain mutations. Bcr-Abl(T315I), however, is resistant to all Abl kinase inhibitors in clinical use and is emerging as the most frequent cause of salvage therapy failure. SGX393 is a potent inhibitor of native and T315I-mutant Bcr-Abl kinase that blocks the growth of leukemia cell lines and primary hematopoietic cells expressing Bcr-Abl(T315I), with minimal toxicity against Bcr-Abl-negative cell lines or normal bone marrow. A screen for Bcr-Abl mutants emerging in the presence of SGX393 revealed concentration-dependent reduction in the number and range of mutations. Combining SGX393 with nilotinib or dasatinib preempted emergence of resistant subclones, including Bcr-Abl(T315I). These findings suggest that combination of a T315I inhibitor with the current clinically used inhibitors may be useful for reduction of Bcr-Abl mutants in Philadelphia chromosome-positive leukemia.

GDF11 expressed in the adult brain negatively regulates hippocampal neurogenesis.

Growth differentiation factor 11 (GDF11) is a transforming factor-ß superfamily member that functions as a negative regulator of neurogenesis during embryonic development. However, when recombinant GDF11 (rGDF11) is administered systemically in aged mice, it promotes neurogenesis, the opposite of its role during development. The goal of the present study was to reconcile this apparent discrepancy by performing the first detailed investigation into the expression of endogenous GDF11 in the adult brain and its effects on neurogenesis. Using quantitative histological analysis, we observed that Gdf11 is most highly expressed in adult neurogenic niches and non-neurogenic regions within the hippocampus, choroid plexus, thalamus, habenula, and cerebellum. To investigate the role of endogenous GDF11 during adult hippocampal neurogenesis, we generated a tamoxifen inducible mouse that allowed us to reduce GDF11 levels. Depletion of Gdf11 during adulthood increased proliferation of neural progenitors and decreased the number of newborn neurons in the hippocampus, suggesting that endogenous GDF11 remains a negative regulator of hippocampal neurogenesis in adult mice. These findings further support the idea that circulating systemic GDF11 and endogenously expressed GDF11 in the adult brain have different target cells or mechanisms of action. Our data describe a role for GDF11-dependent signaling in adult neurogenesis that has implications for how GDF11 may be used to treat CNS disease.

Medication Errors at a Tertiary Hospital Intensive Care Unit.

Background The intensive care unit (ICU) generates more medication prescriptions per patient day than any other unit in the hospital. The dynamics of the ICU environment, coupled with the complexity of patient pathology, increases the risk of medication errors. This study aimed to evaluate the incidence and spectrum of medication errors in an adult general ICU in Johannesburg, South Africa. Methods A retrospective chart review was conducted at a 19-bed ICU in a tertiary-level hospital in Johannesburg. Data were independently collected by two of the study investigators. The doctors' prescription and the nurses' administration section of patient bedside charts were scrutinized for drug prescription and administration errors. Results Of the 656 patient days studied, 3237 drugs (5.6 drugs per patient day) were prescribed. There were a total of 359 medication errors, comprising 237 (66.0%) prescription and 122 (34.0%) administration errors. The total error rate per 1000 patient days was 621.1, while the total error rate per 1000 drug prescriptions was 110.9. The most common errors were incorrect dose prescribed (n=69, 19.2%), incorrect dosing interval prescribed (n=48, 13.4%), incorrect dose administered (n=42, 11.7%) and failure to administer the prescribed drug (n=38, 10.6%). Conclusion The overall occurrence of medication errors is high but is in keeping with general international trends. Targeted interventions should be implemented to minimize the frequency of medication errors in the ICU and consequent risk to patients.