Activity

TAS-119 is a novel orally active, selective inhibitor of Aurora kinase A identified as a clinical candidate for efficacy testing in combination with taxanes. In vitro, TAS-119 enhanced cell growth inhibition of paclitaxel in multiple human cancer cell lines derived from various tissues, including paclitaxel-resistant cell lines. Interestingly, TAS-119 did not enhance paclitaxel antitumor activity in normal lung diploid fibroblast cell lines WI-38 and MRC5. In vivo, TAS-119 enhanced the antitumor efficacy of paclitaxel and docetaxel in multiple models at doses inhibitory to Aurora A in tumors. Moreover, the drug combination was well tolerated, and TAS-119 did not exaggerate clinically documented side effects of taxanes, neutropenia and neurotoxicity, in rats. The same TAS-119 concentration enhanced the cell growth inhibitory activity of three clinically approved taxanes, paclitaxel, docetaxel, and cabazitaxel. Dibutyryl-cAMP chemical structure The degree of enhancement calculated as fold of change of the IC50 value for each taxane was almost the same among the three taxanes. We conducted in vitro and in vivo experiments to develop an optimized combination therapy regimen for TAS-119 with paclitaxel/docetaxel. Using in vitro and in vivo models, we tested the drug administration order for TAS-119 combined with paclitaxel and the TAS-119 treatment duration. The best regimen in preclinical models was combining paclitaxel or docetaxel treatment with 4 days of TAS-119 dosing, which was initiated on the same day as the paclitaxel or docetaxel administration or one day later. This information provided guidance for the design of a clinical trial of TAS-119 and paclitaxel or docetaxel combination.Guanylyl cyclase C (GCC) is a unique therapeutic target with expression restricted to the apical side of epithelial cell tight junctions thought to be only accessible by intravenously administered agents on malignant tissues where GCC expression is aberrant. In this study, we sought to evaluate the therapeutic potential of a second-generation investigational antibody-dug conjugate (ADC), TAK-164, comprised of a human anti-GCC mAb conjugated via a peptide linker to the highly cytotoxic DNA alkylator, DGN549. The in vitro binding, payload release, and in vitro activity of TAK-164 was characterized motivating in vivo evaluation. The efficacy of TAK-164 and the relationship to exposure, pharmacodynamic marker activation, and biodistribution was evaluated in xenograft models and primary human tumor xenograft (PHTX) models. We demonstrate TAK-164 selectively binds to, is internalized by, and has potent cytotoxic effects against GCC-expressing cells in vitro A single intravenous administration of TAK-164 (0.76 mg/kg) resulted in significant growth rate inhibition in PHTX models of metastatic colorectal cancer. Furthermore, imaging studies characterized TAK-164 uptake and activity and showed positive relationships between GCC expression and tumor uptake which correlated with antitumor activity. Collectively, our data suggest that TAK-164 is highly active in multiple GCC-positive tumors including those refractory to TAK-264, a GCC-targeted auristatin ADC. A strong relationship between uptake of 89Zr-labeled TAK-164, levels of GCC expression and, most notably, response to TAK-164 therapy in GCC-expressing xenografts and PHTX models. These data supported the clinical development of TAK-164 as part of a first-in-human clinical trial (NCT03449030).The national implementation groups of early warning systems in the UK and Ireland have identified a need to understand implementation, adoption and maintenance of these complex interventions. The literature on how to implement, scale, spread and sustain these systems is sparse. We describe a successful adoption and maintenance over 10 years of a paediatric early warning system as a sociotechnical intervention using the Nonadoption, Abandonment, Challenges to the Scale-Up, Spread, and Sustainability Framework for Health and Care Technologies. The requirement for iterative processes within environment, culture, policy, human action and the wider system context may explain the possible reasons for improved outcomes in small-scale implementation and meta-analyses that are not reported in multicentre randomised control trials of early warning systems.

Nocturnal pulse oximetry can be used to screen for obstructive sleep apnoea (OSA) using the McGill Oximetry Score (MOS). The MOS has a time threshold for a technically adequate study of 6 hours. It has been suggested that one night of oximetry is sufficient to screen for OSA using the MOS.

(1) To evaluate night-to-night variation of the MOS. (2) To determine the impact of recording three nights of oximetry on the screening yield for OSA. (3) To explore whether useful MOS data are discarded when a threshold of 6 hours of oximetry recording is used.

A retrospective study of nocturnal pulse oximetry done at home over three consecutive nights in paediatric patients with suspected OSA. Studies were scored (MOS) using thresholds of ≥6 and ≥4 hours of recording.

A total of 329 patients were studied. MOS scores over three nights showed only fair to moderate agreement. On the first night 126 patients (38%) screened positive for OSA. When three nights of oximetry were done 195 patients (59%) screened positive on at least one of the nights. There were 48 patients with studies of between 4 and 6 hours duration on one or more nights. If these studies are scored 20 patients (42%) would screen positive for OSA on at least one night based on scoring these studies alone.

One night of oximetry screening may not be sufficient to screen for OSA. Lowering the time threshold to ≥4 hours may increase the screening capability of nocturnal oximetry.

One night of oximetry screening may not be sufficient to screen for OSA. Lowering the time threshold to ≥4 hours may increase the screening capability of nocturnal oximetry.

Electronic health records (EHRs) are routinely used to identify family violence, yet reliable evidence of their validity remains limited. We conducted a systematic review and meta-analysis to evaluate the positive predictive values (PPVs) of coded indicators in EHRs for identifying intimate partner violence (IPV) and child maltreatment (CM), including prenatal neglect.

We searched 18 electronic databases between January 1980 and May 2020 for studies comparing any coded indicator of IPV or CM including prenatal neglect defined as neonatal abstinence syndrome (NAS) or fetal alcohol syndrome (FAS), against an independent reference standard. We pooled PPVs for each indicator using random effects meta-analyses.

We included 88 studies (3 875 183 individuals) involving 15 indicators for identifying CM in the prenatal period and childhood (0-18 years) and five indicators for IPV among women of reproductive age (12-50 years). Based on the International Classification of Disease system, the pooled PPV was over 80% for NAS (16 studies) but lower for FAS (<40%; seven studies).