Cost-effectiveness analysis of cell-based versus egg-based quadrivalent influenza vaccines in the pediatric population in Taiwan.

Cell-based influenza vaccines avoid egg-adaptive mutations, potentially improving vaccine effectiveness. We assessed the one-season cost-effectiveness of cell-based quadrivalent influenza vaccine (QIVc) against that of egg-derived quadrivalent influenza vaccines (QIVe) in children (6 months to 17 years of age) from payer and societal perspectives in Taiwan using an age-stratified static model. Base case and high egg adaptation scenarios were assessed. Deterministic and probabilistic sensitivity analyses were performed. The incremental cost-effectiveness ratio (ICER) threshold in Taiwan was assumed to be USD 99 177/quality-adjusted life year (QALY). Compared to QIVe, QIVc would prevent 15 665 influenza cases, 2244 complicated cases, and 259 hospitalizations per year. The base case ICER was USD 68 298/QALY and USD 40 085/QALY from the payer and societal perspective, respectively. In the high egg adaptation scenario, the ICER was USD 45 782/QALY from the payer's perspective and USD 17 489/QALY from the societal perspective. Deterministic sensitivity analyses indicated that infection incidence rate, vaccination coverage, and prevalence of the A/H3N2 strain were the main drivers of ICER. In conclusion, switching the immunization strategy from QIVe to QIVc is predicted to reduce the influenza-associated disease burden and be cost-effective for the pediatric population in Taiwan. The potential benefits of QIVc would be even higher during influenza seasons with high levels of egg adaptation.

Antibody-Conjugated Nanodiamonds as Dual-Functional Immunosensors for In Vitro Diagnostics.

Nanodiamonds (NDs) are carbon nanoparticles with a large refractive index, a high density, and exceptional chemical stability. When excited by green light, they can emit bright red fluorescence from implanted nitrogen-vacancy (NV) centers. Taking advantage of these properties, we have developed antibody-conjugated NDs as in vitro diagnostic sensors for two complementary assays: particle-enhanced turbidimetric immunoassay (PETIA) and spin-enhanced lateral flow immunoassay (SELFIA). To achieve this goal, monocrystalline diamond powders (∼100 nm in diameter) with or without NV implantation were first treated in molten KNO3 to reduce their size and shape inhomogeneity, followed by surface carboxylation in strong oxidative acids and non-covalent conjugation with antibodies in water. PETIA and SELFIA were carried out separately with a microplate reader and a magnetically modulated fluorescence analyzer. Using C-reactive protein (CRP) as the target antigen, we found that anti-CRP-conjugated NDs exhibited high colloidal stability over 1 month at 4 °C in buffer solution. The limits of detection for 3 µL of CRP sample solution were 0.06 µg/mL and 1 ng/mL with variation coefficients of less than 10 and 15% for PETIA and SELFIA, respectively. These two methods together provide a detection range of 1 ng/mL-10 µg/mL, potentially useful for clinical applications. This work represents the first practical use of rounded monocrystalline NDs as in vitro diagnostic reagents.

Direct Thermal Growth of Gold Nanopearls on 3D Interweaved Hydrophobic Fibers as Ultrasensitive Portable SERS Substrates for Clinical Applications.

Surface-enhanced Raman spectroscopy (SERS)-based biosensors have attracted much attention for their label-free detection, ultrahigh sensitivity, and unique molecular fingerprinting. In this study, a wafer-scale, ultrasensitive, highly uniform, paper-based, portable SERS detection platform featuring abundant and dense gold nanopearls with narrow gap distances, are prepared and deposited directly onto ultralow-surface-energy fluorosilane-modified cellulose fibers through simple thermal evaporation by delicately manipulating the atom diffusion behavior. The as-designed paper-based SERS substrate exhibits an extremely high Raman enhancement factor (3.9 × 1011 ), detectability at sub-femtomolar concentrations (single-molecule level) and great signal reproductivity (relative standard deviation: 3.97%), even when operated with a portable 785-nm Raman spectrometer. This system is used for fingerprinting identification of 12 diverse analytes, including clinical medicines (cefazolin, chloramphenicol, levetiracetam, nicotine), pesticides (thiram, paraquat, carbaryl, chlorpyrifos), environmental carcinogens (benzo[a]pyrene, benzo[g,h,i]perylene), and illegal drugs (methamphetamine, mephedrone). The lowest detection concentrations reach the sub-ppb level, highlighted by a low of 16.2 ppq for nicotine. This system appears suitable for clinical applications in, for example, i) therapeutic drug monitoring for individualized medication adjustment and ii) ultra-early diagnosis for pesticide intoxication. Accordingly, such scalable, portable and ultrasensitive fibrous SERS substrates open up new opportunities for practical on-site detection in biofluid analysis, point-of-care diagnostics and precision medicine.

SnO2-xNx based tpod nanostructure for SARS-CoV2 spike protein detection.

The worldwide spreading of severe acute respiratory syndrome SARS-CoV2 pandemic, a massive setback to every human being. In response to strategies actions against Covid-19 spreading many detection, prevention, and post-measures are being studied in large capacities. Association of SARS-CoV2 with ACE2 is well acknowledged and used for developing point-of-care detection kits. Recently, cases and studies have surfaced showing relation of ACE I/D polymorphism with spreading of SARS-CoV2 and highlighted a slip section towards detection and these studies show specificity with older males, high diabetes, and hypertension. To address the raised concern, we report synthesis of unique SnO2-xNx tpod nanostructure, showing affirmative attachment to both ACE1 and ACE2 efficiently. The attachment is examined in different ratios and studied with µ-Raman spectroscopy. The tpod nanostructure has served with its signature raman signals and used as probe for detection of SARS-CoV2 spike protein (S1). The linearity response for tpod raman signal at 630.4 cm-1 shows R2 0.9705, comparatively peak 1219.13 cm-1 show R2 0.9865 and calculated limit of detection of 35 nM.

Heterogeneous Fusion of Camera and mmWave Radar Sensor of Optimizing Convolutional Neural Networks for Parking Meter System.

In this article, a novel heterogeneous fusion of convolutional neural networks that combined an RGB camera and an active mmWave radar sensor for the smart parking meter is proposed. In general, the parking fee collector on the street outdoor surroundings by traffic flows, shadows, and reflections makes it an exceedingly tough task to identify street parking regions. The proposed heterogeneous fusion convolutional neural networks combine an active radar sensor and image input with specific geometric area, allowing them to detect the parking region against different tough conditions such as rain, fog, dust, snow, glare, and traffic flow. They use convolutional neural networks to acquire output results along with the individual training and fusion of RGB camera and mmWave radar data. To achieve real-time performance, the proposed algorithm has been implemented on a GPU-accelerated embedded platform Jetson Nano with a heterogeneous hardware acceleration methodology. The experimental results exhibit that the accuracy of the heterogeneous fusion method can reach up to 99.33% on average.

Age-related volumetric alterations in hippocampal subiculum region are associated with reduced retention of the "when" memory component.

Although age-related differences in episodic memory function are well established, the differential reduction in fine-grain memory components and its underlying hippocampal mechanism remains unclear. Hence, the current study investigated, first, age-related differences in the recollection of the four components (who, when, where, and what) of verbal episodic memory and, second, these components' associations with volumetric alterations in the hippocampal subfields. A total of 60 older and younger adults completed the Logical Memory test. The measurements of the volumes of the hippocampal subfields were obtained. The results revealed that older age was associated with poorer learning performance for when, where, and what components but not for who component; the reduced learning scores were differentially correlated with the age-related regional vulnerability of the dentate gyrus, CA1 subfield, and subiculum. The age-related vulnerability in the retention of the when component was associated with smaller subiculum, CA1, CA4, and dentate gyrus, but a reduction in the subiculum alone mediated the inverse relationship between age and the retention score for the when component. Our findings underscore the value of differentiating between memory components in evaluations of verbal contextual episodic memory which allows the analyst to examine aging-related associations between subtle cognitive changes and hippocampal substructures.

High-Sensitivity Dual-Probe Detection of Urinary miR-141 in Cancer Patients via a Modified Screen-Printed Carbon Electrode-Based Electrochemical Biosensor.

The screening and diagnosis of cancer are hallmarks of medicine in the aging population. Recently, microRNAs have shown potential for use as biomarkers, which could advance the field of diagnostics. The presence of miRNA-141 in the serum has been well described in several malignancies. However, the invasive approach used for sampling represents the major limitation for its practical application and, hence, its notable absence as a method for screening the general population. In light of this, we aimed to develop a high-sensitivity microRNA (miR) biosensor for application in the diagnosis of all miR-141-associated cancers, such as colorectal cancer (CRC) and breast cancer (BC). The novelty lies in our dual-probe design, which is reliant on the hybridization of the fluorescein isothiocyanate (FITC) targeting probe onto an existing sample of urinary miR-141 in the first step, followed by complementary binding with a biotinylated probe that has been coated on a modified screen-printed carbon electrode (SPCE). The hybridization of the probe and sensor produces signals via the catalytic reduction of H2O2 at HRP-modified SPCEs in the presence of H2O, which was measured by either cyclic voltammetry or chronoamperometry (CA) currents. In our study, the detection and expression of miR-141 in a cohort of colorectal cancer (n = 6) and breast cancer (n = 4) samples showed that its levels were significantly higher than in a healthy cohort (n = 9) (p < 0.004). Moreover, our miR sensor demonstrated high stability, reliability, and sensitivity (p < 0.0001). This work hopefully provides new information for the detection and monitoring of de novo and existing cancers.

Probiotic, Bacillus subtilis E20 alters the immunity of white shrimp, Litopenaeus vannamei via glutamine metabolism and hexosamine biosynthetic pathway.

The purpose of this study was to profile the mechanisms of action of probiotic, Bacillus subtilis E20 in activating the immunity of white shrimp, Litopenaeus vannamei. Two groups of shrimp were studied. One group was fed a control diet without probiotic supplementation and the other was fed a probiotic-containing diet at a level of 109 cfu kg diet-1. After the 8-week feeding regimen, the metabolite composition in the hepatopancreas of shrimp were investigated using 1H nuclear magnetic resonance (1H NMR) based metabolomic analysis. Results from the 1H NMR analysis revealed that 16 hepatopancreatic metabolites were matched and identified among groups, of which 2 metabolites, creatinine and glutamine were significantly higher in probiotic group than in the control group. This result was confirmed by the reverse-phase high-performance liquid chromatography (RP-HPLC) and spectrophotometric analysis. Transcriptome analysis indicated the expressions of 10 genes associated with antioxidant enzymes, pattern recognition proteins and antimicrobial molecules, more active expression in the shrimp fed a diet supplemented with probiotic as compared to that of shrimp in control. In addition, the expressions of 4 genes involved with hexosamine biosynthesis pathway (HBP) and UDP-N-acetylglucosamine-peptide N-acetylglucosaminyltransferase for protein O-glycosylation were also higher in hepatopancreas of probiotic-treated shrimp than in shrimp fed a control diet. Western blot and enzyme-linked immunosorbent assay showed that heat shock factor 1, heat shock protein 70, and protein O-glycosylation in hepatopancreas were higher in probiotic group than the control group. These findings suggest that probiotic, B. subtilis E20 promotes the digestibility of glutamine in the diet, and that the increased glutamine in shrimp can be used as fuel for immune cells or may be used to regulate immune molecule expressions and protein O-glycosylation via the HBP to increase protein O-glycosylation, thereby improving the health of shrimp.

SoC FPGA Accelerated Sub-Optimized Binary Fully Convolutional Neural Network for Robotic Floor Region Segmentation.

In this article, a new Binary Fully Convolutional Neural Network (B-FCN) based on Taguchi method sub-optimization for the segmentation of robotic floor regions, which can precisely distinguish floor regions in complex indoor environments is proposed. This methodology is quite suitable for robot vision in an embedded platform and the segmentation accuracy is up to 84.80% on average. A total of 6000 training datasets were used to improve the accuracy and reach convergence. On the other hand, to reach real-time computation, a PYNQ FPGA platform with heterogeneous computing acceleration was used to accelerate the proposed B-FCN architecture. Overall, robots would benefit from better navigation and route planning in our approach. The FPGA synthesis of our binarization method indicates an efficient reduction in the BRAM size to 0.5-1% and also GOPS/W is sufficiently high. Notably, the proposed faster architecture is ideal for low power embedded devices that need to solve the shortest path problem, path searching, and motion planning.

Learning rate and subjective mental workload in five truck driving tasks.

Both learning curve models and subjective mental workload are useful tools for determining the length of training for new workers and predicting future task performance. An experiment was designed to collect the task completion times and subjective mental workload of five driving tasks including (a) reverse into garage, (b) 3-point turn, (c) parallel parking, (d) S-curve and (e) up-down-hill. The results indicated that task completion times of truck driving can be predicted with a learning curve. Practice significantly reduced the mental workload rating. However, the novice trainees tended to have a more significant reduction because, compared to experienced trainees, they tended to give greater or lower workload scores than the experienced trainees before and after practice, respectively. The current study may not be complete enough to provide guidelines for a training programme, but it is adequate to suggest that learning rate and workload measure can serve as indexes for factoring in the individual differences. Practitioner summary: Learning curves can be used to determine the length of training for new workers and performance standards for a particular task. Learning rate and mental workload were found to be important measures for comparing individual differences in order to better design a training programme. However, mental workload must be evaluated by experienced participants.

A synbiotic improves the immunity of white shrimp, Litopenaeus vannamei: Metabolomic analysis reveal compelling evidence.

In this study, we examined the synergistic effects of a diet-administered synbiotic comprising galactooligosaccharide (GOS) and the probiotic Lactobacillus plantarum 7-40 on immune responses, immune-related gene expressions, and disease resistance to Vibrio alginolyticus in white shrimp Litopenaeus vannamei. To unravel the regulatory role of the synbiotic in activating the immune system of shrimp, 1H nuclear magnetic resonance (NMR)-based metabolomic analysis were used to investigate hepatopancreas metabolites, then significantly altered metabolites were confirmed in both the hepatopancreas and plasma by reverse-phase high-performance liquid chromatography (RP-HPLC) and spectrophotometric analysis. Shrimp were fed four experimental diets for 60 days, including a basal diet with no GOS or probiotic (control), 0.4% GOS (PRE), probiotic (PRO), and 0.4% GOS in combination with the probiotic (SYN). Results showed that the SYN diet significantly increased survival of L. vannamei 24 h after a V. alginolyticus injection. Immune parameters such as phenoloxidase activity, respiratory bursts, phagocytic activity and gene expressions, including prophenoloxidase I, serine proteinase, and peroxinectin, of shrimp fed the SYN diet significantly increased, compared to the other treatments and control. In addition, results from the 1H NMR analysis revealed that 22 hepatopancreas metabolites were matched and identified between the SYN and control groups, among which three metabolites, i.e., inosine monophosphate (IMP), valine, and betaine, significantly increased in the SYN group. Confirmation using RP-HPLC and spectrophotometric methods showed that IMP presented high amounts in the hepatopancreas, but not in the plasma of shrimp; in contrast, valine and betaine metabolites were in high concentrations in both the hepatopancreas and plasma. Our results suggested that GOS and the probiotic had a synergistic effect on enhancing immunity and disease resistance of L. vannamei against V. alginolyticus infection through inducing syntheses of a nucleotide (IMP), a branched amino acid (valine), and a methyl group donor (betaine) in the hepatopancreas, which were then released into the plasma and directly taken up by hemocytes, resulting in a triggering of melanization and phagocytosis processes in cells.

Older Age, Low Socioeconomic Status, and Multiple Comorbidities Lower the Probability of Receiving Inpatient Rehabilitation Half a Year After Stroke.

OBJECTIVE: To determine the predictors of receiving inpatient rehabilitation during 7 to 12 months after stroke. DESIGN: Retrospective cohort study. SETTING: A nationally representative sample of 1 million National Health Insurance enrollees. PARTICIPANTS: Patients with new-onset stroke (N=13,828) were included. Studied participants were patients who received inpatient rehabilitation during 4 to 6 months after stroke. Patients who died within 1 year of the stroke event were excluded (n=488). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The outcome variable of interest was the probability of receiving inpatient rehabilitation during 7 to 12 months after stroke. The characteristics of both patients and medical care providers were investigated to determine their effect on patients receiving inpatient rehabilitation. RESULTS: Older patients, patients of low socioeconomic status, patients with Charlson Comorbidity Index ≥5, and patients who received outpatient rehabilitation during 4 to 6 months after stroke have a lower rate of receiving inpatient rehabilitation than do their counterparts. In addition, receiving inpatient rehabilitation during 7 to 9 months after stroke is a strong positive predictor of receiving inpatient rehabilitation during 10 to 12 months after stroke (odds ratio, 38.556; P<.0001). CONCLUSIONS: This study revealed that older age, lower socioeconomic status, and multiple comorbidities are negative predictive factors with a cumulative predictive power for the probability of receiving inpatient rehabilitation during 7 to 12 months after stroke.

The perceived quality of in-vehicle auditory signals: a structural equation modelling approach.

The current study applied Structural Equation Modelling to analyse the relationship among pitch, loudness, tempo and timbre and their relationship with perceived sound quality. Twenty-eight auditory signals of horn, indicator, door open warning and parking sensor were collected from 11 car brands. Twenty-one experienced drivers were recruited to evaluate all sound signals with 11 semantic differential scales. The results indicate that for the continuous sounds, pitch, loudness and timbre each had a direct impact on the perceived quality. Besides the direct impacts, pitch also had an impact on loudness perception. For the intermittent sounds, tempo and timbre each had a direct impact on the perceived quality. These results can help to identify the psychoacoustic attributes affecting the consumers' quality perception and help to design preferable sounds for vehicles. In the end, a design guideline is proposed for the development of auditory signals that adopts the current study's research findings as well as those of other relevant research. Practitioner Summary: This study applied Structural Equation Modelling to analyse the relationship among pitch, loudness, tempo and timbre and their relationship with perceived sound quality. The result can help to identify psychoacoustic attributes affecting the consumers' quality perception and help to design preferable sounds for vehicles.

Discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as novel, highly potent and selective, orally bioavailable inhibitors of Tyrosine Threonine Kinase, TTK.

TTK/Mps1 is a key kinase controlling progression of cell division via participation in the mitotic spindle assembly checkpoint and is overexpressed in a number of human cancers. Herein we report the discovery of 4-(4-aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)benzamides as a potent, novel class of TTK inhibitors. The series was identified by means of bioisosteric replacement of the related imidazopyrazine and imidazopyridazine scaffolds. Optimization led to the identification of compounds with excellent potency (Ki=0.8nM) and exceptional kinase selectivity. The SAR indicates a strong dependence of activity on the presence of the N-cyclopropyl-2-methylbenzamide moiety delineating the geometry for 1½ type kinase inhibitor. Molecular modeling indicates the extensive and optimal contacts, mediated through H-bonds and hydrophobic interactions, are responsible for the selectivity and potency of the inhibitors. The compounds demonstrate a strong anti-proliferative activity in a panel of human cancer cell lines (HCT116 GI50<15nM) and good rodent pharmacokinetics (oral %F 97%).

Effects of hirami lemon, Citrus depressa Hayata, leaf meal in diets on the immune response and disease resistance of juvenile barramundi, Lates calcarifer (bloch), against Aeromonas hydrophila.

The present study was conducted to evaluate the dietary supplementation of leaf meal from Citrus depressa Hayata on the growth, innate immune response, and disease resistance of juvenile barramundi, Lates calcarifer. Four diets were formulated to contain 0% (control), 1% (C1), 3% (C3), and 5% (C5) leaf meal, respectively. During a 56 d feeding trial, fish survival, growth performance, and feed efficiency were not significantly different among all groups. For immune response, respiratory burst, superoxide dismutase and lysozyme activities were not significantly different among all groups. However, fish fed the C5 diet for 56 d had significantly higher phagocytic activity. Also, fish fed C3 and C5 diets had significantly higher Mx gene expressions in spleens and head kidneys with nerve necrosis virus injections after 24 h. Disease resistance against Aeromonas hydrophila was increased by the C5 diet. In this study, barramundi fed on a diet containing 5% C. depressa Hayata leaf meal had significantly better innate immune response and disease resistance against A. hydrophila.

Association Between Physical Therapy and Risk of Coronary Artery Disease and Dyslipidemia Among Osteoarthritis Patients: A Nationwide Database Study.

OBJECTIVE: To provide empirical evidence on the effect of early physical therapy (PT) within the first year of osteoarthritis (OA) diagnosis on reduction in OA-related comorbidities in patients with OA. DESIGN: Retrospective cohort study. SETTING: The study was conducted using a nationally representative sample of 1 million National Health Insurance enrollees. PARTICIPANTS: Newly diagnosed patients with OA (N=13,545). One-to-one propensity score matching was used to match patients who received PT within the first year of OA diagnosis (PT group; n=3403) with an equal number of patients with OA who did not receive PT (non-PT group). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The 4-year cumulative risk of comorbidities including coronary artery disease (CAD), diabetes mellitus, dyslipidemia, osteoporosis, gastrointestinal tract ulcer, and renal failure was estimated. A Cox proportional hazards regression analysis was performed to identify the dose-response relation between the PT dosage and the risk of OA-related comorbidities. RESULTS: A total of 3403 patients (25.1%) received PT within the first year of OA diagnosis. The PT group had a significantly lower 4-year cumulative risk of dyslipidemia (P=.05) and a potentially lower 4-year cumulative risk of CAD (P=.09). After adjusting for other potential confounders, the Cox proportional hazards regression analysis showed that patients with OA who received a high PT dosage had a low risk of CAD and dyslipidemia. CONCLUSIONS: Patients with OA who received PT had a lower risk of OA-related comorbidities such as dyslipidemia or CAD.

Expanding school-district/university partnerships to advance health promoting schools implementation and efficacy in Taiwan.

In 2011, the Taiwan government expanded its support of school-district/university partnership programs that promote the implementation of the evidenced-based Health Promoting Schools (HPS) program. This study examined whether expanding the support for this initiative was effective in advancing HPS implementation, perceived HPS impact and perceived HPS efficacy in Taiwan. In 2011 and 2013, a total of 647 and 1195 schools, respectively, complemented the questionnaire. Univariate analysis results indicated that the HPS implementation levels for six components were significantly increased from 2011 to 2013. These components included school health policies, physical environment, social environment, teaching activities and school-community relationships. Participant teachers also reported significantly greater levels of perceived HPS impact and HPS efficacy after the expansion of support for school-district/university partnership programs. Multivariate analysis results indicated that after controlling for school level, HPS funding and HPS action research approach variables, the expansion had a positive impact on increasing the levels of HPS implementation, perceived HPS impact and perceived HPS efficacy.

Panton-Valentine leukocidin facilitates the escape of Staphylococcus aureus from human keratinocyte endosomes and induces apoptosis.

Skin and soft-tissue infections (SSTIs) caused by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) have emerged as major health problems throughout the world. Most SSTI CA-MRSA strains produce Panton-Valentine leukocidin (PVL), but its contribution to CA-MRSA pathogenesis is poorly defined. Here, we used an endemic PVL-positive SSTI-causing CA-MRSA strain from Taiwan, together with an isogenic PVL-knockout mutant (Δpvl) and complemented PVL-positive derivative, to evaluate the role of PVL in the pathogenesis of CA-MRSA in the RHEK-1 human keratinocyte cell line and a rabbit skin infection model. We found that both PVL-positive CA-MRSA and isogenic Δpvl strains attached and were engulfed into endosomes of RHEK-1 cells within 1 hour following infection. However, by 2 hours after infection PVL-positive CA-MRSA more effectively disrupted endosomes, escaped into the cytoplasm, and replicated intracellularly. By 6 hours after infection, the PVL-positive strain caused significantly more caspase-dependent keratinocyte apoptosis than the isogenic Δpvl mutant. In the rabbit infection model, 1 week following infection the wild-type strain produced significantly more widespread lesions and cell apoptosis than the isogenic Δpvl mutant. These findings indicate that PVL is an important virulence factor that enables CA-MRSA to produce necrotizing skin infections by allowing the bacteria to escape from endosomes, replicate intracellularly, and induce apoptosis.

Discovery of inhibitors of the mitotic kinase TTK based on N-(3-(3-sulfamoylphenyl)-1H-indazol-5-yl)-acetamides and carboxamides.

TTK kinase was identified by in-house siRNA screen and pursued as a tractable, novel target for cancer treatment. A screening campaign and systematic optimization, supported by computer modeling led to an indazole core with key sulfamoylphenyl and acetamido moieties at positions 3 and 5, respectively, establishing a novel chemical class culminating in identification of 72 (CFI-400936). This potent inhibitor of TTK (IC50=3.6nM) demonstrated good activity in cell based assay and selectivity against a panel of human kinases. A co-complex TTK X-ray crystal structure and results of a xenograft study with TTK inhibitors from this class are described.