Hepatitis A Virus Infection in Cynomolgus Monkeys Confounds the Safety Evaluation of a Drug Candidate.

In a 3-month toxicity study in cynomolgus monkeys at a European contract laboratory, animals were infected with HAV, initially resulting in hepatic injury being incorrectly attributed to the test compound. Elevated serum ALT/AST/GLDH (5- to 10-fold) were noted in individual animals from all groups including controls, with no apparent dose, exposure, or time-related relationship. Liver histopathology revealed minimal to slight inflammatory cell accumulation in periportal zones of most animals, and minimal to slight hepatocyte degeneration/necrosis in 10/42 animals from all groups. As these findings were more pronounced in 6 drug-treated animals, including 2/6 in the low dose group, the draft report concluded: "treatment-related hepatotoxicity at all dose levels precluded determination of a NOAEL." However, the unusual pattern of hepatotoxicity suggested a factor other than drug exposure might have caused the hepatic effects. Therefore, snap-frozen liver samples were tested for hepatitis viruses using a PCR method. Tests for hepatitis B, C, and E virus were negative; however, 20/42 samples were positive for hepatitis A virus (HAV). Infection was strongly associated with increased serum ALT/GLDH, and/or hepatocyte degeneration/necrosis. Re-evaluation of the study in light of these data concluded that the hepatic injury was not drug-related. A subsequent 6-month toxicology study in HAV-vaccinated cynomolgus monkeys confirmed the absence of hepatotoxicity. Identification of HAV infection supported progression of the drug candidate into later clinical trials. Although rarely investigated, subclinical HAV infection has occasionally been reported in laboratory primates, including those used for toxicology studies and it may be more prevalent than the literature indicates.

The Open acidification Tank Controller: An open-source device for the control of pH and temperature in ocean acidification experiments.

Ocean acidification is the process by which the increase in atmospheric CO2 causes a corresponding increase in seawater CO2 and results in lowering the seawater pH. While this process is likely to have substantial impacts on marine ecosystems, research into the effect of ocean acidification has been limited by the high costs of quality tools to perform ocean acidification treatments in the lab. The Open Acidification Tank Controller is designed to reduce the cost of ocean acidification research by providing a device that can monitor and control pH and temperature of aquaria as well as or better than commercially available research-grade devices, but for less than $250 USD per aquarium. The device is centered around an Arduino Mega 2560 and is assembled into a 3D printed housing. It monitors pH using a BNC glass pH probe and temperature using a three-wire waterproof PT100 temperature sensor. The Open Acidification Tank Controller also features web-based parameter reporting, and data storage to a micro-SD card. This device can hold aquarium pH and temperature at given setpoints, ramp between two values over a user-defined time period, or produce a sine-wave fluctuation in values.

The critical role of peer reviewers: Challenges and future steps.

The critical role of peer reviewers in the publishing process is examined. Examples of typical challenges are provided, including the relative lack of rewards for this important task. Particular attention is paid to the need to consider the diversity of the peer reviewers recruited and impediments to the selection beyond Areas of Competence, often due to the small available pool. Finally, recommendations for improvement are suggested.

Liver, visceral and subcutaneous fat in men and women of South Asian and white European descent: a systematic review and meta-analysis of new and published data.

AIMS/HYPOTHESIS: South Asians have a two- to fivefold higher risk of developing type 2 diabetes than those of white European descent. Greater central adiposity and storage of fat in deeper or ectopic depots are potential contributing mechanisms. We collated existing and new data on the amount of subcutaneous (SAT), visceral (VAT) and liver fat in adults of South Asian and white European descent to provide a robust assessment of potential ethnic differences in these factors. METHODS: We performed a systematic review of the Embase and PubMed databases from inception to August 2021. Unpublished imaging data were also included. The weighted standardised mean difference (SMD) for each adiposity measure was estimated using random-effects models. The quality of the studies was assessed using the ROBINS-E tool for risk of bias and overall certainty of the evidence was assessed using the GRADE approach. The study was pre-registered with the OSF Registries ( https://osf.io/w5bf9 ). RESULTS: We summarised imaging data on SAT, VAT and liver fat from eight published and three previously unpublished datasets, including a total of 1156 South Asian and 2891 white European men, and 697 South Asian and 2271 white European women. Despite South Asian men having a mean BMI approximately 0.5-0.7 kg/m2 lower than white European men (depending on the comparison), nine studies showed 0.34 SMD (95% CI 0.12, 0.55; I2=83%) more SAT and seven studies showed 0.56 SMD (95% CI 0.14, 0.98; I2=93%) more liver fat, but nine studies had similar VAT (-0.03 SMD; 95% CI -0.24, 0.19; I2=85%) compared with their white European counterparts. South Asian women had an approximately 0.9 kg/m2 lower BMI but 0.31 SMD (95% CI 0.14, 0.48; I2=53%) more liver fat than their white European counterparts in five studies. Subcutaneous fat levels (0.03 SMD; 95% CI -0.17, 0.23; I2=72%) and VAT levels (0.04 SMD; 95% CI -0.16, 0.24; I2=71%) did not differ significantly between ethnic groups in eight studies of women. CONCLUSIONS/INTERPRETATION: South Asian men and women appear to store more ectopic fat in the liver compared with their white European counterparts with similar BMI levels. Given the emerging understanding of the importance of liver fat in diabetes pathogenesis, these findings help explain the greater diabetes risks in South Asians. FUNDING: There was no primary direct funding for undertaking the systematic review and meta-analysis.

"Dragons" on the landscape: Modeling the abundance of large carnivorous dinosaurs of the Upper Jurassic Morrison Formation (USA) and the Upper Cretaceous Dinosaur Park Formation (Canada).

Counts of the number of skeletal specimens of "adult" megaherbivores and large theropods from the Morrison and Dinosaur Park formations-if not biased by taphonomic artifacts-suggest that the big meat-eaters were more abundant, relative to the number of big plant-eaters, than one would expect on the basis of the relative abundance of large carnivores and herbivores in modern mammalian faunas. Models of megaherbivore population density (number of individuals per square kilometer) that attempt to take into account ecosystem productivity, the size structure of megaherbivore populations, and individual megaherbivore energy requirements, when combined with values of the large theropod/megaherbivore abundance ratio, suggest that large theropods may have been more abundant on the landscape than estimates extrapolated from the population density versus body mass relationship of mammalian carnivores. Models of the meat production of megaherbivore populations and the meat requirements of "adult" large theropods suggest that herbivore productivity would have been insufficient to support the associated number of individuals of "adult" large theropods, unless the herbivore production/biomass ratio was substantially higher, and/or the large theropod meat requirement markedly lower, than expectations based on modern mammals. Alternatively, or in addition to one or both of these other factors, large theropods likely included dinosaurs other than megaherbivores as significant components of their diet.

Self-Reported Sleep during the COVID Lockdown in a Sample of UK University Students and Staff.

The link between disturbed sleep and the extended lockdown period resulting from COVID-19 is well established. Data from an online survey of 2341 of university students (n = 1972, 84.2%) and staff were reported. Overall (n = 1710, 73.1%) were female and the mean age for the sample was 29.26 (SD = 12.86). 1799 (76.8%) provided self-reported data from the Nottingham Health Profile (NHP) Sleep Subscale that allowed sleep to be compared prior to the lockdown period and during the lockdown period. Sociodemographic data which included, gender, age, whether an individual was a student or member of the university staff, ethnicity, caring responsibilities, and highest educational level were collected. Other data included, the NHP Sleep Sub-scale, change in alcohol consumption during the lockdown period, routine behaviours during the lockdown period, self-efficacy and health and wellbeing. There was a significant deterioration in NHP Sleep scores (p < 0.001) and all areas of sleep that were assessed significantly deteriorated during the lockdown period. These included indicators of sleep quality, sleep latency, sleep duration, sleep disturbance and increased use of sleep medication. Following a multinomial logit regression with change of NHP sleep scores entered as the dependent variable there were several significant predictors. Women had greater sleep dysfunction than men. Increased alcohol consumption, lower educational status and a deterioration in health and well-being scores were associated with greater sleep dysfunction. Not having a designated area to work in and not putting on clothes and make-up were both associated with greater sleep dysfunction during the lockdown period. These findings confirm the importance of taking steps to maintain sleep hygiene during extended lockdown periods.

FOXA1 regulates alternative splicing in prostate cancer.

Dysregulation of alternative splicing in prostate cancer is linked to transcriptional programs activated by AR, ERG, FOXA1, and MYC. Here, we show that FOXA1 functions as the primary orchestrator of alternative splicing dysregulation across 500 primary and metastatic prostate cancer transcriptomes. We demonstrate that FOXA1 binds to the regulatory regions of splicing-related genes, including HNRNPK and SRSF1. By controlling trans-acting factor expression, FOXA1 exploits an "exon definition" mechanism calibrating alternative splicing toward dominant isoform production. This regulation especially impacts splicing factors themselves and leads to a reduction of nonsense-mediated decay (NMD)-targeted isoforms. Inclusion of the NMD-determinant FLNA exon 30 by FOXA1-controlled oncogene SRSF1 promotes cell growth in vitro and predicts disease recurrence. Overall, we report a role for FOXA1 in rewiring the alternative splicing landscape in prostate cancer through a cascade of events from chromatin access, to splicing factor regulation, and, finally, to alternative splicing of exons influencing patient survival.

3T-MRI-based age, sex and site-specific markers of musculoskeletal health in healthy children and young adults.

Objective: The aim of this study is to investigate the role of 3T-MRI in assessing musculoskeletal health in children and young people. Design: Bone, muscle and bone marrow imaging was performed in 161 healthy participants with a median age of 15.0 years (range, 8.0, 30.0). Methods: Detailed assessment of bone microarchitecture (constructive interference in the steady state (CISS) sequence, voxel size 0.2 × 0.2 × 0.4 mm3), bone geometry (T1-weighted turbo spin echo (TSE) sequence, voxel size 0.4 × 0.4 × 2 mm3) and bone marrow (1H-MRS, point resolved spectroscopy sequence (PRESS) (single voxel size 20 × 20 × 20 mm3) size and muscle adiposity (Dixon, voxel size 1.1 × 1.1 × 2 mm3). Results: There was an inverse association of apparent bone volume/total volume (appBV/TV) with age (r = -0.5, P < 0.0005). Cortical area, endosteal and periosteal circumferences and muscle cross-sectional area showed a positive association to age (r > 0.49, P < 0.0001). In those over 17 years of age, these parameters were also higher in males than females (P < 0.05). This sex difference was also evident for appBV/TV and bone marrow adiposity (BMA) in the older participants (P < 0.05). AppBV/TV showed a negative correlation with BMA (r = -0.22, P = 0.01) which also showed an association with muscle adiposity (r = 0.24, P = 0.04). Cortical geometric parameters were highly correlated with muscle area (r > 0.57, P < 0.01). Conclusions: In addition to providing deep insight into the normal relationships between bone, fat and muscle in young people, these novel data emphasize the role of MRI as a non-invasive method for performing a comprehensive and integrated assessment of musculoskeletal health in the growing skeleton.

Accumulation of molybdenum in major organs following repeated oral administration of bis-choline tetrathiomolybdate in the Sprague Dawley rat.

Molybdenum is an essential dietary trace element required for several critical enzyme systems. High intake is associated with toxicity in ruminants and animal studies. The proposed therapeutic use of molybdenum-based drugs poses a potential risk for accumulation through chronic administration of therapeutic doses of this element. The current experiment was designed to study the effect of daily dosing of a molybdenum compound, bis-choline tetrathiomolybdate (TTM), in Sprague Dawley rats using laser ablation inductively coupled plasma time-of-flight mass spectrometry (LA-ICP-ToF-MS) and two dosing levels of TTM for up to 3 months. To investigate if molybdenum accumulation was associated with tissue toxicity, histopathology, haematology and clinical biochemistry markers of toxicity were incorporated into the study design. There were no behavioural signs of toxicity to the rats, and no clinical or anatomic pathology was associated with treatment. The current data did show a progressive accumulation of molybdenum within the adrenal gland, kidneys, liver, spleen, brain and testes. Although this was not associated with tissue toxicity within the 3-month study design, greater exposure over a longer period of time has the potential for producing adverse pathophysiological cellular function. Tissue toxicity, as a result of local excessive accumulation of molybdenum over time, has clear implications for the therapeutic use of molybdenum in humans and demands sensitive monitoring of tissue molybdenum levels to avoid toxicity. The current study highlights the shortcomings of conventional biomonitoring approaches to detect molybdenum accumulation with the goal of avoiding molybdenum-associated toxicity.

Regulation of Escherichia coli fim gene transcription by GadE and other acid tolerance gene products.

Uropathogenic Escherichia coli (UPEC) cause millions of urinary tract infections each year in the United States. Type 1 pili are important for adherence of UPEC to uroepithelial cells in the human and murine urinary tracts where osmolality and pH vary. Previous work has shown that an acidic pH adversely affects the expression of type 1 pili. To determine if acid tolerance gene products may be regulating E. coli fim gene expression, a bank of K-12 strain acid tolerance gene mutants were screened using fimA-lux, fimB-lux, and fimE-lux fusions on single copy number plasmids. We have determined that a mutation in gadE increased transcription of all three fim genes, suggesting that GadE may be acting as a repressor in a low pH environment. Complementation of the gadE mutation restored fim gene transcription to wild-type levels. Moreover, mutations in gadX, gadW, crp, and cya also affected transcription of the three fim genes. To verify the role GadE plays in type 1 pilus expression, the NU149 gadE UPEC strain was tested. The gadE mutant had higher fimE gene transcript levels, a higher frequency of Phase-OFF positioning of fimS, and hemagglutination titres that were lower in strain NU149 gadE cultured in low pH medium as compared to the wild-type bacteria. The data demonstrate that UPEC fim genes are regulated directly or indirectly by the GadE protein and this could have some future bearing on the ability to prevent urinary tract infections by acidifying the urine and shutting off fim gene expression.

Strong suppression of heat conduction in a laboratory replica of galaxy-cluster turbulent plasmas.

In conventional gases and plasmas, it is known that heat fluxes are proportional to temperature gradients, with collisions between particles mediating energy flow from hotter to colder regions and the coefficient of thermal conduction given by Spitzer's theory. However, this theory breaks down in magnetized, turbulent, weakly collisional plasmas, although modifications are difficult to predict from first principles due to the complex, multiscale nature of the problem. Understanding heat transport is important in astrophysical plasmas such as those in galaxy clusters, where observed temperature profiles are explicable only in the presence of a strong suppression of heat conduction compared to Spitzer's theory. To address this problem, we have created a replica of such a system in a laser laboratory experiment. Our data show a reduction of heat transport by two orders of magnitude or more, leading to large temperature variations on small spatial scales (as is seen in cluster plasmas).

Alcohol Consumption during the COVID-19 Lockdown Period: Predictors of At-Risk Drinking at Different AUDIT-C Cut-Off Thresholds.

During the COVID-19 pandemic, alcohol consumption was largely confined to drinking in the home. There has been little research examining variables associated with risk in home drinking. The study employed an online survey of (n = 1128) individuals who had been recruited for their face recognition skills (n = 838, 70.9% females, mean age 45.05 (12.3 SD)). The main dependent variables were three different AUDIT-C cut-off scores for at-risk drinking: (a) 5 for both genders as recommended by Public Health England, (b) 7 for females and 8 for males (cut-off for students and young people) and (c) 8 for both genders (individuals seeking online help for their drinking). Among the independent variables were gender and age, motivations for home drinking using the Home Drinking Assessment Scale (HDAS), purchasing patterns, context of drinking and health and wellbeing. The predictors following hierarchical logistic regressions were for (a) purchasing alcohol online or at a supermarket and emotional HDAS scores, (b) purchasing alcohol online or at a supermarket and for parties, drinking alone and with other members of the household and emotional and practical reason HDAS scores, (c) as for b with the addition that men were more likely to be at-risk drinkers. At-risk drinking in the pandemic was explained by motivational reasons, purchasing patterns and situational factors.

Subpacket structure in strong VLF chorus rising tones: characteristics and consequences for relativistic electron acceleration.

Van Allen Probes in situ observations are used to examine detailed subpacket structure observed in strong VLF (very low frequency) rising-tone chorus elements observed at the time of a rapid MeV electron energization in the inner magnetosphere. Analysis of the frequency gap between lower and upper chorus-band waves identifies f ceEQ, the electron gyrofrequency in the equatorial wave generation region. Initial subpackets in these strong chorus rising-tone elements begin at a frequency near 1/4 f ceEQ and exhibit smooth gradual frequency increase across their > 10 ms temporal duration. A second much stronger subpacket is seen at frequencies around the local value of 1/4 f ce with small wave normal angle (< 10°) and steeply rising df/dt. Smooth frequency and phase variation across and between the initial subpackets support continuous phase trapping of resonant electrons and increased potential for MeV electron acceleration. The total energy gain for individual seed electrons with energies between 100 keV and 3 MeV ranges between 2 and 15%, in their nonlinear interaction with a single chorus element.

A toxicological evaluation of geranylgeraniol.

Geranylgeraniol (GGOH) is an isoprenoid compound found in annatto seeds and an intermediate of the mevalonate pathway found within organisms serving various functions. Toxicological studies on its safety profile are not readily available. To assess the safety of GGOH, a molecularly distilled, food grade annatto oil, consisting of approximately 80% trans-GGOH, was subjected to a bacterial reverse mutation test, an in vitro mammalian chromosomal aberration test, and an in vivo mammalian micronucleus test in order to investigate its genotoxic potential and a 90-day repeated-dose oral toxicity study in rats in order to investigate its potential subchronic toxicity and identify any target organs. No evidence of mutagenicity or genotoxic activity was observed under the applied test systems. In the 90-day study, male and female Hsd. Han Wistar rats were administered daily doses of 0, 725, 1450, and 2900 mg/kg bw/day by gavage. Treatment-related adverse effects were observed in the forestomach at all dose levels and in the liver at the intermediate- and high-dose levels. Based on these results, the lowest observed adverse effect level (LOAEL) for local effects and the no observed adverse effect level (NOAEL) for systemic effects were determined as 725 mg/kg bw/day.

Intracellular detection of singlet oxygen using fluorescent nanosensors.

Detection of singlet oxygen is of great importance for a range of therapeutic applications, particularly photodynamic therapy, plasma therapy and also during photo-endosomolytic activity. Here we present a novel method of intracellular detection of singlet oxygen using biocompatible polymeric nanosensors, encapsulating the organic fluorescent dye, Singlet Oxygen Sensor Green (SOSG) within its hydrophobic core. The singlet oxygen detection efficiency of the nanosensors was quantified experimentally by treating them with a plasma source and these results were further validated by using Monte Carlo simulations. The change in fluorescence intensity of the nanosensors serves as a metric to detect singlet oxygen in the local micro-environment inside mammalian cancer cells. We used these nanosensors for monitoring singlet oxygen inside endosomes and lysosomes of cancer cells, during cold plasma therapy, using a room-temperature Helium plasma jet.

Nootkatone Is an Effective Repellent against Aedes aegypti and Aedes albopictus.

We tested a nootkatone product for insecticide activity against the most prominent vectors of Zika virus (ZIKV), Aedes aegypti, and Aedes albopictus. We tested the permethrin-resistant (PERM-R) Vergel strain of A. aegypti and the permethrin-susceptible (PERM-S) New Orleans strain of A. aegypti to determine if insecticide resistance affected their susceptibility to nootkatone. Bottle bioassays showed that the PERM-S strain (New Orleans) was more susceptible to nootkatone than the confirmed A. aegypti permethrin-resistant (PERM-R) strain, Vergel. The A. albopictus strain ATM-NJ95 was a known PERM-S strain and Coatzacoalcos permethrin susceptibility was unknown but proved to be similar to the ATM-NJ95 PERM-S phenotype. The A. albopictus strains (ATM-NJ95 and Coatzacoalcos) were as susceptible to nootkatone as the New Orleans strain. Bottle bioassays conducted with ZIKV-infected mosquitoes showed that the New Orleans (PERM-S) strain was as susceptible to nootkatone as the mock-infected controls, but the PERM-R strain was less susceptible to nootkatone than the mock-infected controls. Repellency/irritancy and biting inhibition bioassays (RIBB) of A. aegypti determined whether the nootkatone-treated arms of three human subjects prevented uninfected A. aegypti mosquitoes from being attracted to the test subjects and blood-feeding on them. The RIBB analyses data calculated the spatial activity index (SAI) and biting inhibition factor (BI) of A. aegypti at different nootkatone concentrations and then compared the SAI and BI of existing repellency products. We concluded that nootkatone repelled mosquitoes at a rate comparable to 7% DEET or 5% picaridin and has the potential to be an efficacious repellent against adult A. aegypti mosquitoes.

A review of species differences in the control of, and response to, chemical-induced thyroid hormone perturbations leading to thyroid cancer.

This review summarises the current state of knowledge regarding the physiology and control of production of thyroid hormones, the effects of chemicals in perturbing their synthesis and release that result in thyroid cancer. It does not consider the potential neurodevelopmental consequences of low thyroid hormones. There are a number of known molecular initiating events (MIEs) that affect thyroid hormone synthesis in mammals and many chemicals are able to activate multiple MIEs simultaneously. AOP analysis of chemical-induced thyroid cancer in rodents has defined the key events that predispose to the development of rodent cancer and many of these will operate in humans under appropriate conditions, if they were exposed to high enough concentrations of the affecting chemicals. There are conditions however that, at the very least, would indicate significant quantitative differences in the sensitivity of humans to these effects, with rodents being considerably more sensitive to thyroid effects by virtue of differences in the biology, transport and control of thyroid hormones in these species as opposed to humans where turnover is appreciably lower and where serum transport of T4/T3 is different to that operating in rodents. There is heated debate around claimed qualitative differences between the rodent and human thyroid physiology, and significant reservations, both scientific and regulatory, still exist in terms of the potential neurodevelopmental consequences of low thyroid hormone levels at critical windows of time. In contrast, the situation for the chemical induction of thyroid cancer, through effects on thyroid hormone production and release, is less ambiguous with both theoretical, and actual data, showing clear dose-related thresholds for the key events predisposing to chemically induced thyroid cancer in rodents. In addition, qualitative differences in transport, and quantitative differences in half life, catabolism and turnover of thyroid hormones, exist that would not operate under normal situations in humans.

Juror Decision Making in Acquaintance and Marital Rape: The Influence of Clothing, Alcohol, and Preexisting Stereotypical Attitudes.

Stereotypical biases about women's roles in intimate relationships including their marital status and lifestyle choices such as clothing and alcohol use influence juror attributions of rape case defendant guilt, potentially reducing access to justice for victims. Across two mock-juror decision-making experiments, participants read identical fictitious sexual assault vignettes varying in intoxicated defendant-complainant relationship (married vs. acquaintance), accompanied by photographs of complainant clothing at the crime (body revealing vs. plain) and in court (smart vs. casual). Experiment 2 additionally described the defendant's alcohol consumption as either under or over the drink drive limit. Most participants delivered guilty verdicts (Experiment 1: 86.7%; Experiment 2: 75.5%), recommending mean prison sentences of 5.04 years in Experiment 1 (n = 218 students) and 4.33 years in Experiment 2 (n = 1,086 members of public). In Experiment 1, guilty verdict rates and sentences were significantly higher when the married-but not the acquaintance-complainant dressed smartly rather than casually in court. In Experiment 2, significantly more guilty verdicts were delivered by females (80.3%) than males (66.9%), while sentence lengths were longer in acquaintance (M = 4.52 years) than married conditions (M = 4.10). Significant interactions between defendant alcohol use and clothing choice of the married-but not the acquaintance complainant-at the crime also influenced sentencing decisions. Higher scores on additionally administered scales measuring rape myth acceptance and sexist attitudes, but not alcohol expectancies, predicted lenient sentencing decisions in both experiments. These findings highlight how "rape myths" concerning marriages drive juror decisions. Prosecuting lawyers should use these results to better challenge these attitudes in court. Internationally, rape is often unreported to the police, and married victims may be more willing to come forward if they believe unbiased access to justice is likely.

A comparison between MRI and CT in the assessment of primary tumour volume in mesothelioma.

INTRODUCTION: Primary tumour staging in Malignant Pleural Mesothelioma (MPM) using Computed Tomography (CT) imaging is confounded by perception errors reflecting low spatial resolution between tumour and adjacent structures. Augmentation using perfusion CT is constrained by radiation dosage. In this study, we evaluated an alternative tumour staging method using perfusion-tuned Magnetic Resonance Imaging (MRI). METHODS: Consecutive patients with suspected MPM were recruited to a prospective observational study. All had MRI (T1-weighted, isotropic, contrast-enhanced 3-Tesla perfusion imaging) and CT (contrast-enhanced) pre-biopsy. Patients diagnosed with MPM underwent MRI and CT volumetry, with readers blinded to clinical data. MRI volumetry was semi-automated, using signal intensity limits from perfusion studies to grow tumour regions within a pleural volume. A similar CT method was not possible, therefore all visible tumour was manually segmented. MRI and CT volumes were compared (agreement, correlation, analysis time, reproducibility) and associations with survival examined using Cox regression. RESULTS: 58 patients were recruited and had MRI before biopsy. 31/58 were diagnosed with MPM and these scans were used for volumetry. Mean (SD) MRI and CT volumes were 370 cm3 and 302 cm3, respectively. MRI volumes were larger (average bias 61.9 cm3 (SD 116), 95 % limits (-165.5 - 289 cm3), moderately correlated with CT (r = 0.56, p = 0.002) and independently associated with survival (HR 4.03 (95 % CI 1.5-11.55), p = 0.006). CT volumes were not associated with survival, took longer to compute than MRI volumes (mean (SD) 151 (19) v 14 (2) minutes, p=<0.0001) and were less reproducible (inter-observer ICC 0.72 for CT, 0.96 for MRI). CONCLUSIONS: MRI and CT generate different tumour volumes in MPM. In this study, MRI volumes were larger and were independently associated with survival. MRI volumetry was quicker and more reproducible than CT.

Inertial flow focusing: a case study in optimizing cellular trajectory through a microfluidic MEMS device for timing-critical applications.

Although microfluidic micro-electromechanical systems (MEMS) are well suited to investigate the effects of mechanical force on large populations of cells, their high-throughput capabilities cannot be fully leveraged without optimizing the experimental conditions of the fluid and particles flowing through them. Parameters such as flow velocity and particle size are known to affect the trajectories of particles in microfluidic systems and have been studied extensively, but the effects of temperature and buffer viscosity are not as well understood. In this paper, we explored the effects of these parameters on the timing of our own cell-impact device, the µHammer, by first tracking the velocity of polystyrene beads through the device and then visualizing the impact of these beads. Through these assays, we find that the timing of our device is sensitive to changes in the ratio of inertial forces to viscous forces that particles experience while traveling through the device. This sensitivity provides a set of parameters that can serve as a robust framework for optimizing device performance under various experimental conditions, without requiring extensive geometric redesigns. Using these tools, we were able to achieve an effective throughput over 360 beads/s with our device, demonstrating the potential of this framework to improve the consistency of microfluidic systems that rely on precise particle trajectories and timing.