Do mechanisms matter? Comparing cancer treatment strategies across mathematical models and outcome objectives.

When eradication is impossible, cancer treatment aims to delay the emergence of resistance while minimizing cancer burden and treatment. Adaptive therapies may achieve these aims, with success based on three assumptions: resistance is costly, sensitive cells compete with resistant cells, and therapy reduces the population of sensitive cells. We use a range of mathematical models and treatment strategies to investigate the tradeoff between controlling cell populations and delaying the emergence of resistance. These models extend game theoretic and competition models with four additional components: 1) an Allee effect where cell populations grow more slowly at low population sizes, 2) healthy cells that compete with cancer cells, 3) immune cells that suppress cancer cells, and 4) resource competition for a growth factor like androgen. In comparing maximum tolerable dose, intermittent treatment, and adaptive therapy strategies, no therapeutic choice robustly breaks the three-way tradeoff among the three therapeutic aims. Almost all models show a tight tradeoff between time to emergence of resistant cells and cancer cell burden, with intermittent and adaptive therapies following identical curves. For most models, some adaptive therapies delay overall tumor growth more than intermittent therapies, but at the cost of higher cell populations. The Allee effect breaks these relationships, with some adaptive therapies performing poorly due to their failure to treat sufficiently to drive populations below the threshold. When eradication is impossible, no treatment can simultaneously delay emergence of resistance, limit total cancer cell numbers, and minimize treatment. Simple mathematical models can play a role in designing the next generation of therapies that balance these competing objectives.

Infectious Disease Notification Practices in Victoria, 2016-17.

INTRODUCTION: Infectious disease surveillance in Victoria, Australia is based upon a legislated requirement for doctors and laboratories to notify suspected or diagnosed cases of specific conditions to the Department of Health and Human Services (DHHS). The department undertakes regular audits of notification practices in Victoria typically every two years. The objective of this particular audit was to describe notification practices in 2016 and 2017, assess the effect of enhanced surveillance programs (ESPs) on Indigenous status data completeness and provide a baseline assessment that can be used to monitor the impact of a recent legislative change to notification requirements for several of the notifiable diseases which came into effect on 1 September 2018. METHODS: Notified cases reported to DHHS between 1 January 2016 and 31 December 2017 which met the confirmed and probable national case definitions were analysed by year, notifier type (doctor-only, laboratory-only, or both) and condition category (urgent versus routine). For three notifiable conditions (gonococcal infection and hepatitis B and hepatitis C of unspecified duration) Indigenous status completeness was compared pre- and post ESP commencement. RESULTS: The number of notified cases in Victoria increased 50% from 76,904 in 2016 to 115,318 in 2017 with a 277% increase in notified influenza alone. Almost half of cases were notified by both laboratory and doctor. Indigenous status was more likely to be complete following the introduction of ESPs (relative risk, RR 1.36 (95%CI: 1.33 - 1.40) p>0 .001). DISCUSSION: DHHS Victoria experienced a 1.5-fold increase in notified cases in 2017 compared with 2016, which was almost entirely attributable to influenza. For three notifiable conditions which had ESPs introduced during this period, Indigenous status reporting significantly improved. Indigenous identifiers on pathology request forms and data linkage are both interventions which are being considered to improve Indigenous status reporting in Victoria.

US FDA's revised consumption factor for polystyrene used in food-contact applications.

US FDA's continual effort to evaluate the safety of food-contact materials includes periodically re-examining our established packaging factors, such as consumption and food-type distribution factors. The use of polystyrene in food-contact and disposable food-packaging applications has expanded and is expected to continue to increase in the future. Therefore, it is important to revise the polystyrene consumption factor to account for increases in consumer exposure to substances migrating from styrenic food packaging. The currently used consumption factor for polystyrene is 0.1, which is based on market data collected around 1980. US FDA has revised the polystyrene consumption factor utilizing three different sources of market data. Using consumption and population data, US FDA calculated a new consumption factor of 0.14 for polystyrene. This consumption factor has been further subdivided to allow for the refinement of exposure estimates for uses limited to specific subcategories of polystyrene packaging.

Preclinical characterization of 2-[3-[3-[(5-ethyl-4'-fluoro-2-hydroxy[1,1'-biphenyl]-4-yl)oxy]propoxy]-2-propylphenoxy]benzoic acid metabolism: in vitro species comparison and in vivo disposition in rats.

Assessment of the pharmacokinetics of [14C]2-[3-[3-[(5-ethyl-4'-fluoro-2-hydroxy[1,1'-biphenyl]-4-yl)oxy]propoxy]-2-propylphenoxy-]benzoic acid ([14C]LY293111), an experimental anti-cancer agent, suggested long-lived circulating metabolites in rats. In vivo metabolites of LY293111 were examined in plasma, bile, urine, and feces of Fischer 344 (F344) rats after oral administration of [14C]LY293111. Metabolites were profiled by high-performance liquid chromatography-radiochromatography, and identified by liquid chromatography (LC)/mass spectrometry and LC/NMR. The major in vivo metabolites of LY293111 identified in rats were phenolic (ether), acyl, and bisglucuronides of LY293111. Measurement of radioactivity in rat plasma confirmed that a fraction of LY293111-derived material was irreversibly bound to plasma protein and that this bound fraction increased over time. This was consistent with the observed disparity in half-lives between LY293111 and total radioactivity in rats and monkeys, and is likely due to covalent modification of proteins by the acyl glucuronide. In vitro metabolism of [14C]LY293111 in liver slices from CD-1 mice, F344 rats, rhesus and cynomolgus monkeys, and humans indicates that glucuronidation was the primary metabolic pathway in all species. The acyl glucuronide was the most prevalent radioactive peak (16% of total 14C) produced by F344 rat slices, whereas the ether glucuronide was the major metabolite in all other species (26-36% of total 14C). Several minor hydroxylated metabolites were detected in F344 rat slice extracts but were not observed in other species. The data presented suggest that covalent modification of proteins by LY293111 acyl glucuronide is possible in multiple species, although the relative reactivity of this metabolite appears to be low compared with those known to cause adverse drug reactions.

Children's use of phonology to infer grammatical class in vocabulary learning.

Prior studies of the relationship between phonological information and grammatical category assignment have focused on whether these relationships exist and whether people have learned them. This study investigates whether these relationships affect preschool children's vocabulary acquisition in a laboratory setting. Child participants learned 12 vocabulary words (6 nouns and 6 verbs) under three conditions, in which, (1) the syllable number/grammatical category relationship matched English, (2) the syllable number/grammatical category relationship was opposite to English, or (3) there was no relationship between syllable number and grammatical category. In the initial presentation of the words, children assumed that the novel words matched the pattern found in English. When the syllable number/grammatical category pattern matched that of English, the children learned more of the words. Phonological information also predicted error patterns. These results suggest that any account of vocabulary acquisition should consider the role of phonological information.

Facial expression of children receiving immunizations: a principal components analysis of the child facial coding system.

OBJECTIVE: To identify the structure of facial reaction to procedural pain and to determine the subset of facial actions that best describe the response. DESIGN: Observational. SETTING: Five rural and five urban physicians' offices. PATIENTS: One hundred twenty-three children aged 4 to 5 years undergoing routine diphtheria, pertussis, tetanus, and polio immunization. OUTCOME MEASURES: The Child Facial Coding System, comprising 13 discrete facial actions, was used to code each second of five 10-second phases from videotape: baseline, preneedle, needle, postneedle, and posthandling. Parents and a technician provided visual analog scale ratings of children's pain. Children provided a self-report using a Faces Pain Scale, and parents and nurses rated the children's pain and anxiety using visual analog scales. RESULTS: A "pain face" similar to that reported in adults emerged with the onset of pain. Principal component analyses revealed the frequency and intensity of facial action during the needle phase could be represented by components reflecting pain sensation, a "brave face," and the children's expectations for pain. Children's Faces Pain Scale and adult visual analog scale ratings were best predicted by components reflecting pain sensation and expectations of high pain. CONCLUSIONS: These results provide a preliminary indication that the Child Facial Coding System can be reduced to components that reflect several aspects of children's acute pain experience and predict self-reports and observer reports of children's pain.

A rat lung model of instilled liquid transport in the pulmonary airways.

When a liquid is instilled in the pulmonary airways during medical therapy, the method of instillation affects the liquid distribution throughout the lung. To investigate the fluid transport dynamics, exogenous surfactant (Survanta) mixed with a radiopaque tracer is instilled into tracheae of vertical, excised rat lungs (ventilation 40 breaths/min, 4 ml tidal volume). Two methods are compared: For case A, the liquid drains by gravity into the upper airways followed by inspiration; for case B, the liquid initially forms a plug in the trachea, followed by inspiration. Experiments are continuously recorded using a microfocal X-ray source and an image-intensifier, charge-coupled device image train. Video images recorded at 30 images/s are digitized and analyzed. Transport dynamics during the first few breaths are quantified statistically and follow trends for liquid plug propagation theory. A plug of liquid driven by forced air can reach alveolar regions within the first few breaths. Homogeneity of distribution measured at end inspiration for several breaths demonstrates that case B is twice as homogeneous as case A. The formation of a liquid plug in the trachea, before inspiration, is important in creating a more uniform liquid distribution throughout the lungs.

Reliability and validity of dyspnea sensory quality descriptors in heart failure patients treated in an emergency department.

BACKGROUND: Sensory qualities of dyspnea are known to differ by diagnosis. Less is known about whether sensory qualities vary with changes in health status in a given diagnosis. PURPOSE: The goal of this study was to evaluate the reliability, validity, and factor structure of dyspnea sensory quality descriptors in patients with heart failure (HF) treated in an emergency department (ED) and to investigate whether change in sensory quality influences HF patients to seek care in an ED. METHODS: HF patients (N = 57) treated in an ED were interviewed retrospectively. Open-ended characterizations of dyspnea at the time of the ED visit were analyzed qualitatively. A subset of subjects (n = 34) rated the intensity of 13 dyspnea descriptors (0 = not endorsed; 1= very mild; 10 = very severe) as the descriptors applied to the time at which they decided to come to the ED (Decision) and a week before the visit (Week Before). Descriptor ratings were analyzed for congruence with open-ended characterizations, endorsement frequency, internal consistency, factor structure, and correlations (by descriptor and within subjects) between the 2 time frames. RESULTS: Open-ended characterizations of dyspnea provided support for the content validity of most descriptors. Internal consistency of numerical ratings was high (alpha >0.90) in both recalled time frames. Factor analysis of descriptor ratings was unifactorial for Week Before, but suggested multiple sensory quality factors at Decision (suffocation, air hunger, effort/impedance, and, possibly, rate). Within-subject concordance and descriptor-by-descriptor correlations across time frames were mostly low, suggesting change in sensory quality from Week Before to Decision. Correlations in descriptor ratings were lowest among subjects who reported duration of dyspnea (as severe as at Decision) of 3 days or less. Subjects who recalled a duration of 6 days or more gave highly concordant ratings across both time frames. CONCLUSION: Sensory quality descriptor-based ratings were internally consistent and content valid. Low correlations in ratings of sensory quality for most subjects across recalled time frames suggest that change in sensory quality may be an aspect of perceived increases in dyspnea severity before an ED visit. Results require replication and extension with larger samples and other diagnoses.

Dyspnea duration, distress, and intensity in emergency department visits for heart failure.

BACKGROUND: Dyspnea is the most common symptom among patients with heart failure (HF) who present to the emergency department (ED), but it is not clear which dimensions of the symptom prompt ED visits, or whether dyspnea characteristics are related to visit disposition. PURPOSE: The goal of this study was to explore the influence of dyspnea duration, distress, and intensity on decisions of patients with HF to come to an ED and the disposition of visits. METHODS: The study population consisted of patients treated for HF in an urban university hospital ED (N = 57) who were interviewed retrospectively. Open-ended questions pertained to symptoms in general and dyspnea at the time of the visit. Subjects rated recalled dyspnea distress (0 = not at all bothered by breathing; 4 = bothered very much by breathing) for when they decided to come to the ED (Decision) and a week before the visit (Week Before), as well as duration--the number of days before the visit that dyspnea was recalled as having been as severe as at Decision. After the interviews, a subsample (n = 34) rated the intensity of a set of dyspnea sensory quality descriptors for Decision and Week Before (0 = not endorsed; 1 = very mild; 10 = very severe). Charts were also reviewed. RESULTS: Seventy percent recalled dyspnea as the most distressing symptom at Decision, or the primary reason for the visit; 88% were admitted. Dyspnea duration was unrelated to admission. Duration was 3 days or less for 65% of the sample, but 6 days or more for 35%. There was no duration-related difference in dyspnea distress or intensity at Decision, but subjects with a duration < or =3 days reported lower levels of both dimensions for Week Before with significant increases from Week Before to Decision. Those with longer episodes reported high levels of distress and intensity in both time frames with no significant change in either dimension. CONCLUSION: Subjects reported high levels of distress and intensity at Decision, regardless of dyspnea duration. Differences in recalled duration were associated with 2 distinct patterns in distress and intensity ratings but were not associated with admission. Dyspnea duration does not appear to be a valid criterion for judging condition severity in HF-related visits to the ED.

Characterization of 2-[[4-[[2-(1H-tetrazol-5-ylmethyl)phenyl]methoxy]methyl]quinoline N-glucuronidation by in vitro and in vivo approaches.

RG 12525 is a new chemical entity recently evaluated for the treatment of type II diabetes. Clinical studies have previously identified the tetrazole N2-glucuronide conjugate of RG 12525 as the predominant metabolite in plasma following oral administration of RG 12525. Species differences in RG 12525 glucuronidation were first investigated with incubations of RG 12525 with rat, monkey, and human hepatocytes. The results showed the N2-glucuronide to be the major metabolite in human and monkey samples, with only low levels observed for the rat. The formation of this glucuronide by human liver microsomes was subsequently characterized. RG 12525 N2-glucuronidation was found to have a pH optimum of 7.0 to 7.5 and demonstrated a high affinity with a K(m) range of 16.6 to 21.1 microM RG 12525 (n = 3). The rate of N2-glucuronide formation ranged from 2.5 to 15.4 nmol of RG 12525 N2-glucuronide formed/min/mg of protein ( approximately 6-fold) in the 21 samples assayed. The reaction was inhibited by known substrates for glucuronidation, with imipramine (62%), naringenin (44%), and scopoletin (38%) producing the largest degree of inhibition at equimolar concentrations of substrate and inhibitor. Of the eight expressed UDP-glucuronosyltransferase (UGT) forms assayed, UGT1A1 and 1A3 displayed the highest rate of RG 12525 N2-glucuronidation (0.109 and 0.125 nmol/min/mg, respectively). Finally, low levels of N2-glucuronidation of RG 12525 by human jejunum microsomes were demonstrated, suggesting that presystemic clearance via glucuronidation may constitute a barrier to bioavailability.

A randomized double-blind, placebo-controlled trial of the EMLA patch for the reduction of pain associated with intramuscular injection in four to six-year-old children.

UNLABELLED: The effectiveness of a eutectic mixture lidocaine-prilocaine topical anaesthetic cream (EMLA) patch compared with a placebo patch in the reduction of pain associated with intramuscular immunization was evaluated. As part of the study, 161 children (aged 4-6-y) undergoing routine diphtheria, pertussis, tetanus and polio (DPTP) immunization in five urban and five rural private office settings were randomly assigned to an EMLA patch (n = 83) or a placebo patch control group (n = 78). Pain measurements included: child's self-report on a Faces Pain Scale; facial action on the Child Facial Coding System; the Children's Hospital of Eastern Ontario Pain Scale and parent and technician ratings on a Visual Analogue Scale. Parents also rated their own and their child's immunization-related anxiety on a Visual Analogue Scale. The EMLA patch group had significantly less pain on all four pain measures compared with the placebo group. Of the children in the placebo group, 43% had clinically significant pain, compared with 17% of children in the EMLA patch group. No severe adverse symptoms occurred as a result of either EMLA or placebo patch application. CONCLUSION: The EMLA patch reduced immunization pain in 4 to 6-y-old children during needle injection.

Liquid plug flow in straight and bifurcating tubes.

A finite-length liquid plug may be present in an airway due to disease, airway closure, or by direct instillation for medical therapy. Air forced by ventilation propagates the plug through the airways, where it deposits fluid onto the airway walls. The plug may encounter single or bifurcating airways, an airway surface liquid, and other liquid plugs in nearby airways. In order to understand how these flow situations influence plug transport, benchtop experiments are performed for liquid plug flow in: Case (i) straight dry tubes, Case (ii) straight pre-wetted tubes, Case (iii) bifurcating dry tubes, and Case (iv) bifurcating tubes with a liquid blockage in one daughter. Data are obtainedfor the trailing film thickness and plug splitting ratio as a function of capillary number and plug volumes. For Case (i), the finite length plug in a dry tube has similar behavior to a semi-infinite plug. For Case (ii), the trailing film thickness is dependent upon the plug capillary number (Ca) and not the precursor film thickness, although the shortening or lengthening of the liquid plug is influenced by the precursor film. For Case (iii), the plug splits evenly between the two daughters and the deposited film thickness depends on the local plug Ca, except for a small discrepancy that may be due to an entrance effect or from curvature of the tubes. For Case (iv), a plug passing from the parent to daughters will deliver more liquid to the unblocked daughter (nearly double, consistently) and then the plug will then travel at greater Ca in the unblocked daughter as the blocked. The flow asymmetry is enhanced for a larger blockage volume and diminished for a larger parent plug volume and parent-Ca.

Quantitation of N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide and 4-amino-3,5-dichloropyridine in rat and mouse plasma by LC/MS/MS.

The metabolism of N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (RP73401), a phosphodiesterase IV (PDE IV) inhibitor is extensive (unpublished); however, until recently, studies for this compound did not report 4-amino-3,5-dichloropyridine (ADCP) as a metabolite either in vitro or in vivo. This prompted a reinvestigation into the metabolism of RP73401 in rats and mice using mass spectrometry. The results of the reinvestigation confirmed that 4-amino-3,5-dichloropyridine was formed via the metabolism of RP73401 both in vitro and in vivo. In order to further investigate RP73401 hydrolysis in vivo, a liquid chromatography/mass spectrometry assay was developed and validated for the simultaneous determination of RP73401 and ADCP in rat and mouse plasma. The method used Waters Oasis HLB brand solid phase extraction cartridges to isolate the analytes (RP73401 and ADCP) and internal standard from the plasma. HPLC chromatographic separation was achieved using a Zorbax SB C18 HPLC column and detection was accomplished using positive ion atmospheric pressure chemical ionization tandem mass spectroscopy in multiple reaction monitoring (MRM) mode. The assay was developed and validated over the range of 0.5-100 ng ml(-1) for RP73401 and 5-500 ng ml(-1) for ADCP using 0.050 ml of plasma. The assay proved to be sensitive, accurate, precise and specific for RP73401 and ADCP. Intraday and interday quality control results routinely showed accuracy and precision to be within +/- 20%. This LC/MS/MS method was subsequently employed to investigate the hydrolysis of RP73401 in the rat and mouse, and determine the effects of tri-o-tolyl phosphate (TOTP, a carboxylesterase inhibitor) preadministration on the hydrolysis reaction in the rat.

Surfactant effects in model airway closure experiments.

The capillary instability that occurs on an annular film lining a tube is studied as a model of airway closure. Small waves in the film can amplify and form a plug across the tube. This dynamical behavior is studied using theoretical models and bench-top experiments. Our model predicts the initial growth rate of the instability and its dependence on surfactant effects. In experiments, an annular film is formed by infusion of water into an initially oil-filled glass capillary tube. The thickness of the oil film varies with the infusion flow rate. The instability growth rate and closure time are measured for a range of film thicknesses. Our theory predicts that a thinner film and higher surfactant activity enhance stability; surfactant can decrease the growth rate to 25% of its surfactant-free value. In experiments, we find that surfactant can decrease the growth rate to 20% and increase the closure time by a factor of 3.8. Functional values of a critical film thickness for closure support the theory that it increases in the presence of surfactant.

How to assess and intervene in domestic violence situations.

The increasing incidence of domestic violence in America requires home care nurses to have a broad understanding of the problem. This article outlines the extent of domestic violent and lists specific ways in which nurses can integrate screening for domestic violence into routine assessments. Specific interventions and a comprehensive resource guide are provided.

Genetic influence on dental arch form in orthodontic patients.

Human arch form varies considerably. This study analyzed the size and shape of the maxillary and mandibular dental arches of 320 adolescents from 155 sibships. A broad battery of measurements (k = 48) was computer-generated from Cartesian coordinates of cusp tips and line angles of the permanent teeth, and heritability estimates were generated from intraclass correlations, controlling for sex and age where indicated. Arch size has a modest genetic component, on the order of 50%, although this estimate may contain shared environmental influences. Tooth rotations have low h2 estimates, most of them indistinguishable from zero. Arch shape, assessed as length-width ratios, also has a modest transmissible component, suggesting that arch length and width growth factors are largely independent. Highest heritability estimates, as a group, were for transverse arch widths, which averaged about 60%. Several measures of left-right asymmetry also were analyzed (k = 31), and, while the arches are systematically asymmetric (generally with left > right), there is only weak evidence of a transmissible component for directional asymmetry and essentially none for fluctuating asymmetry. In all, arch size and shape are seen to be more subject to environmental influences than to heredity. These findings direct attention toward the need to better understand what extrinsic factors modulate arch size and shape during development.

Three- and four-year-old children's ability to use desire- and belief-based reasoning.

Recently, several researchers have claimed that young 3-year-old children rely on desire when making behavioral predictions and that this causes poor performance on standard measures of false-belief understanding. This study investigates this claim. Results suggest that young children may, in fact, be using desire to predict behavior in these standard paradigms. Importantly, it is the desires of the agent, not the child's own desires that are used to make the prediction. Further, older preschool children also have some difficulty coordinating both belief and desire when processing demands are increased.

Preschoolers' use of desires to solve theory of mind problems in a pretense context.

K. Bartsch and H. M. Wellman (1995) have suggested that 3-year-old children's preference to construe behavior in terms of desire may interfere with their ability to reason according to belief in standard false belief tasks. Other researchers have suggested that young children fail typical measures of theory of mind because they have a reality bias (e.g., P. Mitchell, 1994). Study 1 demonstrates that even young children are able to correctly attribute a false belief to an agent when that belief is about the status of a pretense. Study 2 shows that children find it easier to attribute a false belief when the desires of the agent are eliminated. However, Study 3 suggests that a reality bias also influences children's ability to consider beliefs. Implications for recent accounts of theory of mind development are discussed.

Immunogenic and protective response in mice immunized with a purified, inactivated, Dengue-2 virus vaccine prototype made in fetal rhesus lung cells.

The feasibility of a purified, inactivated vaccine (PIV) against dengue type 2 (DEN-2) virus was explored. Dengue-2 virus strain 16681 was used for producing a monotypic PIV. Virus adapted to fetal rhesus lung (FRhL-2) cells was harvested from roller bottle culture supernatant fluids, concentrated, and purified on sucrose gradients. Analysis of purified virus preparations by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting showed primarily envelope (E) and premembrane (prM) antigens. These preparations had a purity, estimated from silver-stained gels, of approximately 70%, and a yield, based on recovery of virus and viral antigen, of 10-20%. The purified virus was inactivated with 0.05% formalin at 22 degrees C, or alternatively, with 7 mRads from a 60Co source. Vaccinated mice developed high titers of anti-DEN-2 virus neutralizing antibody and were partially protected from virus challenge. These results warrant further testing and development of PIVs for the other DEN virus serotypes.

"Sucrose analgesia" and diphtheria-tetanus-pertussis immunizations at 2 and 4 months.

In human newborns, small amounts of sucrose reduce crying with procedural pain by about 50%. To determine whether "sucrose analgesia" could be extended to painful procedures beyond the newborn period, 57 infants were randomly assigned to receive three 250-microliters doses of 50% sucrose solution (g/100 mL) or water before their diphtheria-tetanus-pertussis immunizations at 2 and 4 months of age. Crying during and after injection was measured separately to determine whether sucrose modified crying during the noxious stimulus, recovery from the stimulus, or both. Sucrose was effective in reducing crying only from 83 to 69%, and the reduction was limited to the postinjection period. We conclude that, although sucrose continues to have some effect beyond the newborn period, the effect is limited to recovery from the noxious stimulus, is clinically modest, and is probably smaller than in the newborn period.