Pragmatic considerations for negative control outcome studies to guide non-randomized comparative analyses: A narrative review.

PURPOSE: This narrative review describes the application of negative control outcome (NCO) methods to assess potential bias due to unmeasured or mismeasured confounders in non-randomized comparisons of drug effectiveness and safety. An NCO is assumed to have no causal relationship with a treatment under study while subject to the same confounding structure as the treatment and outcome of interest; an association between treatment and NCO then reflects the potential for uncontrolled confounding between treatment and outcome. METHODS: We focus on two recently completed NCO studies that assessed the comparability of outcome risk for patients initiating different osteoporosis medications and lipid-lowering therapies, illustrating several ways in which confounding may result. In these studies, NCO methods were implemented in claims-based data sources, with the results used to guide the decision to proceed with comparative effectiveness or safety analyses. RESULTS: Based on this research, we provide recommendations for future NCO studies, including considerations for the identification of confounding mechanisms in the target patient population, the selection of NCOs expected to satisfy required assumptions, the interpretation of NCO effect estimates, and the mitigation of uncontrolled confounding detected in NCO analyses. We propose the use of NCO studies prior to initiating comparative effectiveness or safety research, providing information on the potential presence of uncontrolled confounding in those comparative analyses. CONCLUSIONS: Given the increasing use of non-randomized designs for regulatory decision-making, the application of NCO methods will strengthen study design, analysis, and interpretation of real-world data and the credibility of the resulting real-world evidence.

Controlled Infection of Humans with the Hookworm Parasite Necator americanus to Accelerate Vaccine Development : The Human Hookworm Vaccination/Challenge Model (HVCM).

In this chapter, we describe the scientific, technical, clinical and regulatory aspects of establishing a controlled human hookworm infection (CHHI) model in non-endemic and endemic geographical regions, to facilitate a pathway towards accelerated vaccine development. The success achieved in establishing the CHHI platform specifically allows the Human Hookworm Vaccine Initiative (HHVI) to accelerate its progress by establishing a human hookworm vaccination/challenge model (HVCM) in a hookworm endemic area of Brazil. The HVCM will permit the rapid and robust determination of clinical efficacy in adults, allowing for early selection of the most efficacious human hookworm vaccine (HHV) candidate(s) to advance into later-stage pivotal paediatric clinical trials and reduce the overall number of participants required to assess efficacy (Diemert et al. 2018).

Towards Quantifying the Uncertainty in Estimating Observed Scaling Rates.

Short-duration precipitation extremes (PE) increase at a rate of around 7%/K explained by the Clausius-Clapeyron relationship. Previous studies show uncertainty in the extreme precipitation-temperature relationship (scaling) due to various thermodynamic/dynamic factors. Here, we show that uncertainty may arise from the choice of data and methods. Using hourly precipitation (PPT) and daily dewpoint temperature (DPT) across 2,905 locations over the United States, we found higher scaling for quality-controlled data, all locations showing positive (median 6.2%/K) scaling, as compared to raw data showing positive (median 5.3%/K) scaling over 97.5% of locations. We found higher scaling for higher measurement precision of PPT (0.25 mm: median 7.8%/K; 2.54 mm: median 6.6%/K). The method that removes seasonality in PPT and DPT gives higher (with seasonality: median 6.2%/K; without seasonality: median 7.2%/K) scaling. Our results demonstrate the importance of quality-controlled, high-precision observations and robust methods in estimating accurate scaling for a better understanding of PE change with warming.

Experimental infection with the hookworm, Necator americanus, is associated with stable gut microbial diversity in human volunteers with relapsing multiple sclerosis.

BACKGROUND: Helminth-associated changes in gut microbiota composition have been hypothesised to contribute to the immune-suppressive properties of parasitic worms. Multiple sclerosis is an immune-mediated autoimmune disease of the central nervous system whose pathophysiology has been linked to imbalances in gut microbial communities. RESULTS: In the present study, we investigated, for the first time, qualitative and quantitative changes in the faecal bacterial composition of human volunteers with remitting multiple sclerosis (RMS) prior to and following experimental infection with the human hookworm, Necator americanus (N+), and following anthelmintic treatment, and compared the findings with data obtained from a cohort of RMS patients subjected to placebo treatment (PBO). Bacterial 16S rRNA high-throughput sequencing data revealed significantly decreased alpha diversity in the faecal microbiota of PBO compared to N+ subjects over the course of the trial; additionally, we observed significant differences in the abundances of several bacterial taxa with putative immune-modulatory functions between study cohorts. Parabacteroides were significantly expanded in the faecal microbiota of N+ individuals for which no clinical and/or radiological relapses were recorded at the end of the trial. CONCLUSIONS: Overall, our data lend support to the hypothesis of a contributory role of parasite-associated alterations in gut microbial composition to the immune-modulatory properties of hookworm parasites.

The significance of building behavior in the evolution of animal architecture.

Animals make a diverse array of architectures including nests, bowers, roosts, traps, and tools. Much of the research into animal architecture has focused on the analysis of physical properties such as the dimensions and material of the architectures, rather than the behavior responsible for creating these architectures. However, the relationship between the architecture itself and the construction behavior that built it is not straightforward, and overlooking behavior risks obtaining an incomplete or even misleading picture of how animal architecture evolves. Here we review data about animal architectures broadly, with a particular focus on building by birds and social insects. We then highlight three ways in which a better understanding of building behavior could benefit the study of animal architecture: by clarifying how behavior leads to physical properties; by examining the costs and benefits of building behavior; and by determining the role of learning and how this interacts with selection on behavior. To integrate questions about building behavior alongside those about architectures, we propose a framework inspired by Niko Tinbergen's four questions, examining the mechanistic, ontogenetic, phylogenetic, and functional basis of animal building. By integrating the study of behavior and architecture across levels of analysis, we can gain a more holistic view of the behavior-architecture interactions, and a better understanding of how behavior, cognition, and evolution interact to produce the diversity seen in animal architecture.

Appearance of peanut agglutinin in the blood circulation after peanut ingestion promotes endothelial secretion of metastasis-promoting cytokines.

Peanut agglutinin (PNA) is a carbohydrate-binding protein in peanuts that accounts for ~0.15% peanut weight. PNA is highly resistant to cooking and digestion and is rapidly detectable in the blood after peanut consumption. Our previous studies have shown that circulating PNA mimics the actions of endogenous galactoside-binding protein galectin-3 by interaction with tumour cell-associated MUC1 and promotes circulating tumour cell metastatic spreading. The present study shows that circulating PNA interacts with micro- as well as macro-vascular endothelial cells and induces endothelial secretion of cytokines MCP-1 (CCL2) and IL-6 in vitro and in vivo. The increased secretion of these cytokines autocrinely/paracrinely enhances the expression of endothelial cell surface adhesion molecules including integrins, VCAM and selectin, leading to increased tumour cell-endothelial adhesion and endothelial tubule formation. Binding of PNA to endothelial surface MCAM (CD146), via N-linked glycans, and subsequent activation of PI3K-AKT-PREAS40 signalling is here shown responsible for PNA-induced secretion of MCP-1 and IL-6 by vascular endothelium. Thus, in addition to its influence on promoting tumour cell spreading by interaction with tumour cell-associated MUC1, circulating PNA might also influence metastasis by enhancing the secretion of metastasis-promoting MCP-1 and IL-6 from the vascular endothelium.

The evolution of IgE-mediated type I hypersensitivity and its immunological value.

The allergic phenotype manifests itself in a spectrum of troublesome to life-threatening diseases, from seasonal hay fever, through the food allergies, atopic eczema, asthma, to anaphylaxis. Allergy, that is an overreaction to allergen in hypersensitive individuals, results from the production of IgE, mast cell and basophil sensitisation and degranulation, requiring a range of medications to manage the conditions. Yet it is highly likely that allergy evolved for a purpose and that allergic diseases are accidental consequences of an insufficiently regulated immune response. This article presents a viewpoint from which to restore the immunological reputation of the allergic phenotype. We consider the evolutionary origins of potential allergens, toxins and parasites, and how they might have influenced early-mammal species in existence when IgE first developed. We conclude that the allergic phenotype has likely saved the lives of many more mammals than have ever died from allergy, so justifying the positive role of IgE in our evolution.

Towards advancing scientific knowledge of climate change impacts on short-duration rainfall extremes.

A large number of recent studies have aimed at understanding short-duration rainfall extremes, due to their impacts on flash floods, landslides and debris flows and potential for these to worsen with global warming. This has been led in a concerted international effort by the INTENSE Crosscutting Project of the GEWEX (Global Energy and Water Exchanges) Hydroclimatology Panel. Here, we summarize the main findings so far and suggest future directions for research, including: the benefits of convection-permitting climate modelling; towards understanding mechanisms of change; the usefulness of temperature-scaling relations; towards detecting and attributing extreme rainfall change; and the need for international coordination and collaboration. Evidence suggests that the intensity of long-duration (1 day+) heavy precipitation increases with climate warming close to the Clausius-Clapeyron (CC) rate (6-7% K-1), although large-scale circulation changes affect this response regionally. However, rare events can scale at higher rates, and localized heavy short-duration (hourly and sub-hourly) intensities can respond more strongly (e.g. 2 × CC instead of CC). Day-to-day scaling of short-duration intensities supports a higher scaling, with mechanisms proposed for this related to local-scale dynamics of convective storms, but its relevance to climate change is not clear. Uncertainty in changes to precipitation extremes remains and is influenced by many factors, including large-scale circulation, convective storm dynamics andstratification. Despite this, recent research has increased confidence in both the detectability and understanding of changes in various aspects of intense short-duration rainfall. To make further progress, the international coordination of datasets, model experiments and evaluations will be required, with consistent and standardized comparison methods and metrics, and recommendations are made for these frameworks. This article is part of a discussion meeting issue 'Intensification of short-duration rainfall extremes and implications for flash flood risks'.

Gastric metastasis before diagnosis of primary invasive lobular breast carcinoma: a rare case presentation from Pakistan.

Metastatic spread of invasive lobular breast carcinoma to stomach is rare especially before diagnosis of primary breast cancer. Incorrect diagnosis might result in delay of appropriate treatment for breast cancer. Recognition of this possibility enables better clinical management. A 62-year-old female presented with upper gastrointestinal symptoms and weight loss and was referred to a gastroenterologist for investigation. At the time of initial diagnosis of stomach cancer, patient was asymptomatic for breast cancer. Multiple gastric biopsies taken showed features suspicious of metastatic breast cancer. Consequently, the initial provisional diagnosis of stomach cancer changed into metastatic invasive lobular breast carcinoma. These findings were corroborated radiologically. The patient was treated with letrozole and zoledronic acid as first-line therapy for one year. Residual metastatic breast cancer was present in the gastric mucosa. The patient was treated with endocrine therapy containing ribociclib and treatment was ineffective confirmed by PET-CT scan. But her symptoms have resolved completely despite her presentation with stage IV. We present rare case of initial presentation of gastric metastasis before diagnosis of a primary invasive lobular breast carcinoma. Correct diagnosis and appropriate treatment were accomplished through initial clinical suspicion, accurate histological examination, and endoscopy together with analysis of disease-specific biomarkers.

Long-Term Iron Deficiency and Dietary Iron Excess Exacerbate Acute Dextran Sodium Sulphate-Induced Colitis and Are Associated with Significant Dysbiosis.

BACKGROUND: Oral iron supplementation causes gastrointestinal side effects. Short-term alterations in dietary iron exacerbate inflammation and alter the gut microbiota, in murine models of colitis. Patients typically take supplements for months. We investigated the impact of long-term changes in dietary iron on colitis and the microbiome in mice. METHODS: We fed mice chow containing differing levels of iron, reflecting deficient (100 ppm), normal (200 ppm), and supplemented (400 ppm) intake for up to 9 weeks, both in absence and presence of dextran sodium sulphate (DSS)-induced chronic colitis. We also induced acute colitis in mice taking these diets for 8 weeks. Impact was assessed (i) clinically and histologically, and (ii) by sequencing the V4 region of 16S rRNA. RESULTS: In mice with long-term changes, the iron-deficient diet was associated with greater weight loss and histological inflammation in the acute colitis model. Chronic colitis was not influenced by altering dietary iron however there was a change in the microbiome in DSS-treated mice consuming 100 ppm and 400 ppm iron diets, and control mice consuming the 400 ppm iron diet. Proteobacteria levels increased significantly, and Bacteroidetes levels decreased, in the 400 ppm iron DSS group at day-63 compared to baseline. CONCLUSIONS: Long-term dietary iron alterations affect gut microbiota signatures but do not exacerbate chronic colitis, however acute colitis is exacerbated by such dietary changes. More work is needed to understand the impact of iron supplementation on IBD. The change in the microbiome, in patients with colitis, may arise from the increased luminal iron and not simply from colitis.

Floral vibrations by buzz-pollinating bees achieve higher frequency, velocity and acceleration than flight and defence vibrations.

Vibrations play an important role in insect behaviour. In bees, vibrations are used in a variety of contexts including communication, as a warning signal to deter predators and during pollen foraging. However, little is known about how the biomechanical properties of bee vibrations vary across multiple behaviours within a species. In this study, we compared the properties of vibrations produced by Bombus terrestris audax (Hymenoptera: Apidae) workers in three contexts: during flight, during defensive buzzing, and in floral vibrations produced during pollen foraging on two buzz-pollinated plants (Solanum, Solanaceae). Using laser vibrometry, we were able to obtain contactless measures of both the frequency and amplitude of the thoracic vibrations of bees across the three behaviours. Despite all three types of vibrations being produced by the same power flight muscles, we found clear differences in the mechanical properties of the vibrations produced in different contexts. Both floral and defensive buzzes had higher frequency and amplitude velocity, acceleration and displacement than the vibrations produced during flight. Floral vibrations had the highest frequency, amplitude velocity and acceleration of all the behaviours studied. Vibration amplitude, and in particular acceleration, of floral vibrations has been suggested as the key property for removing pollen from buzz-pollinated anthers. By increasing frequency and amplitude velocity and acceleration of their vibrations during vibratory pollen collection, foraging bees may be able to maximise pollen removal from flowers, although their foraging decisions are likely to be influenced by the presumably high cost of producing floral vibrations.

Diagnostic test interpretation and referral delay in patients with interstitial lung disease.

BACKGROUND: Diagnostic delays are common in patients with interstitial lung disease (ILD). A substantial percentage of patients experience a diagnostic delay in the primary care setting, but the factors underpinning this observation remain unclear. In this multi-center investigation, we assessed ILD reporting on diagnostic test interpretation and its association with subsequent pulmonology referral by a primary care physician (PCP). METHODS: A retrospective cohort analysis of patients referred to the ILD programs at UC-Davis and University of Chicago by a PCP within each institution was performed. Computed tomography (CT) of the chest and abdomen and pulmonary function test (PFT) were reviewed to identify the date ILD features were first present and determine the time from diagnostic test to pulmonology referral. The association between ILD reporting on diagnostic test interpretation and pulmonology referral was assessed, as was the association between years of diagnostic delay and changes in fibrotic features on longitudinal chest CT. RESULTS: One hundred and forty-six patients were included in the final analysis. Prior to pulmonology referral, 66% (n = 97) of patients underwent chest CT, 15% (n = 21) underwent PFT and 15% (n = 21) underwent abdominal CT. ILD features were reported on 84, 62 and 33% of chest CT, PFT and abdominal CT interpretations, respectively. ILD reporting was associated with shorter time to pulmonology referral when undergoing chest CT (1.3 vs 15.1 months, respectively; p = 0.02), but not PFT or abdominal CT. ILD reporting was associated with increased likelihood of pulmonology referral within 6 months of diagnostic test when undergoing chest CT (rate ratio 2.17, 95% CI 1.03-4.56; p = 0.04), but not PFT or abdominal CT. Each year of diagnostic delay was associated with a 1.8% increase in percent fibrosis on chest CT. Patients with documented dyspnea had shorter time to chest CT acquisition and pulmonology referral than patients with documented cough and lung crackles. CONCLUSIONS: Determinants of ILD diagnostic delays in the primary care setting include underreporting of ILD features on diagnostic testing and prolonged time to pulmonology referral even when ILD is reported. Interventions to modulate these factors may reduce ILD diagnostic delays in the primary care setting.

Haematophagic Caenorhabditis elegans.

Caenorhabditis elegans is a free-living nematode that resides in soil and typically feeds on bacteria. We postulate that haematophagic C. elegans could provide a model to evaluate vaccine responses to intestinal proteins from hematophagous nematode parasites, such as Necator americanus. Human erythrocytes, fluorescently labelled with tetramethylrhodamine succinimidyl ester, demonstrated a stable bright emission and facilitated visualization of feeding events with fluorescent microscopy. C. elegans were observed feeding on erythrocytes and were shown to rupture red blood cells upon capture to release and ingest their contents. In addition, C. elegans survived equally on a diet of erythrocytes. There was no statistically significant difference in survival when compared with a diet of Escherichia coli OP50. The enzymes responsible for the digestion and detoxification of haem and haemoglobin, which are key components of the hookworm vaccine, were found in the C. elegans intestine. These findings support our postulate that free-living nematodes could provide a model for the assessment of neutralizing antibodies to current and future hematophagous parasite vaccine candidates.

What is the optimal treatment time for larval therapy? A study on incubation time and tissue debridement by bagged maggots of the greenbottle fly, Lucilia sericata.

The effective use of larvae of the greenbottle fly, Lucilia sericata, in wound debridement requires a working knowledge of how feeding changes over time. Using a laboratory assay and bagged larval dressings, the effect of incubation time on larval feeding rates and body mass was investigated for up to 120 hours at 32°C. The mass of tissue digested increased significantly in incremental 24-hour periods up to 72 hours, with no significant consumption occurring afterwards. Larval mass increased only up to 48 hours. A further test comparing the efficacy of a single 96-hour application of larvae against two consecutive 48-hour applications found that the mass of tissue digested in the latter was 14.3% higher than the former, a difference that was statistically significant. Current clinical guidance suggests a 4-day application period for bagged larvae. Based on these results, an incubation time of 72 hours (3 days) for bagged larvae would be the most effective at the study temperature. However, it is acknowledged that wound temperature can vary, whereby feeding rates would likely differ. In view of this, we conclude that a period of 3 to 4 days is optimum for the application of larvae, and current guidelines should be adhered to.

Taking an insect-inspired approach to bird navigation.

Navigation is an essential skill for many animals, and understanding how animal use environmental information, particularly visual information, to navigate has a long history in both ethology and psychology. In birds, the dominant approach for investigating navigation at small-scales comes from comparative psychology, which emphasizes the cognitive representations underpinning spatial memory. The majority of this work is based in the laboratory and it is unclear whether this context itself affects the information that birds learn and use when they search for a location. Data from hummingbirds suggests that birds in the wild might use visual information in quite a different manner. To reconcile these differences, here we propose a new approach to avian navigation, inspired by the sensory-driven study of navigation in insects. Using methods devised for studying the navigation of insects, it is possible to quantify the visual information available to navigating birds, and then to determine how this information influences those birds' navigation decisions. Focusing on four areas that we consider characteristic of the insect navigation perspective, we discuss how this approach has shone light on the information insects use to navigate, and assess the prospects of taking a similar approach with birds. Although birds and insects differ in many ways, there is nothing in the insect-inspired approach of the kind we describe that means these methods need be restricted to insects. On the contrary, adopting such an approach could provide a fresh perspective on the well-studied question of how birds navigate through a variety of environments.

Associations between acculturation, ethnic identity, and diet quality among U.S. Hispanic/Latino Youth: Findings from the HCHS/SOL Youth Study.

BACKGROUND: Acculturation among Hispanic/Latinos has been linked to deteriorating dietary quality that may contribute to obesity risks. This study examined the relationship between acculturation, ethnic identity, and dietary quality in U.S. Hispanic/Latino youth. METHODS: This cross-sectional study included 1298 Hispanic/Latino youth ages 8-16 from the Hispanic Community Health Study/Study of Latino Youth (HCHS/SOL Youth), an ancillary study of offspring of participants in the adult HCHS/SOL cohort. Multivariable regression analyses assessed relationships between acculturation and ethnic identity with dietary quality as measured by Healthy Eating Index (HEI) scores, accounting for covariates, design effects, and sample weights. We also compared HEI scores by immigrant generation and language of interview. RESULTS: Youth were 12 ±â€¯2.5 -years and 49.3% female. They were placed into five acculturation categories-including 48% integrated (bicultural orientation), 32.7% assimilated (high U.S. and low Latino orientation), 5.9% separated (high Latino and low U.S. orientation) or marginalized (neither U.S. nor Latino orientation), and 13.3% unclassified. Mean HEI was 53.8; there were no differences in HEI scores by acculturation category, but integrated youth had higher whole grains scores, lower sodium scores, and lower empty calories scores compared to assimilated youth. There were no differences in HEI scores by ethnic identity scores, and no consistent trend between dietary quality and ethnic identity. First- and second-generation youth had higher HEI scores, compared to third-generation youth, and, Spanish-speaking youth had higher HEI scores compared to English-speaking youth. CONCLUSION: Results suggest that integrated youth in the U.S. may engage in healthier eating behaviors than those who are assimilated. Additional research on Hispanic/Latino youths' acculturation and diet can inform health promotion efforts to improve eating habits and health outcomes among this population.

Experience with integrating pharmacist documenters on cardiac arrest teams to improve quality.

OBJECTIVES: To determine if adding a clinical pharmacist to the cardiac arrest team in a documenter role improves completeness of documentation and quality of advanced cardiovascular life support (ACLS). SETTING: A 1541-bed, tertiary care, academic medical center with an integrated clinical pharmacy practice model. PRACTICE DESCRIPTION: In 2012, we identified documentation of resuscitation activities during cardiac arrest events and compliance with published ACLS guidelines as opportunities for systematic quality improvement at our tertiary care academic medical center. Although clinical pharmacists provided pharmacotherapy support through active participation on multidisciplinary patient care rounds, pharmacists were not routinely accountable for care provided during cardiac arrest events. PRACTICE INNOVATION: We integrated pharmacists on the cardiac arrest team in the unique role of documenter and pharmacotherapy consultant. The pharmacist documenter was responsible for recording all activities (e.g., medication administered, endotracheal intubation, vital signs), providing real-time quality assurance during the event, and assisting with any clinical or operational needs of the team. Participating pharmacists received didactic lectures, practical assessments, and a written examination to ensure baseline competency in ACLS and teamwork principles. EVALUATION: Using a before-and-after study design, we conducted a retrospective chart review to evaluate our pilot program. All cardiac arrest events requiring activation of the cardiac arrest team from January 2012 through December 2013 were included (n = 80). RESULTS: Pharmacists attended all cardiac arrest team events in the postintervention period during the scheduled coverage hours. The percentage of forms with all documentation components complete increased from 0% at baseline to 28% postintervention (P = 0.002). ACLS compliance also increased from 8% preintervention to 31% postintervention (P = 0.024). CONCLUSION: Implementation of a dedicated pharmacist for documentation and pharmacotherapy consultation during cardiac arrest events is associated with improved documentation completeness and ACLS compliance. This was achieved without funding or additional pharmacist resources.

The "PepSAVI-MS" Pipeline for Natural Product Bioactive Peptide Discovery.

The recent increase in extensively drug-resistant bacterial pathogens and the associated increase of morbidity and mortality demonstrate the immediate need for new antibiotic backbones with novel mechanisms of action. Here, we report the development of the PepSAVI-MS pipeline for bioactive peptide discovery. This highly versatile platform employs mass spectrometry and statistics to identify bioactive peptide targets from complex biological samples. We validate the use of this platform through the successful identification of known bioactive peptides from a botanical species, Viola odorata. Using this pipeline, we have widened the known antimicrobial spectrum for V. odorata cyclotides, including antibacterial activity of cycloviolacin O2 against A. baumannii. We further demonstrate the broad applicability of the platform through the identification of novel anticancer activities for cycloviolacins by their cytotoxicity against ovarian, breast, and prostate cancer cell lines.

Delirium in Hospitalized Children with Cancer: Incidence and Associated Risk Factors.

OBJECTIVE: To assess the incidence of delirium and its risk factors in hospitalized children with cancer. STUDY DESIGN: In this cohort study, all consecutive admissions to a pediatric cancer service over a 3-month period were prospectively screened for delirium twice daily throughout their hospitalization. Demographic and treatment-related data were collected from the medical record after discharge. RESULTS: A total of 319 consecutive admissions, including 186 patients and 2731 hospital days, were included. Delirium was diagnosed in 35 patients, for an incidence of 18.8%. Risk factors independently associated with the development of delirium included age <5 years (OR = 2.6, P = .026), brain tumor (OR = 4.7, P = .026); postoperative status (OR = 3.3, P = .014), and receipt of benzodiazepines (OR = 3.7,P < .001). Delirium was associated with increased hospital length of stay, with median length of stay for delirious patients of 10 days compared with 5 days for patients who were not delirious during their hospitalization (P < .001). CONCLUSIONS: In this cohort, delirium was a frequent complication during admissions for childhood cancer, and was associated with increased hospital length of stay. Multi-institutional prospective studies are warranted to further characterize delirium in this high-risk population and identify modifiable risk factors to improve the care provided to hospitalized children with cancer.

Endotoxin testing of a wound debridement device containing medicinal Lucilia sericata larvae.

Alimentary products of medicinal Lucilia sericata larvae are studied to determine their mechanisms of action, particularly in the contexts of wound debridement and disinfection. Furthermore, the larvae can be applied to patients in contained medical devices (such as the BioBag; BioMonde). Here, we tested the materials and larval content of the most commonly used debridement device (the "BB-50") to explore the possibility that endotoxins may be contributing to the bio-activity of the product, given that endotoxins are potent stimulants of cellular activation. Using standardised protocols to collect larval alimentary products (LAP), we proceeded to determine residual endotoxin levels in LAP derived from the device, before and after the neutralisation of interfering enzymatic activity. The debridement device and its associated larval content was not a significant source of lipopolysaccharide (LPS) activity. However, it is clear from these experiments that a failure to remove the confounding serine proteinase activity would have resulted in spuriously high and erroneous results. The residual LPS levels detected are unlikely to be active in wound healing assays, following cross-referencing to publications where LPS at much higher levels has been shown to have positive and negative effects on processes associated with wound repair and tissue regeneration.