Integrated Exposure-Response of Dupilumab in Children, Adolescents, and Adults With Atopic Dermatitis Using Categorical and Continuous Efficacy Assessments: A Population Analysis.

BACKGROUND: While the majority of patients with atopic dermatitis (AD) achieve disease control with dupilumab treatment, there is variability in which patients achieve clear disease. The predictors of these responses are currently unclear. Integrated models were developed to evaluate the exposure-response (E-R) relationship of dupilumab in children, adolescents, and adults with AD. METHODS: Data from six Phase II and III clinical studies were pooled (2,366 adults [> 18 years], 243 adolescents [≥ 12 to < 18 years] and 359 children [≥ 6 to < 12 years]) for model development. Efficacy was assessed using the Eczema Area and Severity Index (EASI) and Investigator's Global Assessment (IGA). Indirect response models were applied to link measures of efficacy and functional serum dupilumab concentrations. The covariates on individual placebo-corrected response were assessed. Clinical trial scenarios were simulated to compare E-R relationships across age groups. Safety was not explored. RESULTS: After correcting for differences in placebo response and dupilumab exposure: 1) older age, higher body weight, lower baseline thymus and activation-regulated chemokine, and Asian race were associated with slightly lower EASI response, and no clear covariates were identified on IGA response; 2) clinical trial simulations generally showed slightly higher response at a given dupilumab concentration in children compared to adults and adolescents with severe and moderate AD. CONCLUSIONS: The collectively tested covariates explain some of the variability in dupilumab response in patients with AD. Patients in all age groups showed adequate response to dupilumab; however, children showed slightly higher drug effects compared to adults and adolescents at equivalent concentrations.

A methodological roadmap to quantify animal-vectored spatial ecosystem subsidies.

Energy, nutrients and organisms move over landscapes, connecting ecosystems across space and time. Meta-ecosystem theory investigates the emerging properties of local ecosystems coupled spatially by these movements of organisms and matter, by explicitly tracking exchanges of multiple substances across ecosystem borders. To date, meta-ecosystem research has focused mostly on abiotic flows-neglecting biotic nutrient flows. However, recent work has indicated animals act as spatial nutrient vectors when they transport nutrients across landscapes in the form of excreta, egesta and their own bodies. Partly due to its high level of abstraction, there are few empirical tests of meta-ecosystem theory. Furthermore, while animals may be viewed as important mediators of ecosystem functions, better integration of tools is needed to develop predictive insights of their relative roles and impacts on diverse ecosystems. We present a methodological roadmap that explains how to do such integration by discussing how to combine insights from movement, foraging and ecosystem ecology to develop a coherent understanding of animal-vectored nutrient transport on meta-ecosystems processes. We discuss how the slate of newly developed technologies and methods-tracking devices, mechanistic movement models, diet reconstruction techniques and remote sensing-that when integrated have the potential to advance the quantification of animal-vectored nutrient flows and increase the predictive power of meta-ecosystem theory. We demonstrate that by integrating novel and established tools of animal ecology, ecosystem ecology and remote sensing, we can begin to identify and quantify animal-mediated nutrient translocation by large animals. We also provide conceptual examples that show how our proposed integration of methodologies can help investigate ecosystem impacts of large animal movement. We conclude by describing practical advancements to understanding cross-ecosystem contributions of animals on the move. Understanding the mechanisms by which animals shape ecosystem dynamics is important for ongoing conservation, rewilding and restoration initiatives around the world, and for developing more accurate models of ecosystem nutrient budgets. Our roadmap will enable ecologists to better qualify and quantify animal-mediated nutrient translocation for animals on the move.

Association of Household Pets, Common Dietary Factors, and Lifestyle Factors with Clostridium difficile Infection.

BACKGROUND: Clostridium difficile infection (CDI) is one of the most common hospital-acquired infections and is associated with significant morbidity and mortality. Since owning a cat or dog could enrich the gut microbiome, we hypothesized that it would be protective against CDI. AIMS: We conducted a survey study on patients tested for CDI in order to assess whether living in the presence of a pet is associated with a decreased risk of CDI. METHODS: We surveyed subjects aged 18-90 over a 14-month period using a retrospective case-control design. Subjects with CDI were matched by gender and age to patients who tested negative and had no prior history of CDI. A web-based survey was provided to subjects by mail or assisted by phone. Conditional logistic regression was used to assess for associations between CDI and the various risk factors. RESULTS: 205 CDI positive and 205 CDI negative subjects (response rate of 50.2%) were included. After matching for age and sex, living with a cat or dog was not associated with negative CDI testing. Exploratory multivariable modeling identified an unexpected association between positive CDI testing and high meat intake (OR 2.13, 95% CI 1.21-3.77) as well as between positive CDI testing and cat allergies (OR 1.88, 95% CI 1.02-3.46). CONCLUSION: Living with a cat or dog was not associated with negative CDI testing. Several novel risk factors for CDI have been identified including high meat intake and cat allergies.

Prevalence and Effect of Intestinal Infections Detected by a PCR-Based Stool Test in Patients with Inflammatory Bowel Disease.

BACKGROUND: The advent of PCR-based stool testing has identified a greatly increased number of infectious agents in IBD, but their clinical significance is unknown. AIMS: To determine the infectious agent prevalence and the clinical significance of these infectious agents in IBD patients. METHODS: This cross-sectional study compared the prevalence of GI infections among IBD patients with active and quiescent disease versus healthy controls. Among actively inflamed patients, we compared clinical characteristics, medication use, and disease course between those with positive and negative tests. RESULTS: Three hundred and thirty-three IBD patients and 52 healthy volunteers were included. The IBD group was divided into active Crohn's disease (CD, n = 113), inactive CD (n = 53), active ulcerative colitis (UC, n = 128), and inactive UC (n = 39). A significantly higher percentage of actively inflamed patients had positive stool tests (31.1%) compared to those with quiescent disease (7.6%, P = < 0.001) and healthy controls (13.5%, P = 0.01). In actively inflamed patients, shorter symptom duration and the use of multiple immunosuppressive agents were significantly associated with positive stool tests. Escalation of immunosuppressive therapy was less frequent in those with positive (61.3%) than with negative tests (77.7%, P = < 0.01). However, the need for surgery (13.3% vs. 18.7%, respectively, P = 0.31) and hospitalization (14.7% vs. 17.5%, respectively, P = 0.57) in 90 days was not significantly different. CONCLUSION: GI infections are common in IBD patients with active disease. Evaluating patients for infection may help avoid unnecessary escalation of immunosuppressants, especially during an acute flare or combination immunosuppression.

Digital Behavior Change Interventions for Younger Children With Chronic Health Conditions: Systematic Review.

BACKGROUND: The prevalence of chronic health conditions in childhood is increasing, and behavioral interventions can support the management of these conditions. Compared with face-to-face treatment, the use of digital interventions may be more cost-effective, appealing, and accessible, but there has been inadequate attention to their use with younger populations (children aged 5-12 years). OBJECTIVE: This systematic review aims to (1) identify effective digital interventions, (2) report the characteristics of promising interventions, and (3) describe the user's experience of the digital intervention. METHODS: A total of 4 databases were searched (Excerpta Medica Database [EMBASE], PsycINFO, Medical Literature Analysis and Retrieval System Online [MEDLINE], and the Cochrane Library) between January 2014 and January 2019. The inclusion criteria for studies were as follows: (1) children aged between 5 and 12 years, (2) interventions for behavior change, (3) randomized controlled trials, (4) digital interventions, and (5) chronic health conditions. Two researchers independently double reviewed papers to assess eligibility, extract data, and assess quality. RESULTS: Searches run in the databases identified 2643 papers. We identified 17 eligible interventions. The most promising interventions (having a beneficial effect and low risk of bias) were 3 targeting overweight or obesity, using exergaming or social media, and 2 for anxiety, using web-based cognitive behavioral therapy (CBT). Characteristics of promising interventions included gaming features, therapist support, and parental involvement. Most were purely behavioral interventions (rather than CBT or third wave), typically using the behavior change techniques (BCTs) feedback and monitoring, shaping knowledge, repetition and substitution, and reward. Three papers included qualitative data on the user's experience. We developed the following themes: parental involvement, connection with a health professional is important for engagement, technological affordances and barriers, and child-centered design. CONCLUSIONS: Of the 17 eligible interventions, digital interventions for anxiety and overweight or obesity had the greatest promise. Using qualitative methods during digital intervention development and evaluation may lead to more meaningful, usable, feasible, and engaging interventions, especially for this underresearched younger population. The following characteristics could be considered when developing digital interventions for younger children: involvement of parents, gaming features, additional therapist support, behavioral (rather than cognitive) approaches, and particular BCTs (feedback and monitoring, shaping knowledge, repetition and substitution, and reward). This review suggests a model for improving the conceptualization and reporting of behavioral interventions involving children and parents.

Systemic Inflammatory Responses in Ulcerative Colitis Patients and Clostridium difficile Infection.

BACKGROUND/AIMS: Finding differences in systemic inflammatory response in ulcerative colitis (UC), UC with Clostridium difficile infection (CDI), and CDI could lead to a better ability to differentiate between UC with symptomatic CDI and UC with C. difficile colonization, and could identify specific inflammatory pathways for UC or CDI, which could be therapeutic targets. METHODS: We prospectively collected sera from symptomatic UC patients whose stools were tested for toxigenic C. difficile, and from CDI patients who did not have UC (CDI-noUC). The UC patients with positive tests (UC-CDI) were further categorized into responders to CDI treatment (UC-CDI-R) and non-responders (UC-CDI-NR). We compared serum inflammatory mediators among groups using unadjusted and adjusted multivariable statistics. RESULTS: We included 117 UC [27 UC-CDI, 90 UC without CDI (UC-noCDI)] and 16 CDI-noUC patients. Principal component analysis (PCA) did not reveal significant differences either between UC-CDI and UC-noCDI groups, or between UC-CDI-R and UC-CDI-NR groups. In contrast, the PCA showed significant separation between the UC and CDI-noUC groups (P = 0.002). In these two groups, hepatocyte growth factor (HGF) and chemokine (C-C motif) ligand 2 (CCL2) levels were significantly lower and IL-23 levels were higher in UC patients in multivariable analyses. The model to distinguish UC from CDI including IL-23, HGF, CCL2, age, gender, and HGB had an AuROC of 0.93. CONCLUSION: Inflammatory profiles could not distinguish UC-CDI from UC-noCDI, and UC-CDI-R from UC-CDI-NR. However, the UC and CDI-noUC groups were significantly different. Future work should examine whether therapeutic agents inhibiting IL-23 or stimulating HGF can treat UC.

Differentiating Clostridium difficile Colitis from Clostridium difficile Colonization in Ulcerative Colitis: A Role for Procalcitonin.

BACKGROUND/AIMS: Clostridium difficile infection (CDI) frequently complicates ulcerative colitis (UC) and can mimic disease flare. Differentiating UC flare from CDI remains a clinical challenge, particularly due to C. difficile colonization. Procalcitonin (PCT) is a serum biomarker for bacterial infections. We hypothesized that PCT would differentiate acute CDI from UC flare and C. difficile colonization. METHODS: A single-center prospective cohort study was conducted from 2013 to 2016. All UC patients with a stool sample for C. difficile testing were eligible. A total of 117 patients were enrolled, while 20 were excluded. Chart review was performed. RESULTS: Among 27 patients with CDI, median PCT was 60.7 (range 26-560.6) pg/mL, while among 90 patients without CDI, median PCT was 56.7 (range 25.1-2,252) pg/mL (p = 0.9). It was found that 14 patients with CDI responded completely to C. difficile treatment (CDI-R), while 8 patients did not and were diagnosed with UC flare (CDI-NR). For CDI-R, median PCT was 104.5 (range 26.3-560.6), compared to 40.3 (range 26.0-116.3) for CDI-NR (p = 0.036). CONCLUSIONS: In UC patients presenting with diarrhea, serum PCT was not significantly higher in UC patients with positive C. difficile testing. However, PCT was significantly elevated in CDI-R versus CDI-NR, suggesting that PCT may have utility in making this discrimination.

A Sustainable, Green-Processed, Ag-Nanoparticle-Incorporated Eggshell-Derived Biomaterial for Wound-Healing Applications.

The eggshell membrane (ESM) is a natural biomaterial with unique physical and mechanical properties that make it a promising candidate for wound-healing applications. However, the ESM's inherent properties can be enhanced through incorporation of silver nanoparticles (AgNPs), which have been shown to have antimicrobial properties. In this study, commercially produced AgNPs and green-processed AgNPs were incorporated into ESM and evaluated for their physical, biological, and antimicrobial properties for potential dermal application. The ESM was extracted using various techniques, and then treated with either commercially produced AgNPs (Sigma-Aldrich, Poole, UK) or green-synthesized AgNPs (Metalchemy, London, UK) to produce AgNPs-ESM samples. The physical characteristics of the samples were evaluated using scanning electron microscopy (SEM), Fourier Transform Infrared (FTIR) spectroscopy, and the biological properties were assessed through in vitro studies using human dermal fibroblasts (HDFs) and BJ cells. The SEM analysis of the AgNPs-ESM samples showed localization of AgNPs on the ESM surface, and that the ESM maintained its structural integrity following AgNP incorporation. The FTIR confirmed loading of AgNPs to ESM samples. The biological studies showed that the 5 µg/mL AgNPs-ESM samples were highly biocompatible with both HDFs and BJ cells, and had good viability and proliferation rates. Additionally, the AgNPs-ESM samples demonstrated pro-angiogenic properties in the CAM assay, indicating their potential for promoting new blood vessel growth. Assessment of the antimicrobial activity of the enhanced AgNPs/ESMs was validated using the International Standard ISO 16869:2008 methodology and exploited Cladosporium, which is one of the most commonly identified fungi in wounds, as the test microorganism (≥5 × 106 cells/mL). The AgNPs-ESM samples displayed promising antimicrobial efficacy as evidenced by the measured zone of inhibition. Notably, the green-synthesized AgNPs demonstrated greater zones of inhibition (~17 times larger) compared to commercially available AgNPs (Sigma-Aldrich). Although both types of AgNP exhibited long-term stability, the Metalchemy-modified samples demonstrated a slightly stronger inhibitory effect. Overall, the AgNPs-ESM samples developed in this study exhibited desirable physical, biological, and antimicrobial properties for potential dermal wound-dressing applications. The use of green-processed AgNPs in the fabrication of the AgNPs-ESM samples highlights the potential for sustainable and environmentally friendly wound-healing therapies. Further research is required to assess the long-term biocompatibility and effectiveness of these biomaterials in vivo.

Therapeutic Application of an Ag-Nanoparticle-PNIPAAm-Modified Eggshell Membrane Construct for Dermal Regeneration and Reconstruction.

Current therapeutic treatments for the repair and/or replacement of damaged skin following disease or traumatic injury is severely limited. The chicken eggshell membrane (ESM) is a unique material: its innate physical and mechanical characteristics offer optimal barrier properties and, as a naturally derived extract, it demonstrates inherent biocompatibility/biodegradability. To further enhance its therapeutic and clinical potential, the ESM can be modified with the thermo-responsive polymer, poly(N-isopropylacrylAmide) (PNIPAAm) as well as the incorporation of (drug-loaded) silver nanoparticles (AgNP); essentially, by a simple change in temperature, the release and delivery of the NP can be targeted and controlled. In this study, ESM samples were isolated using a decellularization protocol, and the physical and mechanical characteristics were profiled using SEM, FT-IR, DSC and DMA. PNIPAAm was successfully grafted to the ESM via amidation reactions and confirmed using FT-IR, which demonstrated the distinctive peaks associated with Amide A (3275 cm−1), Amide B (2970 cm−1), Amide I (1630 cm−1), Amide II (1535 cm−1), CH2, CH3 groups, and Amide III (1250 cm−1) peaks. Confirmation of the incorporation of AgNP onto the stratified membrane was confirmed visually with SEM, qualitatively using FT-IR and also via changes in absorbance at 380 nm using UV-Vis spectrophotometry during a controlled release study for 72 h. The biocompatibility and cytotoxicity of the novel constructs were assessed using human dermal fibroblast (HDFa) and mouse dermal fibroblast (L929) cells and standard cell culture assays. Metabolic activity assessment (i.e., MTS assay), LDH-release profiles and Live/Dead staining demonstrated good attachment and spreading to the samples, and high cell viability following 3 days of culture. Interestingly, longer-term viability (>5 days), the ESM-PNIPAAm and ESM-PNIPAAm (AgNP) samples showed a greater and sustained cell viability profile. In summary, the modified and enhanced ESM constructs were successfully prepared and characterized in terms of their physical and mechanical profiles. AgNP were successfully loaded into the construct and demonstrated a desirable release profile dependent on temperature modulation. Fibroblasts cultured on the extracted ESM samples and ESM-PNIPAAm demonstrated high biocompatibility in terms of high cell attachment, spreading, viability and proliferation rates. As such, this work summarizes the development of an enhanced ESM-based construct which may be exploited as a clinical/therapeutic wound dressing as well as a possible application as a novel biomaterial scaffold for drug development.

Concentration-QTc Modeling of Ozanimod's Major Active Metabolites in Adult Healthy Subjects.

Ozanimod, approved by regulatory agencies in multiple countries for the treatment of adults with relapsing multiple sclerosis, is a sphingosine 1-phosphate (S1P) receptor modulator, which binds with high affinity selectively to S1P receptor subtypes 1 and 5. The relationships between plasma concentrations of ozanimod and its major active metabolites, CC112273 and CC1084037, and the QTc interval (C-QTc) from a phase I multiple-dose study in healthy subjects were analyzed using nonlinear mixed effects modeling. QTc was modeled linearly as the sum of a sex-related fixed effect, baseline, and concentration-related random effects that incorporated interindividual and residual variability. Common linear, power, and maximum effect (Emax ) functions were assessed for characterizing the relationship of QTc with concentrations. Model goodness-of-fit and performance were evaluated by standard diagnostic tools, including a visual predictive check. The placebo-corrected change from baseline in QTc (ΔΔQTc) was estimated based on the developed C-QTc model using a nonparametric bootstrapping approach. QTc was better derived using a study-specific population formula (QTcP). Among the investigated functions, an Emax function most adequately described the relationship of QTcP with concentrations. Separate models for individual analytes characterized the C-QTcP relationship better than combined analytes models. Attributing QT prolongation independently to CC1084037 or CC112273, the upper bound of the 95% confidence interval of the predicted ΔΔQTcP was ~ 4 msec at the plateau of the Emax curves. Therefore, ΔΔQTcP is predicted to remain below 10 msec at the supratherapeutic concentrations of the major active metabolites.

Hyponatraemia compounding pre-eclamptic toxaemia in a patient with type 1 diabetes.

We report a case of profound, symptomatic hyponatraemia in association with pre-eclamptic toxaemia (PET) in a 38-year-old nulliparous woman with type 1 diabetes mellitus. This patient developed hypertension and proteinuria at 31+6 weeks' gestation and was admitted for management of pre-eclampsia. Severe headache, visual disturbance and nausea were associated with a hyponatraemia of 115 mmol/L followed by ketoacidosis. This was reversed through fluid restriction, supplementation with 1.8%-3.0% hypertonic saline and a volume-reduced variable-rate insulin infusion. Clinical stability was achieved and she was subsequently worked up for an induction of labour for worsening pre-eclampsia. Hyponatraemia in the context of PET has been previously reported as rare. However, it has complications that may significantly compound the sequelae of severe PET. We propose that specific and focused monitoring of serum sodium levels should become common practice in the management of women with this condition to allow for timely, measured correction of abnormalities.

Temporal Gut Microbial Changes Predict Recurrent Clostridiodes Difficile Infection in Patients With and Without Ulcerative Colitis.

BACKGROUND: Ulcerative colitis (UC) carries an increased risk of primary and recurrent Clostridiodes difficile infection (rCDI), and CDI is associated with UC flares. We hypothesized that specific fecal microbial changes associate with UC flare and rCDI. METHODS: We conducted a prospective observational cohort study of 57 patients with UC and CDI, CDI only, and UC only. Stool samples were collected at baseline, at the end of antibiotic therapy, and after reconstitution for 16S rRNA sequencing. The primary outcomes were recurrent UC flare and rCDI. Logistic regression and Lasso models were constructed for analysis. RESULTS: There were 21 (45.7%) patients with rCDI, whereas 11 (34.4%) developed UC flare. Patients with rCDI demonstrated significant interindividual (P = 0.008) and intraindividual differences (P = 0.004) in community structure by Jensen-Shannon distance (JSD) compared with non-rCDI. Two cross-validated Lasso regression models predicted risk of rCDI: a baseline model with female gender, hospitalization for UC in the past year, increased Ruminococcaceae and Verrucomicrobia, and decreased Eubacteriaceae, Enterobacteriaceae, Lachnospiraceae, and Veillonellaceae (AuROC, 0.94); and a model 14 days after completion of antibiotics with female gender, increased Shannon diversity, Ruminococcaceae and Enterobacteriaceae, and decreased community richness and Faecalibacterium (AuROC, 0.9). Adding JSD between baseline and post-treatment samples to the latter model improved fit (AuROC, 0.94). A baseline model including UC hospitalization in the past year and increased Bacteroidetes was associated with increased risk for UC flare (AuROC, 0.88). CONCLUSION: Fecal microbial features at baseline and after therapy predict rCDI risk in patients with and without UC. These results may help risk stratify patients to guide management.

Clinical Pharmacokinetics and Pharmacodynamics of Dalcetrapib.

The cholesterol ester transfer protein (CETP) inhibitor dalcetrapib has been under evaluation for its potential to prevent cardiovascular (CV) events for almost two decades. The current clinical development program, representing new advances in precision medicine and focused on a genetically defined population with acute coronary syndrome (ACS), is supported by a large body of pharmacokinetic and pharmacodynamic data as well as substantial clinical experience in over 13,000 patients and volunteers. Dalcetrapib treatment of 600 mg/day produces significant inhibition of CETP activity, and has been utilized in phase II and III studies, including CV endpoint trials. Numerous studies have investigated the interactions between dalcetrapib and most drugs commonly prescribed to CV patients and have not demonstrated any clinically significant effects. Evaluations in patients with renal and hepatic impairment demonstrate a greater exposure to dalcetrapib than in the non-impaired population, but long-term clinical studies including patients with mild to moderate hepatic and renal dysfunction demonstrate no increase in adverse events. Safety pharmacology and toxicology studies as well as the clinical safety experience support the continuing development of dalcetrapib as an adjunct to 'standard of care' for the ACS population. This article provides a full review of the pharmacokinetics, as well as pharmacodynamics and pharmacology, of dalcetrapib in the context of a large clinical program.