Retrospective Analysis Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation Offers Improvements in Efficiency of the Design of Volunteer Infection Studies for Antimalarial Drug Development

Volunteer infection studies using the induced blood stage malaria (IBSM) model have been shown to facilitate antimalarial drug development. Such studies have traditionally been undertaken in single‐dose cohorts, as many as necessary to obtain the dose‐response relationship. To enhance ethical and logistic aspects of such studies, and to reduce the number of cohorts needed to establish the dose‐response relationship, we undertook a retrospective in silico analysis of previously accrued data to improve study design. A pharmacokinetic (PK)/pharmacodynamic (PD) model was developed from initial fictive‐cohort data for OZ439 (mixing the data of the three single‐dose cohorts as: n = 2 on 100 mg, 2 on 200 mg, and 4 on 500 mg). A three‐compartment model described OZ439 PKs. Net growth of parasites was modeled using a Gompertz function and drug‐induced parasite death using a Hill function. Parameter estimates for the PK and PD models were comparable for the multidose single‐cohort vs. the pooled analysis of all cohorts. Simulations based on the multidose single‐cohort design described the complete data from the original IBSM study. The novel design allows for the ascertainment of the PK/PD relationship early in the study, providing a basis for rational dose selection for subsequent cohorts and studies.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Volunteer infection studies are routinely used in antimalarial drug development to generate early pharmacokinetic/pharmacodynamic data for compounds.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ Can in silico analyses be used to suggest improvements to volunteer infection study designs?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Multiple dose adaptive trial designs can potentially reduce the number of cohorts needed to establish the dose‐response relationship in volunteer infection studies.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ Real time data analyses can be used to recommend doses for adaptive volunteer infection studies.

Volunteer infection studies using the induced blood stage malaria (IBSM) model have been recognized as a valuable system for defining the key pharmacokinetic (PK) and pharmacodynamic (PD) relationships for dose selection in antimalarial drug development. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ In such studies, healthy volunteers are inoculated intravenously with a given quantity (with small variability) of Plasmodium‐infected red cells. Parasitemia is then followed by quantitative polymerase chain reaction until a prespecified treatment threshold is reached when the test drug is administered. Parasite and drug concentrations are then measured. These studies are conducted prior to phase II dose‐response (D‐R) trials and can be included in an integrated first‐in‐human study protocol, or after completion of the first‐in‐human PK and safety study. IBSM studies have been typically designed as flexible multiple cohort studies where each volunteer of one cohort receives a single dose of the same amount of drug (“single dose per cohort”). ² , ³ , ⁴ , ⁵ After each cohort, a decision is made to stop or to add a cohort to test a lower or higher dose based on the response observed in the previous cohorts.For the multiple single‐dose‐per‐cohort design, the starting dose is typically selected based on safety and PK information from a phase I single ascending dose (SAD) study and, more recently, on preclinical data from a severe combined immunodeficient mouse model, with the dose selected on the basis of being best able to inform the D‐R relationship, rather than aiming for cure. This approach, where a single dose is tested in all subjects of the initial cohort, risks missing the dose likely to be most informative for defining the PK/PD relationship.An alternative approach is to spread a range of doses across a smaller number of subjects within the initial cohort and use PK/PD models developed based on data from this cohort to support dose selections of subsequent cohorts and studies. Using data from a previous study, ² we undertook an in silico investigation of such an adaptive study design, aiming to reduce the number of subjects exposed to inefficacious doses, and to establish a D‐R relationship. This multiple‐dose‐groups‐per‐cohort design, referred to as the “2‐2‐4” design, is contrasted with the already implemented study design depicted in Figure  1 .Open in a separate windowFigure 1Comparison of standard and adaptive designs of IBSM studies. A/B/C, dose levels to be selected during the progress of the study based on pharmacokinetic/pharmacodynamic results of the initial cohort; CHMI, controlled human malaria infection; D‐R, dose‐response; IBSM, induced blood stage malaria infection; n, number of subjects at each dose.The objectives of this retrospective analysis were to: (i) compare PK/PD parameter estimates from the initial cohort of the 2‐2‐4 study design with the prior results from the data of the full study and (ii) propose a preliminary workflow to establish D‐R early in an IBSM study, and use modeling and simulation (M&S) to support dose selections for subsequent cohorts and later phase clinical trials.     

Rural barriers to early lung cancer detection: Exploring access to lung cancer screening programs in New Hampshire and Vermont

BackgroundRural populations face many health disadvantages compared to urban areas. There is a critical need to better understand the current lung cancer screening landscape in these communities to identify targeted areas to improve the impact of this proven tool.MethodsData from the County Health Rankings of New Hampshire and Vermont was reviewed for population density, distribution of adult smokers, and level of education compared to the distribution of Lung Cancer Screening Facilities throughout these two states.ResultsScreening programs in southern counties of Vermont with lower levels of education have decreased access. In New Hampshire, there are no programs within 30 miles of the areas with the largest distribution of smokers, and decreased access in some areas with the lowest levels of education.ConclusionsImproving equitable access to high-quality screening services in rural regions and the creation of targeted interventions to address decreased access in areas of high tobacco use and low education is vital to decreasing the incidence of latestage presentations of lung cancer within these populations.     

Differences in self-awareness of functional deficits between amnestic single- and multidomain mild cognitive impairment

Introduction: Prior research examining self-awareness of deficits in those with mild cognitive impairment (MCI) has been inconsistent, suggesting that preservation of insight at this disease stage may be conditional on the domain(s) examined as well as individual characteristics. The current study is the first to examine differences in objective performance and self-awareness of difficulties between older adults with amnestic single- (MCI–ASD) and multidomain MCI (MCI–AMD) across six instrumental activities of daily living (IADLs).

Method: Seventy-five individuals (M_age = 73.9 years, range = 55–88 years; 56% female) with MCI–ASD (n = 30) and MCI–AMD (n = 45) were recruited primarily from a hospital-based memory disorders clinic. Participants were administered self-report and objective measures assessing six functional domains: financial management, driving, telephone use, nutrition evaluation, grocery shopping, and medication management. Self-awareness discrepancy scores were calculated for each of these IADLs, and participants were classified as either “overestimating ability” or “accurately/underestimating ability.”

Results: Individuals with MCI–AMD performed significantly worse on objective measures of financial management, driving, and nutrition evaluation than those with MCI–ASD. Across MCI subtypes, participants were most likely to lack awareness of their difficulties in nutrition evaluation (31%), financial management (25%), and driving (23%) domains. Individuals with MCI–AMD were significantly more likely than those with MCI–ASD to overestimate performance on driving and telephone use domains.

Conclusion: Individuals with MCI–AMD are more likely than those with MCI–ASD to have impairment in their everyday function and to lack awareness into their IADL difficulties. When possible, clinicians should obtain objective measures in combination with detailed informant reports of functional abilities in order to evaluate capacity to independently engage in various daily activities. Finally, level of self-awareness varies across IADL domains, providing further evidence that insight is not a unitary construct.     

Too little,too much or just right: Injury/illness sensitivity and intentions to drink as a basis for alcohol consumer segmentation

Background: Although alcohol is the most socially accepted drug, little is known about the classification of alcohol consumers into clusters influencing drinking outcomes. Past research has demonstrated that injury/illness sensitivity predicts health protecting behaviors. Objectives: The present study explored whether alcohol consumers can be classified based on injury/illness sensitivity and intentions to reduce drinking, and whether the identified clusters exhibited meaningful differences in negative affect and drinking levels. Methods: Four-hundred and eighty-six participants (54.3% male; mean [SD] age?=?26.5 [7.2] years) completed online questionnaires between July and October of 2017. Questions were asked pertaining to injury/illness sensitivity, intentions to reduce drinking, negative affect, and heavy drinking behavior. A k-means cluster analysis was performed on illness/injury sensitivity and intentions to reduce drinking scores. We then examined whether clusters varied according to negative affect or drinking variables. Results: The k-means cluster analysis identified four clusters: Insensitive non-internalizers, Insensitive internalizers, Sensitive non-internalizers, and Sensitive internalizers. Sensitive internalizers reported the highest, whereas Insensitive non-internalizers reported the lowest, negative affect. Sensitive internalizers also had the lowest percentage of heavy drinkers. Conclusion/importance: Current findings add to the alcohol literature by indicating that high sensitivity to illnesses/injuries and the internalization of sensitivities via behavior change intentions may provide the best protection against high alcohol consumption levels.     

Increasing the rate of the hydrogen evolution reaction in neutral water with protic buffer electrolytes

Electrocatalytic generation of H₂ is challenging in neutral pH water, where high catalytic currents for the hydrogen evolution reaction (HER) are particularly sensitive to the proton source and solution characteristics. A tris(hydroxymethyl)aminomethane (TRIS) solution at pH 7 with a [2Fe-2S]-metallopolymer electrocatalyst gave catalytic current densities around two orders of magnitude greater than either a more conventional sodium phosphate solution or a potassium chloride (KCl) electrolyte solution. For a planar polycrystalline Pt disk electrode, a TRIS solution at pH 7 increased the catalytic current densities for H₂ generation by 50 mA/cm² at current densities over 100 mA/cm² compared to a sodium phosphate solution. As a special feature of this study, TRIS is acting not only as the primary source of protons and the buffer of the pH, but the protonated TRIS ([TRIS-H]⁺) is also the sole cation of the electrolyte. A species that is simultaneously the proton source, buffer, and sole electrolyte is termed a protic buffer electrolyte (PBE). The structure–activity relationships of the TRIS PBE that increase the HER rate of the metallopolymer and platinum catalysts are discussed. These results suggest that appropriately designed PBEs can improve HER rates of any homogeneous or heterogeneous electrocatalyst system. General guidelines for selecting a PBE to improve the catalytic current density of HER systems are offered.

Molecular hydrogen (H₂), a clean-burning and energy-dense fuel source, has been widely discussed as an attractive way to store intermittent energy from solar and wind through water electrolysis (1, 2). Current commercial electrolyzers can be separated into two categories based on their operating pH. The first are acidic polymer electrolyte membrane electrolyzers that work best with rare and expensive platinum-based electrocatalysts for the hydrogen evolution reaction (HER) (3). The second are strongly alkaline electrolyzers that suffer from caustic basic reaction conditions (4). Neutral pH conditions with inexpensive catalysts composed of Earth-abundant elements are a target for practical solar-to-hydrogen fuel devices due to lower cost and fewer safety concerns (5), but achieving fast rates with mild overpotentials under neutral conditions remains a challenge (6–12). In the pH range from 5 to 9, the electrocatalytic activity of platinum (Pt) itself does not conform to the expected thermodynamic potential shift with pH dependence of −59 mV/pH (13). This is due to the low concentration of the hydronium ion in this pH range and a transition to water as the primary reactant, which has a higher thermodynamic requirement for hydrogen evolution (13). Studies of electrocatalysts using buffers to maintain the pH in this range and ionic salts such as potassium chloride (KCl) to provide ionic strength to ensure high solution conductivity have shown that the buffer can aid the HER activity, presumably by acting as a proton donor (6, 14–18). To extend the scope of water-soluble electrocatalysts, biopolymers and bioinspired metallopolymer catalysts have also been studied (7, 12, 17–26). Bren and coworkers recently reported particularly enlightening studies of the effects of buffer pK_a and structure on the mechanism of the hydrogen evolution reaction for cobalt minienzymes (17, 18).We recently reported a new metallopolymer catalyst system built around a customized [2Fe-2S] catalyst site with a bridging aryldithiolato ligand which exhibits remarkable catalytic activity, air stability, and chemical stability (21). The electrocatalytic mechanism of the [2Fe-2S] catalysts with aryldithiolato ligands is known from previous studies and these catalysts operate at rates of 10⁵ s⁻¹ and faster (27–30). The readily synthesized and water-soluble metallopolymer composed of tertiary amine side-chain groups, PDMAEMA-g-[2Fe-2S] (Fig. 1), approached the current density of Pt operating in neutral water under the same conditions and matched the Faradaic yield (97 ± 3%) (21). Although the detailed structural and mechanistic causality of these profound improvements for these metallopolymer electrocatalysts remain subjects of study, the nature of this molecular system is ideal for studying solution effects on the HER reaction at neutral pH for complexes that are normally insoluble in water. In the course of characterizing these electrocatalysts, solutions containing tris(hydroxymethyl)aminomethane (TRIS) at pH 7 were discovered to be exceptionally advantageous to the catalytic rate. In contrast to the few previous studies of TRIS buffer with electrocatalysts (14, 15, 18), we utilized TRIS at a high concentration. At pH 7, TRIS is sufficiently in the cationic protonated form that additional electrolyte such as KCl is not needed for conductance. This important distinction from conventional studies allows TRIS to simultaneously play the roles of pH buffer, proton source, and sole electrolyte. There is precedence in employing buffers in a manner in which they are the sole electrolyte (7, 31–34). Referring to such species simply as a “buffer” or as an “electrolyte” is inadequate in representing the three functions including proton source. For the purposes of this paper we term a species that serves all three functions a protic buffer electrolyte (PBE). In the following discussion, a TRIS PBE solution is one in which [TRIS-H]⁺Cl⁻ is the sole electrolyte and the cation is a proton source, and a sodium phosphate PBE solution is one in which Na⁺[H₂PO₄]⁻ is the sole electrolyte and the anion is a proton source.Open in a separate windowFig. 1.(A) Depiction of the 2e⁻ electrocatalytic HER with POEGMA-g-[2Fe-2S] and/or PDMAEMA-g-[2Fe-2S] metallopolymers using TRIS or sodium phosphate protic buffer electrolytes at pH 7. (B) Image of POEGMA-g-[2Fe-2S] with MW = 14,216 grown in silico. The [2Fe-2S] active site is in the center of the polymer, blue represents the polymer backbone, and the rest are the oligo(ethylene glycol) side chains. See SI Appendix for the details of modeling and a larger image.One of the key unanswered questions for these new catalyst systems is whether the metallopolymer composition (i.e., amine side-chain groups) or the PBEs are more important to afford this outstanding catalytic activity. Herein we study the effects of PBEs by comparing the HER performances of a standard platinum catalyst and a [2Fe-2S] metallopolymer catalyst in TRIS PBE solutions, sodium phosphate PBE solutions, and a KCl electrolyte solution without a PBE. For this study, nonionic water-soluble metallopolymers were used, which were made using oligo(ethylene glycol) side-chain groups on the polymer to avoid the possibility of contributing effects of the protonated amino groups of PDMAEMA-g-[2Fe-2S] referred to earlier. The metallopolymer catalyst used in this work is designated as POEGMA-g-[2Fe-2S] (Fig. 1). We previously reported that this water-soluble metallopolymer was largely inactive for H₂ electrocatalysis at neutral pH in phosphate buffer (22). The current findings suggest that the use of electrolytes composed of inexpensive cationic organic proton donors can be readily applied to any homogeneous or heterogeneous electrocatalyst system as a facile means to enhance HER activity.     

Non-Alcoholic Beverage Cues as Specific Comparison Images to Alcohol Image Cues

Background: Visual alcohol cues are often used to elicit craving (e.g., cue-reactivity), and selection of appropriate comparison cues is important to isolate the specific effect of craving for alcohol. Objectives: In the current study, via the development of a new set of non-alcoholic beverage cues, we examine measurement and methodological choices in testing alcohol images for cue-reactivity studies. Methods: The current project combined two independent studies of hazardous (Study 1; n = 80) and recent drinkers (Study 2; n = 244) recruited from Amazon Mechanical Turk. Participants viewed either alcohol cues (Lovett, Ham, &; Veilleux, 2015 Lovett, D. E., Ham, L. S., &; Veilleux, J. C. (2015). Psychometric evaluation of a standardized set of alcohol cue photographs to assess craving. Addictive Behaviors, 48, 58–61. doi: 10.1016/j.addbeh.2015.05.002[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]) or newly developed non-alcoholic beverage cues. We also randomly assigned people to rate the cues regarding motivational (e.g., affect, craving for alcohol, resistance to alcohol) responses or non-motivational features (e.g., artistry). Results: In Study 1, we included presentation of non-beverage objects, and found that beverages were rated as more positive, less negative and with higher craving than non-beverage objects. In the combined sample, we found that the alcohol beverage cues were associated with greater craving than non-alcoholic beverage cues, and that there were no differences between cue types on either positive or negative affect. We also found an interaction between drinking experience and cue type in predicting resistance to drinking. Conclusions: We conclude that the choice of control cues in alcohol cue-reactivity studies is important, and that the currently developed non-alcoholic beverage cue set provides an adequate control for alcohol beverage cues for use in cue-reactivity paradigms.     

The Influence of Organizational Culture on School‐Based Obesity Prevention Interventions: A Systematic Review of the Literature

BACKGROUND

Although the influence of organizational culture has been examined on a variety of student outcomes, few studies consider the influence that culture may have on school‐based obesity prevention interventions. We present a systematic review of the literature to examine how elements of organizational culture may affect the adoption, implementation, and sustainability of school‐based obesity prevention interventions.

METHODS

Fourteen studies examining the impact of organizational‐level characteristics on school‐based obesity prevention interventions were identified through the online databases EBSCO (CINAHL, ERIC, Agricola), Web of Science, Medline (PubMed), and Scopus.

RESULTS

Five themes were identified as elements of organizational culture that influence the adoption, implementation, and sustainability of school‐based obesity prevention interventions: organizational response to limited resources, value placed on staff training and professional development, internal support, organizational values, and school climate.

CONCLUSIONS

Organizational culture can greatly influence the success of school‐based obesity interventions. The collection of data related to organizational‐level factors may be used to identify strategies for creating and sustaining a supportive environment for obesity prevention interventions in the school setting.