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Purpose: Professional organizations have emphasized the growing need for pharmacists to possess advanced research skills; however, there is a scarcity of training programs aimed at nurturing clinician-scientists. This report outlines 3 critical care-focused research programs, each offering a unique approach to training clinician-scientists., Summary: Limited resources and formalized programs are available to bridge the gap between the demand for and availability of skilled clinician-scientists. Several programs have stepped forward to share their experiences in establishing and executing training initiatives aimed at cultivating skilled clinician-scientists in the critical care practice space., Conclusion: Enhancing the development of clinician-scientists for clinical and translational research is necessary in the critical care clinical pharmacy community., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Retrograde Endovascular Balloon Occlusion of the Aorta (REBOA) is an effective management for the transient responder, but the ischemic consequences of complete aortic occlusion currently limit its use. Multiple DoD-funded preclinical studies have clearly demonstrated that partial REBOA reduces distal ischemia to potentially extend safe occlusion times, while still providing effective temporization of noncompressible torso hemorrhage. Early versions of REBOA devices were designed to completely occlude the aorta and had little ability to provide partial occlusion. Recently, a new REBOA device (pREBOA-PRO) was designed specifically to allow for partial occlusion, with the hypothesis that this may reduce the complications of aortic occlusion and extend safe occlusion times while maintaining the benefits on cardiac and cerebrovascular circulation as well as reductions in resuscitation requirements., Materials and Methods: To ascertain the impact of a new purpose-built partial REBOA device on the extension of safe occlusion time, the Partial REBOA Outcomes Multicenter ProspecTive (PROMPT) trial compared available data from the pREBOA-PRO with existing data from 200 clinical uses of pREBOA-PRO and available data in the AAST AORTA Registry were reviewed to design primary endpoints and clinical evidence for a prospective multi-center trial, the PROMPT Study. Together with the endpoints identified in preclinical studies of partial REBOA, primary endpoints for the PROMPT study were identified and power analyses were conducted to determine the target patient enrollment goals., Results: Results from the clinical implementation of partial REBOA at a single trauma center were used to conduct the initial power analysis for the primary endpoint of Acute Kidney Injury (AKI) after prolonged occlusion. The rate of AKI after complete REBOA was 55% (12/20) compared to 33% (4/12) after partial REBOA (Madurska et al., 2021). With an alpha of 0.05 and power (β) of 0.8, the projected sample size for comparison on a dichotomous outcome is 85 patients for the assessment of AKI. Initial power and endpoint analyses have been confirmed and extended with the ongoing analysis of partial and complete REBOA reported in the AORTA database. These analyses confirm preclinical findings which show that compared to complete REBOA, partial REBOA is associated with extended occlusion time in zone 1 (complete: 31 min vs. partial: 45 min, P = 0.003), lower rates of AKI after zone 1 occlusion (complete: 33% vs. partial: 19%, P = 0.05) and reduced resuscitation requirements (e.g., 25% reduction in pRBC administration: complete: 18 units vs. partial: 13 units, P = 0.02)., Conclusions: The DoD-funded PROMPT study of partial REBOA will provide prospective observational clinical data on patients being treated with pREBOA-PRO. Outcomes will be stratified based on partial or complete occlusion to address whether partial REBOA has additional clinical benefits over complete REBOA, such as decreased distal ischemia, extension of safe occlusion time, improved hemodynamics during transition to and from occlusion, and reduced interoperative bleeding and blood product use. The results from this study are expected to confirm previous data demonstrating reduction of ischemic sequalae, improved transition to reperfusion, and reduced resuscitative requirements compared to complete REBOA., (© The Association of Military Surgeons of the United States 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Competing Interests: Dr. Hamblin’s institution received funding from Prytime. Dr. Devlin has disclosed that he does not have any potential conflicts of interest.

Background: In an acute hospital setting, diabetes can require intensive management with medication modification, monitoring and education. Yet little is known about the experiences and perspectives of nursing/midwifery staff and patients. The aim of this study was to investigate diabetes management and care for patients with diabetes in an acute care setting from the perspectives of nursing/midwifery staff and patients., Methods: A convergent mixed-methods study design. Patients with diabetes (Type 1, Type 2 or gestational diabetes) recruited from a public health service in Melbourne, Australia completed a survey and nurses and midwives employed at the health service participated in focus groups. Descriptive statistics were used to summarise the survey data. Thematic analysis was used for the free-text survey comments and focus group data., Results: Surveys were completed by 151 patients. Although more than half of the patients were satisfied with the diabetes care they had received (n = 96, 67.6%), about a third felt the hospital nursing/midwifery staff had ignored their own knowledge of their diabetes care and management (n = 43, 30.8%). Few reported having discussed their diabetes management with the nursing/midwifery staff whilst in hospital (n = 47, 32.6%) or thought the nurses and midwives had a good understanding of different types of insulin (n = 43, 30.1%) and their administration (n = 47, 33.3%). Patients also reported food related barriers to their diabetes management including difficulties accessing appropriate snacks and drinks (n = 46, 30.5%), restricted food choices and timing of meals (n = 41, 27.2%). Fourteen nurses and midwives participated in two focus groups. Two main themes were identified across both groups: 1. challenges caring for patients with diabetes; and 2. lack of confidence and knowledge about diabetes management., Conclusions: Patients and nursing/midwifery staff reported challenges managing patients' diabetes in the hospital setting, ensuring patients' optimal self-management, and provision of suitable food and timing of meals. It is essential to involve patients in their diabetes care and provide regular and up-to-date training and resources for nursing/midwifery staff to ensure safe and high-quality inpatient diabetes care and improve patient and staff satisfaction., (© 2022. The Author(s).)

Objective: Continuous glucose monitoring (CGM) is increasingly used in type 1 diabetes management; however, funding models vary. This study determined the uptake rate and glycemic outcomes following a change in national health policy to introduce universal subsidized CGM funding for people with type 1 diabetes aged <21 years., Research Design and Methods: Longitudinal data from 12 months before the subsidy until 24 months after were analyzed. Measures and outcomes included age, diabetes duration, HbA1c, episodes of diabetic ketoacidosis and severe hypoglycemia, insulin regimen, CGM uptake, and percentage CGM use. Two data sources were used: the Australasian Diabetes Database Network (ADDN) registry (a prospective diabetes database) and the National Diabetes Service Scheme (NDSS) registry that includes almost all individuals with type 1 diabetes nationally., Results: CGM uptake increased from 5% presubsidy to 79% after 2 years. After CGM introduction, the odds ratio (OR) of achieving the HbA1c target of <7.0% improved at 12 months (OR 2.5, P < 0.001) and was maintained at 24 months (OR 2.3, P < 0.001). The OR for suboptimal glycemic control (HbA1c ≥9.0%) decreased to 0.34 (P < 0.001) at 24 months. Of CGM users, 65% used CGM >75% of time, and had a lower HbA1c at 24 months compared with those with usage <25% (7.8 ± 1.3% vs. 8.6 ± 1.8%, respectively, P < 0.001). Diabetic ketoacidosis was also reduced in this group (incidence rate ratio 0.49, 95% CI 0.33-0.74, P < 0.001)., Conclusions: Following the national subsidy, CGM use was high and associated with sustained improvement in glycemic control. This information will inform economic analyses and future policy and serve as a model of evaluation diabetes technologies., (© 2022 by the American Diabetes Association.)

Background: Successful management of gestational diabetes mellitus (GDM) reduces the risk of morbidity in women and newborns. A woman's blood glucose readings and risk factors are used by clinical staff to make decisions regarding the initiation of pharmacological treatment in women with GDM. Mobile health (mHealth) solutions allow the real-time follow-up of women with GDM and allow timely treatment and management. Machine learning offers the opportunity to quickly analyze large quantities of data to automatically flag women at risk of requiring pharmacological treatment., Objective: The aim of this study is to assess whether data collected through an mHealth system can be analyzed to automatically evaluate the switch to pharmacological treatment from diet-based management of GDM., Methods: We collected data from 3029 patients to design a machine learning model that can identify when a woman with GDM needs to switch to medications (insulin or metformin) by analyzing the data related to blood glucose and other risk factors., Results: Through the analysis of 411,785 blood glucose readings, we designed a machine learning model that can predict the timing of initiation of pharmacological treatment. After 100 experimental repetitions, we obtained an average area under the receiver operating characteristic curve of 0.80 (SD 0.02) and an algorithm that allows the flexibility of setting the operating point rather than relying on a static heuristic method, which is currently used in clinical practice., Conclusions: Using real-time data collected via an mHealth system may further improve the timeliness of the intervention and potentially improve patient care. Further real-time clinical testing will enable the validation of our algorithm using real-world data., (©Carmelo Velardo, David Clifton, Steven Hamblin, Rabia Khan, Lionel Tarassenko, Lucy Mackillop. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 10.03.2021.)

Our ability to collect large datasets is growing rapidly. Such richness of data offers great promise in terms of addressing detailed scientific questions in great depth. However, this benefit is not without scientific difficulty: many traditional analysis methods become computationally intractable for very large datasets. However, one can frequently still simulate data from scientific models for which direct calculation is no longer possible. In this paper we propose a Bayesian perspective for such analyses, and argue for the advantage of a simulation-based approximate Bayesian method that remains tractable when tractability of other methods is lost. This method, which is known as "approximate Bayesian computation" [ABC], has now been used in a variety of contexts, such as the analysis of tumor data (a tumor being a complex population of cells), and the analysis of human genetic variation data (which arise from a population of individual people). We review a number of ABC methods, with specific attention to the use of ABC in agent-based models, and give pointers to software that allows straightforward implementation of the ABC approach. In this way we demonstrate the utility of simulation-based analyses of large datasets within a rigorous statistical framework.

Associative learning is essential for resource acquisition, predator avoidance and reproduction in a wide diversity of species, and is therefore a key target for evolutionary and comparative cognition research. Automated operant devices can greatly enhance the study of associative learning and yet their use has been mainly restricted to laboratory conditions. We developed a portable, weatherproof, battery-operated operant device and conducted the first fully automated colour-associative learning experiment using free-ranging individuals in the wild. We used the device to run a colour discrimination task in a monitored population of tits (Paridae). Over two winter months, 80 individuals from four species recorded a total of 5,128 trials. Great tits (Parus major) were more likely than other species to visit the devices and engage in trials, but there were no sex or personality biases in the sample of great tits landing at the devices and registering key pecks. Juveniles were more likely than adults to visit the devices and to register trials. Individuals that were successful at solving a novel technical problem in captivity (lever-pulling) learned faster than non-solvers when at the operant devices in the wild, suggesting cross-contextual consistency in learning performance in very different tasks. There was no significant effect of personality or sex on learning rate, but juveniles' choice accuracy tended to improve at a faster rate than adults. We discuss how customisable automated operant devices, such as the one described here, could prove to be a powerful tool in evolutionary ecology studies of cognitive traits, especially among inquisitive species such as great tits.

Background: A major goal of molecular evolution is to determine how natural selection has shaped the evolution of a gene. One approach taken by methods such as KA/KS and the McDonald-Kreitman (MK) test is to compare the frequency of non-synonymous and synonymous changes. These methods, however, rely on the assumption that a change in frequency of one mutation will not affect changes in frequency of other mutations., Results: We demonstrate that linkage between sites can bias measures of selection based on synonymous and non-synonymous changes. Using forward simulation of a Wright-Fisher process, we show that hitch-hiking of deleterious mutations with advantageous mutations can lead to overestimation of the number of adaptive substitutions, while background selection and clonal interference can distort the site frequency spectrum to obscure the signal for positive selection. We present three diagnostics for detecting these effects of linked selection and apply them to the human influenza (H3N2) hemagglutinin gene., Conclusion: Various forms of linked selection have characteristic effects on MK-type statistics. The extent of background selection, hitch-hiking and clonal interference can be evaluated using the diagnostic statistics presented here. The diagnostics can also be used to determine how well we expect the MK statistics to perform and whether one form of the statistic may be preferable to another.

Background: Niche construction has received increasing attention in recent years as a vital force in evolution and examples of niche construction have been identified in a wide variety of taxa, but viruses are conspicuously absent. In this study we explore how niche construction can lead to viruses engineering their hosts (including behavioural manipulation) with feedback on selective pressures for viral transmission and virulence. To illustrate this concept we focus on Baculoviridae, a family of invertebrate viruses that have evolved to modify the feeding behaviour of their lepidopteran hosts and liquefy their cadavers as part of the course of infection., Results: We present a mathematical model showing how niche construction leads to feedback from the behavioural manipulation to the liquefaction of the host, linking the evolution of both of these traits, and show how this association arises from the action of niche construction. Model results show that niche construction is plausible in this system and delineates the conditions under which niche construction will occur. Niche construction in this system is also shown to be sensitive to parameter values that reflect ecological forces., Conclusions: Our model demonstrates that niche construction can be a potent force in viral evolution and can lead to the acquisition and maintenance of the behavioural manipulation and liquefaction traits in Baculoviridae via the niche constructing effects on the host. These results show the potential for niche construction theory to provide new insights into viral evolution.

A series of compounds based on a 4-phenyl-2-phenylaminopyridine scaffold that are potent and selective inhibitors of Traf2- and Nck-interacting kinase (TNIK) activity are described. These compounds were used as tools to test the importance of TNIK kinase activity in signaling and proliferation in Wnt-activated colorectal cancer cells. The results indicate that pharmacological inhibition of TNIK kinase activity has minimal effects on either Wnt/TCF4/β-catenin-driven transcription or viability. The findings suggest that the kinase activity of TNIK may be less important to Wnt signaling than other aspects of TNIK function, such as its putative role in stabilizing the TCF4/β-catenin transcriptional complex., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Many viruses, particularly RNA viruses, mutate at a very high rate per genome per replication. One possible explanation is that high mutation rates are selected to meet the challenge of fluctuating environments, including the host immune response. Alternatively, recent studies argue that viruses evolve under a trade-off between replication speed and fidelity such that fast replication is selected, and, along with it, high mutation rates. Here, in addition to these factors, we consider the role of viral life-history properties: namely, the within-host dynamics of viruses resulting from their interaction with the host. We develop mathematical models incorporating factors occurring within and between hosts, including deleterious and advantageous mutations, host death owing to virulence and clearance of viruses by the host. Beneficial mutations confer both a within-host and a transmission advantage. First, we find that advantageous mutations have only a weak effect on the optimal genomic mutation rate. Second, viral life-history properties have a large effect on the mutation rate. Third, when the speed-fidelity trade-off is included, there can be two locally optimal mutation rates. Our analysis provides a way to consider how life-history properties combine with biochemical trade-offs to shape mutation rates.

Background: The financial benefit of an established clinical pharmacy service in the trauma intensive care unit has not been well-described. This study was conducted to identify adverse drug events prevented by the clinical pharmacy team and to determine the net cost savings associated with their input on a multidisciplinary trauma service., Methods: Between July 2010 and June 2011, we conducted a retrospective analysis of clinical pharmacy activities and interventions on our 31-bed trauma unit managed by a multidisciplinary team. At the initiation of the study, a Web-based pharmacy documentation system was officially integrated into the trauma pharmacy work process. Based on this system, the type of intervention and a value of cost savings ($0-$6,000) were assigned to each activity. Cost-saving values for interventions were calculated from the literature describing the costs of adverse drug events and average drug costs., Results: Over the year, a total of 2,574 pharmacy activity entries were documented in the Quantifi system. The total conservative estimate of cost savings associated with clinical pharmacy interventions amounted to $565,664. Considering the mean US hospital pharmacist salary and the highest quoted cost associated with the Quantifi program, the net cost savings associated with our clinical pharmacist interventions on the trauma service was $428,327. Most of the interventions (53%) fell under the category of pharmacotherapy improvement, with 21% in the category of quality/safety improvement and 18% as antibiotic stewardship. Prevention of 34 serious adverse drug events was documented. Antibiotic changes and discontinuing medications were other common interventions. Antimicrobial medications (668), anticoagulants (270), and gastrointestinal medications (231) were the most common medication classes involved in pharmacy interventions., Conclusion: Using a Web-based pharmacy documentation system, we were able to demonstrate prevention of serious adverse drug events and a significant cost savings by including clinical pharmacy in a multidisciplinary approach to caring for the seriously injured., Level of Evidence: Economic analysis, level III; therapeutic study, level IV.

Individuals foraging in groups can use two different tactics for obtaining food resources. Individuals can either search for food sources themselves (producing) or they can join food discoveries of others (scrounging). In this study we use a genetic algorithm in a spatially explicit producer-scrounger game to explore how individuals compromise between exploration (an important axis of animal personality) and scrounging and how characteristics of the environment affect this compromise. Agents varied in exploration and scrounging and a genetic algorithm searched for the optimal combination of exploration and scrounging. The foraging environments featured different levels of patch richness, predation and patch density. Our simulations show that under conditions of low patch densities slow exploring scroungers were favored whereas high patch density favored fast exploring individuals that either produced (at low patch richness) or scrounged (at high patch richness). In high predation environments fast exploring individuals were selected for but only at low to intermediate patch densities. Predation did not affect scrounging behavior. We did not find a divergence of exploration 'types' within a given environment, but there was a general association between exploration and scrounging across different environments: high rates of scrounging were observed over nearly the full spectrum of exploration values, whereas high rates of producing were only observed at high exploration values, suggesting that cases in which slow explorers start producing should be rare. Our results indicate that the spatial arrangement of food resources can affect the optimal social attraction rules between agents, the optimality of foraging tactic and the interaction between both.

Sir Philip Sidney games are a widely used model of simple signaling. Johnstone and Grafen [Johnstone, R.A., Grafen, A., 1993. Dishonesty and the handicap principle. Animal Behaviour 46, 759-764] present a version in which the Evolutionarily Stable Strategy (ESS) is for most signalers to "honestly" signal, with a small minority of signalers who "cheat". This model is among the most frequently cited papers on the topic of "dishonest" signaling and supports the view that signals may be "dishonest" as long as they are "honest on average". Using genetic algorithms, we demonstrate that another solution exists to the game, an evolutionarily stable set of Nash equilibria in which members of the set never signal and all donors give their resource. Payoffs to players using this set of strategies is greater those when playing the "dishonest" signaling ESS. We demonstrate that a random population is far more likely to evolve to this non-communicating strategy set than the "dishonest" signaling ESS. We also discuss the dynamics of biological game theory models and the advances of genetic algorithms as a heuristic solution method for these models.

Objective: Other investigators have shown that reductions in active sodium pump units increase uterine contractility. Therefore, our goal was to determine whether uterine sodium pump abundance is decreased in mouse models of term and preterm labor., Study Design: Mice were studied during the final one-third of pregnancy. Other pregnant mice had preterm labor induced with lipopolysaccharide and were studied at timed intervals thereafter. Uterine sodium pump alpha3-isoform messenger RNA and protein were measured. Data were analyzed by analysis of variance., Results: Uterine sodium pump alpha3-isoform messenger RNA fell significantly from day 14 to day 18 and remained low on the day of birth. Uterine sodium pump alpha3-isoform protein levels decreased significantly also. In lipopolysaccharide-induced preterm labor, uterine sodium pump alpha3-isoform protein, but not messenger RNA, decreased significantly., Conclusion: Sodium pump alpha3-isoform protein levels decreased in uterus before term labor and lipopolysaccharide-induced preterm labor. These findings are similar to those in humans, which suggests that this mouse model may be useful in the study of the sodium pump in human pregnancy. Reductions in sodium pump number can increase uterine contractile force and may contribute to labor.

Objective: Microarray technology was used to comprehensively analyze gene expression during human labor in the myometrium., Study Design: cDNA micro-array was used to compare the transcriptomes of myometrium obtained from patients in spontaneous labor and those not in labor. Expression of four labor-specific genes was confirmed in the myometrium obtained from patients in spontaneous labor using RT-PCR, Northern blot analysis, and in-situ hybridization., Results: Of the >6000 cDNAs evaluated, 56 were found to be differentially expressed during labor. The labor-specific expression of 4 genes was confirmed using RT-PCR and Northern blot analysis. The relative increased expression of thrombospondin-1 in myometrium obtained from patients in spontaneous labor was also confirmed using in-situ hybridization., Conclusion: cDNA microarray was used to identify 56 differentially expressed genes in myometrium obtained from patients in spontaneous labor. The up-regulation of four genes was confirmed by multiple methods. Elucidation of the role(s) of the genes identified by microarray should improve our understanding of normal labor physiology and may ultimately lead to more effective treatments for abnormal labor.