Resident cardiac macrophages mediate adaptive myocardial remodeling.

Cardiac macrophages represent a heterogeneous cell population with distinct origins, dynamics, and functions. Recent studies have revealed that C-C Chemokine Receptor 2 positive (CCR2+) macrophages derived from infiltrating monocytes regulate myocardial inflammation and heart failure pathogenesis. Comparatively little is known about the functions of tissue resident (CCR2-) macrophages. Herein, we identified an essential role for CCR2- macrophages in the chronically failing heart. Depletion of CCR2- macrophages in mice with dilated cardiomyopathy accelerated mortality and impaired ventricular remodeling and coronary angiogenesis, adaptive changes necessary to maintain cardiac output in the setting of reduced cardiac contractility. Mechanistically, CCR2- macrophages interacted with neighboring cardiomyocytes via focal adhesion complexes and were activated in response to mechanical stretch through a transient receptor potential vanilloid 4 (TRPV4)-dependent pathway that controlled growth factor expression. These findings establish a role for tissue-resident macrophages in adaptive cardiac remodeling and implicate mechanical sensing in cardiac macrophage activation.

Estimating causal effects for binary outcomes using per-decision inverse probability weighting.

Micro-randomized trials are commonly conducted for optimizing mobile health interventions such as push notifications for behavior change. In analyzing such trials, causal excursion effects are often of primary interest, and their estimation typically involves inverse probability weighting (IPW). However, in a micro-randomized trial, additional treatments can often occur during the time window over which an outcome is defined, and this can greatly inflate the variance of the causal effect estimator because IPW would involve a product of numerous weights. To reduce variance and improve estimation efficiency, we propose two new estimators using a modified version of IPW, which we call "per-decision IPW." The second estimator further improves efficiency using the projection idea from the semiparametric efficiency theory. These estimators are applicable when the outcome is binary and can be expressed as the maximum of a series of sub-outcomes defined over sub-intervals of time. We establish the estimators' consistency and asymptotic normality. Through simulation studies and real data applications, we demonstrate substantial efficiency improvement of the proposed estimator over existing estimators. The new estimators can be used to improve the precision of primary and secondary analyses for micro-randomized trials with binary outcomes.

Incorporating nonparametric methods for estimating causal excursion effects in mobile health with zero-inflated count outcomes.

In mobile health, tailoring interventions for real-time delivery is of paramount importance. Micro-randomized trials have emerged as the "gold-standard" methodology for developing such interventions. Analyzing data from these trials provides insights into the efficacy of interventions and the potential moderation by specific covariates. The "causal excursion effect," a novel class of causal estimand, addresses these inquiries. Yet, existing research mainly focuses on continuous or binary data, leaving count data largely unexplored. The current work is motivated by the Drink Less micro-randomized trial from the UK, which focuses on a zero-inflated proximal outcome, i.e., the number of screen views in the subsequent hour following the intervention decision point. To be specific, we revisit the concept of causal excursion effect, specifically for zero-inflated count outcomes, and introduce novel estimation approaches that incorporate nonparametric techniques. Bidirectional asymptotics are established for the proposed estimators. Simulation studies are conducted to evaluate the performance of the proposed methods. As an illustration, we also implement these methods to the Drink Less trial data.

User engagement in clinical trials of digital mental health interventions: a systematic review.

INTRODUCTION: Digital mental health interventions (DMHIs) overcome traditional barriers enabling wider access to mental health support and allowing individuals to manage their treatment. How individuals engage with DMHIs impacts the intervention effect. This review determined whether the impact of user engagement was assessed in the intervention effect in Randomised Controlled Trials (RCTs) evaluating DMHIs targeting common mental disorders (CMDs). METHODS: This systematic review was registered on Prospero (CRD42021249503). RCTs published between 01/01/2016 and 17/09/2021 were included if evaluated DMHIs were delivered by app or website; targeted patients with a CMD without non-CMD comorbidities (e.g., diabetes); and were self-guided. Databases searched: Medline; PsycInfo; Embase; and CENTRAL. All data was double extracted. A meta-analysis compared intervention effect estimates when accounting for engagement and when engagement was ignored. RESULTS: We identified 184 articles randomising 43,529 participants. Interventions were delivered predominantly via websites (145, 78.8%) and 140 (76.1%) articles reported engagement data. All primary analyses adopted treatment policy strategies, ignoring engagement levels. Only 19 (10.3%) articles provided additional intervention effect estimates accounting for user engagement: 2 (10.5%) conducted a complier-average-causal effect (CACE) analysis (principal stratum strategy) and 17 (89.5%) used a less-preferred per-protocol (PP) population excluding individuals failing to meet engagement criteria (estimand strategies unclear). Meta-analysis for PP estimates, when accounting for user engagement, changed the standardised effect to -0.18 95% CI (-0.32, -0.04) from - 0.14 95% CI (-0.24, -0.03) and sample sizes reduced by 33% decreasing precision, whereas meta-analysis for CACE estimates were - 0.19 95% CI (-0.42, 0.03) from - 0.16 95% CI (-0.38, 0.06) with no sample size decrease and less impact on precision. DISCUSSION: Many articles report user engagement metrics but few assessed the impact on the intervention effect missing opportunities to answer important patient centred questions for how well DMHIs work for engaged users. Defining engagement in this area is complex, more research is needed to obtain ways to categorise this into groups. However, the majority that considered engagement in analysis used approaches most likely to induce bias.

Unintentional overdoses: understanding the fentanyl landscape and reducing harm.

PURPOSE OF REVIEW: Adolescent and young adult overdoses and overdose fatalities continue to increase despite reductions in self-reported substance use. This review aims to explore factors contributing to this overdose epidemic, highlight signs of overdose and the role of the overdose reversal medication naloxone, and provide recommendations for practice change to support patients and decrease their risk of unintentional overdose. RECENT FINDINGS: The potent opioid fentanyl is a common contaminant in nonopioid substances, as well as in heroin and counterfeit pills, heightening risk of fatal overdose. Adolescents and young adults who die of overdose are rarely engaged in substance use disorder treatment. Medications for opioid use disorder are effective at reducing risk of fatal overdose but are underutilized, as is the opioid reversal medication naloxone. SUMMARY: Pediatric clinician engagement in harm reduction with adolescents and young adults, starting with screening through a confidential interview, may enhance pathways to care and reduce the risk of overdose.

How and to what extent did the Coventry City of Culture 'City Host' volunteer programme effect the volunteers' mental wellbeing? A qualitative study.

BACKGROUND: A team of volunteers, known as City Hosts, were recruited to support UK City of Culture 2021 awarded to Coventry. City Hosts held various roles facilitating cultural event delivery and promoting a positive experience for visitors. This study aimed to (i) understand how and to what extent the volunteering programme impacted volunteer subjective wellbeing, and (ii) explore the mechanisms of change and intermediate outcomes between volunteering and subjective wellbeing. METHODS: This qualitative study comprised inductive and deductive analysis of data collected through semi-structured interviews, conducted between December 2021-May 2022 with City Hosts. This was complimented with secondary qualitative analysis of free text responses within Monitoring and Evaluation data collected from City Hosts in surveys conducted in August and November 2021, and April 2022. RESULTS: Approximately 180 City Hosts responded to the free text questions in each survey and 27 completed interviews. Analysis of data collected from City Hosts suggested positive wellbeing impacts from volunteering and supported theorised pathways to improved wellbeing. Strengths of the City Host programme included (i) facilitating the full range of mechanisms of change that mediate improved volunteer wellbeing, particularly promoting social connections and developing a strong role and group identity and (ii) flexibility around what volunteers do, how much, and how often. CONCLUSIONS: This study offers lessons for others designing volunteering programmes who wish to promote wellbeing among associated volunteers. We also offer evidence that exposure to culture may be one mechanism by which volunteering can improve wellbeing.

The English national health service diabetes prevention programme (NHS DPP): A scoping review of existing evidence.

AIMS: The English National Health Service Diabetes Prevention Programme (NHS DPP) is commissioned by NHS England and has been rolled out across England to adults identified as being at high risk of type 2 diabetes. The present scoping review aimed to identify the extent and nature of evidence to date on the NHS DPP and describe what the evidence has reported. METHODS: A scoping review involving searches of various sources (including MEDLINE, CINAHL, MediArXiv, Google Scholar and GreyLit) was conducted on 31 August 2021 and repeated on 09 February 2022. Only articles reporting on the NHS DPP made available since 2015 were eligible for inclusion. RESULTS: 65 articles were included. Of these, 37 were journal publications. Most articles were made available in 2018 and 2020 (total n = 25). The majority of articles reported on uptake and retention (n = 27) whilst others reported on implementation considerations (n = 24), programme outcomes (n = 21), stakeholder experience (n = 8) and screening and referral processes (n = 3). Various research methods were reported and included qualitative (n = 9) and document analysis (n = 8). Articles revealed preliminary evidence on service user characteristics, rates of referral, uptake and retention as well as how far the NHS DPP is being delivered in line with its evidence base and service specification. CONCLUSIONS: The evidence is accumulating on NHS DPP uptake and retention most, with emerging evidence on programme outcomes (such as weight loss and HbA1c). More evidence is warranted on stakeholder experience to decipher how to overcome low initial and long-term engagement reported by the current evidence base.

Standing Crop, Turnover, and Production Dynamics of Macrocystis pyrifera and Understory Species Hedophyllum nigripes and Neoagarum fimbriatum in High Latitude Giant Kelp Forests.

Production rates reported for canopy-forming kelps have highlighted the potential contributions of these foundational macroalgal species to carbon cycling and sequestration on a globally relevant scale. Yet, the production dynamics of many kelp species remain poorly resolved. For example, productivity estimates for the widely distributed giant kelp Macrocystis pyrifera are based on a few studies from the center of this species' range. To address this geospatial bias, we surveyed giant kelp beds in their high latitude fringe habitat in southeast Alaska to quantify foliar standing crop, growth and loss rates, and productivity of M. pyrifera and co-occurring understory kelps Hedophyllum nigripes and Neoagarum fimbriatum. We found that giant kelp beds at the poleward edge of their range produce ~150 g C · m-2 · year-1 from a standing biomass that turns over an estimated 2.1 times per year, substantially lower rates than have been observed at lower latitudes. Although the productivity of high latitude M. pyrifera dwarfs production by associated understory kelps in both winter and summer seasons, phenological differences in growth and relative carbon and nitrogen content among the three kelp species suggests their complementary value as nutritional resources to consumers. This work represents the highest latitude consideration of M. pyrifera forest production to date, providing a valuable quantification of kelp carbon cycling in this highly seasonal environment.

Use of Project ECHO to promote evidence based care for justice involved adults with opioid use disorder.

Background: People with opioid use disorders (OUDs) are at heightened risk for involvement with the criminal justice system. Growing evidence supports the safety and effectiveness of providing empirically supported treatments for OUD, such as medications for OUD (M-OUD), to people with criminal justice involvement including during incarceration or upon reentry into the community. However, several barriers limit availability and accessibility of these treatment options for people with OUDs, including a shortage of healthcare and justice professionals trained in how to implement them. This study evaluated a novel education program, the Indiana Jail OUD Treatment ECHO, designed to disseminate specialty knowledge and improve attitudes about providing M-OUD in justice settings. Methods: Through didactic presentations and case-based learning (10 bimonthly, 90-min sessions), a multidisciplinary panel of specialists interacted with a diverse group of community-based participants from healthcare, criminal justice, law enforcement, and related fields. Participants completed standardized surveys about OUD knowledge and attitudes about delivering M-OUD in correctional settings. Thematic analysis of case presentations was conducted. Results: Among 43 participants with pre- and post-series evaluation data, knowledge about OUD increased and treatment was viewed as more practical after the ECHO series compared to before. Cases presented during the program typically involved complicated medical and psychiatric comorbidities, and recommendations addressed several themes including harm reduction, post-release supports, and integration of M-OUD and non-pharmacological interventions. Conclusions: Evaluation of future iterations of this innovative program should address attendance and provider behavior change as well as patient and community outcomes associated with ECHO participation.

Comparing Practices Used in Overdose Fatality Review Teams to Recommended Implementation Guidelines.

OBJECTIVES: Overdose fatality review teams are a public health and public safety collaboration that reviews fatality cases using a multidisciplinary team to provide recommendations for overdose prevention. No research exists on the case review practices currently being used in these programs. DESIGN: We administered a cross-sectional survey measuring case review practices and perceptions to a convenience sample of overdose fatality review teams. SETTING: We administered the online survey to participants at a national virtual forum on overdose fatality review. PARTICIPANTS: In this study, we examined 30 county-level overdose fatality review teams from 6 states who completed the survey. MAIN OUTCOME MEASURES: We developed measures of case review practices from an overdose fatality review implementation guide. We provided descriptive statistics on the survey items used to measure these practices and examined how practice uptake varied by overdose fatality review team characteristics. RESULTS: Most overdose fatality review teams had adequate representation and membership, but none adhered to all of the practices measured from the implementation guide. The largest gap was in perceived effectiveness and implementation of case review recommendations. In addition, teams that had been reviewing cases for longer reported more adherence to recommended practices. CONCLUSIONS: Overdose fatality case review is a collaboration between local public health and public safety agencies that holds great promise. However, these teams will require additional training and technical assistance with local community support to ensure that recommendations are actionable.

Ecological change in dynamic environments: Accounting for temporal environmental variability in studies of ocean change biology.

The environmental conditions in the ocean have long been considered relatively more stable through time compared to the conditions on land. Advances in sensing technologies, however, are increasingly revealing substantial fluctuations in abiotic factors over ecologically and evolutionarily relevant timescales in the ocean, leading to a growing recognition of the dynamism of the marine environment as well as new questions about how this dynamism may influence species' vulnerability to global environmental change. In some instances, the diurnal or seasonal variability in major environmental change drivers, such as temperature, pH and seawater carbonate chemistry, and dissolved oxygen, can exceed the changes expected with continued anthropogenic global change. While ocean global change biologists have begun to experimentally test how variability in environmental conditions mediates species' responses to changes in the mean, the extensive literature on species' adaptations to temporal variability in their environment and the implications of this variability for their evolutionary responses has not been well integrated into the field. Here, we review the physiological mechanisms underlying species' responses to changes in temperature, pCO2 /pH (and other carbonate parameters), and dissolved oxygen, and discuss what is known about behavioral, plastic, and evolutionary strategies for dealing with variable environments. In addition, we discuss how exposure to variability may influence species' responses to changes in the mean conditions and highlight key research needs for ocean global change biology.

Engagement With a Behavior Change App for Alcohol Reduction: Data Visualization for Longitudinal Observational Study.

BACKGROUND: Behavior change apps can develop iteratively, where the app evolves into a complex, dynamic, or personalized intervention through cycles of research, development, and implementation. Understanding how existing users engage with an app (eg, frequency, amount, depth, and duration of use) can help guide further incremental improvements. We aim to explore how simple visualizations can provide a good understanding of temporal patterns of engagement, as usage data are often longitudinal and rich. OBJECTIVE: This study aims to visualize behavioral engagement with Drink Less, a behavior change app to help reduce hazardous and harmful alcohol consumption in the general adult population of the United Kingdom. METHODS: We explored behavioral engagement among 19,233 existing users of Drink Less. Users were included in the sample if they were from the United Kingdom; were 18 years or older; were interested in reducing their alcohol consumption; had a baseline Alcohol Use Disorders Identification Test score of 8 or above, indicative of excessive drinking; and had downloaded the app between May 17, 2017, and January 22, 2019 (615 days). Measures of when sessions begin, length of sessions, time to disengagement, and patterns of use were visualized with heat maps, timeline plots, k-modes clustering analyses, and Kaplan-Meier plots. RESULTS: The daily 11 AM notification is strongly associated with a change in engagement in the following hour; reduction in behavioral engagement over time, with 50.00% (9617/19,233) of users disengaging (defined as no use for 7 or more consecutive days) 22 days after download; identification of 3 distinct trajectories of use, namely engagers (4651/19,233, 24.18% of users), slow disengagers (3679/19,233, 19.13% of users), and fast disengagers (10,903/19,233, 56.68% of users); and limited depth of engagement with 85.076% (7,095,348/8,340,005) of screen views occurring within the Self-monitoring and Feedback module. In addition, a peak of both frequency and amount of time spent per session was observed in the evenings. CONCLUSIONS: Visualizations play an important role in understanding engagement with behavior change apps. Here, we discuss how simple visualizations helped identify important patterns of engagement with Drink Less. Our visualizations of behavioral engagement suggest that the daily notification substantially impacts engagement. Furthermore, the visualizations suggest that a fixed notification policy can be effective for maintaining engagement for some users but ineffective for others. We conclude that optimizing the notification policy to target both effectiveness and engagement is a worthwhile investment. Our future goal is to both understand the causal effect of the notification on engagement and further optimize the notification policy within Drink Less by tailoring to contextual circumstances of individuals over time. Such tailoring will be informed from the findings of our micro-randomized trial (MRT), and these visualizations were useful in both gaining a better understanding of engagement and designing the MRT.

The effect of solifenacin on postvoid dribbling in women: results of a randomized, double-blind placebo-controlled trial.

INTRODUCTION AND HYPOTHESIS: To determine the effectiveness of the muscarinic receptor antagonist solifenacin (VESIcare®) in the treatment of postvoid dribbling (PVD). METHODS: We carried out a multicenter, 12-week, double-blind, randomized, placebo-controlled, parallel design study. Between 2012 and 2015, a total of 118 women (age 18-89 years) with PVD at least twice/weekly, were randomized to receive solifenacin (5 mg; n = 58) or placebo (n = 60) once daily. The primary outcome was the percentage reduction in PVD episodes. Secondary outcomes included the percentage of patients with ≥50% reduction in PVD episodes and changes in quality of life. RESULTS: There were no differences in either the primary or secondary outcome variables. Subgroup analysis, based on those with more severe disease (>10 PVD episodes/week), showed a greater and significant percentage reduction in the frequency of PVD episodes per day (60.3% vs 32.1%; p = 0.035) and a higher percentage of patients showing ≥50% reduction in the frequency of PVD episodes with solifenacin (68.1% vs 45.8%; p = 0.0476). A significant solifenacin effect occurred at week 2 and continued through week 12 for the subgroup. For solifenacin, PVD reduction was the same for the entire cohort and subgroup, whereas for placebo, it was 10% lower in the subgroup, declining from 42% to 32%. CONCLUSION: There were no differences in PVD outcomes between the solifenacin and placebo groups. Solifenacin may play a role in treating women with the most severe symptoms. Because of the powerful placebo response seen in this study, behavior-based interventions may be useful for treating PVD.

Factors associated with participation and completion of a survey-based study.

PURPOSE: The Healthy Work Place (HWP) study investigated methods to improve clinicians' dissatisfaction and burnout. The purpose of this paper is to identify factors that influenced study enrollment and completion and assess effects of initial clinic site enrollment rates on clinician outcomes, including satisfaction, burnout, stress and intent to leave practice. DESIGN/METHODOLOGY/APPROACH: In total, 144 primary care clinicians (general internists, family physicians, nurse practitioners and physician assistants) at 14 primary care clinics were analyzed. FINDINGS: In total, 72 clinicians enrolled in the study and completed the first survey (50 percent enrollment rate). Of these, 10 did not complete the second survey (86 percent completion rate). Gender, type, burnout, stress and intervention did not significantly affect survey completion. Hence, widespread agreement about most moral/ethical issues (72 percent vs 22 percent; p=0.0060) and general agreement on treatment methods (81 percent vs 50 percent; p=0.0490) were reported by providers that completed both surveys as opposed to just the initial survey. Providers with high initial clinic site enrollment rates (=50 percent providers) obtained better outcomes, including improvements in or no worsening of satisfaction (odds ratio (OR)=19.16; p=0.0217) and burnout (OR=6.24; p=0.0418). SOCIAL IMPLICATIONS: More providers experiencing workplace agreement completed the initial and final surveys, and providers at sites with higher initial enrollment rates obtained better outcomes including a higher rate of improvement or no worsening of job satisfaction and burnout. ORIGINALITY/VALUE: There is limited research on clinicians' workplace and other factors that influence their participation in survey-based studies. The findings help us to understand how these factors may affect quality of data collecting and outcome. Thus, the study provides us insight for improvement of quality in primary care.

Exploring how workplace and social policies relate to caregivers' financial strain.

Informal caregiving is a critical component of the US long-term care system, but can have significant negative impacts on caregiver employment, finances, and well-being. An online survey of Colorado caregivers was piloted in 2016-17 to explore whether workplace and social policies such as access to paid family leave and public health insurance can buffer the negative financial impacts of caregiving and help caregivers to remain in the workforce. Using standardized measures, the survey assessed caregivers' employment and financial status, well-being (physical and mental health, caregiver strain, benefits of caregiving), access to workplace supports, and covariates (e.g., caregiver demographics, health, social support, and service utilization). Ninety-five caregivers, recruited through community agency partners, completed the survey. Respondents were predominately female (89%), middle-aged (M = 57), non-Hispanic White (64%) or Latino/a (22%), and caring for a parent (40%) or spouse (30%) for over one year. Half (51%) reported working full- or part-time jobs, while 16.4% had stopped working because of caregiving. In multivariate regression modeling, predictors of financial strain included the care recipients' financial strain and the caregiver's reduction or ceasing of work. Medicare may be protective to minimize caregivers' need to reduce or cease work. Implications for caregivers' ability to stay engaged in the workforce and prepare for their own retirement are explored.

Thromboembolic complications following a first isolated episode of superficial vein thrombosis: a cross-sectional retrospective study.

Superficial vein thrombosis (SVT) may be associated with complications such as venous thromboembolism (VTE) and recurrent SVT. The purpose of this study was to explore risk factors among patients with a first isolated episode of SVT (index SVT) involving upper and lower extremities and to estimate the prevalence of VTE complications within 1 year of index SVT. Retrospective chart review of electronic records at Marshfield Clinic in Wisconsin identified 381 subjects with a first isolated SVT diagnosis (male/female: 170/211; median age 59.4 years). Patients were stratified based on whether they did (n = 44; 11.5 %) or did not (n = 337; 88.5 %) experience VTE complications and whether they did (n = 25; 6.6 %) or did not (n = 356; 93.4 %) experience pulmonary embolism (PE) and/or deep vein thrombosis (DVT) within 1 year of index SVT. There were 49 complications among 44 patients; these included DVT (n = 18, 36.7 %), propagation of SVT (n = 18, 36.7 %), PE (n = 9, 18.4 %), new SVT at different location (n = 3, 6.1 %), and recurrent SVT (n = 1, 2.0 %). Univariate analysis of all VTE complications identified seven potential risk factors and similar analysis of PE/DVT complications identified eight potential risk factors, with six common risk factors identified in both analyses. Multivariate analysis identified indwelling venous catheter 30 days prior to SVT (p = 0.044), cancer history with treatment in the previous year (p = 0.001), and non-surgical trauma 7 days prior to SVT (p < 0.001) as independent risk factors for PE/DVT complications. Independent risk factors identified in the current study may convey greater risk for VTE complications, especially PE/DVT, following an initial isolated SVT episode.

Ozone Exposure Increases Circulating Stress Hormones and Lipid Metabolites in Humans.

RATIONALE: Air pollution has been associated with increased prevalence of type 2 diabetes; however, the mechanisms remain unknown. We have shown that acute ozone exposure in rats induces release of stress hormones, hyperglycemia, leptinemia, and glucose intolerance that are associated with global changes in peripheral glucose, lipid, and amino acid metabolism. OBJECTIVES: To examine ozone-induced metabolic derangement in humans using serum metabolomic assessment, establish human-to-rodent coherence, and identify novel nonprotein biomarkers. METHODS: Serum samples were obtained from a crossover clinical study that included two clinic visits (n = 24 each) where each subject was blindly exposed in the morning to either filtered air or 0.3 parts per million ozone for 2 hours during 15-minute on-off exercise. Serum samples collected within 1 hour after exposure were assessed for changes in metabolites using a metabolomic approach. MEASUREMENTS AND MAIN RESULTS: Metabolomic analysis revealed that ozone exposure markedly increased serum cortisol and corticosterone together with increases in monoacylglycerol, glycerol, and medium- and long-chain free fatty acids, reflective of lipid mobilization and catabolism. Additionally, ozone exposure increased serum lysolipids, potentially originating from membrane lipid breakdown. Ozone exposure also increased circulating mitochondrial ß-oxidation-derived metabolites, such as acylcarnitines, together with increases in the ketone body 3-hydroxybutyrate. These changes suggested saturation of ß-oxidation by ozone in exercising humans. CONCLUSIONS: As in rodents, acute ozone exposure increased stress hormones and globally altered peripheral lipid metabolism in humans, likely through activation of a neurohormonally mediated stress response pathway. The metabolomic assessment revealed new biomarkers and allowed for establishment of rodent-to-human coherence. Clinical trial registered with www.clinicaltrials.gov (NCT 01492517).

Metabolites in stored platelets associated with platelet recoveries and survivals.

BACKGROUND: Transfusion of platelets (PLTs) is a common therapy in a number of clinical settings. However, it is well understood that there is substantial donor-to-donor variation in how well PLTs store and thus the quality of the products that are transfused. The basis of such variation is poorly understood, and there are limited metrics by which units of PLTs can be assessed for their posttransfusion performance. It has repeatedly been demonstrated that myriad biologic changes take place during PLT storage; however, which of the changes correlate with quality of the stored PLTs and/or are mechanistically involved in PLT function remains undetermined. STUDY DESIGN AND METHODS: The current study tested stored PLTs from 21 normal subjects, combining high-resolution metabolomics of stored PLTs with in vivo PLT recoveries and survivals. Both individual analytes and metabolic pathways that correlate with posttransfusion PLT viability were identified. RESULTS: Caffeine metabolites were associated with poor PLT recovery; caffeine metabolism was not ongoing in the PLT bag and remained at prestorage levels. Acylcarnitines, particular fatty acid metabolites, and oxidized fatty acids were associated with poor PLT survivals. Of the myriad metabolic changes during PLT storage, these are the first reported metabolic findings to begin distinguishing which changes are of functional importance regarding posttransfusion PLT performance. CONCLUSIONS: Together, these findings provide novel mechanistic insights into the functional biology of the PLT storage lesion as well as identifying potential targets for modifying donor environment (e.g., caffeine consumption) and also metrics of quality assessment for stored human PLTs.

From metabolomics to fluxomics: a computational procedure to translate metabolite profiles into metabolic fluxes.

We describe a believed-novel procedure for translating metabolite profiles (metabolome) into the set of metabolic fluxes (fluxome) from which they originated. Methodologically, computational modeling is integrated with an analytical platform comprising linear optimization, continuation and dynamic analyses, and metabolic control. The procedure was tested with metabolite profiles obtained from ex vivo mice Langendorff-heart preparations perfused with glucose. The metabolic profiles were analyzed using a detailed kinetic model of the glucose catabolic pathways including glycolysis, pentose phosphate (PP), glycogenolysis, and polyols to translate the glucose metabolome of the heart into the fluxome. After optimization, the ability of the model to simulate the initial metabolite profile was confirmed, and metabolic fluxes as well as the structure of control and regulation of the glucose catabolic network could be calculated. We show that the step catalyzed by phosphofructokinase together with ATP demand and glycogenolysis exert the highest control on the glycolytic flux. The negative flux control exerted by phosphofructokinase on the PP and polyol pathways revealed that the extent of glycolytic flux directly affects flux redirection through these pathways, i.e., the higher the glycolytic flux the lower the PP and polyols. This believed-novel methodological approach represents a step forward that may help in designing therapeutic strategies targeted to diagnose, prevent, and treat metabolic diseases.