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Background: The Uganda Ministry of Health (MoH) and implementing partners instituted an infection prevention and control (IPC) response strategy during the Uganda SVD outbreak in 2022 that involved rapid enhancement of screening capacity at HCFs. Rapid scale-up of screening for infectious diseases, such as SVD, is critical for early identification and triage of suspected or confirmed cases in HCFs. We describe the rapid deployment of a multimodal IPC strategy implemented in response to the SVD outbreak and the resulting impact on screening measures at HCFs. Methods: We implemented a multimodal IPC strategy in HCFs from five high risk districts to improve screening practices from November 2022–January 2023. The strategy included training health workers (HCWs) identified as IPC mentors; establishing screening areas; and providing screening supplies and communication materials. The three-day training utilized an MoH standardized training package with didactic and practice sessions. The mentors then cascaded screening information and skills to other HCWs through onsite trainings and mentorships and established screening areas. Baseline and endline (3 months after baseline) cross-sectional assessments were conducted using the MoH IPC Assessment Tool adapted from the WHO Ebola IPC Scorecard. The five main screening parameters assessed included presence of ≥ 1 meter distance between screener and the person screened, availability of a functional handwashing facility and infrared thermometer, correct record of each person’s temperature, and appropriate referral process for those suspected of having SVD to holding areas. IPC capacity was measured through the summation of each of these parameter results and calculated as an overall percentage. IBM SPSS Statistics 20 software was used for data analysis and a paired t-test done to determine any significant findings between mean scores (percentage) at baseline and endpoint. Results: A total of 296 IPC mentors were trained, screening information was cascaded to 3,899 HCWs, and screening areas were established in 1,135 HCFs. Based on the screening results from the MoH IPC assessment tool, capacity improved from 44% (SD=37) at baseline to 67% (SD=34) at endpoint. Screening capacity improved from baseline to endpoint among level II and public HCFs from 33% (SD=35) to 60% (SD=35) (p < 0 .05) and from 54% (SD=38) to 76% (SD=31) (p < 0 .05), respectively. Conclusion: Rapid implementation of a multimodal IPC strategy was successful in enhancing screening capacity across Uganda’s HCFs during a SVD response, which is critical for early identification of infected patients to interrupt transmission. This multimodal approach should be recommended for future response actions.

CONTEXT: To ensure interpretability and replicability of clinical experiments, methods must be adequately explicit and should elicit the same decision from different clinicians who comply with the study protocol. OBJECTIVE: The objective of this study was to determine whether clinician compliance with protocol recommendations exceeds 90%. DESIGN: We developed an adequately explicit computerized protocol (eProtocol-insulin) for managing critically ill adult patient blood glucose. We monitored clinician compliance with eProtocol-insulin recommendations in four intensive care units in four hospitals and compared blood glucose distributions with those of a simple clinical guideline at one hospital and a paper-based protocol at another. All protocols and the guideline used intravenous insulin and 80 to 110 mg/dL (4.4-6.1 mmol/L) blood glucose targets. SETTING: The setting for this study was four academic hospital intensive care units. PATIENTS: This study included critically ill adults requiring intravenous insulin. INTERVENTION: Intervention used in this study was a bedside computerized protocol for managing blood glucose. MAIN OUTCOME MEASURE: The main outcome measure was clinician compliance with eProtocol-insulin recommendations. RESULTS: The number of patients was 31 to 458 and the number of blood glucose measurements was 2,226 to 19,925 among the four intensive care units. Clinician compliance with eProtocol-insulin recommendations was 91% to 98%. Blood glucose distributions were similar in the four hospitals (generalized linear model p = .18). Compared with the simple guideline, eProtocol-insulin glucose measurements within target increased from 21% to 39%, and mean blood glucose decreased from 142 to 115 mg/dL (generalized linear model p < .001). Compared with the paper-based protocol, eProtocol-insulin glucose measurements within target increased from 28% to 42%, and mean blood glucose decreased from 134 to 116 mg/dL (generalized linear model p = .001). CONCLUSIONS: The 91% to 98% clinician compliance indicates eProtocol-insulin is an exportable instrument that can establish a replicable experimental method for clinical trials of blood glucose management in critically ill adults. Control of blood glucose was better with eProtocol-insulin than with a simple clinical guideline or a paper-based protocol. [ABSTRACT FROM AUTHOR]

Objectives: We document clinicians' stated blood glucose control practice patterns in North American pediatric and adult ICUs.Methods: Using a Web-based self-administered questionnaire, we conducted a nationwide survey of North American pediatric and adult ICUs. Participants included ICU medical directors, nurses, fellows in training, and attending intensivists from participating ICUs in three critical care research networks.Measurements and Main Results: Item generation and item selection were performed according to standard scientific survey methods. Questions were designed to describe clinicians' perceptions about glucose control practices. The questionnaire topics included the following: respondent characteristics; ICU description; hyperglycemia; hypoglycemia; and glucose measurement. The institutional response rate was 96% (50 of 52 institutions). The clinician response rate was 58% (163 of 282 physicians). Adult ICU clinicians defined hyperglycemia (120 mg/dL [6.2 mmol/L]) at a lower threshold than pediatric ICU clinicians (150 mg/dL [8.3 mmol/L]). Hypoglycemia was defined similarly by both groups (median, < or = 60 mg/dL [3.3 mmol/L]; range, 40 to 80 mg/dL [2.2 to 4.4 mmol/L]). More pediatric ICU clinicians (84.5%) than adult ICU clinicians (59.1%) considered hypoglycemia to be more dangerous than hyperglycemia. A larger percentage of adult ICU clinicians (82.5%) than pediatric ICU clinicians (49.3%) preferred a target blood glucose level between 80 and 110 mg/dL (4.4 to 6.1 mmol/L). Clinical algorithms for glucose management varied among clinicians and across institutions.Conclusions: Blood glucose control with insulin is used frequently for critically ill adults and children. A wide variation in practice exists in blood glucose targets, hyperglycemia and hypoglycemia definitions, and decision algorithms among North American adult and pediatric ICUs. [ABSTRACT FROM AUTHOR]

Socialization includes internalization of attitudes and values critical to the development of a professional identity. Resocialization relates to the returning registered nurse student's development of professional values and roles. Nurse educators' challenge is to consider socialization/resocialization as a formation/re-formation process. The purpose of this article is to report findings from a replication qualitative descriptive study that examined the process of change in knowledge and attitudes of recent MSN graduates using Mezirow's (1994)Transformative Learning Theory. Findings substantiated the changes in attitudes, knowledge and skills of MSN graduates identified by Cragg and Andrusyszyn (2005). Results further inform nurse educators of the process of transformation in MSN graduates according to Mezirow's Phases of Perspective Transformation. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) prevention is currently limited by the lack of diagnostic tools able to identify disease before autoimmune destruction of the pancreatic β cells. Autoantibody tests are used to predict risk and, in combination with glucose dysregulation indicative of β cell loss, to determine administration of immunotherapies. Our objective was to remotely identify immune changes associated with the disease, and we have employed a subcutaneously implanted microporous poly(e-caprolactone) (PCL) scaffold to function as an immunological niche (IN) in two models of T1D. Biopsy and analysis of the IN enables disease monitoring using transcriptomic changes at a distal site from autoimmune destruction of the pancreas, thereby gaining cellular level information about disease without the need for a biopsy of the native organ. Using this approach, we identified gene signatures that stratify healthy and diseased mice in both an adoptive transfer model and a spontaneous onset model of T1D. The gene signatures identified herein demonstrate the ability of the IN to identify immune activation associated with diabetes across models., (© 2024 The Author(s). Biotechnology and Bioengineering published by Wiley Periodicals LLC.)

Background: Ataxic breathing (AB) is a well-known manifestation of opioid effects in animals and humans, but is not routinely included in monitoring for opioid-induced respiratory depression (OIRD). We quantified AB in normal volunteers receiving increasing doses of remifentanil. We used a support vector machine (SVM) learning approach with features derived from a modified Poincaré plot. We tested the hypothesis that AB may be found when bradypnea and reduced mental status are not present., Methods: Twenty-six healthy volunteers (13 female) received escalating target effect-site concentrations of remifentanil with a low baseline dose of propofol to simulate typical breathing patterns in drowsy patients who had received parenteral opioids. We derived respiratory rate (RR) from respiratory inductance plethysmography, mental alertness from the Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S), and AB severity on a 0 to 4 scale (categories ranging from none to severe) from the SVM. The primary outcome measure was sensitivity and specificity for AB to detect OIRD., Results: All respiratory measurements were obtained from unperturbed subjects during steady state in 121 assessments with complete data. The sensitivity of AB for detecting OIRD by the conventional method was 92% and specificity was 28%. As expected, 69 (72%) of the instances not diagnosed as OIRD using conventional measures were observed to have at least moderate AB., Conclusions: AB was frequently present in the absence of traditionally detected OIRD as defined by reduced mental alertness (MOAA/S score of <4) and bradypnea (RR <8 breaths/min). These results justify the need for future trials to explore replicability with other opioids and clinical utility of AB as an add-on measure in recognizing OIRD., Competing Interests: Conflicts of interest, Funding: See Disclosures at the end of the article., (Copyright © 2024 International Anesthesia Research Society.)

Antibodies to programmed cell death protein1 (anti-PD-1) have become a promising immunotherapy for triple negative breast cancer (TNBC), blocking PD-L1 signaling from pro-tumor cells through T cell PD-1 receptor binding. Nevertheless, only 10-20% of PD-L1 + metastatic TNBC patients who meet criteria benefit from ICB, and biomarkers to predict patient response have been elusive. We have previously developed an immunological niche, consisting of a microporous implant in the subcutaneous space, that supports tissue formation whose immune composition is consistent with that within vital organs. Herein, we investigated dynamic gene expression within this immunological niche to provide biomarkers of response to anti-PD-1. In a 4T1 model of metastatic TNBC, we observed sensitivity and resistance to anti-PD-1 based on primary tumor growth and survival. The niche was biopsied before, during, and after anti-PD-1 therapy, and analyzed for cell types and gene expression indicative of treatment refractivity. Myeloid cell-to-lymphocyte ratios were altered between ICB-sensitivity and resistance. Longitudinal analysis of gene expression implicated dynamic myeloid cell function that stratified sensitivity from resistance. A niche-derived gene signature predicted sensitivity or resistance prior to therapy. Analysis of the niche to monitor immunotherapy response presents a new opportunity to personalize care and investigate mechanisms underlying treatment resistance., Competing Interests: Conflict of Interest Statement: L.D.S. and J.S.J. consult and have financial interests in COUR Pharmaceutical Development, Inc.

Biomaterial scaffolds mimicking the environment in metastatic organs can deconstruct complex signals and facilitate the study of cancer progression and metastasis. Here we report that a subcutaneous scaffold implant in mouse models of metastatic breast cancer in female mice recruits lung-tropic circulating tumor cells yet suppresses their growth through potent in situ antitumor immunity. In contrast, the lung, the endogenous metastatic organ for these models, develops lethal metastases in aggressive breast cancer, with less aggressive tumor models developing dormant lungs suppressing tumor growth. Our study reveals multifaceted roles of neutrophils in regulating metastasis. Breast cancer-educated neutrophils infiltrate the scaffold implants and lungs, secreting the same signal to attract lung-tropic circulating tumor cells. Second, antitumor and pro-tumor neutrophils are selectively recruited to the dormant scaffolds and lungs, respectively, responding to distinct groups of chemoattractants to establish activated or suppressive immune environments that direct different fates of cancer cells., (© 2023. Springer Nature Limited.)

Resolution of inflammation and mucosal wound healing are crucial processes required to re-establish homeostasis following injury of mucosal tissues. Maresin-2 (MaR2), a lipid specialized pro-resolving mediator derived from omega-3 polyunsaturated fatty acid, has been reported to promote resolution of inflammation. However, a potential role for MaR2 in regulating mucosal repair remains undefined. Using lipidomic analyses, we demonstrate biosynthesis of MaR2 in healing intestinal mucosal wounds in vivo. Importantly, administration of exogenous MaR2 promoted mucosal repair following dextran sulfate sodium-induced colitis or biopsy-induced colonic mucosal injury. Functional analyses revealed that MaR2 promotes mucosal wound repair by driving intestinal epithelial migration through activation of focal cell-matrix adhesion signaling in primary human intestinal epithelial cells. Because of its labile nature, MaR2 is easily degradable and requires ultracold storage to maintain functionality. Thus, we created thermostable polylactic acid MaR2 nanoparticles that retain biological activity following extended storage at 4 °C or above. Taken together, these results establish MaR2 as a potent pro-repair lipid mediator with broad therapeutic potential for use in promoting mucosal repair in inflammatory diseases.

How to deliver best care in various clinical settings remains a vexing problem. All pertinent healthcare-related questions have not, cannot, and will not be addressable with costly time- and resource-consuming controlled clinical trials. At present, evidence-based guidelines can address only a small fraction of the types of care that clinicians deliver. Furthermore, underserved areas rarely can access state-of-the-art evidence-based guidelines in real-time, and often lack the wherewithal to implement advanced guidelines. Care providers in such settings frequently do not have sufficient training to undertake advanced guideline implementation. Nevertheless, in advanced modern healthcare delivery environments, use of eActions (validated clinical decision support systems) could help overcome the cognitive limitations of overburdened clinicians. Widespread use of eActions will require surmounting current healthcare technical and cultural barriers and installing clinical evidence/data curation systems. The authors expect that increased numbers of evidence-based guidelines will result from future comparative effectiveness clinical research carried out during routine healthcare delivery within learning healthcare systems., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Clinical decision-making is based on knowledge, expertise, and authority, with clinicians approving almost every intervention-the starting point for delivery of "All the right care, but only the right care," an unachieved healthcare quality improvement goal. Unaided clinicians suffer from human cognitive limitations and biases when decisions are based only on their training, expertise, and experience. Electronic health records (EHRs) could improve healthcare with robust decision-support tools that reduce unwarranted variation of clinician decisions and actions. Current EHRs, focused on results review, documentation, and accounting, are awkward, time-consuming, and contribute to clinician stress and burnout. Decision-support tools could reduce clinician burden and enable replicable clinician decisions and actions that personalize patient care. Most current clinical decision-support tools or aids lack detail and neither reduce burden nor enable replicable actions. Clinicians must provide subjective interpretation and missing logic, thus introducing personal biases and mindless, unwarranted, variation from evidence-based practice. Replicability occurs when different clinicians, with the same patient information and context, come to the same decision and action. We propose a feasible subset of therapeutic decision-support tools based on credible clinical outcome evidence: computer protocols leading to replicable clinician actions (eActions). eActions enable different clinicians to make consistent decisions and actions when faced with the same patient input data. eActions embrace good everyday decision-making informed by evidence, experience, EHR data, and individual patient status. eActions can reduce unwarranted variation, increase quality of clinical care and research, reduce EHR noise, and could enable a learning healthcare system., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Pancreatic ductal adenocarcinoma (PDA) is accompanied by reprogramming of the local microenvironment, but changes at distal sites are poorly understood. We implanted biomaterial scaffolds, which act as an artificial premetastatic niche, into immunocompetent tumor-bearing and control mice, and identified a unique tumor-specific gene expression signature that includes high expression of C1qa , C1qb , Trem2 , and Chil3 Single-cell RNA sequencing mapped these genes to two distinct macrophage populations in the scaffolds, one marked by elevated C1qa , C1qb , and Trem2 , the other with high Chil3 , Ly6c2 and Plac8 In mice, expression of these genes in the corresponding populations was elevated in tumor-associated macrophages compared with macrophages in the normal pancreas. We then analyzed single-cell RNA sequencing from patient samples, and determined expression of C1QA , C1QB , and TREM2 is elevated in human macrophages in primary tumors and liver metastases. Single-cell sequencing analysis of patient blood revealed a substantial enrichment of the same gene signature in monocytes. Taken together, our study identifies two distinct tumor-associated macrophage and monocyte populations that reflects systemic immune changes in pancreatic ductal adenocarcinoma patients., (© 2021 Kemp et al.)

Nitrogen (N) pollution from N inputs to agricultural soils contributes to widespread eutrophication and global climate change. One period susceptible to N losses is between winter grain harvest in summer and corn planting in spring in a corn (Zea mays L.)-soybean [Glycine max (L.) Merr.]-winter grain rotation. Cover crops used to immobilize N during this period often depend on tillage, which can exacerbate N losses. Therefore, we evaluated whether reduced-till cover crops could decrease nitrate (NO 3 - ) leaching and nitrous oxide (N 2 O) emissions during this period. We tested this strategy in a cropping systems experiment on a 4-ha plot in central Pennsylvania over 2 yr. This experiment compared a clover (Trifolium pratense L.)-timothy (Phleum pratense L.) cover crop no-till underseeded into a standing spelt crop with a vetch (Vicia villosa Roth)-triticale (× Triticosecale Wittm. ex A. Camus) cover crop established with tillage after spelt harvest. These systems were compared based on fortnightly N 2 O emissions using static chambers (n = 4 per six sample dates) and potential NO 3 - leaching using anion resin bags (n = 4 per system per year). Reduced-till cover crops minimized peak N 2 O emissions during the fall compared with tilled cover crops. However, reduced-till cover crops did not decrease potentially leachable NO 3 - relative to tilled cover crops despite decreases in soil inorganic N. Cover crop N isotopes revealed that clover N may have mineralized and leached over the winter. Our results suggest that reduced-till cover crops can decrease N 2 O emissions to mitigate the climate impact of agriculture but that winter-hardy cover crops should be chosen to mitigate leaching., (© 2021 The Authors. Journal of Environmental Quality © 2021 American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America.)

Amazonian rainforest is undergoing increasing rates of deforestation, driven primarily by cattle pasture expansion. Forest-to-pasture conversion has been associated with increases in soil methane (CH 4 ) emission. To better understand the drivers of this change, we measured soil CH 4 flux, environmental conditions, and belowground microbial community structure across primary forests, cattle pastures, and secondary forests in two Amazonian regions. We show that pasture soils emit high levels of CH 4 (mean: 3454.6 ± 9482.3 μg CH 4 m -2 d -1 ), consistent with previous reports, while forest soils on average emit CH 4 at modest rates (mean: 9.8 ± 120.5 μg CH 4 m -2 d -1 ), but often act as CH 4 sinks. We report that secondary forest soils tend to consume CH 4 (mean: -10.2 ± 35.7 μg CH 4 m -2 d -1 ), demonstrating that pasture CH 4 emissions can be reversed. We apply a novel computational approach to identify microbial community attributes associated with flux independent of soil chemistry. While this revealed taxa known to produce or consume CH 4 directly (i.e. methanogens and methanotrophs, respectively), the vast majority of identified taxa are not known to cycle CH 4 . Each land use type had a unique subset of taxa associated with CH 4 flux, suggesting that land use change alters CH 4 cycling through shifts in microbial community composition. Taken together, we show that microbial composition is crucial for understanding the observed CH 4 dynamics and that microorganisms provide explanatory power that cannot be captured by environmental variables., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cancer metastasis poses a challenging problem both clinically and scientifically, as the stochastic nature of metastatic lesion formation introduces complexity for both early detection and the study of metastasis in preclinical models. Engineered metastatic niches represent an emerging approach to address this stochasticity by creating bioengineered sites where cancer can preferentially metastasize. As the engineered niche captures the earliest metastatic cells at a nonvital location, both noninvasive and biopsy-based monitoring of these sites can be performed routinely to detect metastasis early and monitor alterations in the forming metastatic niche. The engineered metastatic niche also provides a new platform technology that serves as a tunable site to molecularly dissect metastatic disease mechanisms. Ultimately, linking the engineered niches with advances in sensor development and synthetic biology can provide enabling tools for preclinical cancer models and fosters the potential to impact the future of clinical cancer care., (©2020 American Association for Cancer Research.)

Relapses in multiple sclerosis can result in irreversible nervous system tissue injury. If these events could be detected early, targeted immunotherapy could potentially slow disease progression. We describe the use of engineered biomaterial-based immunological niches amenable to biopsy to provide insights into the phenotype of innate immune cells that control disease activity in a mouse model of multiple sclerosis. Differential gene expression in cells from these niches allow monitoring of disease dynamics and gauging the effectiveness of treatment. A proactive treatment regimen, given in response to signal within the niche but before symptoms appeared, substantially reduced disease. This technology offers a new approach to monitor organ-specific autoimmunity, and represents a platform to analyze immune dysfunction within otherwise inaccessible target tissues.

Belowground ecosystem processes can be highly variable and difficult to predict using microbial community data. Here, we argue that this stems from at least three issues: (a) complex covariance structure of samples (with environmental conditions or spatial proximity) can make distinguishing biotic drivers a challenge; (b) communities can control ecosystem processes through multiple mechanisms, making the identification of these controls a challenge; and (c) ecosystem function assessments can be broad in physiological scale, encapsulating multiple processes with unique microbially mediated controls. We test these assertions using methane (CH 4 )-cycling processes in soil samples collected along a wetland-to-upland habitat gradient in the Congo Basin. We perform our measurements of function under controlled laboratory conditions and statistically control for environmental covariates to aid in identifying biotic drivers. We divide measurements of microbial communities into four attributes (abundance, activity, composition, and diversity) that represent different forms of community control. Lastly, our process measurements differ in physiological scale, including broader processes (gross methanogenesis and methanotrophy) that involve more mediating groups, to finer processes (hydrogenotrophic methanogenesis and high-affinity CH 4 oxidation) with fewer mediating groups. We observed that finer scale processes can be more readily predicted from microbial community structure than broader scale processes. In addition, the nature of those relationships differed, with broad processes limited by abundance while fine-scale processes were associated with diversity and composition. These findings demonstrate the importance of carefully defining the physiological scale of ecosystem function and performing community measurements that represent the range of possible controls on ecosystem processes., (© 2020 John Wiley & Sons Ltd.)

Monitoring metastatic events in distal tissues is challenged by their sporadic occurrence in obscure and inaccessible locations within these vital organs. A synthetic biomaterial scaffold can function as a synthetic metastatic niche to reveal the nature of these distal sites. These implanted scaffolds promote tissue ingrowth, which upon cancer initiation is transformed into a metastatic niche that captures aggressive circulating tumor cells. We hypothesized that immune cell phenotypes at synthetic niches reflect the immunosuppressive conditioning within a host that contributes to metastatic cell recruitment and can identify disease progression and response to therapy. We analyzed the expression of 632 immune-centric genes in tissue biopsied from implants at weekly intervals following inoculation. Specific immune populations within implants were then analyzed by single-cell RNA-seq. Dynamic gene expression profiles in innate cells, such as myeloid-derived suppressor cells, macrophages, and dendritic cells, suggest the development of an immunosuppressive microenvironment. These dynamics in immune phenotypes at implants was analogous to that in the diseased lung and had distinct dynamics compared with blood leukocytes. Following a therapeutic excision of the primary tumor, longitudinal tracking of immune phenotypes at the implant in individual mice showed an initial response to therapy, which over time differentiated recurrence versus survival. Collectively, the microenvironment at the synthetic niche acts as a sentinel by reflecting both progression and regression of disease. SIGNIFICANCE: Immune dynamics at biomaterial implants, functioning as a synthetic metastatic niche, provides unique information that correlates with disease progression. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/3/602/F1.large.jpg. See related commentary by Wolf and Elisseeff, p. 377 ., (©2019 American Association for Cancer Research.)

Background: In addition to hyperglycemia, hypoglycemia, and glycemic variability, reduced time in targeted blood glucose range (TIR) is associated with increased risk of death in critically ill patients. This relation between TIR and mortality may be confounded by diabetic status and antecedent glycemic control., Methods: This study retrospectively analyzed critically ill patients managed with the same IV insulin protocol at multiple centers. The percentage of TIR between 70 and 139 mg/dL was calculated. Patients with diabetic ketoacidosis, patients who had < 10 blood glucose readings, and patients with repeat admissions were excluded. The highest recorded glycosylated hemoglobin value in the preceding 3 months or up to 1 month following admission were used as a surrogate for the patient's preexisting glucose control. Stratified regression analyses were performed for 30-day mortality, with covariates of age, sex, TIR ≥ 80%, Acute Physiology Score, and Charlson Comorbidity Index., Results: A total of 9,028 patients, 53.2% of whom had diabetes, were studied. Median TIR was 84.1% for nondiabetic patients and 64.5% for patients with diabetes. Mortality was lower in those with TIR > 80% compared with those with TIR ≤ 80% (12.4% vs 19.2%; P < .001). TIR > 80% was independently associated with reduced mortality in nondiabetic patients (OR, 0.52; P < .001), patients with diabetes (OR, 0.69; P = .001), and patients with well-controlled disease (OR, 0.50; P < .001) but not in patients with poorly controlled disease (OR, 0.86; P = .40)., Conclusions: TIR was independently associated with mortality in critically ill patients, particularly those with good antecedent glucose control., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Impaired wound healing is a major complication of diabetes, and despite the associated risks, treatment strategies for diabetic wounds remain limited. This is due, in part, to an incomplete understanding of the underlying pathological mechanisms, including the effects of hyperglycemia on components of the extracellular matrix (ECM). In the current study, we explored whether the expression of thrombospondin 2 (TSP2), a matricellular protein with a demonstrated role in response to injury, was associated with delayed healing in diabetes. First, we found that TSP2 expression was elevated in diabetic mice and skin from patients with diabetes. Then, to determine the contribution of TSP2 to impaired healing in diabetes, we developed a novel diabetic TSP2-deficient model. Though the TSP2-deficient mice developed obesity and hyperglycemia comparable with diabetic control mice, they exhibited significantly improved healing, characterized by accelerated reepithelialization and increased granulation tissue formation, fibroblast migration, and blood vessel maturation. We further found that hyperglycemia increased TSP2 expression in fibroblasts, the major cellular source of TSP2 in wounds. Mechanistically, high glucose increased activation of the hexosamine pathway and nuclear factor-κB signaling to elevate TSP2 expression. Our studies demonstrate that hyperglycemia-induced TSP2 expression contributes to impaired healing in diabetes., (© 2019 by the American Diabetes Association.)

Background: Vascular smooth muscle cells (SMCs) synthesize extracellular matrix (ECM) that contributes to tissue remodeling after revascularization interventions. The cytokine transforming growth factor β (TGF-β) is induced on tissue injury and regulates tissue remodeling and wound healing, but dysregulated signaling results in excess ECM deposition and fibrosis. The LIM (Lin11, Isl-1 & Mec-3) domain protein LIM domain only 7 (LMO7) is a TGF-β1 target gene in hepatoma cells, but its role in vascular physiology and fibrosis is unknown., Methods: We use carotid ligation and femoral artery denudation models in mice with global or inducible smooth muscle-specific deletion of LMO7, and knockout, knockdown, overexpression, and mutagenesis approaches in mouse and human SMC, and human arteriovenous fistula and cardiac allograft vasculopathy samples to assess the role of LMO7 in neointima and fibrosis., Results: We demonstrate that LMO7 is induced postinjury and by TGF-β in SMC in vitro. Global or SMC-specific LMO7 deletion enhanced neointimal formation, TGF-β signaling, ECM deposition, and proliferation in vascular injury models. LMO7 loss of function in human and mouse SMC enhanced ECM protein expression at baseline and after TGF-β treatment. TGF-β neutralization or receptor antagonism prevented the exacerbated neointimal formation and ECM synthesis conferred by loss of LMO7. Notably, loss of LMO7 coordinately amplified TGF-β signaling by inducing expression of Tgfb1 mRNA, TGF-β protein, αv and β3 integrins that promote activation of latent TGF-β, and downstream effectors SMAD3 phosphorylation and connective tissue growth factor. Mechanistically, the LMO7 LIM domain interacts with activator protein 1 transcription factor subunits c-FOS and c-JUN and promotes their ubiquitination and degradation, disrupting activator protein 1-dependent TGF-β autoinduction. Importantly, preliminary studies suggest that LMO7 is upregulated in human intimal hyperplastic arteriovenous fistula and cardiac allograft vasculopathy samples, and inversely correlates with SMAD3 phosphorylation in cardiac allograft vasculopathy., Conclusions: LMO7 is induced by TGF-β and serves to limit vascular fibrotic responses through negative feedback regulation of the TGF-β pathway. This mechanism has important implications for intimal hyperplasia, wound healing, and fibrotic diseases.

Hydrogels composed of solubilized decellularized extracellular matrix (ECM) are attractive materials because they combine the complexity of native ECM with injectability and ease of use. Nevertheless, these materials are typically only tunable by altering the concentration, which alters the ligand landscape, or by incorporating synthetic components, which can result in an unfavorable host response. Herein, we demonstrate the fabrication of genetically tunable ECM-derived materials, by utilizing wild type (WT) and (thrombospondin-2 knockout) TSP-2 KO decellularized skins to prepare hydrogels. The resulting materials exhibited distinct mechanical properties characterized by rheology and different concentrations of collagens when characterized by quantitative proteomics. Mixtures of the gels achieved intermediate effects between the WT and the KO, permitting tunability of the gel properties. In vivo, the hydrogels exhibited tunable cell invasion with a correlation between the content of TSP-2 KO hydrogel and the extent of cell invasion. Additionally, TSP-2 KO hydrogels significantly improved diabetic wound healing at 10 and 21 days. Furthermore, hydrogels derived from genetically engineered in vitro cell-derived matrix mimicked the trends observed for tissue-derived matrix, providing a platform for faster screening of novel manipulations and easier clinical translation. Overall, we demonstrate that genetic engineering approaches impart tunability to ECM-based hydrogels and can result in materials capable of enhanced regeneration.

Background: Practice guidelines recommend against intensive insulin therapy in patients who are critically ill based on trials that had high rates of severe hypoglycemia. Intermountain Healthcare uses a computerized IV insulin protocol that allows choice of blood glucose (BG) targets (80-110 vs 90-140 mg/dL) and has low rates of severe hypoglycemia. We sought to study the effects of BG target on mortality in adult patients in cardiac ICUs that have very low rates of severe hypoglycemia., Methods: Critically ill patients receiving IV insulin were treated with either of two BG targets (80-110 vs 90-140 mg/dL). We created a propensity score for BG target using factors thought to have influenced clinicians' choice, and then we performed a propensity score-adjusted regression analysis for 30-day mortality., Results: There were 1,809 patients who met inclusion criteria. Baseline patient characteristics were similar. Median glucose was lower in the 80-110 mg/dL group (104 vs 122 mg/dL, P < .001). Severe hypoglycemia occurred at very low rates in both groups (1.16% vs 0.35%, P = .051). Unadjusted 30-day mortality was lower in the 80-110 mg/dL group (4.3% vs 9.2%, P < .001). This remained after propensity score-adjusted regression (OR, 0.65; 95% CI, 0.43-0.98; P = .04)., Conclusions: Tight glucose control can be achieved with low rates of severe hypoglycemia and is associated with decreased 30-day mortality in a cohort of largely patients in cardiac ICUs. Although such findings should not be used to guide clinical practice at present, the use of tight glucose control should be reexamined using a protocol that has low rates of severe hypoglycemia., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Rationale: Current guidelines recommend using forced expiratory volume in 1 second (FEV 1 ) % predicted to categorize the severity of airflow obstruction. There are limitations to using FEV 1 % predicted for this purpose, including bias associated with demographic factors and the inability to correct for "lung size." Other methods for grading the severity of airflow obstruction have been proposed to address these limitations., Objectives: Our objectives were to categorize airflow obstruction severity using these methods and then determine which method results in a categorization most closely associated with mortality., Methods: Study subjects were patients aged 40-80 years tested in our pulmonary function test laboratories in the period 2002 to 2013 with airflow obstruction based on an FEV 1 /forced vital capacity (FVC) less than the lower limit of normal. Categorization of airflow obstruction severity was determined using four methods: FEV 1 % predicted; FEV 1 % predicted adjusted by FVC % predicted; FEV 1 /FVC confidence interval approach; and FEV 1 z-scores. Receiver operating characteristic curve analysis was used to determine which categorization method best predicts 5-year survival., Results: We identified 2,000 patients with airflow obstruction. Important differences in the categorization of airflow obstruction severity were observed using the different methods. More patients were categorized as having severe obstruction using FEV 1 % predicted and FEV 1 z-scores compared with FEV 1 % predicted adjusted by FVC % predicted and FEV 1 /FVC confidence interval approach. FEV 1 % predicted was the best predictor of 5-year survival among the four methods studied., Conclusions: In our study, categorizing airflow obstruction severity using FEV 1 % predicted best predicted 5-year survival. This validates the current guideline recommendation that FEV 1 % predicted be used to categorize the severity of airflow obstruction.

Polarization of macrophages by chemical, topographical and mechanical cues presents a robust strategy for designing immunomodulatory biomaterials. Here, we studied the ability of nanopatterned bulk metallic glasses (BMGs), a new class of metallic biomaterials, to modulate murine macrophage polarization. Cytokine/chemokine analysis of IL-4 or IFNγ/LPS-stimulated macrophages showed that the secretion of TNF-α, IL-1α, IL-12, CCL-2 and CXCL1 was significantly reduced after 24-hour culture on BMGs with 55 nm nanorod arrays (BMG-55). Additionally, under these conditions, macrophages increased phagocytic potential and exhibited decreased cell area with multiple actin protrusions. These in vitro findings suggest that nanopatterning can modulate biochemical cues such as IFNγ/LPS. In vivo evaluation of the subcutaneous host response at 2 weeks demonstrated that the ratio of Arg-1 to iNOS increased in macrophages adjacent to BMG-55 implants, suggesting modulation of polarization. In addition, macrophage fusion and fibrous capsule thickness decreased and the number and size of blood vessels increased, which is consistent with changes in macrophage responses. Our study demonstrates that nanopatterning of BMG implants is a promising technique to selectively polarize macrophages to modulate the immune response, and also presents an effective tool to study mechanisms of macrophage polarization and function., Statement of Significance: Implanted biomaterials elicit a complex series of tissue and cellular responses, termed the foreign body response (FBR), that can be influenced by the polarization state of macrophages. Surface topography can influence polarization, which is broadly characterized as either inflammatory or repair-like. The latter has been linked to improved outcomes of the FBR. However, the impact of topography on macrophage polarization is not fully understood, in part, due to a lack of high moduli biomaterials that can be reproducibly processed at the nanoscale. Here, we studied macrophage interactions with nanopatterned bulk metallic glasses (BMGs), a class of metallic alloys with amorphous microstructure and formability like polymers. We show that nanopatterned BMGs modulate macrophage polarization and transiently induce less fibrotic and more angiogenic responses. Overall, we demonstrate nanopatterning of BMG implants as a technique to polarize macrophages and modulate the FBR., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Decellularized biologic scaffolds are gaining popularity over synthetic biomaterials as naturally derived materials capable of promoting improved healing. Nevertheless, the most widely used biologic material - acellular dermal matrix (ADM) - exhibits slow repopulation and remodeling, which prevents integration. Additionally, engineering control of these materials is limited because they require a natural source for their production. In the current report, we demonstrate the feasibility of using genetically engineered animals to create decellularized biologic scaffolds with favorable extracellular matrix (ECM) properties. Specifically, we utilized skin from thrombospondin (TSP)-2 KO mice to derive various decellularized products. Scanning electron microscopy and mechanical testing showed that TSP-2 KO ADM exhibited an altered structure and a reduction in elastic modulus and ultimate tensile strength, respectively. When a powdered form of KO ADM was implanted subcutaneously, it was able to promote enhanced vascularization over WT. Additionally, when implanted subcutaneously, intact slabs of KO ADM were populated by higher number of host cells when compared to WT. In vitro studies confirmed the promigratory properties of KO ADM. Specifically, degradation products released by pepsin digestion of KO ADM induced greater cell migration than WT. Moreover, cell-derived ECM from TSP-2 null fibroblasts was more permissive to fibroblast migration. Finally, ADMs were implanted in a diabetic wound model to examine their ability to accelerate wound healing. KO ADM exhibited enhanced remodeling and vascular maturation, indicative of efficient integration. Overall, we demonstrate that genetic manipulation enables engineered ECM-based materials with increased regenerative potential., (Copyright © 2018 Elsevier Ltd. All rights reserved.)