Gadolinium retention effect on macrophages - a potential cause of MRI contrast agent Dotarem toxicity.

Gadolinium is a component of the MRI contrast agent Dotarem. Although Dotarem is the least toxic among MRI contrasts used, gadolinium present in Dotarem accumulates for many years in various organs and tissues exerting toxic effects. We showed previously that gadolinium remains in macrophages for at least 7 days after exposure to Dotarem. However, very little is known about the effect of gadolinium retention on the immune cells such as macrophages. We studied the effect of 1-day and 7-day retention of gadolinium on various functions and molecular pathways of macrophages. Gadolinium retention for 7 days decreased macrophage adhesion and motility and dysregulated the expression of adhesion and fibrotic pathway-related proteins such as Notch1 and its ligand Jagged1, adhesion/migration-related proteins PAK1 and Shp1, immune response-related transcription factors Smad3 and TCF19, and chemokines CXCL10 and CXCL13, and dysregulated the mRNA expression of fibrosis-related genes involved in extracellular matrix (ECM) synthesis, such as Col6a1, Fibronectin, MMP9, and MMP12. It also completely (below a level of detection) shut down the transcription of anti-inflammatory M2 macrophage polarization marker the Arg-1. Such changes, if they occur in MRI patients, can be potentially detrimental to the patient's immune system and immune response-related processes.

Use of interactive mathematical simulations in fundamentals of biochemistry, a LibreText online educational resource, to promote understanding of dynamic reactions.

Biology is perhaps the most complex of the sciences, given the incredible variety of chemical species that are interconnected in spatial and temporal pathways that are daunting to understand. Their interconnections lead to emergent properties such as memory, consciousness, and recognition of self and non-self. To understand how these interconnected reactions lead to cellular life characterized by activation, inhibition, regulation, homeostasis, and adaptation, computational analyses and simulations are essential, a fact recognized by the biological communities. At the same time, students struggle to understand and apply binding and kinetic analyses for the simplest reactions such as the irreversible first-order conversion of a single reactant to a product. This likely results from cognitive difficulties in combining structural, chemical, mathematical, and textual descriptions of binding and catalytic reactions. To help students better understand dynamic reactions and their analyses, we have introduced two kinds of interactive graphs and simulations into the online educational resource, Fundamentals of Biochemistry, a LibreText biochemistry book. One is available for simple binding and kinetic reactions. The other displays progress curves (concentrations vs. time) for simple reactions and complex metabolic and signal transduction pathways. Users can move sliders to change dissociation and kinetic constants as well as initial concentrations and see instantaneous changes in the graphs. They can also export data into a spreadsheet for further processing, such as producing derivative Lineweaver-Burk and traditional Michaelis-Menten graphs of initial velocity (v0) versus substrate concentration.

Use of Interactive Simulations in Fundamentals of Biochemistry, a LibreText Online Educational Resource, to Promote Understanding of Dynamic Reactions.

Biology is perhaps the most complex of the sciences, given the incredible variety of chemical species that are interconnected in spatial and temporal pathways that are daunting to understand. Their interconnections lead to emergent properties such as memory, consciousness, and recognition of self and non-self. To understand how these interconnected reactions lead to cellular life characterized by activation, inhibition, regulation, homeostasis, and adaptation, computational analyses and simulations are essential, a fact recognized by the biological communities. At the same time, students struggle to understand and apply binding and kinetic analyses for the simplest reactions such as the irreversible first-order conversion of a single reactant to a product. This likely results from cognitive difficulties in combining structural, chemical, mathematical, and textual descriptions of binding and catalytic reactions. To help students better understand dynamic reactions and their analyses, we have introduced two kinds of interactive graphs and simulations into the online educational resource, Fundamentals of Biochemistry, a multivolume biochemistry textbook that is part of the LibreText collection. One type is available for simple binding and kinetic reactions. The other displays progress curves (concentrations vs time) for both simple reactions and more complex metabolic and signal transduction pathways, including those available through databases using systems biology markup language (SBML) files. Users can move sliders to change dissociation and kinetic constants as well as initial concentrations and see instantaneous changes in the graphs. They can also export data into a spreadsheet for further processing, such as producing derivative Lineweaver-Burk and traditional Michaelis-Menten graphs of initial velocity (v0) vs substrate concentration.

Macrophages and stem/progenitor cells interplay in adipose tissue and skeletal muscle: a review.

Like all immune cells, macrophages do not act autonomously but in unison with other immune cells, surrounding tissues, and the niche they occupy. Constant exchange of information between cellular and noncellular participants within a tissue allows for preserving homeostasis and defining responses in a pathologic environment. Although molecular mechanisms and pathways involved in reciprocal signaling between macrophages and other immune cells have been known for decades, much less is known about interactions between macrophages and stem/progenitor cells. Based on the time when stem cells form, there are two stem cell types: embryonic stem cells existing only in an early embryo, which are pluripotent and can differentiate into any cell type present in an adult, and somatic (adult) stem cells formed in fetus and persisting for whole adult life. Tissues and organs have their own (tissue-specific and organ-specific) adult stem cells, which serve as a reserve for tissue homeostasis and regeneration after injury. It is still uncertain whether organ- and tissue-specific stem cells are actual stem cells or just progenitor cells. The important question is how stem/progenitor cells can sculpt macrophage phenotype and functions. Even less is known if or how macrophages can shape stem/progenitor cell functions, their divisions, and fate. We describe here examples from recent studies of how stem/progenitor cells can affect macrophages and how macrophages can influence stem/progenitor cell properties, functions, and destiny.

Comparative transcriptome profile of mouse macrophages treated with the RhoA/Rock pathway inhibitors Y27632, Fingolimod (Gilenya), and Rezurock (Belumosudil, SLx-2119).

Macrophages play a crucial role in, the currently uncurable, chronic rejection of transplants. In rodent transplantation models, inhibition of the RhoA/Rock pathway disrupts actin-related functions of macrophages, preventing them from entering the graft, and reducing vessel occlusion, fibrosis, and chronic rejection. Among RhoA/Rock inhibitors that inhibit chronic rejection in mouse transplantation are Y27632, Fingolimod, and Rezurock. In a mouse model, Rezurok is more effective in preventing fibrosis and less effective in preventing vessel occlusion than Y27632 or Fingolimod. Fingolimod is FDA-approved for treating multiple sclerosis (MS) and Rezurock for chronic graft versus host disease (GVHD). Still, none had been tested for chronic rejection in humans. To explain the differences in the anti-chronic rejection properties of Y27632, Fingolimod, and Rezurock, we compared the transcriptome profile of mouse macrophages treated with these compounds separately. Treatment with Y27632 or Fingolimod downregulated GTPase and actin pathways involved in cell migration. Rezurock downregulated genes related to fibrosis, such as PTX3, CCR2, CCL2, cell cycle, DNA replication, adaptive immune response, and organelle assembly, while Fingolimod also specifically downregulated NOTCH1 at mRNA . The result of this study not only uncovers which pathways are shared or specific for these drugs but will help in the development of macrophage pathway-targeted therapies in human transplantation, MS, and GVHD. Because macrophages are the major players in immune response, tissue regeneration, renewal, and homeostasis, and development of many diseases, including cancer, the data compiled here will help in designing novel or improved therapies in many clinical applications.

EARLY DIFFERENTIATION BETWEEN SEPSIS AND STERILE INFLAMMATION VIA URINARY GENE SIGNATURES OF METABOLIC DYSREGULATION.

ABSTRACT: Objective: The aim of this study was to characterize early urinary gene expression differences between patients with sepsis and patients with sterile inflammation and summarize in terms of a reproducible sepsis probability score. Design: This was a prospective observational cohort study. Setting: The study was conducted in a quaternary care academic hospital. Patients: One hundred eighty-six sepsis patients and 78 systemic inflammatory response syndrome (SIRS) patients enrolled between January 2015 and February 2018. Interventions: Whole-genome transcriptomic analysis of RNA was extracted from urine obtained from sepsis patients within 12 hours of sepsis onset and from patients with surgery-acquired SIRS within 4 hours after major inpatient surgery. Measurements and Main Results: We identified 422 of 23,956 genes (1.7%) that were differentially expressed between sepsis and SIRS patients. Differentially expressed probes were provided to a collection of machine learning feature selection models to identify focused probe sets that differentiate between sepsis and SIRS. These probe sets were combined to find an optimal probe set (UrSepsisModel) and calculate a urinary sepsis score (UrSepsisScore), which is the geometric mean of downregulated genes subtracted from the geometric mean of upregulated genes. This approach summarizes the expression values of all decisive genes as a single sepsis score. The UrSepsisModel and UrSepsisScore achieved area under the receiver operating characteristic curves 0.91 (95% confidence interval, 0.86-0.96) and 0.80 (95% confidence interval, 0.70-0.88) on the validation cohort, respectively. Functional analyses of probes associated with sepsis demonstrated metabolic dysregulation manifest as reduced oxidative phosphorylation, decreased amino acid metabolism, and decreased oxidation of lipids and fatty acids. Conclusions: Whole-genome transcriptomic profiling of urinary cells revealed focused probe panels that can function as an early diagnostic tool for differentiating sepsis from sterile SIRS. Functional analysis of differentially expressed genes demonstrated a distinct metabolic dysregulation signature in sepsis.

Civilian Ballistic Femoral Shaft Fractures Compared With Blunt Femur Shaft Fractures.

OBJECTIVE: To assess ballistic femoral shaft fracture outcomes in comparison with closed and open femoral shaft fractures sustained by blunt mechanisms. We hypothesized that ballistic femoral shaft fractures would have similar outcomes to blunt open fractures. DESIGN: Retrospective cohort study. SETTING: Academic Level I trauma center. PARTICIPANTS: Patients 16 years and older presenting with ballistic (140), blunt closed (317), or blunt open (71) femoral shaft fractures. MAIN OUTCOMES: Unplanned return to operating room, fracture-related infection, soft tissue reconstruction, nonunion, implant failure, length of stay, Injury Severity Scores, hospital charges, and compartment syndrome. RESULTS: A total of 528 femoral shaft fractures were identified. A group of 140 ballistic fractures and comparison groups of all femoral shaft fractures sustained by blunt mechanisms and treated with intramedullary nailing were included in the analysis. Among the 2 subgroups of nonballistic injuries, 317 were blunt closed fractures and 71 were blunt open fractures. The ballistic group was associated with a 3-fold increase in overall complications (30%) compared with the blunt closed group (10%, P < 0.001), had a higher occurrence of thigh compartment syndrome (P < 0.001), and required more soft tissue reconstruction (P < 0.001) than either of the blunt fracture groups. CONCLUSIONS: Ballistic femoral shaft fractures do not perfectly fit with blunt closed or open femoral fractures. A high index of suspicion for the development of thigh compartment syndrome should be maintained in ballistic femoral shaft fractures. The overall rates of nonunion and infection were comparable between all groups, but the all-cause complication rate was significantly higher in the ballistic group compared with the blunt closed group. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

BioSimulators: a central registry of simulation engines and services for recommending specific tools.

Computational models have great potential to accelerate bioscience, bioengineering, and medicine. However, it remains challenging to reproduce and reuse simulations, in part, because the numerous formats and methods for simulating various subsystems and scales remain siloed by different software tools. For example, each tool must be executed through a distinct interface. To help investigators find and use simulation tools, we developed BioSimulators (https://biosimulators.org), a central registry of the capabilities of simulation tools and consistent Python, command-line and containerized interfaces to each version of each tool. The foundation of BioSimulators is standards, such as CellML, SBML, SED-ML and the COMBINE archive format, and validation tools for simulation projects and simulation tools that ensure these standards are used consistently. To help modelers find tools for particular projects, we have also used the registry to develop recommendation services. We anticipate that BioSimulators will help modelers exchange, reproduce, and combine simulations.

Risk Factors for Deep Infection and Conversion Total Hip Arthroplasty After Operative Combined Pelvic Ring and Acetabular Fractures.

OBJECTIVES: To determine risk factors for deep infection and conversion total hip arthroplasty (THA) after operative management of combined pelvic ring and acetabular injuries. DESIGN: Retrospective case control study. SETTING: Level 1 trauma center. PATIENTS AND INTERVENTION: We reviewed 150 operative combined pelvic ring and acetabular injuries at our institution from 2010 to 2019, with an average follow-up of 690 (90-3282) days. MAIN OUTCOME MEASUREMENTS: Deep infection and conversion THA. RESULTS: Patients who developed deep infection (N = 17, 11.3%) had higher rates of hip dislocation ( P = 0.030), intraoperative transfusion ( P = 0.030), higher body mass index (BMI) ( P = 0.046), increased estimated blood loss ( P < 0.001), more intraoperative units transfused ( P = 0.004), and longer operative times ( P = 0.035). Of the 84 patients with 1-year follow-up, 24 (28.6%) required conversion to THA. Patients requiring conversion THA were older ( P = 0.022) and had higher rates of transverse posterior wall fracture pattern ( P = 0.034), posterior wall involvement ( P < 0.001), hip dislocation ( P = 0.031), wall comminution ( P = 0.002), and increased estimated blood loss ( P = 0.024). The order of the pelvic ring versus acetabular fixation did not affect rates of conversion to THA ( P = 0.109). Multiple logistic regression showed that an increased number of intraoperative units transfused [adjusted odds ratio (aOR) = 1.56, 95% confidence interval (CI) = 1.16-2.09, P = 0.003] and higher BMI (aOR = 1.10, 95% CI = 1.01-1.16, P = 0.024) were independently associated with an increased odds of deep infection. Posterior wall involvement was independently associated with an increased odds of conversion THA (aOR = 5.73, 95% CI = 1.17-27.04, P = 0.031). CONCLUSIONS: Rates of deep infection and conversion THA after operative fixation of combined injuries were 11.3% and 28.6%, respectively. Higher average BMI and number of intraoperative units of blood transfused were independently associated with deep infection, whereas posterior wall involvement was independently associated with conversion to THA in these patients. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Improved COVID-19 outcomes in a large non-invasive respiratory support cohort despite emergence of the alpha variant.

INTRODUCTION: Respiratory high-dependency units (rHDUs) are used to manage respiratory failure in COVID-19 outside of the intensive care unit (ICU). The alpha variant of COVID-19 has been linked to increased rates of mortality and admission to ICU; however, its impact on a rHDU population is not known. We aimed to compare rHDU outcomes between the two main UK waves of COVID-19 infection and evaluate the impact of the alpha variant on second wave outcomes. METHODS: We conducted a single-centre, retrospective analysis of all patients with a diagnosis of COVID-19 admitted to the rHDU of our teaching hospital for respiratory support during the first and second main UK waves. RESULTS: In total, 348 patients were admitted to rHDU. In the second wave, mortality (26.7% s vs 50.7% first wave, χ2=14.7, df=1, p=0.0001) and intubation rates in those eligible (24.3% s vs 58.8% first wave, χ2=17.3, df=2, p=0.0002) were improved compared with the first wave. In the second wave, the alpha variant had no effect on mortality (OR 1.18, 95% CI 0.60 to 2.32, p=0.64). Continuous positive airway pressure (CPAP) (89.5%) and awake proning (85.6%) were used in most patients in the second wave. DISCUSSION: Our single-centre experience shows that rHDU mortality and intubation rates have improved over time in spite of the emergence of the alpha variant. Our data support the use of CPAP and awake proning, although improvements in outcome are likely to be multifactorial.

Quality Improvement Tools in Total Joint Arthroplasty: A Systematic Review.

Systems review and quality improvement (QI) is a significant need within orthopaedic surgery. The focus of this paper is to systematically review QI principles utilized in total joint arthroplasty to determine most successful QI tools. A systematic search on MEDLINE/Pubmed, Embase, Cochrane Library and other sources was conducted from September 1991 through October 2018. The three primary improved outcomes from each article were recorded along with the date, author and subspecialty. Thirty-four eligible studies related to joint arthroplasty were identified for inclusion in the systematic review. The most common outcomes that were improved in these publications were: length of stay (LOS), cost, medication management, and patient education. Lean, clinical care pathways (CCP), plan-do-check-act (PDCA), and shared decision-making improved those metrics. Four metrics were found that were consistently improved by certain quality improvement tools: LOS, cost, medication management, and patient education. Further research is warranted to continue to build a framework for quality improvement in orthopaedic surgery. (Journal of Surgical Orthopaedic Advances 30(3):125-130, 2021).

Chronic Critical Illness Elicits a Unique Circulating Leukocyte Transcriptome in Sepsis Survivors.

Surgical sepsis has evolved into two major subpopulations: patients who rapidly recover, and those who develop chronic critical illness (CCI). Our primary aim was to determine whether CCI sepsis survivors manifest unique blood leukocyte transcriptomes in late sepsis that differ from transcriptomes among sepsis survivors with rapid recovery. In a prospective cohort study of surgical ICU patients, genome-wide expression analysis was conducted on total leukocytes in human whole blood collected on days 1 and 14 from sepsis survivors who rapidly recovered or developed CCI, defined as ICU length of stay ≥ 14 days with persistent organ dysfunction. Both sepsis patients who developed CCI and those who rapidly recovered exhibited marked changes in genome-wide expression at day 1 which remained abnormal through day 14. Although summary changes in gene expression were similar between CCI patients and subjects who rapidly recovered, CCI patients exhibited differential expression of 185 unique genes compared with rapid recovery patients at day 14 (p < 0.001). The transcriptomic patterns in sepsis survivors reveal an ongoing immune dyscrasia at the level of the blood leukocyte transcriptome, consistent with persistent inflammation and immune suppression. Furthermore, the findings highlight important genes that could compose a prognostic transcriptomic metric or serve as therapeutic targets among sepsis patients that develop CCI.

Survival analysis for patients with cancer in Gaza applying for Israeli permits to exit the Gaza Strip for health care: a retrospective cohort study of patients from 2008 to 2017.

BACKGROUND: Gaza has been under land, sea, and aerial blockade for more than 13 years, during which time Israel has continued its permit regime to control access for Palestinian patients from Gaza to health facilities in the West Bank (including East Jerusalem), Israel, and Jordan. Specific groups, such as patients with cancer, have a high need for permits owing to a lack of services in Gaza. The approval rate for patient permits to exit Gaza dropped from 94% in 2012 to 54% in 2017. We aimed to assess the effect of access restrictions due to permit denials or delays on all-cause mortality for patients with cancer from Gaza who were referred for chemotherapy, radiotherapy, or both. METHODS: This study matched 17 072 permit applications for 3816 patients referred for chemotherapy, radiotherapy, or both, from Jan 1, 2008, to Dec 31, 2017, with referral data for the same period and mortality data from Jan 1, 2008, to Jun 30, 2018. We stratified survival analysis by period of first application (2008-14, 2015-17), in light of varying access to Egypt during these times. Primary analysis compared survival of patients according to their first referral decision (approved versus denied or delayed) using Kaplan-Meier methods and Cox regression. Consent for the study was granted by the Palestinian Ministry of Health, and ethical approval was granted by the Helsinki Committee of the Palestinian Ministry of Health. FINDINGS: Mortality was significantly higher among patients who were initially unsuccessful in permit applications from 2015 to 2017 (141 events over 493 person-years, corresponding to a rate of 286 per 100 person-years) than among patients who were initially successful in the same period (375 events over 1923 person-years, corresponding to a rate of 195 per 100 person-years) with a hazard ratio of 1·45 (95% CI 1·19-1·78, p=0.0009) after adjusting for age, sex, type of procedure, and type of cancer. There was no significant difference in mortality risk between the two groups in the 2008-14 period, with a hazard ratio of 0·84 (95% CI 0·69-1·01, p=0·071). INTERPRETATION: Barriers to patient access to health care through denied or delayed permit applications had a significant impact on mortality for patients with cancer who applied for chemotherapy, radiotherapy, or both, in the period 2015-17. Relative ease of access through Rafah from 2008 to 2014 may have mitigated the health effects of access restrictions. FUNDING: WHO received funding from the Swiss Agency for Development and Cooperation.

Health attacks and protection strategies during Gaza's Great March of Return: a mixed methods study using data from WHO's Surveillance System for Attacks on Healthcare.

BACKGROUND: WHO defines an attack on health care as "any act of verbal or physical violence or obstruction or threat of violence that interferes with the availability, access and delivery of curative and/or preventive health services during emergencies." Gaza's Great March of Return (GMR) began on Mar 30, 2018, with 322 Palestinians killed and 33 141 injured by December, 2019, and first-response health-care teams exposed to high levels of violence. The aims of this study were threefold: to explore the vulnerabilities of health workers to attacks during the GMR; to understand the effectiveness and comprehensiveness of systems for monitoring health attacks; and to identify potential strategies and interventions to improve protection. METHODS: WHO's Surveillance System for Attacks on Healthcare (SSA) verifies and records health attacks. We analysed SSA data for the Gaza Strip from Mar 30, 2018, to Dec 31, 2019, examining the number and type of attacks, the mechanisms of injury, and the distribution of attacks by gender, time, and location. We analysed the correlation of health worker injuries and deaths with total injuries and deaths of Palestinians during the GMR. We held interviews and focus groups with individuals working for organizations defined as partners contributing to the SSA in the Gaza Strip, to understand data comprehensiveness, the nature and impact of violence, and protection gaps and strategies. FINDINGS: During the study period, there were 567 confirmed incidents, in which three health workers were killed, 845 health workers were injured, and 129 ambulances and vehicles and 7 health facilities were damaged, including one hospital and three medical field stations. Of the total health personnel killed and injured, 166 of 848 (20%) were in the Gaza governorate, 274 (32%) were in the Khan Yunis governorate, 119 (14%) were in the middle governorate, 192 (22%) were in North governorate, and 96 (11%) were in the Rafah governorate. Of 845 injuries, 743 (88%) were in men, 45 (5%) were live ammunition injuries, 62 (7%) were rubber bullet injuries, 151 (18%) were gas canister injuries, 41 (5%) were shrapnel injuries, and 533 (64%) were gas inhalation injuries. Injuries and deaths among health workers correlated moderately (R2=0·54) with and accounted for 2% of the total. Qualitative findings highlighted the incidental and structural nature of violence, normalisation and under-reporting of attacks, the need for improved coordination of protection for health care, and gaps in the availability of protective equipment. INTERPRETATION: Health-care workers function at great personal risk. The correlation of attacks against health care with total injuries and deaths points to the need for alignment of efforts to protect health care with strategies to safeguard civilian populations, including protection of populations living under occupation and those engaged in civil demonstrations. Health-care workers identified the need for systemic measures to improve protection through training, monitoring, and coordination, and through linking of monitoring and documentation of health attacks with stronger accountability measures for prevention. FUNDING: In 2017 and 2018, WHO's Right to Health Advocacy programme received funding from the Swiss Development Cooperation and the oPt Humanitarian Fund.

Identification of unique microRNA expression patterns in bone marrow hematopoietic stem and progenitor cells after hemorrhagic shock and multiple injuries in young and old adult mice.

BACKGROUND: After severe trauma, the older host experiences more dysfunctional hematopoiesis of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs), and dysfunctional differentiation of circulating myeloid cells into effective innate immune cells. Our main objective was to compare BM HSPC microRNA (miR) responses of old and young mice in a clinically relevant model of severe trauma and shock. METHODS: C57BL/6 adult male mice aged 8 to 12 weeks (young) and 18 to 24 months (old) underwent multiple injuries and hemorrhagic shock (polytrauma [PT]) that engenders the equivalent of major trauma (Injury Severity Score, >15). Pseudomonas pneumonia (PNA) was induced in some young and old adult mice 24 hours after PT. MicroRNA expression patterns were determined from lineage-negative enriched BM HSPCs isolated from PT and PT-PNA mice at 24 and 48 hours postinjury, respectively. Genome-wide expression and pathway analyses were also performed on bronchoalveolar lavage (BAL) leukocytes from both mouse cohorts. RESULTS: MicroRNA expression significantly differed among all experimental conditions (p < 0.05), except for old-naive versus old-injured (PT or PT-PNA) mice, suggesting an inability of old mice to mount a robust early miR response to severe shock and injury. In addition, young adult mice had significantly more leukocytes obtained from their BAL, and there were greater numbers of polymorphonuclear cells compared with old mice (59.8% vs. 2.2%, p = 0.0069). Despite increased gene expression changes, BAL leukocytes from old mice demonstrated a more dysfunctional transcriptomic response to PT-PNA than young adult murine BAL leukocytes, as reflected in predicted upstream functional pathway analysis. CONCLUSION: The miR expression pattern in BM HSPCs after PT (+/-PNA) is dissimilar in old versus young adult mice. In the acute postinjury phase, old adult mice are unable to mount a robust miR HSPC response. Hematopoietic stem and progenitor cell miR expression in old PT mice reflects a diminished functional status and a blunted capacity for terminal differentiation of myeloid cells.

Profiling malaria infection among under-five children in the Democratic Republic of Congo.

INTRODUCTION: In 2018, Malaria accounted for 38% of the overall morbidity and 36% of the overall mortality in the Democratic Republic of Congo (DRC). This study aimed to identify malaria socioeconomic predictors among children aged 6-59 months in DRC and to describe a socioeconomic profile of the most-at-risk children aged 6-59 months for malaria infection. MATERIALS AND METHODS: This study used data from the 2013 DRC Demographic and Health Survey. The sample included 8,547 children aged 6-59 months who were tested for malaria by microscopy. Malaria infection status, the dependent variable, is a dummy variable characterized as a positive or negative test. The independent variables were child's sex, age, and living arrangement; mother's education; household's socioeconomic variables; province of residence; and type of place of residence. Statistical analyses used the chi-square automatic interaction detector (CHAID) model and logistic regression. RESULTS: Of the 8,547 children included in the sample, 25% had malaria infection. Four variables-child's age, mother's education, province, and wealth index-were statistically associated with the prevalence of malaria infection in bivariate analysis and multivariate analysis (CHAID and logistic regression). The prevalence of malaria infection increases with child's age and decreases significantly with mother's education and the household wealth index. These findings suggest that the prevalence of malaria infection is driven by interactions among environmental factors, socioeconomic characteristics, and probably differences in the implementation of malaria programs across the country. The effect of mother's education on malaria infection was only significant among under-five children living in Ituri, Kasaï-Central, Haut-Uele, Lomami, Nord-Ubangi, and Maniema provinces, and the effect of wealth index was significant in Mai-Ndombe, Tshopo, and Haut-Katanga provinces. CONCLUSION: Findings from this study could be used for targeting malaria interventions in DRC. Although malaria infection is common across the country, the prevalence of children at high risk for malaria infection varies by province and other background characteristics, including age, mother's education, wealth index, and place of residence. In light of these findings, designing provincial and multisectoral interventions could be an effective strategy to achieve zero malaria infection in DRC.

The role of bone marrow microRNA (miR) in erythropoietic dysfunction after severe trauma.

BACKGROUND: Previous data has shown that severe traumatic injury is associated with bone marrow dysfunction, which manifests as persistent injury-associated anemia. This study sought to identify whether the expression of erythropoiesis-related microRNAs were altered in the bone marrow of trauma patients to determine if these microRNAs play a role in persistent injury-associated anemia. METHODS: Bone marrow was collected from severely injured trauma patients who underwent fracture fixation as well as patients who underwent elective hip replacement. There were 27 trauma patients and 10 controls analyzed. Total RNA and microRNA were isolated from CD34-positive cells using the RNeasy Plus Mini kit, and genome-wide microRNA expression patterns were assayed. Genes with significant expression differences were found using BRB-ArrayTools with a significance of P < .01. RESULTS: There were marked differences in expression of 108 microRNAs in the trauma group when compared with hip replacement patients. Four of these microRNAs play a role in regulating erythropoiesis: microRNA-150, microRNA-223, microRNA15a, and microRNA-24. These microRNAs were all upregulated significantly, with trauma/hip replacement fold changes of 1.7, 1.8, 1.2, and 1.2 respectively, and all act to suppress or regulate erythropoiesis. CONCLUSION: Assessment of the bone marrow microRNA profile in trauma patients compared to those undergoing elective hip replacement revealed the differential expression of microRNA-150, microRNA-223, microRNA-15a, and microRNA-24. These microRNAs all play a role in decreased erythroid progenitor cell growth and provide important insight to the erythropoietic dysfunction seen after trauma.

Introducing climate change into the biochemistry and molecular biology curriculum.

Our climate is changing due to anthropogenic emissions of greenhouse gases from the production and use of fossil fuels. Present atmospheric levels of CO2 were last seen 3 million years ago, when planetary temperature sustained high Arctic camels. As scientists and educators, we should feel a professional responsibility to discuss major scientific issues like climate change, and its profound consequences for humanity, with students who look up to us for knowledge and leadership, and who will be most affected in the future. We offer simple to complex backgrounds and examples to enable and encourage biochemistry educators to routinely incorporate this most important topic into their classrooms.

Transcriptomic responses from improved murine sepsis models can better mimic human surgical sepsis.

Historically, murine models of inflammation in biomedical research have been shown to minimally correlate with genomic expression patterns from blood leukocytes in humans. In 2019, our laboratory reported an improved surgical sepsis model of cecal ligation and puncture (CLP) that provides additional daily chronic stress (DCS), as well as adhering to the Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS) guidelines. This model phenotypically recapitulates the persistent inflammation, immunosuppression, and catabolism syndrome observed in adult human surgical sepsis survivors. Whether these phenotypic similarities between septic humans and mice are replicated at the circulating blood leukocyte transcriptome has not been demonstrated. Our analysis, in contrast with previous findings, demonstrated that genome-wide expression in our new murine model more closely approximated human surgical sepsis patients, particularly in the more chronic phases of sepsis. Importantly, our new model of murine surgical sepsis with chronic stress did not reflect well gene expression patterns from humans with community-acquired sepsis. Our work indicates that improved preclinical murine sepsis modeling can better replicate both the phenotypic and transcriptomic responses to surgical sepsis, but cannot be extrapolated to other sepsis etiologies. Importantly, these improved models can be a useful adjunct to human-focused and artificial intelligence-based forms of research in order to improve septic patients' morbidity and mortality.

Discovery and Validation of Urinary Molecular Signature of Early Sepsis.

Identify alterations in gene expression unique to systemic and kidney-specific pathophysiologic processes using whole-genome analyses of RNA isolated from the urinary cells of sepsis patients. DESIGN: Prospective cohort study. SETTING: Quaternary care academic hospital. PATIENTS: A total of 266 sepsis and 82 control patients enrolled between January 2015 and February 2018. INTERVENTIONS: Whole-genome transcriptomic analysis of messenger RNA isolated from the urinary cells of sepsis patients within 12 hours of sepsis onset and from control subjects. MEASUREMENTS AND MAIN RESULTS: The differentially expressed probes that map to known genes were subjected to feature selection using multiple machine learning techniques to find the best subset of probes that differentiates sepsis from control subjects. Using differential expression augmented with machine learning ensembles, we identified a set of 239 genes in urine, which show excellent effectiveness in classifying septic patients from those with chronic systemic disease in both internal and independent external validation cohorts. Functional analysis indexes disrupted biological pathways in early sepsis and reveal key molecular networks driving its pathogenesis. CONCLUSIONS: We identified unique urinary gene expression profile in early sepsis. Future studies need to confirm whether this approach can complement blood transcriptomic approaches for sepsis diagnosis and prognostication.