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The devaluation of women of Color (WoC) by way of gender discrimination and systemic racism is well documented. For WoC in engineering a chief cause is the observable wage gap. Women who identify as Asian, Black/African American, Latina/Chicana, Indigenous/Native American, Native Hawaiian, Pacific Islander, Native Alaskan, and/or multiracial have reported stark wage disparities. In this paper, we offer a phenomenological study of how WoC engineering faculty across U.S. academic institutions describe the challenges and practices associated with wage disparities and how they navigate these disparities. This study, which is based on participant interviews, is guided by three research questions: (1) What do WoC engineering tenure-track faculty perceive about wage disparities based on their race and gender? (2) How do WoC faculty understand the institutional practices that contribute to wage disparities? and (3) How do WoC engineering faculty respond to and address wage disparities? Using structural racism and intersectionality as our guiding conceptual framework, we interviewed 32 self-identified WoC who identified structures and systems of institutional racism related to the maintenance of wage disparities. In terms of findings, we note that WoC have two primary strategies to respond to wage disparity: advocacy and agency. The experiences of WoC engineering faculty in our study highlight unsatisfying institutional responses, and thus WoC often rely on their own agency to advocate for themselves and to advocate for and mentor other WoC faculty. We found a few notable cases where men advocated for women to help close the wage gap. Our work reveals that pay inequity for WoC is often coupled with other forms of exclusion and marginalization. Reducing wage disparities in academia is critical to advancing diversity efforts and ensuring equitable support for WoC faculty. Our findings suggest that institutions can work diligently to rectify wage inequality, including making sustainable structural and salary modifications and sharing the burden of combatting wage inequities. Finally, our findings also highlight the importance of making policy changes to reduce pay inequalities, such as providing transparent pay information and more opportunities to earn merit raises.

Abstract Background The World Health Organization has set ambitious goals to eliminate cervical cancer, necessitating evidence on increasing coverage and access to screening and treatment in high-burden areas. We implemented a pilot program to assess the feasibility of obtaining self-collected specimens for high-risk human papillomavirus (hr-HPV) testing in Nzulezo stilt village, a hard-to-reach community in Ghana, and inviting only hr-HPV-positive women to a central location for colposcopy and possible treatment. Subsequently, this study aimed to investigate the prevalence of hr-HPV infection and cervical lesions among the women and to explore factors potentially associated with hr-HPV infection among them. Methods This pilot community-based cross-sectional study utilized data from screening sessions held from 2 to 20 November 2021 with specimens collected by participants using Evalyn brushes. HPV DNA testing was performed using the Sansure MA-6000 platform, while visual inspection utilized the Enhanced Visual Assessment (EVA) mobile colposcope. Univariate and multivariable nominal logistic regression was employed to explore factors associated with hr-HPV positivity. Results Among 100 women screened (mean age, 43.6 ± 14.5 years), the overall hr-HPV prevalence rate was 39.0% (95% CI, 29.4–49.3). The prevalence rates of hr-HPV genotypes were stratified as follows: HPV16–8.0% (95% CI, 3.5–15.2), HPV18–5.0% (95% CI, 1.6–11.2), and other genotype(s) – 31.0% (95% CI, 22.1–41.0). Single-genotype infections with HPV16 and HPV18 were found in 4.0% (95% CI, 1.1–9.9) and 3.0% (95% CI, 0.6–8.5) of women, respectively. Mixed infections were observed in 1.0% (95% CI, 0.0–5.4) for HPV16 + 18, 3.0% (95% CI, 0.6–8.5) for HPV16 + other type(s), and 1.0% (95% CI, 0.0–5.4) for HPV18 + other type(s). The prevalence of cervical lesions among hr-HPV-positive women screened via colposcopy was 11.4% (95% CI, 3.2–26.7). In the multivariable model, reliance on other sources for medical bill payment was associated with hr-HPV infection (aOR, 0.20; 95% CI, 0.04–0.93), whereas age was not (aOR, 1.02; 95% CI, 0.99–1.05). Conclusions A high hr-HPV infection prevalence was recorded among the women. Utilizing technologies such as self-sampling, HPV DNA testing, and mobile colposcopy enables screening and treatment in remote and hard-to-reach communities where access to cervical cancer screening and treatment would otherwise be limited. Further research is warranted to assess the value and scalability of this approach in similar remote areas and its potential implementation in future programs.

Abstract Background Epigenome‐wide association studies have identified multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. This study aimed to test the hypothesis that an alcohol consumption epigenetic risk score (ERS) is associated with blood pressure (BP) traits. Results We implemented an ERS based on a previously reported epigenetic signature of 144 alcohol-associated CpGs in meta-analysis of participants of European ancestry. We found a one-unit increment of ERS was associated with eleven drinks of alcohol consumed per day, on average, across several cohorts (p

Abstract Background MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Perturbations in plasma miRNA levels are known to impact disease risk and have potential as disease biomarkers. Exploring the genetic regulation of miRNAs may yield new insights into their important role in governing gene expression and disease mechanisms. Results We present genome-wide association studies of 2083 plasma circulating miRNAs in 2178 participants of the Rotterdam Study to identify miRNA-expression quantitative trait loci (miR-eQTLs). We identify 3292 associations between 1289 SNPs and 63 miRNAs, of which 65% are replicated in two independent cohorts. We demonstrate that plasma miR-eQTLs co-localise with gene expression, protein, and metabolite-QTLs, which help in identifying miRNA-regulated pathways. We investigate consequences of alteration in circulating miRNA levels on a wide range of clinical conditions in phenome-wide association studies and Mendelian randomisation using the UK Biobank data (N = 423,419), revealing the pleiotropic and causal effects of several miRNAs on various clinical conditions. In the Mendelian randomisation analysis, we find a protective causal effect of miR-1908-5p on the risk of benign colon neoplasm and show that this effect is independent of its host gene (FADS1). Conclusions This study enriches our understanding of the genetic architecture of plasma miRNAs and explores the signatures of miRNAs across a wide range of clinical conditions. The integration of population-based genomics, other omics layers, and clinical data presents opportunities to unravel potential clinical significance of miRNAs and provides tools for novel miRNA-based therapeutic target discovery.

Despite rich insights that the experience of Global South countries like the Philippines could offer in understanding emerging trends in SLA research, i.e. learning languages other than English (LOTEs), studies conducted in this context are few and far apart. The study explored the motivations and emotions of 389 Filipino learners of LOTEs who accomplished a 76-item questionnaire. Six factors of LOTE motivation and two factors of LOTE emotions were simultaneously analysed using Structural Equation Modelling (SEM). Composite reliability measures showed that these factors were valid and reliable. Six sets of model fit measures indicated a good fit for the final SEM model. Initial and final direct effects showed that the six factors of LOTE motivation significantly influenced LOTE enjoyment and LOTE anxiety. Against the backdrop of studies dominated by the Japanese and Chinese experiences, the Filipino experience has shown to be equally susceptible to the influences of globalisation and the hegemony of English on learning languages other than English. The final SEM model of LOTE learning among Filipinos is instructive of the multifaceted LOTE motivation, but it also captures the effects of motivational constructs in the 'flowering of emotions' in the context of learners acquiring a language other than English.

Abstract Integrating multi-omics data into predictive models has the potential to enhance accuracy, which is essential for precision medicine. In this study, we developed interpretable predictive models for multi-omics data by employing neural networks informed by prior biological knowledge, referred to as visible networks. These neural networks offer insights into the decision-making process and can unveil novel perspectives on the underlying biological mechanisms associated with traits and complex diseases. We tested the performance, interpretability and generalizability for inferring smoking status, subject age and LDL levels using genome-wide RNA expression and CpG methylation data from the blood of the BIOS consortium (four population cohorts, N total = 2940). In a cohort-wise cross-validation setting, the consistency of the diagnostic performance and interpretation was assessed. Performance was consistently high for predicting smoking status with an overall mean AUC of 0.95 (95% CI: 0.90–1.00) and interpretation revealed the involvement of well-replicated genes such as AHRR, GPR15 and LRRN3. LDL-level predictions were only generalized in a single cohort with an R 2 of 0.07 (95% CI: 0.05–0.08). Age was inferred with a mean error of 5.16 (95% CI: 3.97–6.35) years with the genes COL11A2, AFAP1, OTUD7A, PTPRN2, ADARB2 and CD34 consistently predictive. For both regression tasks, we found that using multi-omics networks improved performance, stability and generalizability compared to interpretable single omic networks. We believe that visible neural networks have great potential for multi-omics analysis; they combine multi-omic data elegantly, are interpretable, and generalize well to data from different cohorts.

Abstract Genetic variation in the human leukocyte antigen (HLA) loci is associated with risk of immune-mediated diseases, but the molecular effects of HLA polymorphism are unclear. Here we examined the effects of HLA genetic variation on the expression of 2940 plasma proteins across 45,330 Europeans in the UK Biobank, with replication analyses across multiple ancestry groups. We detected 504 proteins affected by HLA variants (HLA-pQTL), including widespread trans effects by autoimmune disease risk alleles. More than 80% of the HLA-pQTL fine-mapped to amino acid positions in the peptide binding groove. HLA-I and II affected proteins expressed in similar cell types but in different pathways of both adaptive and innate immunity. Finally, we investigated potential HLA-pQTL effects on disease by integrating HLA-pQTL with fine-mapped HLA-disease signals in the UK Biobank. Our data reveal the diverse effects of HLA genetic variation and aid the interpretation of associations between HLA alleles and immune-mediated diseases.

Women of color (WoC) continue to be underrepresented in engineering programs across the United States. Many scholarly reports on faculty demographic characteristics do not provide measures regarding the representation of WoC faculty due to data reporting restrictions or lack of relevant data. Using 14 years of data from the American Society for Engineering Education, this study examined the trends in the prevalence of WoC faculty and PhDs in engineering between 2005 and 2018. Informed by intersectionality theory and Kanter's theory of proportions, descriptive analyses were used to disaggregate the prevalence of engineering faculty by gender, race/ethnicity, and engineering discipline. Findings indicate that there were slight growths in the representation of African American/Black, Native American/Native Hawaiian, and Hispanic/Latina women engineering faculty. The low representation of WoC is also evident among engineering PhDs. Changes in the shares of WoC in assistant, associate, and full professor ranks and in the production of PhDs provide insights for future demographic shifts in engineering education. Greater efforts and investments are needed in the recruitment of WoC into PhD programs and, subsequently, as assistant professors across engineering disciplines. Although interventions and programs aimed at helping increase the participation of WoC faculty in engineering have made progress, findings suggest that larger scale structural and cultural changes are needed to shift prevailing demographic trends in the engineering professoriate, including expanding student access to doctoral education in engineering. Research findings have the potential to provide foundational information for developing strategies to increase the representation of WoC engineering PhDs and faculty.

Glycoproteins are an underexploited drug target for cancer therapeutics. In this work, we integrated computational methods in network pharmacology and in silico docking approaches to identify phytochemical compounds that could potentially interact with several cancer-associated glycoproteins. We first created a database of phytochemicals from selected plant species, Manilkara zapota (sapodilla/chico), Mangifera indica (mango), Annona muricata (soursop/guyabano), Artocarpus heterophyllus (jackfruit/langka), Lansium domesticum (langsat/lanzones), and Antidesma bunius (bignay), and performed pharmacokinetic analysis to determine their drug-likeness properties. We then constructed a phytochemical-glycoprotein interaction network and characterized the degree of interactions between the phytochemical compounds and with cancer-associated glycoproteins and other glycosylation-related proteins. We found a high degree of interactions from α-pinene (Mangifera indica), cyanomaclurin (Artocarpus heterophyllus), genistein (Annona muricata), kaempferol (Annona muricata and Antidesma bunius), norartocarpetin (Artocarpus heterophyllus), quercetin (Annona muricata, Antidesma bunius, Manilkara zapota, Mangifera indica), rutin (Annona muricata, Antidesma bunius, Lansium domesticum), and ellagic acid (Antidesma bunius and Mangifera indica). Subsequent docking analysis confirmed that these compounds could potentially bind to EGFR, AKT1, KDR, MMP2, MMP9, ERBB2, IGF1R, MTOR, and HRAS proteins, which are known cancer biomarkers. In vitro cytotoxicity assays of the plant extracts showed that the n-hexane, ethyl acetate, and methanol leaf extracts from A. muricata, L. domesticum and M. indica gave the highest growth inhibitory activity against A549 lung cancer cells. These may help further explain the reported cytotoxic activities of select compounds from these plant species.

Gender disparities in Science, Technology, Engineering, and Mathematics (STEM) faculty composition remain a major issue in U.S. higher education. Specifically, the underrepresentation of women of color has been described as a crisis. We developed the Workplace Climate and Persistence Scale (WCPS) for STEM faculty to assess departmental-level climate factors associated with faculty persistence, using a framework of the intersectionality of gender, race/ethnicity, and socioeconomic background. To validate the WCPS, we conducted analyses for construct validity, internal consistency reliability, and criterion validity evidence using data from 394 STEM faculty at three universities. Exploratory and confirmatory factor analyses resulted in 43 items loading across nine factors in a good model fit range. The nonlinear SEM reliability coefficients ranged from 0.811 to 0.971, with the overall Omega = 0.991. The correlation matrix indicated that the WCPS differentiates STEM faculty's perceptions by multiple social identities. We expect the WCPS to help administrators identify where to target approaches to improve climate and assess the effectiveness of such interventions.

Preserving vascular function is crucial for preventing multiorgan failure and death in ischemic and low-pressure states such as trauma/hemorrhagic shock (T/HS). It has recently been reported that inhibiting circulating proteases released from the bowel to the circulation during T/HS may preserve vascular function and improve outcomes following T/HS. This study aimed to evaluate the role of the serine protease inhibitor gabexate mesilate (GM) in preserving vascular function during T/HS when given enterally. We studied the vascular reactivity of mesenteric arteries from male Wistar rats treated with enteral GM (10 mg/kg) (GM-treated, n = 6) or control (Shock-control, n = 6) following (T/HS) using pressure myography. Concentration-response curves of endothelial-dependent and endothelial-independent agonists (e.g., acetylcholine, sodium nitroprusside) ranging from 10-10 to 10-5 M were performed. In a second set of experiments, ex-vivo arteries from healthy rats were perfused with plasma from shocked animals from both groups and vascular performance was similarly measured. Arteries from the GM-treated group demonstrated a preserved concentration-response curve to the α1 adrenergic agonist phenylephrine compared to arteries from Shock-control animals (- logEC50: - 5.73 ± 0.25 vs. - 6.48 ± 0.2, Shock-control vs. GM-treated, p = 0.04). When perfused with plasma from GM-treated rats, healthy arteries exhibited an even greater constriction and sensitivity to phenylephrine (- logEC50: - 6.62 ± 0.21 vs. - 7.13 ± 0.21, Shock-control vs. GM-treated, p = 0.02). Enteral GM also preserved the endothelium-dependent vascular response to agonists following T/HS and limited syndecan-1 shedding as a marker of glycocalyx compromise (41.84 ± 9 vs. 17.63 ± 3.97 ng/mL, Shock-control vs. GM-treated, p = 0.02). Syndecan-1 cleavage was correlated with plasma trypsin-like activity (r2 = 0.9611). Enteral gabexate mesilate was able to maintain vascular function in experimental T/HS, which was reflected by improved hemodynamics (mean arterial pressure 50.39 ± 7.91 vs. 64.95 ± 3.43 mmHg, Shock-control vs. GM treated, p = 0.0001). Enteral serine protease inhibition may be a potential therapeutic intervention in the treatment of T/HS.

Introduction: Infection by SARS-CoV-2 and subsequent COVID-19 can cause viral sepsis. We investigated plasma protease activity patterns in COVID-19-induced sepsis with bacterial superinfection, as well as plasma proteomics and peptidomics in order to assess the possible implications of enhanced proteolysis on major protein systems (e.g., coagulation). Methods: Patients (=4) admitted to the intensive care units (ICUs) at the University of California, San Diego (UCSD) Medical Center with confirmed positive test for COVID-19 by real-time reverse transcription polymerase chain reaction (RT-PCR) were enrolled in a study approved by the UCSD Institutional Review Board (IRB# 190699, Protocol #20-0006). Informed consent was obtained for the collection of blood samples and de-identified use of the data. Blood samples were collected at multiple time points and analyzed to quantify a) the circulating proteome and peptidome by mass spectrometry; b) the aminopeptidase activity in plasma; and c) the endopeptidase activity in plasma using fluorogenic substrates that are cleaved by trypsin-like endopeptidases, specific clotting factors and plasmin. The one patient who died was diagnosed with bacterial superinfection on day 7 after beginning of the study. Results: Spikes in protease activity (factor VII, trypsin-like activity), and corresponding increases in the intensity of peptides derived by hydrolysis of plasma proteins, especially of fibrinogen degradation products and downregulation of endogenous protease inhibitors were detected on day 7 for the patient who died. The activity of the analyzed proteases was stable in survivors. Discussion: The combination of multiomics and enzymatic activity quantification enabled to i) hypothesize that elevated proteolysis occurs in COVID-19-induced septic shock with bacterial superinfection, and ii) provide additional insight into malfunctioning protease-mediated systems, such as hemostasis.

Purpose: The underrepresentation of women in engineering has important consequences for meeting the need for a larger, talented scientific and technological labor force. Increasing the proportion of women faculty in engineering will help increase the persistence probabilities of women undergraduate and graduate students in engineering, as well as contribute to the range and diversity of ideas toward innovations and solutions to the greatest engineering challenges. This study aims to examine the association among gender, family formation and post-PhD employment patterns of a cohort of engineering doctorates. Design/methodology/approach: Using the National Science Foundation's Survey of Doctorate Recipients data, 2001-2010, descriptive and multinomial logit regression analyses are conducted to illustrate the career trajectories of engineering PhDs over a ten-year period. Findings: The career trajectories of engineering PhDs are nonlinear, and transitions between employment sectors commonly occur over the ten-year time period studied. Although women engineering PhDs with young dependents are less likely to be employed initially after PhD completion, they tend to enter the workforce in the academic sector as time progresses. Early post-PhD employment as a postdoctoral researcher or in the academic sector contributes to the pursuit of the professoriate downstream. Originality/value: While previous studies tend to focus on the early career outcomes of science and engineering students, this study contributes to the literature by focusing on the long-term career outcomes of engineering doctorates. Research findings provide engineering PhD students and PhDs with more information regarding potential post-PhD career trajectories, highlighting the multitude of career options and transitions that occur over time. Research findings also provide higher education administrators and doctoral program stakeholders with foundational information toward designing and revitalizing professional development programs to help PhD students prepare for the workforce. The findings have the potential to be applied toward helping increase diversity by shaping policies and programs to encourage multiple alternative career pathways to the professoriate.

IntroductionTraumatic brain injury (TBI) is an important public health concern and that may lead to severe neural sequels, such as color vision deficits.MethodsWe evaluated the color vision of 10 TBI patients with normal cognitive function using a color discrimination test in a fixed saturation level. We also analyzed computerized tomography scans to identify the local of the brain damages.ResultsFour TBI patients that had lesions in brain areas of the ventral visual streams, five TBI patients had lesions inferred in brain areas of the dorsal visual stream, and one TBI patient had lesion in the occipital area. All the patients had cognitive and color vision screened and they had characterized the chromatic discrimination at high and low saturation. All participants had no significant cognitive impairment in the moment of the color vision test. Additionally, they had perfect performance for discrimination of chromatic stimulus at high saturation and similar to controls (n = 37 age-matched participants). Three of four TBI patients with lesions in the ventral brain and one patient with lesion in the occipital area had impairment of the chromatic discrimination at low saturation. All TBI patients with lesions in the dorsal brain had performance similar or slightly worse than the controls.ConclusionChromatic discrimination at low saturation was associated to visual damage in the ventral region of the brain and is a potential tool for functional evaluation of brain damage in TBI patients.

Cancer progression is linked to aberrant protein glycosylation due to the overexpression of several glycosylation enzymes. These enzymes are underexploited as potential anticancer drug targets and the development of rapid-screening methods and identification of glycosylation inhibitors are highly sought. An integrated bioinformatics and mass spectrometry-based glycomics-driven glycoproteomics analysis pipeline was performed to identify an N-glycan inhibitor against lung cancer cells. Combined network pharmacology and in silico screening approaches were used to identify a potential inhibitor, pictilisib, against several glycosylation-related proteins, such as Alpha1-6FucT, GlcNAcT-V, and Alpha2,6-ST-I. A glycomics assay of lung cancer cells treated with pictilisib showed a significant reduction in the fucosylation and sialylation of N-glycans, with an increase in high mannose-type glycans. Proteomics analysis and in vitro assays also showed significant upregulation of the proteins involved in apoptosis and cell adhesion, and the downregulation of proteins involved in cell cycle regulation, mRNA processing, and protein translation. Site-specific glycoproteomics analysis further showed that glycoproteins with reduced fucosylation and sialylation were involved in apoptosis, cell adhesion, DNA damage repair, and chemical response processes. To determine how the alterations in N-glycosylation impact glycoprotein dynamics, modeling of changes in glycan interactions of the ITGA5-ITGB1 (Integrin alpha 5-Integrin beta-1) complex revealed specific glycosites at the interface of these proteins that, when highly fucosylated and sialylated, such as in untreated A549 cells, form greater hydrogen bonding interactions compared to the high mannose-types in pictilisib-treated A549 cells. This study highlights the use of mass spectrometry to identify a potential glycosylation inhibitor and assessment of its impact on cell surface glycoprotein abundance and protein-protein interaction.

The standard of care for fluid resuscitation of trauma/hemorrhagic shock (T/HS) is the infusion of blood. However, in many instances, blood product transfusion may not be feasible. Consequently, crystalloid solutions may be utilized as temporizing cost-effective resuscitation fluids. In this study, we explored an alternative therapeutic strategy of enteral protease inhibition adjunctive to intravenous Lactated Ringer's (LR) reperfusion after T/HS. Male Wistar rats underwent midline laparotomy (trauma) and an enteral catheter was inserted orally and positioned post-pyloric for the infusion of vehicle (Golytely®) with or without the serine protease inhibitor gabexate mesilate (GM) (n=8/group). Hemorrhagic shock was induced by blood removal to reduce the mean arterial blood pressure (MAP) to 35-40 mmHg for 90 minutes, before resuscitation with LR. Animals treated with enteral GM required significantly less crystalloid volume to achieve hemodynamic stability and displayed improvements in both blood pressure and autonomic function (via increased baroreflex sensitivity to vasopressors, heightened vascular sympathetic modulation, elevated levels of circulating catecholamines, and increased α1-adrenergic receptor density) compared to untreated (control) shocked animals. Resistance arteries isolated from healthy donor animals and perfused with plasma from untreated T/HS animals revealed impaired vascular response to the α1 adrenergic agonist phenylephrine and decreased reactivity to sodium nitroprusside that was preserved in the GM-treated group. These findings suggest that blockade of serine proteases within the intestinal lumen in non-blood resuscitated experimental T/HS preserves and enhances peripheral sympathetic modulation, improving hemodynamics. Enteral infusion of gabexate mesilate may be a new and promising approach to the management of trauma/hemorrhagic shock.

Annona muricata L. (Guyabano) leaves are reported to exhibit anticancer activity against cancer cells. In this study, the ethyl acetate extract from guyabano leaves was purified through column chromatography, and the cytotoxic effects of the semi-purified fractions were evaluated against A549 lung cancer cells using in vitro MTS cytotoxicity and scratch/wound healing assays. Fractions F15-16C and F15-16D exhibited the highest anticancer activity in the MTS assay, with % cytotoxicity values of 99.6% and 99.4%, respectively. The bioactivity of the fractions was also consistent with the results of the scratch/wound healing assay. Moreover, untargeted metabolomics was employed on the semi-purified fractions to determine the putative compounds responsible for the bioactivity. The active fractions were processed using LC-MS/MS analysis with the integration of the following metabolomic tools: MS-DIAL (for data processing), MetaboAnalyst (for data analysis), GNPS (for metabolite annotation), and Cytoscape (for network visualization). Results revealed that the putative compounds with a significant difference between active and inactive fractions in PCA and OPLS-DA models were pheophorbide A and diphenylcyclopropenone.

Abstract Objective: To evaluate temporal trends in the prevalence of gram-negative bacteria (GNB) with difficult-to-treat resistance (DTR) in the southeastern United States. Secondary objective was to examine the use of novel β-lactams for GNB with DTR by both antimicrobial use (AU) and a novel metric of adjusted AU by microbiological burden (am-AU). Design: Retrospective, multicenter, cohort. Setting: Ten hospitals in the southeastern United States. Methods: GNB with DTR including Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter spp. from 2015 to 2020 were tracked at each institution. Cumulative AU of novel β-lactams including ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilastatin/relebactam, and cefiderocol in days of therapy (DOT) per 1,000 patient-days was calculated. Linear regression was utilized to examine temporal trends in the prevalence of GNB with DTR and cumulative AU of novel β-lactams. Results: The overall prevalence of GNB with DTR was 0.85% (1,223/143,638) with numerical increase from 0.77% to 1.00% between 2015 and 2020 (P = .06). There was a statistically significant increase in DTR Enterobacterales (0.11% to 0.28%, P = .023) and DTR Acinetobacter spp. (4.2% to 18.8%, P = .002). Cumulative AU of novel β-lactams was 1.91 ± 1.95 DOT per 1,000 patient-days. When comparing cumulative mean AU and am-AU, there was an increase from 1.91 to 2.36 DOT/1,000 patient-days, with more than half of the hospitals shifting in ranking after adjustment for microbiological burden. Conclusions: The overall prevalence of GNB with DTR and the use of novel β-lactams remain low. However, the uptrend in the use of novel β-lactams after adjusting for microbiological burden suggests a higher utilization relative to the prevalence of GNB with DTR.

Refractory vascular failure due to the inability of vascular smooth muscle to respond to vasoconstrictors such as phenylephrine is a final common pathway for severe circulatory shock of any cause, including trauma/hemorrhagic shock. Increased inflammation, Toll-like receptor 4 activation, and decreased response of the alpha-1 adrenergic receptors which control vascular tone have been reported in trauma/hemorrhagic shock.HypothesisIn trauma/hemorrhagic shock, Toll-like receptor 4 activation contributes to vascular failure via decreased bioavailability of adrenergic receptors.Design and measurementsTrauma/hemorrhagic shock was induced in Wistar rats (laparotomy combined with mean arterial pressure at 40 mm Hg for 90 min followed by 2 hr resuscitation with Lactated Ringers solution). To inhibit Toll-like receptor 4, resatorvid (TAK-242) and resveratrol were used, and plasma was collected. Smooth muscle cells were incubated with lipopolysaccharide (10 ng/mL) or plasma. Inflammatory cytokines were screened using dot-blot. Toll-like receptor 4 and nuclear factor κB activation and cellular localization of the alpha-1 adrenergic receptor were measured by immunofluorescence imaging and Western blot analysis. Clustered regularly interspaced short palindromic repeats/Cas9 was used to knock out Toll-like receptor 4, and calcium influx following stimulation with phenylephrine was recorded.Main resultsTrauma/hemorrhagic shock caused a decreased response to phenylephrine, whereas Toll-like receptor 4 inhibition improved blood pressure. Trauma/hemorrhagic shock plasma activated the Toll-like receptor 4/nuclear factor κB pathway in smooth muscle cells. Double labeling of Toll-like receptor 4 and the alpha-1 adrenergic receptor showed that these receptors are colocalized on the cell membrane. Activation of Toll-like receptor 4 caused cointernalization of both receptors. Calcium influx was impaired in cells incubated with trauma/hemorrhagic shock plasma but restored when Toll-like receptor 4 was knocked out or inhibited.ConclusionsActivation of the Toll-like receptor 4 desensitizes vascular smooth muscle cells to vasopressors in experimental trauma/hemorrhagic shock by reducing the levels of membrane alpha-1 adrenergic receptor.