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Background: Sepsis and septic shock are associated with significant morbidity and mortality. Rapid initiation of appropriate antibiotic therapy is essential, as inadequate therapy early during septic shock has been shown to increase the risk of mortality. However, despite the importance of appropriate antibiotic initiation, in clinical practice, concerns for renal dysfunction frequently lead to antibiotic dose reduction, with scant evidence on the impact of this practice in septic shock patients. Objective: The purpose if this article is to investigate the rate and impact of piperacillin-tazobactam dose adjustment in early phase septic shock patients using real-world electronic health record (EHR) data. Methods: A multicenter, observational, retrospective cohort study was conducted of septic shock patients who received at least 48 hours of piperacillin-tazobactam therapy and concomitant receipt of norepinephrine. Subjects were stratified into 2 groups according to their cumulative 48-hour piperacillin-tazobactam dose: low piperacillin-tazobactam dosing (LOW; Results: In all, 1279 patients met study criteria. After propensity score matching (n = 608), the NORM group had more median NFD (23.9 days [interquartile range, IQR: 0-27] vs 13.6 days [IQR: 0-27], P = 0.021). The NORM group also had lower rates of in-hospital mortality/hospice disposition (25.9% [n = 79] vs 35.5% [n = 108]), P = 0.014). Other secondary outcomes were similar between the treatment groups. Conclusions and Relevance: In the propensity score–matched cohort, the NORM group had significantly more 28-day NFD. Piperacillin-tazobactam dose reduction in early phase septic shock is associated with worsened clinical outcomes. Clinicians should be vigilant to avoid piperacillin-tazobactam dose reduction in early phase septic shock.

Black patients suffer worse outcomes after percutaneous coronary intervention (PCI) than White patients. Inequities in antiplatelet prescribing may contribute to this health disparity. We compared P2Y

Team-based learning (TBL) has been successfully applied to multiple healthcare education disciplines. A primary tenet of TBL is the development of solutions leveraging the collective knowledge of a team rather than the individual competency of any one student. In an effort to enhance individual student accountability, an individual verbal defense (IVD) format was implemented in a multi-campus TBL-based pharmacotherapeutics course. The study sought to investigate the use of TBL-IVD embedded within a traditional TBL format on student engagement, teaching style preferences, and exam performance compared to a TBL-only format.In this cross-sectional study, second-year pharmacy students enrolled in a pharmacotherapeutics course during fall 2019 completed an 11-item survey. The survey was designed to assess TBL-IVD on student engagement and teaching style preference. Free-response qualitative feedback was solicited to assess positive-negative themes related to the activity. Aggregate exam performance for community-acquired pneumonia (CAP) related content was compared to historical exam data to assess the impact on student performance.The majority of students (72%, n = 54) preferred the TBL-IVD compared to a TBL-only format. Students reported higher engagement with TBL-IVD (84%, n = 63). Correct exam responses for CAP related content were higher in the TBL-IVD group (67% vs. 55%, P .001). Positive themes included an increased opportunity to defend recommendations verbally and increased interaction with an on-campus faculty member.The study demonstrates the addition of IVD can enhance student perceptions, confidence, and performance within a large, multi-campus, TBL-based pharmacotherapeutics course.

Experimental, methodological, and biological variables must be accounted for statistically to maximize accuracy and comparability of published neuroscience data. However, accounting for all variables is nigh impossible. Thus we aimed to identify particularly influential variables within published neurological data, from cat, rat, and mouse studies, via a robust statistical process. Our goal was to develop tools to improve rigor in the collection and analysis of data. We strictly constrained experimental and methodological variables and then assessed four key biological variables within motoneuron research: species, age, sex, and cell type. We quantified intraexperimental and interexperimental variances in 11 commonly reported electrophysiological properties of spinal motoneurons. We first assessed variances without accounting for biological variables and then reassessed them while accounting for all four variables. We next assessed variances with all possible combinations of these four variables. We concluded that some motoneuron properties have low intraexperimental, but high interexperimental, variance; that individual motoneuron properties are impacted differently by biological variables; and that some unexplained variances still remain. We report here the optimal combinations of biological variables to reduce interexperimental variance for all 11 parameters. We also rank each parameter by intra- and interexperimental consistency. We expect these results to assist with design of experimental and analytical methods, and to support accuracy in simulations. Furthermore, although demonstrated on spinal motoneuron electrophysiology literature, our approach is applicable to biological data from all fields of neuroscience. This approach represents an important aid to experimental design, comparison of reported data, and reduction of unexplained variance in neuroscience data. NEW & NOTEWORTHY Our meta-analysis shows the impact of species, age, sex, and cell type on lumbosacral motoneuron electrophysiological properties by thoroughly quantifying variances across literature for the first time. We quantify the variances of 11 motoneuron properties with consideration of biological variables, thus providing specific insights for motoneuron modelers and experimenters, and providing a general methodological template for the quantification of variance in neurological data with the consideration of any experimental, methodological, or biological variables of interest.

Background: Pain management is a substantial component of the care of patients with pancreatic cancer (PC). PC-related pain occurs in up to 75% of patients at diagnosis, 90% of patients with late-stage disease, and overall is the most frequently reported adverse event in this patient population. PC-related pain is multifactorial and includes visceral, somatic, and neuropathic origins. Furthermore, PC-related pain can be disease-induced or a result of adverse side effects of treatment. PC-related pain is primarily managed by supportive care medications (SCM), including opioid and non-opioid analgesics, corticosteroids, and antiepileptics. Among these, opioids are by far the most utilized treatment. Recent evidence suggests that opioid use in PC patients is associated with increased survival. Previous literature suggests racial/ethnic differences in the use of some SCMs including opioids in patients with cancer, but there is no research confirming these findings in patients with PC. Methods: Utilizing the National Cancer Institute Surveillance Epidemiology and End Results (NCI SEER)- Medicare linked database, our analysis included all patients with a PC diagnosis and a newly initiated outpatient prescription claim for pain medications from 2009-2018. Patients who were on pain medications before PC diagnosis, or of unspecified race/ethnicity were excluded from the analysis. We assessed three separate classes of pain medications including opioids, non-opioid analgesics, and neuropathic analgesics. Prescription claims were specific to patients diagnosed with PC and stratified by self-identified race/ethnicity. Our objective was to characterize the relationship between race and receipt of pain medications in the first year following the diagnosis of PC. Results: After application of the inclusion/exclusion criteria, 71,700 patients with PC were identified and included in the analysis (White: 80.3%; Black/African American: 11.8%; Asian/Pacific Islander: 4.5%; Hispanic: 3.1%; Native American 0.25%). As compared to White patients, Black/African American (Relative Risk [RR] 0.97; 95% Confidence Interval [CI]: 0.96-0.99) and Asian/Pacific Islander patients (RR 0.88; 95% CI: 0.85-0.90) were less likely to be prescribed an opioid analgesic. Black/African American (RR 1.09; 95% CI: 1.02-1.16), Asian/Pacific Islander (RR 1.52; 95% CI: 1.41-1.65), and Hispanic (RR 1.45; 95% CI: 1.31-1.59) patients were more likely to be prescribed a non-opioid analgesic. Black/African American (RR: 1.11; 95% CI: 1.05-1.18) patients were more likely to be prescribed a neuropathic analgesic. No other differences were noted in pain medication use by race/ethnicity. Conclusion: Our study findings suggest that pain medication usage in patients with PC varies for racial/ethnic minorities as compared to White patients, in particular for Black/African Americans. Future research should explore the impact of sociocultural, and psychosocial factors on pain medication usage patterns in racial/ethnic minority patients with PC. Citation Format: John M. Allen, MegCholack Awunti, Yi Guo, Sherise Rogers, Lisa Scarton, Diana J. Wilkie. Disparities in the use of pain medication in patients with pancreatic cancer: Focus on racial and ethnic minorities [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A026.

Background Pancreatic Ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer mortality and is projected to increase in incidence by 2030 in the United States. Compared to Caucasians, African Americans (AA) have a significantly increased risk for PDAC, even after adjusting for risk factors (e.g., SES, obesity and smoking), and worse survival outcomes. Somatic and germline mutations are found in 90% and 10% PDAC cases, respectively. These mutations are known to alter the incidence and therapeutic response of PDAC, and studies show significant differences in genetic expression between AA and Caucasians. Our study focused on the current understanding of genetic mutations that influence the pharmacoethnicity of FDA approved PDAC drugs. Methods For this narrative review, multiple searches were generated from the PubMed database using several variations of the following keywords: pharmacogenetics, pancreatic cancer, race, ethnicity, African, Black, toxicity, and the FDA approved drug names: Fluoropyrimidines, Topoisomerase inhibitors, Gemcitabine, Nab-Paclitaxel, Platinum agents, Pembrolizumab, PARP-inhibitors, and NTRK fusion inhibitors. Names of genes were extracted from studies with established data on pharmacogenetic-related racial disparities. Additional studies were found from the cited section. After searches for PubMed was thoroughly reviewed, the same keywords were imputed in Web of Science. The University of Alabama at Birmingham (UALCAN) database was used to verify if overall survival was significant for the expression of the genes identified in literature. Only genes that were found in the literature and UALCAN database were included. Results The following genes were identified as influencing pharmacogenetic-related disparities and then assessed for significance in overall survival using the UALCAN database: CDA, TYMS, UGT1A1, SLC and ABCB transporters, BRCA 2, PALB2, ERCC1, ERCC2, NTRK 1-3, POLA2, and CY2C8. The following genes were not significant for overall survival: CDA, UGT1A1, PALB2, ERCC1, ECCR2, NTRK 1-3. TYMS (p=0.0052), POLA2 (p=0.022), CYP2C8 (p=0.027), BRCA2 (p=0.027) genes were significant for impacting overall survival outcomes. The UALCAN database has low sample size of African Americans (n=6) therefore, significance for overall survival based on race could not be properly stratified. Conclusion In conclusion, racial differences in gene expression can influence the therapeutic response of PDAC. The UALCAN database provides overall survival for patients with PDAC, but conclusions about race could not be properly stratified due to the low sample size of African Americans. As targeted therapy advancements improve, referrals for genetic testing should also because it can direct treatment course for avoiding toxicities and improving medical precision for AA. Citation Format: Guettchina Telisnor, Esther Frimpong, Edward Agyare, John M. Allen, Sherise C. Rogers. Pharmacogenetics of pancreatic ductal adenocarcinoma: A review of racial disparities [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C026.

Purpose Angiotensin II (ATII) is a potent endogenous vasoconstrictor that has recently garnered regulatory approval for the treatment of distributive shock, including septic shock. Traditional vasoactive substances used in the management of distributive shock include norepinephrine, epinephrine, phenylephrine, and vasopressin. However, their use can be associated with deleterious adverse drug effects, such as splanchnic vasoconstriction and associated hypoperfusion. The purpose of this review is to describe ATII, including its pharmacologic mechanisms, pharmacokinetic profile, evidence of efficacy and tolerability, and potential role in contemporary critical care practice. Methods Peer-reviewed clinical trials and relevant treatment guidelines published from 1966 to September 14, 2019, were identified from Medline/PubMed using the following search terms: angiotensin II OR angiotensin 2 AND shock OR septic shock OR vasodilatory shock. Pertinent review articles were reviewed for additional studies for inclusion and discussion. The final decision on the inclusion of studies in the current review was based on the expert opinion of the authors. Findings On the basis of the available evidence, ATII is effective at elevating blood pressure in patients with distributive shock and appears to reduce the dose of concurrent vasopressors to maintain adequate blood pressure. ATII has been investigated for other causes of shock; however, robust evidence of off-label indications is lacking and is much needed. Clinical and cost benefits compared with traditional vasopressors have yet to be established. Implications ATII represents a welcome addition to the armamentarium of critical care clinicians. Enthusiasm for the use of ATII should be balanced with the current gaps in our understanding of ATII in patients with shock. Until further evidence provides more clinically meaningful benefits, as well as cost-effectiveness compared with currently available vasopressors, critical care clinicians should reserve ATII for salvage therapy in patients with septic shock.

Most mammals cannot easily overcome degenerative disease or traumatic injuries. In contrast, an innate ability to regenerate is observed across animal phyla. Freshwater planarians are amongst the organisms that are capable of stem cell-mediated whole-body regeneration and have served as an exemplary model to study how pluripotency is maintained and regulated in vivo. Here, we review findings on the role of post-translational modifications and the genes regulating phosphorylation, ubiquitylation, and chromatin remodeling in planarian regeneration. Furthermore, we discuss how technological advances for identifying cellular targets of these processes will fill gaps in our knowledge of the signaling mechanisms that underlie regeneration in planarians, which should inform how tissue repair can be stimulated in non-regenerative model organisms and in humans.

Introduction: Human Papillomavirus (HPV) is the most common sexually transmitted disease. The contraction of HPV is associated with the development of several different types of cancers, including anal, cervical, and oropharyngeal cancers. These cancers have proven to impact Black and Hispanic women disproportionately across the United States, suffering from high rates of HPV infection and high incidence of cervical cancer. Despite knowledge of this risk, HPV vaccination rates remain low among minority women. Personal beliefs and access surrounding HPV vaccination may be contributors to these disparities. This survey aims to study the motivations behind the choice to receive HPV vaccination among health science students. Health science students are the target for this study as they are uniquely situated as the future providers of their communities. If the study is able to gauge how they feel about HPV vaccination, then the scientific community can target interventions to impact change beginning with the providers themselves. Females specifically were chosen as they are the primary targets of HPV vaccination. HPV vaccination rates among female health science students are a secondary result. Methods: A 37-item electronic survey was sent out to female health science students at the University of Florida which include the schools of Dentistry, Medicine, Nursing, Pharmacy, Public Health, and Veterinary Science. The online survey was then distributed in July of 2021 through Qualtrics. The survey evaluated previous HPV knowledge, motivations for or against HPV vaccination, and beliefs surrounding HPV vaccination. Results: The survey was delivered and distributed in July of 2021. In this study there are four different types of questions analyzed to gather information on previous HPV knowledge, attitudes, beliefs and external influences. Results will be categorized and compared based on race/ethnicity. By analyzing these groups there is an opportunity to understand how one's racial or ethnic background can affect their medical decisions in health science students and the recommendations they give to others. Results are pending. Conclusion: This being the first study of its kind warrants further investigation as health science students are trusted individuals of the medical community. If these students are against HPV vaccination, then medical schools could target interventions to teach students about racial disparities in HPV infection and vaccination recommendation. So, when given the opportunity as a provider these students can recommend vaccination to their patients. These results are indicative of knowledge gaps and attitudes within the younger generations of the medical community. Citation Format: Katya M Marcia, John M Allen. Evaluation of attitudes, beliefs and influences and their impact on HPV vaccination rates among minority health science students [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-270.

Objective: Describe recent developments in the pharmacological management of sepsis and septic shock, focusing on fluid resuscitation, vasopressors, and corticosteroids. Data Sources: A literature search limited to randomized controlled trials written in the English language reporting mortality and other clinically relevant outcomes that were published from July 1, 2016, to August 31, 2018, in patients aged ≥ 18 years. Titles and abstracts were reviewed for relevance. References for pertinent review articles were also reviewed. Study Selection and Data Extraction: Relevant randomized controlled trials conducted in patients meeting the pre-defined inclusion criteria were considered for inclusion. Data Synthesis: From an initial search that identified 147 studies, 14 original research studies met inclusion criteria and were included in this review. Risk of bias (ROB) was assessed using the Revised Cochrane ROB assessment tool, with most included studies having a low ROB. Relevance to Patient Care and Clinical Practice: Sepsis and septic shock pose a significant burden on public health. Despite advances in our understanding of sepsis, mortality remains unacceptably high. Recent developments in the pharmacological management of septic shock have focused on determining optimal composition and dosage of fluid resuscitation, enhanced use of vasopressor therapy, and clarifying the role of corticosteroids. This systematic review will provide recommendations for application to practice focusing on recent research on these topics. Conclusions: Although recent developments in the pharmacological management of sepsis are encouraging, clinicians must be keen to utilize patient-specific factors to guide therapy and continue to strive to address the remaining unanswered questions.

Gold(I)-containing complexes are used in drug discovery research for rheumatoid arthritis, cancer, and parasitic infections. In this study, we tested the bioactivity of gold(I) complexes in vivo using planarians. The planarian Schmidtea mediterranea possesses orthologues of tumor suppressor genes, such as p53, that, when silenced, cause deregulation of cell proliferation and apoptosis. In this context, we tested two triethylphosphine-gold(I) complexes (AdO and AdT) to determine if they can attenuate phenotypes that result from p53 inhibition. First, we identified the drug concentration that did not affect survival or regeneration and evaluated the drug’s effect on cell division and apoptosis. We found that AdT treatment decreased the number of mitotic cells and that all drug treatments increased the number of apoptotic cells. We then performed p53(RNAi) and drug treatments concomitantly and observed the phenotype progression. Drug treatment increased survival three-fold and decreased apoptosis, which resulted in an attenuated phenotype. Our results indicate that planarians can be treated with gold(I) complexes, and that this treatment can diminish the p53(RNAi) phenotype and extend survival. In this work we show that planarians can be used as a model to study the in vivo effect of gold(I) complexes and to further investigate their mechanisms of action.

The ubiquitin system plays a role in nearly every aspect of eukaryotic cell biology. The enzymes responsible for transferring ubiquitin onto specific substrates are the E3 ubiquitin ligases, a large and diverse family of proteins, for which biological roles and target substrates remain largely undefined. Studies using model organisms indicate that ubiquitin signaling mediates key steps in developmental processes and tissue regeneration. Here, we used the freshwater planarian, Schmidtea mediterranea, to investigate the role of Cullin-RING ubiquitin ligase (CRL) complexes in stem cell regulation during regeneration. We identified six S. mediterranea cullin genes, and used RNAi to uncover roles for homologs of Cullin-1, -3 and -4 in planarian regeneration. The cullin-1 RNAi phenotype included defects in blastema formation, organ regeneration, lesions, and lysis. To further investigate the function of cullin-1-mediated cellular processes in planarians, we examined genes encoding the adaptor protein Skp1 and F-box substrate-recognition proteins that are predicted to partner with Cullin-1. RNAi against skp1 resulted in phenotypes similar to cullin-1 RNAi, and an RNAi screen of the F-box genes identified 19 genes that recapitulated aspects of cullin-1 RNAi, including ones that in mammals are involved in stem cell regulation and cancer biology. Our data provides evidence that CRLs play discrete roles in regenerative processes and provide a platform to investigate how CRLs regulate stem cells in vivo.

INTRODUCTION: The study purpose was to evaluate the impact of a multimedia educational approach composed of a Storyline 360 activity (online interactive video-based learning), a virtual intensive care unit environment (VICU) visitation, and classroom simulation utilizing a physical code tray on rapid response team (RRT) training in a critical care pharmacy elective Impact was assessed via: 1-Content interaction, 2-Understanding of, and comfort and preparedness with RRT treatments and roles METHODS: A Storyline 360 learning activity simulating a pharmacist, RRT orientation experience was developed As part of the activity, students went to the VICU environment to learn more about rapid responses and created a medication reference card The VICU was part of existing course content and was further developed for this activity Upon completion, students responded, in a virtual class setting, to RRT scenarios utilizing a physical code tray The class was virtual due to course transition to online instruction during the COVID-19 Pandemic Students documented time spent in the VICU as part of course activities Perception of impact on understanding, comfort, and preparedness were assessed via post-course survey and VICU exit questions RESULTS: All students completed the storyline activity and visited the RRT VICU Time, in minutes, spent in the VICU was: 1-15 (14/35, 40%), 16-30 (15/35, 43%), +30 (6/35, 17%) Compared to 2019, there was a significant difference in the time spent in the VICU with a larger % documenting longer time periods (p

Background: Immune checkpoint inhibitors (ICIs) are commonly used in the treatment of multiple types of cancer. Several small studies have identified an association between antibiotic exposure and ICI failure. Furthermore, ICI failure has also been associated with decreased tumor mutation burden (TMB), with racial disparities being noted. However, to date there are no studies that have investigated the relationship of potential racial disparities and antibiotic exposure on clinical outcomes in patients receiving ICI therapy. The purpose of our systematic review and meta-analysis is to determine the impact of antibiotic (ATB) exposure on overall survival in patients receiving ICI therapy. An additional goal is to determine if racial disparities are present. Methods: We conducted a systematic review and meta-analysis utilizing PRISMA guidance of all randomized controlled trials, or observational studies that evaluated the impact of antibiotic exposure on ICI efficacy. We excluded studies that did not report overall survival. The primary outcome of this study is overall survival (OS) among ICI patients with antibiotic exposure, compared to patients who received ICI therapy alone. Secondary outcomes include response rate (RR), and progression-free survival (PFS). An a priori subgroup analysis for the primary outcome will be conducted based on race, cancer type, and specific ICI utilized. Results: A total of twelve studies (n=1,868 patients) were included in the final analysis. Among all patients, the most common reasons for ICI use were NSCLC (n=1,180), melanoma (n=316) and RCC (n=238). Among all patients, the most commonly used ICI was anti PD-1/PD-L1 (n=708), nivolumab (n=440) and pembrolizumab (n=63). Of the total patients analyzed, 446 patients (23.9%) received ATB within 6 months surrounding ICI therapy, and 1,422 patients (76.1%) did not receive any ATB surrounding ICI therapy. No studies reported ethnicity in their published results. Patients treated with ATB had lower overall survival compared to those without antibiotic exposure (ATB- 7.5 months; No ATB- 18.9 months). RR (ATB- 14.7%; No ATB 50.9%) and PFS (ATB- 2.4 months; No ATB- 5.1 months) were also shorter. Conclusions: ATB use was associated with less overall survival compared to non-ATB use in patients receiving ICI therapy. Our findings suggest that measures to promote reduced ATB use in patients receiving ICI therapy may help to improve clinical outcomes. No studies in the final analysis reported race and ethnicity. While it is hypothesized that race and ethnicity may play a role in ICI response, further research to evaluate the role of race and ethnicity is needed, which may help clinicians to better identify patients most likely to benefit from ICI therapy. Citation Format: Armani B Hayes, John Allen. Impact of antibiotic exposure on the overall survival in patients receiving immune checkpoint inhibitors: Does race matter? [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D057.

Undergraduate research experiences are excellent opportunities to engage students in science alongside experienced scientists, but at large institutions, it is challenging to accommodate all students. To address and engage a larger number of students, we developed a modular laboratory course based on the course-based undergraduate research experiences model. This new course was integrated with the scientific aims of a research laboratory studying the cellular and molecular mechanisms underlying tissue regeneration in planarians. In this course, students were asked to identify genes with roles in planarian biology. Students analyzed and cloned an assigned gene, determined its expression pattern in situ and examined its function in regeneration. Additionally, we developed critical thinking and scientific communication skills by incorporating activities focused on critical concepts. Students obtained high quality primary data and were successful in completing and mastering the course learning outcomes. They benefitted by developing basic research skills, learning to perform, trouble-shooting experiments, reading and critically analyzing primary literature, and using the information to defend and explain their experimental results. Through this course, students also increased their confidence and ability to perform independent scientific research. The course was designed to make it accessible to the community to implement and adapt as appropriate in diverse institutions. © 2019 International Union of Biochemistry and Molecular Biology, 47(5):547-559, 2019.

Historically, osteopathic medicine has focused primarily on clinical medicine. Research was a secondary concern, although scientific inquiry was originally part of the vision of founder Andrew Taylor (A.T.) Still, MD, DO.[1][1] With increased recognition of the connection between research and

Recent reports confirm that the standard dose of enoxaparin in obese patients is often subtherapeutic, leading to a higher incidence of venous thromboembolism. All patients receiving subcutaneous enoxaparin 30 mg twice a day (b.i.d.) for venous thromboembolism prophylaxis were prospectively enrolled in this study. Trough antiXa levels were obtained and any level less than 0.1 IU/mL was considered subtherapeutic and the final dosage requirement was recorded. Body mass index (BMI), abdominal wall thickness, and fluid balance were collected. Thirty-four patients were prospectively enrolled in the study, 14 (50%) of which had a BMI >30. Sixty-five per cent of obese patients were initially nontherapeutic, compared with 53 per cent of the nonobese ( P = 0.73). However, elevated BMI ( P < 0.05) and abdominal wall thickness ( P < 0.05) correlated to an increased final dose required to attain an anti Xa ≥0.1 when not initially therapeutic, whereas fluid balance demonstrated no correlation ( P = 0.232). Subcutaneous enoxaparin dosing of 30 mg b.i.d. is not sufficient for the majority adult trauma patients in the intensive care unit, regardless of BMI. When enoxaparin 30 mg b.i.d. is initially subtherapeutic, obese patients may require a larger dose necessary to achieve necessary anticoagulation.

Critically ill patients often are at high-risk for adverse drug reactions (ADRs), mainly due to alterations in pharmacokinetic and pharmacodynamic (PK/PD) parameters. These PK/PD differences in can also lead to inadequate therapeutic response to many commonly used drugs in this patient population. Frequently in the critically ill patient, medications are utilized based on a "trial-and-error" approach. Furthermore, drug dosing in the critically ill largely remains a "one-size-fits-all" phenomenon, utilizing dosing based on PK studies in healthy volunteers. Known differences in gene variation among the general population can greatly alter response to drug therapy. The use of pharmacogenomics (PGX) to aid in the development of individualized pharmacotherapeutic regimens, potentially may reduce ADRs and increase therapeutic efficacy. Potential uses of PGX include: identification of patients who are particularly susceptible to ADRs; and patients whom are more likely to benefit from a particular drug therapy, based on the patient's own genetic profile. This review will focus on potential applications of PGX in the critically ill, including management of acute coronary syndromes (ACS), invasive fungal infections, and pain management. Current barriers to PGX-guided therapy in the critically ill and recent patent developments in the clinical application of PGX will also be discussed.

In the care of the critically ill patient, the use of vasoactive substances such as vasopressors and inotropes can be a potentially lifesaving intervention. An understanding of the pathophysiology of the various types of shock and pharmacology of the pharmacological agents used in the treatment of shock is necessary for intensive care unit clinicians to make appropriate decisions regarding when vasopressors or inotropes are indicated and assess their effectiveness. This review article will provide background on the different types of shock, compare and contrast the commonly used vasoactive substances in critically ill patients, discuss titration strategies for these agents, and review management of extravasation of these agents.

Background The treatment of ventilator-associated pneumonia (VAP) secondary to methicillin-resistant Staphylococcus aureus (MRSA) remains controversial. Methods We performed a review of all blunt trauma patients diagnosed with MRSA VAP from June 2005 to June 2011. VAP for the first 3 years was diagnosed by sputum aspiration and treated with vancomycin. For the last 3 years of the study period, VAP was diagnosed with bronchoalveolar lavage and treated with linezolid. Results MRSA VAP patients treated with vancomycin had an average hospital length of stay (LOS) of 49 days (range 9–99 days), an average intensive care unit (ICU) LOS of 43 days (range 6–98 days), and average ventilator days of 34.4 (range 3–76 days). Seventeen MRSA VAP patients treated with linezolid had an average hospital LOS of 27 days (range 11–61), an average ICU LOS of 22 days (range 10–42) days, and average ventilator days of 16.6 (range 2–42). Conclusions Trauma patients who develop MRSA VAP appear to have fewer ventilator days and shorter ICU and hospital LOS when treated with linezolid.

Critically ill patients often require specialized nutrition via the enteral route. The benefits of enteral feeding, particularly early in the care of the critically ill patient, are well documented. Controversy exists regarding the provision of enteral nutrition (EN) in critically ill patients with hemodynamic instability who require vasopressors or inotropes. Concerns center on the potential for gut ischemia that may develop in the face of an imbalance between oxygen supply and demand. Current guidelines offer some guidance as to when to it is safe to initiate enteral feeding in patients on vasopressors, but the decision on when to start EN in hemodynamically unstable patients requiring vasoactive substances remains a clinical dilemma for most critical care practitioners. This review focuses on the effects of vasoactive substances such as pressors and inotropes on the gastrointestinal tract, as well as their use in combination with EN.

PurposeAt present, there are a scarcity of data available evaluating off-label prescribing patterns of recombinant factor VIIa (rFVIIa), pharmacoeconomic impact, and patient outcomes in clinical practice in an acute care setting with guidelines in place to influence prescribing practices. The primary objective of this study was to retrospectively evaluate the off-label usage and prescribing patterns of rFVIIa at a large acute care hospital with established rFVIIa guidelines.ResultsDuring the study period, a total of 199 patients were ordered rFVIIa, of which 181 (91%) received at least one dose of rFVIIa for an off-label use (n=181). Refractory bleeding and intracerebral hemorrhage were the 2 leading uses for rFVIIa, accounting for 30% (n = 54) and 29% (n = 51) of all uses, respectively. Overall, the mean number of doses per patient for all uses was 1.79. The mean number of doses per patient by non–FDA-approved use was highest in patients with cardiac surgery and refractory bleeding. The total yearly acquisition of rFVIIa for the study institution has decreased from 5.25 mcg/patient-day in 2005 to 2.52 mcg/patient-day in 2009.ConclusionThe findings are encouraging and support the impact that education of pharmacy, nursing, and physician staff along with guideline development may have on off-label rFVIIa usage. Further research evaluating the impact of rFVIIa guidelines and/or order sets is warranted.

Objective Computational models often require tradeoffs, such as balancing detail with efficiency; yet optimal balance should incorporate sound design features that do not bias the results of the specific scientific question under investigation. The present study examines how model design choices impact simulation results. Approach We developed a rigorously-validated high-fidelity computational model of the spinal motoneuron pool to study three long-standing model design practices which have yet to be examined for their impact on motoneuron recruitment, firing rate, and force simulations. The practices examined were the use of: (1) generic cell models to simulate different motoneuron types, (2) discrete property ranges for different motoneuron types, and (3) biological homogeneity of cell properties within motoneuron types. Main results Our results show that each of these practices accentuates conditions of motoneuron recruitment based on the size principle, and minimizes conditions of mixed and reversed recruitment orders, which have been observed in animal and human recordings. Specifically, strict motoneuron orderly size recruitment occurs, but in a compressed range, after which mixed and reverse motoneuron recruitment occurs due to the overlap in electrical properties of different motoneuron types. Additionally, these practices underestimate the motoneuron firing rates and force data simulated by existing models. Significance Our results indicate that current modeling practices increase conditions of motoneuron recruitment based on the size principle, and decrease conditions of mixed and reversed recruitment order, which, in turn, impacts the predictions made by existing models on motoneuron recruitment, firing rate, and force. Additionally, mixed and reverse motoneuron recruitment generated higher muscle force than orderly size motoneuron recruitment in these simulations and represents one potential scheme to increase muscle efficiency. The examined model design practices, as well as the present results, are applicable to neuronal modeling throughout the nervous system.

The diverse functional roles for RNA molecules in cells of the developing embryo have been an area of intense study in the last few years. Progress reported at the 49th Annual Drosophila Research C...