Diagnosis of Renal Artery Aneurysm by Point-of-Care Ultrasound in the Emergency Department: A Case Report and Brief Review of the Literature.

BACKGROUND: Renal artery aneurysm (RAA) is defined as a focal dilatation of ≥50% of the adjacent, disease-free artery. Although typically asymptomatic, RAA can lead to hypertension, hematuria, and rupture. The risk of rupture is higher in pregnant patients and may result in the death of the mother and the fetus. We describe a case of RAA discovered on point-of-care ultrasound (POCUS) in the emergency department. CASE REPORT: A 46-year-old woman with no medical history presented to the emergency department with lower abdominal pain, vomiting, diarrhea, and increased urination. POCUS was performed to evaluate the cause of the patient's symptoms. This study revealed a 2.40 cm × 3.65 cm aneurysm in the right kidney. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Rupture of RAA occurs in 3% to 5% of cases. Mortality to both the mother and the fetus is particularly high in gravid patients. RAA may be mistaken for other renal entities such as prominent renal veins or hydronephrosis. Properly identifying this pathology via POCUS can lead to early intervention. © 2022 Elsevier Inc.

Development of a novel observed structured clinical exam to assess clinical ultrasound proficiency in undergraduate medical education.

OBJECTIVES: A pilot study was performed to develop and test an observed structured clinical exam (OSCE) for clinical ultrasound in second-year medical students. The goal was to assess a longitudinal clinical ultrasound curriculum for medical students and to help determine readiness to perform ultrasound during clinical clerkships. METHODS: The OSCE contained 40 tasks over 30 min in a one-to-one examiner to examinee environment using standardized patients covering cardiac, pulmonary, and inferior vena cava (IVC) ultrasound exams along with 6 critical diagnoses. Examinees were assessed using a binary checklist approach. A two-way ANOVA analysis was performed to determine if there were differences between the day and session the OSCE was administered. Results are presented as mean ± standard deviation. RESULTS: One hundred fifty-two students were tested with an overall mean score of 64.9 ± 17.6%. Scores between the cardiac, IVC, and lung sections varied-67.8% ± 18.8%, 62.4% ± 26.2%, and 57.1% ± 20.6%, respectively. One hundred twenty-six (82.9%) answered at least one critical diagnosis incorrectly. Students in the late session performed better than the early session (1: 60% vs 2: 69%, p = .001). CONCLUSIONS: Students performed better in later sessions. Additionally, the number of questions left blank at the end of the exam suggests that the length of the OSCE should be evaluated. Incorporating critical diagnoses was challenging for examinees. The proposed OSCE is a valuable assessment tool that could be adapted to assess student's readiness to use clinical ultrasound prior to clerkships.

Utility of Point-of-Care Ultrasound for the Rapid Evaluation of Acute Sialadenitis: A Case Report.

Acute suppurative sialadenitis is a bacterial infection of the salivary glands which leads to a painful, tender, and swollen salivary gland. Point-of-care ultrasound (POCUS) is a limited ultrasound performed by the provider to answer a specific clinical question. We present a case describing the efficient utilization of POCUS for the rapid diagnosis of acute suppurative sialadenitis in the Emergency Department.

Point-of-Care Ultrasound for Bedside Diagnosis of Lower Extremity DVT.

The point-of-care ultrasound DVT (POCUS DVT) examination can facilitate rapid bedside diagnosis and treatment of lower extremity DVT. Awaiting radiology-performed Doppler ultrasonography and interpretation by radiologists can lead to delays in lifesaving anticoagulation, and the POCUS DVT examination can provide timely diagnostic information in the patient with lower extremity symptoms. This article outlines accepted techniques for the POCUS DVT examination, discusses the historical context from which the current recommendations have evolved, and provides illustrations alongside ultrasound images of relevant venous anatomy to orient the clinician. Finally, common pitfalls and methods to avoid them are described.

Quantitative characterization of left ventricular function during pulseless electrical activity using echocardiography during out-of-hospital cardiac arrest.

BACKGROUND: Several prospective studies have demonstrated that the echocardiographic detection of any myocardial activity during PEA is strongly associated with higher rates of return of spontaneous circulation (ROSC). We hypothesized that PEA represents a spectrum of disease in which not only the presence of myocardial activity, but more specifically that the degree of left ventricular (LV) function would be a predictor of outcomes. The purpose of this study was to retrospectively assess the association between LV function and outcomes in patients with OHCA. MATERIALS AND METHODS: Using prospectively obtained data from an observational cohort of patients receiving focused echocardiography during cardiopulmonary resuscitation (CPR) in the Emergency Department (ED) setting, we analyzed 312 consecutive subjects with available echocardiography images with initial rhythm of PEA. We used left ventricular systolic fractional shortening (LVFS), a unidimensional echocardiographic parameter to perform the quantification of LV function during PEA. Regression analyses were performed independently to evaluate for relationships between LVFS and a primary outcome of ROSC and secondary outcome of survival to hospital admission. We analyzed LVFS both as a continuous variable and as a categorial variable using the quartiles and the median to perform multiple different comparisons and to illustrate the relationship of LVFS and outcomes of interest. We performed survival analysis using Cox proportional hazards model to evaluate the hazard corresponding to length of resuscitation. RESULTS: We found a positive association between LVFS and the primary outcome of ROSC (OR 1.04, 95%CI 1.01-1.08), but not with the secondary outcome of survival to hospital admission (OR 1.02, 95%CI 0.96-1.08). Given that the relationship was not linear and that we observed a threshold effect in the relationship between LVFS and outcomes, we performed an analysis using quartiles of LVFS. The predicted probability of ROSC was 75% for LVFS between 23.4-96% (fourth quartile) compared to 47% for LVFS between 0-4.7% (first quartile). The hazard of not achieving ROSC was significantly greater for subjects with LVFS below the median (13.1%) compared to the subgroup with LVFS greater than 13.1% (p < 0.05), with the separation of the survival curves occurring at approximately 40 min of resuscitation duration. CONCLUSIONS: Left ventricular function measured by LVFS is positively correlated with higher probability of ROSC and may be associated with higher chances of survival in patients with PEA arrest.

Early toxicology signal generation in the mouse.

The rat has been the preferred rodent toxicology species since before regulatory requirements have been in place, and there exists in the pharmaceutical industry and the regulatory agencies a significant amount of historical data for the rat. The resulting experience base with the rat makes the possibility of replacing it with the mouse for regulated toxicology studies untenable for all but the most extreme circumstances. However, toxicologists are very familiar with the mouse as a model for chronic carcinogenicity studies, and there exist multiple preclinical mouse models of disease. The authors evaluated the use of the mouse for early in vivo toxicology signal generation and prioritization of small molecule lead compounds prior to nomination of a development candidate. In five-day oral gavage studies with three test agents in the mouse, the authors were able to identify the same dose-limiting toxicities as those identified in the rat, including examples of compound-mediated hemolysis as well as microscopic lesions in the alimentary canal, kidney, and pancreas. Performing early signal generation studies in the mouse allows for earlier assessment of the safety liabilities of small molecules, requires significantly less compound, and allows evaluation of more compounds earlier in the project's life cycle.

Acute lymphoid and gastrointestinal toxicity induced by selective p38alpha map kinase and map kinase-activated protein kinase-2 (MK2) inhibitors in the dog.

Exposure to moderately selective p38alpha mitogen-activated protein kinase (MAPK) inhibitors in the Beagle dog results in an acute toxicity consisting of mild clinical signs (decreased activity, diarrhea, and fever), lymphoid necrosis and depletion in the gut-associated lymphoid tissue (GALT), mesenteric lymph nodes and spleen, and linear colonic and cecal mucosal hemorrhages. Lymphocyte apoptosis and necrosis in the GALT is the earliest and most prominent histopathologic change observed, followed temporally by neutrophilic infiltration and acute inflammation of the lymph nodes and spleen and multifocal mucosal epithelial necrosis and linear hemorrhages in the colon and cecum. These effects are not observed in the mouse, rat, or cynomolgus monkey. To further characterize the acute toxicity in the dog, a series of in vivo, in vitro, and immunohistochemical studies were conducted to determine the relationship between the lymphoid and gastrointestinal (GI) toxicity and p38 MAPK inhibition. Results of these studies demonstrate a direct correlation between p38alpha MAPK inhibition and the acute lymphoid and gastrointestinal toxicity in the dog. Similar effects were observed following exposure to inhibitors of MAPK-activated protein kinase-2 (MK2), further implicating the role of p38alpha MAPK signaling pathway inhibition in these effects. Based on these findings, the authors conclude that p38alpha MAPK inhibition results in acute lymphoid and GI toxicity in the dog and is unique among the species evaluated in these studies.

The application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates.

Toxicity is a leading cause of attrition at all stages of the drug development process. The majority of safety-related attrition occurs preclinically, suggesting that approaches to identify 'predictable' preclinical safety liabilities earlier in the drug development process could lead to the design and/or selection of better drug candidates that have increased probabilities of becoming marketed drugs. In this Review, we discuss how the early application of preclinical safety assessment--both new molecular technologies as well as more established approaches such as standard repeat-dose rodent toxicology studies--can identify predictable safety issues earlier in the testing paradigm. The earlier identification of dose-limiting toxicities will provide chemists and toxicologists the opportunity to characterize the dose-limiting toxicities, determine structure-toxicity relationships and minimize or circumvent adverse safety liabilities.

Development of a high-throughput human HepG(2) dual luciferase assay for detection of metabolically activated hepatotoxicants and genotoxicants.

Hepatic toxicity remains a major concern for drug failure; therefore, a thorough examination of chemically induced liver toxicity is essential for a robust safety evaluation. Current hypotheses suggest that the metabolic activation of a drug to a reactive intermediate is an important process. In this article, we describe a new high-throughput GADD45beta reporter assay developed for assessing potential liver toxicity. Most importantly, this assay utilizes a human cell line and incorporates metabolic activation and thus provides significant advantage over other comparable assays used to determine hepatotoxicity. Our assay has low compound requirement and relies upon 2 reporter genes cotransfected into the HepG(2) cells. The gene encoding Renilla luciferase is fused to the CMV promoter and provides a control for cell numbers. The firefly luciferase gene is fused to the GADD45beta promoter and used to report an increase in DNA damage. A dual luciferase assay is performed by measuring the firefly and Renilla luciferase activities in the same sample. Results are expressed as the ratio of the 2 luciferase activities; increases over the control are interpreted as evidence of stress responses. This mammalian dual luciferase reporter has been characterized with, and without, metabolic activation using positive and negative control agents. Our data demonstrate that this assay provides for an assessment of potential toxic metabolites, is adaptable to a high-throughput platform, and yields data that accurately and reproducibly detect hepatotoxicants.

Development of a highthroughput yeast-based assay for detection of metabolically activated genotoxins.

The potential genotoxicity of drug candidates is a serious concern during drug development. Therefore, it is important to assess the potential genotoxicity and mutagenicity of a compound early in the discovery phase of drug development. AMES Salmonella assay is the most widely used assay for the assessment of mutagenicity and genotoxicity. However, the AMES assay is not readily adaptable to highthroughput screening and several strains of Salmonella must be employed to ensure that different types of DNA damage can be studied. Therefore, an additional robust highthroughput genotoxicity screen would be of significant value in the early detection and elimination of genotoxicity. The complexity of DNA damage requires numerous cellular pathways, thus using single model organism to predict genotoxicity in early stage is challenging. Another critical component of such screens is that they incorporate the capability of metabolic activation to ensure that no genotoxic metabolites are generated. We have developed a novel highthroughput reporter assay for DNA repair that detects genotoxicity, and which incorporates metabolic activation. The assay has a low compound requirement as compared to Ames, and relies upon two different reporter genes cotransfected into a yeast strain. The gene encoding Renilla luciferase is fused to the constitutive 3-phosphoglycerate kinase (PGK1) promoter and integrated into the yeast genome to provide a control for cell numbers. The firefly luciferase gene is fused to the RAD51 (bacterial RecA homolog) promoter and used to report an increase in DNA repair activity. A dual luciferase assay is performed by measuring the firefly and Renilla luciferase activities in the same sample. The result is expressed as the ratio of the two luciferase activities; changes from the base level (control) are interpreted as induction of the RAD51 promoter and evidence of DNA repair activity in eukaryote cells due to DNA damage. The yeast dual luciferase reporter has been characterized with and without S-9 activation using positive and negative control agents. This assay is efficient, requires little time and low amounts of compound. The assay is compatible with metabolic activation, adaptable to a highthroughput platform, and yields data that accurately and reproducibly detects DNA damage. Whereas the normal yeast cell wall, plasma membrane composition and the presence of active transporters can prevent the entry or persistence of some compounds internally in yeast cells, our assay did show concordance with regulatory mutagenicity assays, many of which require metabolic activation and are poorly detected by bacterial mutagenicity assays. Although there were false negative results, in our hands this assay performs as well as or better than other commercially available genetox assays. Furthermore, the RAD51 gene is strongly inducible by homologous intrachromosomal recombination; thus this assay may provide a means to detect clastogens. The RAD51 promoter fused dual luciferase assay represents a valuable addition to the armamentarium for the early detection of genotoxic compounds.

Identification of platform-independent gene expression markers of cisplatin nephrotoxicity.

Within the International Life Sciences Institute Committee on Genomics, a working group was formed to focus on the application of microarray technology to preclinical assessments of drug-induced nephrotoxicity. As part of this effort, Sprague-Dawley rats were treated with the nephrotoxicant cisplatin at doses of 0.3-5 mg/kg over a 4- to 144-hr time course. RNA prepared from these animals was run on a variety of microarray formats at multiple sites. A set of 93 differentially expressed genes associated with cisplatin-induced renal injury was identified on the National Institute of Environmental Health Sciences (NIEHS) custom cDNA microarray platform using quadruplicate measurements of pooled animal RNA. The reproducibility of this profile of statistically significant gene changes on other platforms, in pooled and individual animal replicate samples, and in an independent study was investigated. A good correlation in response between platforms was found among the 48 genes in the NIEHS data set that could be matched to probes on the Affymetrix RGU34A array by UniGene identifier or sequence alignment. Similar results were obtained with genes that could be linked between the NIEHS and Incyte or PHASE-1 arrays. The degree of renal damage induced by cisplatin in individual animals was commensurate with the number of differentially expressed genes in this data set. These results suggest that gene profiles linked to specific types of tissue injury or mechanisms of toxicity and identified in well-performed replicated microarray experiments may be extrapolatable across platform technologies, laboratories, and in-life studies.

Overview on the application of transcription profiling using selected nephrotoxicants for toxicology assessment.

Microarrays allow for the simultaneous measurement of changes in the levels of thousands of messenger RNAs within a single experiment. As such, the potential for the application of transcription profiling to preclinical safety assessment and mechanism-based risk assessment is profound. However, several practical and technical challenges remain. Among these are nomenclature issues, platform-specific data formats, and the lack of uniform analysis methods and tools. Experiments were designed to address biological, technical, and methodological variability, to evaluate different approaches to data analysis, and to understand the application of the technology to other profiling methodologies and to mechanism-based risk assessment. These goals were addressed using experimental information derived from analysis of the biological response to three mechanistically distinct nephrotoxins: cisplatin, gentamicin, and puromycin aminonucleoside. In spite of the technical challenges, the transcription profiling data yielded mechanistically and topographically valuable information. The analyses detailed in the articles from the Nephrotoxicity Working Group of the International Life Sciences Institute Health and Environmental Sciences Institute suggest at least equal sensitivity of microarray technology compared to traditional end points. Additionally, microarray analysis of these prototypical nephrotoxicants provided an opportunity for the development of candidate bridging biomarkers of nephrotoxicity. The potential future extension of these applications for risk assessment is also discussed.

Toxicogenomics: an opportunity to optimise drug development and safety evaluation.

'Toxicogenomics', the use of complex populations of mRNA to understand toxicity, is a relatively new field which combines the wealth of gene sequence information with advances in miniaturisation technology. In a parallel evolutionary path that the broader field of toxicology has encountered, toxicogenomics is steadily changing from descriptive to mechanistic research and will ultimately progress to a predictive science. This review focuses on the application of microarray research tools to toxicology studies in preclinical development. In particular, the 'testing funnel' approach to candidate selection in drug development is used to discuss the strategic implementation of toxicogenomics to help develop drugs that harbour less toxicity. Examples of where toxicogenomics has increased mechanistic and descriptive understanding of cellular toxicity are discussed, as are early efforts to develop molecular biomarkers that are predictive of longer-term toxicity.

The role of investigative molecular toxicology in early stage drug development.

Molecular toxicology, the application of molecular biology principles and technologies to preclinical safety assessment, represents a key tool for understanding mechanisms of toxicity and assessing the risks associated with specific toxicities. The application of gene expression markers to early stage preclinical safety assessment has the potential to impact pipelines in two main areas: lead optimisation and issue management. Lead optimisation focuses on deprioritising leads with significant, development-limiting toxicological liabilities while advancing those compounds with the greatest chance of successfully navigating the gauntlet of preclinical and clinical safety studies. Issue management utilises mechanistic toxicology studies to position non-development-limiting findings prior to the onset of Good Laboratory Practice studies in full development, and can help to identify and validate gene expression markers predictive of adverse events to avoid issues in second-generation projects. In this review, the authors describe the application of molecular toxicology to a standard pharmaceutical testing funnel, provide examples of the successful application of gene expression markers, and discuss the potential for future impact in several broad categories of clinically relevant toxicity.

The Importance of Residual Effects When Choosing a Hypnotic: The Unique Profile of Zaleplon.

BACKGROUND: Insomnia is a prevalent medical disorder that has significant effects on occupational performance, health, and quality of life. Insomnia places an enormous burden on society through increased visits to physicians, loss of productivity in the workplace, and an increased rate of accidents. An estimated sum of $100 million is spent each year on direct treatment of unresolved insomnia. Physicians need to initiate early effective treatment to prevent development of chronic insomnia and its associated morbidity. Institution of good sleep hygiene practices may be useful in some patients but may not be adequate for resolution of all sleep problems. Behavioral treatments, while effective and durable, are time consuming and not widely utilized in clinical practice. Pharmacotherapy includes benzodiazepine hypnotics, but concerns regarding adverse effects (e.g., residual sedation) prompted the search for safer options. DATA SOURCES: Published and presented studies containing clinical data on zaleplon, a new nonbenzodiazepine sleep medication, were identified via MEDLINE, Current Contents (ISI database), bibliographic reviews, and consultation with sleep specialists. RESULTS: Zaleplon effectively shortens sleep onset time and improves the quality of sleep in patients with insomnia. Whether administered at bedtime or later at night, zaleplon is devoid of residual sedative effects that impair next-day functioning. Follow-up studies evaluating the long-term efficacy and safety of zaleplon showed that decreased time to sleep onset was maintained during therapy lasting up to 52 weeks, without a withdrawal syndrome after discontinuation. CONCLUSION: Insomnia is recurrent and unpredictable in nature. Despite the long-term morbidity of this sleep disorder, research evidence and practice guidelines have not explored long-term use of hypnotics. Many patients could benefit from long-term drug therapy with a sleep medication that is devoid of residual effects and can be taken at bedtime or later as symptoms occur, rather than nightly in anticipation of a sleep problem.

Management of insomnia--the role of zaleplon.

CONTEXT: Insomnia is the most frequently reported sleep symptom, severely affecting up to 15% of the US population. The need to effectively treat this disorder is underscored by the significant adverse consequences on the productivity, safety, overall health, and quality of life of the affected individual. Pharmacologic intervention has traditionally involved the use of benzodiazepine receptor agonists (BzRAs), for which efficacy and general safety have been established. OBJECTIVE: The purpose of this paper is to examine the potentially unique role of zaleplon in the treatment of insomnia. DATA SOURCE: The clinical experience of the authors was critically applied to peer-reviewed published papers or abstracts regarding zaleplon, which were identified via MEDLINE (1995-September 2000). RESULTS: Adverse effects, usually related to residual sedation, impose limits on the use of older BzRAs and have prompted the development of new sleep medications with advantageous adverse event profiles. Zaleplon demonstrates a very rapid onset and offset of effect that permits symptomatic rather than prophylactic administration, resulting in comparable efficacy and reduced risk of the adverse effects associated with longer half-life agents. CONCLUSIONS: The characteristics of zaleplon may translate into distinct and significant clinical advances in the treatment of insomnia.

In vivo toxicology of excipients commonly employed in drug discovery in rats.

INTRODUCTION: Toxicology and pharmacology studies conducted in the early stages of drug discovery often require formulation strategies involving the use of excipients with limited knowledge regarding their preclinical safety liabilities. The use of excipients is vital to efforts to solubilize and deliver small molecules in drug discovery. Whilst excipients can have a significant impact on pharmacology and toxicology studies by enabling solubility to maximize systemic exposure, they also have the potential to obscure clinical pathology endpoints. In this article, we report on the in vivo safety in rats for 18 excipients commonly employed in formulations for preclinical pharmacology and toxicology studies. METHODS: The test articles were administered once daily for five days, by oral gavage to male Sprague Dawley rats, and the animals monitored for visible clinical signs. At the end of the study, routine necropsy and clinical pathology endpoints were investigated. RESULTS: None of the excipients tested were acutely toxic. However, there were effects on parameters commonly evaluated as indicators of health and/or toxicological response in regulated preclinical safety studies. DISCUSSION: While the excipients tested were generally well tolerated, several were found to affect common clinical pathology endpoints in a manner that might confound or conceivably mask the interpretation of compound mediated adverse/pharmacological effects.