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.

One-year outcomes of spinal cord stimulation of the dorsal root ganglion in the treatment of chronic neuropathic pain.

OBJECTIVES: Spinal cord stimulation of the dorsal root ganglion (DRG-SCS) is a new therapy for treating chronic neuropathic pain. Previous work has demonstrated the effectiveness of DRG-SCS for pain associated with failed back surgery syndrome, complex regional pain syndrome, chronic postsurgical pain, and other etiologies through 6 months of treatment; this report describes the maintenance of pain relief, improvement in mood, and quality of life through 12 months. MATERIALS AND METHODS: Subjects with intractable pain in the back and/or lower limbs were implanted with an active neurostimulator device. Up to four percutaneous leads were placed epidurally near DRGs. Subjects were tracked prospectively for 12 months. RESULTS: Overall, pain was reduced by 56% at 12 months post-implantation, and 60% of subjects reported greater than 50% improvement in their pain. Pain localized to the back, legs, and feet was reduced by 42%, 62%, and 80%, respectively. Measures of quality of life and mood were also improved over the course of the study, and subjects reported high levels of satisfaction. Importantly, excellent pain-paresthesia overlap was reported, remaining stable through 12 months. DISCUSSION: Despite methodological differences in the literature, DRG-SCS appears to be comparable to traditional SCS in terms of pain relief and associated benefits in mood and quality of life. Its benefits may include the ability to achieve precise pain-paresthesia concordance, including in regions that are typically difficult to target with SCS, and to consistently maintain that coverage over time.

Effect of electrical field stimulation on dorsal root ganglion neuronal function.

OBJECTIVES: Neural stimulation may provide analgesia for a variety of painful conditions. Activation of primary sensory neurons, which underlies pain relief by spinal cord stimulation, also may be achieved by stimulation at the level of the dorsal root ganglion (DRG). The DRG also is a site of pain pathogenesis, particularly in neuropathic pain. We therefore examined the hypothesis that field stimulation of the DRG directly suppresses excitability of sensory neurons. MATERIALS AND METHODS: Intercellular Ca2+ level (Fura-2 microfluorimetry) and membrane potential were recorded in excised rat DRGs with ganglionic field stimulation (GFS) delivered by wire electrodes in the bath solution adjacent to the DRG. Neuronal excitability was evaluated by number of action potentials (APs) generated during neuronal depolarization, conduction velocity during axonal stimulation, and AP propagation failure. These were measured before and after 90 sec of GFS at 60 Hz. Data analysis employed chi-square, paired t-test, and analysis of variance. RESULTS: GFS using 400-µsec pulses and 30 V generated Ca2+ influx, indicative of DRG neuronal activation. Fewer neurons were able to fire one or more APs after GFS (N = 23) than in control neurons without GFS (N = 24, p < 0.05), and fewer neurons were able to generate multiple APs after GFS compared with time controls (p < 0.05). GFS significantly reduced conduction velocity compared with baseline before GFS (N = 16, p < 0.05) while there was no change in the controls (N = 18). The peak rate at which APs could be propagated was reduced in 9 of 16 neurons by GFS, but propagation efficiency was reduced in only 4 of 18 control neurons (p < 0.05), and the total number of APs generated in an ensemble of stimuli at different frequencies was reduced by GFS (N = 16, p < 0.05) but not in time controls (N = 18). CONCLUSIONS: Our findings indicate that direct excitation of the DRG by electrical fields reduces neuronal excitability and may provide a new analgesic approach.

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.

Not-for-profit hospital CEO performance and pay: some evidence from Connecticut.

This paper uses observations from a panel data set of 35 chief executive officers (CEOs) from 29 not-for-profit hospitals in Connecticut over the period 1998 to 2006 to investigate the relationship between CEO performance and pay. Both economic and charity performance measures are specified in the empirical model. The multiple regression results reveal that not-for-profit hospital CEOs, at least in Connecticut, are driven at the margin to increase the occupancy rate of privately insured patients at the expense of uncompensated care and public-pay patients. This type of behavior on the part of not-for-profit hospital CEOs calls into question the desirability of allowing these hospitals a tax exemption on earned income, property, and purchases.

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.

Surgical Removal of a Calcified Right Atrial Mass Related to Venous Access Port: A Case Report.

INTRODUCTION: Intracardiac masses pose a difficult diagnostic and therapeutic dilemma. Indwelling catheters can lead to thrombus calcification causing untoward sequelae. CASE PRESENTATION: We report on a patient who presented after computed tomography identified a large calcified right atrial mass. Her history included treatment for rectal cancer and breast cancer, thus we feared the mass could represent metastasis. The intracardiac mass was successfully resected via a right atriotomy. Her postoperative course was uneventful and the histopathology revealed a calcified thrombus. DISCUSSION: In this report we discuss our findings and pre- and intraoperative considerations, as well as suggestions for management of implantable venous catheters. This is a rare complication of an indwelling catheter. CONCLUSION: Operative management of intracardiac lesions is the standard of care. When related to implantable catheters, the best patient care would be prevention of such lesions. This would include routine flushing of the indwelling catheters and prompt removal once not in use.

Therapy Habituation at 12 Months: Spinal Cord Stimulation Versus Dorsal Root Ganglion Stimulation for Complex Regional Pain Syndrome Type I and II.

The ACCURATE randomized, controlled trial compared outcomes of dorsal root ganglion (DRG) stimulation versus tonic spinal cord stimulation (SCS) in 152 subjects with chronic lower extremity pain due to complex regional pain syndrome (CRPS) type I or II. This ACCURATE substudy was designed to evaluate whether therapy habituation occurs with DRG stimulation as compared to SCS through 12-months. A modified intention-to-treat analysis was performed to assess percentage pain relief (PPR) and responder rates at follow-up visits (end-of-trial, 1, 3, 6, 9, 12-months postpermanent implant) for all subjects that completed trial stimulation (DRG:N = 73, SCS:N = 72). For both groups, mean PPR was significantly greater at end-of-trial (DRG = 82.2%, SCS =0 77.0%) than all other follow-ups. Following permanent DRG system implantation, none of the time points were significantly different from one another in PPR (range = 69.3-73.9%). For the SCS group, PPR at 9-months (58.3%) and 12-months (57.9%) was significantly less than at 1-month (66.9%). The responder rate also decreased for the SCS group from 1-month (68.1%) to 12-months (61.1%). After stratifying by diagnosis, it was found that only the CRPS-I population had diminishing pain relief with SCS. DRG stimulation resulted in more stable pain relief through 12-months, while tonic SCS demonstrated therapy habituation at 9- and 12-months. Trial Registration: The ACCURATE study was registered at ClinicalTrials.gov with Identifier NCT01923285. PERSPECTIVE: This article reports on an ACCURATE substudy, which found that long-term therapy habituation occurred at 12-months with SCS, but not DRG stimulation, in patients with CRPS. The underlying mechanisms of action for these results remain unclear, although several lines of inquiry are proposed.

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.

Workforce analysis in orthopaedic surgery: how can we improve the accuracy of our predictions?

Since the 1970s, workforce analysis for orthopaedic surgery has predicted a surplus of physicians into the 21st century. In 1998, the RAND study predicted a surplus of 4,100 orthopaedists in 2010. As we approach 2010, we find no surplus. The projected population growth during the next 20 years of those older than age 65 years presupposes a greater need for orthopaedists, given an increase in degenerative disease and fragility fractures associated with aging. The federal government predicts an overall shortage of physicians by 2020. Given the current nature of workforce analysis models and the concerns evoked by these disparate predictions, we, the authors, advocate change. Rather than large studies separated by decades, we recommend routine monitoring of the orthopaedic workforce. Further, we suggest that national, regional, and local organizations, as well as subspecialty societies, work together to monitor current and future orthopaedic workforce needs. Orthopaedic organizations should develop collaborative relationships with experts in the field and devise a true working model that allows for ongoing strategic planning.

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.