A pilot study of radiation-induced bystander effect in radio-adapting frogs at a radiologically contaminated site located on the chalk river laboratories property.

PURPOSE: To measure medium borne bystander effects, to study the influence of radioadaptive response (RAR) on bystander response, and to discover reliable radioresponsive biomarkers in radio-adapting frogs from Duke Swamp contaminated with an above-background radiation level and in naïve frogs from Twin Lake as the background control site. MATERIALS AND METHODS: Frogs were captured at Duke Swamp and Twin Lake and brought to the lab at the Canadian Nuclear Laboratories facility. Half of the frogs from each site were irradiated with 4 Gy while the other half of the frogs were left with no further radiation treatment. Frog bladders were removed and placed in sterile culture media. Upon arrival at McMaster University, the bladders were processed for tissue cultures. After 48 h, the culture media conditioned by the bladder explants were harvested for clonogenic reporter survival assay and calcium flux measurements for assessing bystander effects. HPV-G cells were used as bystander reporter cells in all radiation-induced bystander effect (RIBE) assays. The frog bladder cultures were incubated for another 10-12 days followed by immunochemical staining for bcl-2 and c-myc expressions to analyze cellular anti-apoptotic (pro-survival) and pro-apoptotic (pro-death) responses, respectively. RESULTS: Only culture media conditioned by bladders from 4-Gy-irradiated naïve frogs from Twin Lake induced bystander effects (reduction of HPV-G reporter cells' clonogenic survival and presence of strong calcium flux activities). The 4 Gy irradiation dose increased pro-apoptotic c-myc expression in naïve frogs' bladder explants. Culture media conditioned by bladders from radio-adapting frogs from Duke Swamp enhanced HPV-G's clonogenic survival and a 4 Gy irradiation challenge did not change the enhanced clonogenic survival nature nor induce calcium flux. In bladder explants from both control and 4-Gy-irradiated radio-adapting frogs, anti-apoptotic bcl-2 expression for pro-survival responses was ubiquitous while c-myc expression for pro-death responses was limited to a small fraction of cells. CONCLUSION: The clonogenic RIBE reporter assay using HPV-G and calcium flux measurements are useful diagnostic tools for RIBE assessment of field biological samples, specifically those from frogs. RAR induced by environmentally relevant low-dose radiation induces protective bystander response. Bcl-2 and c-myc are reliable biomarkers for evaluating low dose radiation responses in wild populations of amphibians. Overall, this pilot study emphasizes the importance of looking at non-targeted effects (NTEs) in natural populations of non-human biota that could be vulnerable to chronic low-dose radiation exposures.

A Novel Case of Yamaguchi Syndrome in a Hispanic Male.

Yamaguchi syndrome or apical hypertrophic cardiomyopathy (HCM) is a unique variant of HCM. It is characterized by localized hypertrophy involving the left ventricular apex rather than the left ventricular septum. This syndrome has been traditionally seen in the Asian population, particularly those of Japanese descent. We present an interesting case of Yamaguchi syndrome seen in a Hispanic male. A 48-year-old Hispanic male presented with epigastric tenderness and was admitted to the hospital for a non-ST-segment elevation myocardial infarction. His diagnostic catheterization revealed no significant coronary artery disease. However, his echocardiogram revealed apical hypertrophy and narrowing of the left ventricular cavity at the apex, consistent with Yamaguchi syndrome. Case reports such as ours serve to help clinicians broaden their differential diagnoses when approaching patients with acute coronary syndrome-like symptoms to include diagnoses such as Yamaguchi syndrome.

Education Following Pediatric Gastrostomy Tube Placement: An Integrative Review.

BACKGROUND: There is a gap in knowledge regarding the necessary components for pediatric gastrostomy tube education. This integrative review addresses the question "What are the educational components following pediatric gastrostomy placement?" METHODS: A literature search was conducted using PubMed, CINAHL, and Cochrane Library electronic databases, along with a hand search. Articles for review included those in the pediatric population, English language, and publication dates between 2010 and 2020. RESULTS: Ultimately, 7 articles met the inclusion criteria for review. Articles were all pediatric focused (0-18 years), and were a mix of quantitative and qualitative designs, along with one non-research paper. Three major themes were identified from the literature including that gastrostomy tube education should be a multidisciplinary effort, that education should take a standardized approach, and that it should include psychosocial elements that enhance caregiver knowledge and empowerment. DISCUSSION: This review demonstrates that while there is no consensus on a superior mode or means of education, pediatric gastrostomy discharge education must be standardized and high quality to promote the best patient and caregiver outcomes. Further research should aim to address which forms of education, if any, lead to the best outcomes, and how education can best be delivered to promote caregiver knowledge and ease.

A Peer-Teaching Model to Reinforce Pharmacy Students' Clinical Knowledge of Commonly Prescribed Medications.

Objective. To implement and assess the effectiveness of a peer teaching series to increase third year Doctor of Pharmacy (PharmD) students' knowledge of and confidence regarding commonly prescribed medications.Methods. All third-year pharmacy students (n=98) at a college of pharmacy were encouraged to participate in the RxReady peer teaching series prior to beginning their advanced pharmacy practice experiences. Each student in the class was assigned a drug to learn in-depth. Twenty-four of the students were randomly selected to provide peer teaching regarding a single medication. These students were required to meet with a faculty member to prepare for their presentation. Assessment methods included completion of pre- and post-intervention quizzes and anonymous surveys regarding the peer-teaching modality. Students also provided qualitative feedback on the series as part of a course survey.Results. Among the 96 students who completed the pre- and post-intervention quizzes, there was a mean increase of 15% (SD=11%) on the post-intervention quiz score compared to the pre-intervention quiz score. Ninety-two (96%) students achieved a higher score on the post-intervention quiz. There was no difference in mean percent change in scores between the pre-and post-intervention quiz for students who presented in class compared with students who did not present (17% [SD=10%] vs 15% [SD=11%], respectively). Student-reported confidence significantly improved across all drug knowledge categories. In each category, the median confidence score increased from 2 (somewhat confident) to 3 (moderately confident). The students' qualitative feedback was generally positive, and they provided suggestions to improve the content and design of the RxReady peer teaching series.Conclusion. A peer teaching approach to reviewing drug information can assist in targeting gaps in PharmD students' drug knowledge and help to build their confidence in their readiness to begin APPEs.

Opportunities for successful de-escalation of proton pump inhibitors at a federally qualified health center.

BACKGROUND: A Proton Pump Inhibitor (PPI) de-escalation initiative was piloted at a Family Medicine Federally Qualified Health Center (FQHC) after a needs assessment showed that PPIs were prescribed inappropriately. The objective was to evaluate implementation of a PPI de-escalation program for an urban, underinsured patient population at a (FQHC). METHODS: Patients receiving PPI with an upcoming appointment with their primary care provider (PCP) were evaluated by a pharmacist for the appropriateness of therapy. The pharmacist administered a questionnaire to patients to assess PPI usage patterns and then evaluated for appropriate PPI therapy which included diagnoses, risk factors for gastrointestinal bleed, symptom control, and duration of PPI therapy. For consenting patients, de-escalation was implemented per pharmacist protocol. RESULTS: A total of 36 patients were evaluated for appropriate PPI use, among those, 21 (58%) were eligible for de-escalation, and 19 agreed to de-escalation. Fifteen patients (15/19) had successful PPI de-escalation after 4 weeks without discomfort or symptoms which disrupted daily activities. CONCLUSIONS: This pharmacist led initiative in collaboration with PCPs resulted in successful de-escalation of PPIs in an underserved primary care setting.

Effects of perineural invasion on biochemical recurrence and prostate cancer-specific survival in patients treated with definitive external beam radiotherapy.

OBJECTIVES: Perineural invasion (PNI) has not yet gained universal acceptance as an independent predictor of adverse outcomes for prostate cancer treated with external beam radiotherapy (EBRT). We analyzed the prognostic influence of PNI for a large institutional cohort of prostate cancer patients who underwent EBRT with and without androgen deprivation therapy (ADT). MATERIAL AND METHODS: We, retrospectively, reviewed prostate cancer patients treated with EBRT from 1993 to 2007 at our institution. The primary endpoint was biochemical failure-free survival (BFFS), with secondary endpoints of metastasis-free survival (MFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Univariate and multivariable Cox proportional hazards models were constructed for all survival endpoints. Hazard ratios for PNI were analyzed for the entire cohort and for subsets defined by NCCN risk level. Additionally, Kaplan-Meier survival curves were generated for all survival endpoints after stratification by PNI status, with significant differences computed using the log-rank test. RESULTS: Of 888 men included for analysis, PNI was present on biopsy specimens in 187 (21.1%). PNI was associated with clinical stage, pretreatment PSA level, biopsy Gleason score, and use of ADT (all P<0.01). Men with PNI experienced significantly inferior 10-year BFFS (40.0% vs. 57.8%, P = 0.002), 10-year MFS (79.7% vs. 89.0%, P = 0.001), and 10-year PCSS (90.9% vs. 95.9%, P = 0.009), but not 10-year OS (67.5% vs. 77.5%, P = 0.07). On multivariate analysis, PNI was independently associated with inferior BFFS (P<0.001), but not MFS, PCSS, or OS. In subset analysis, PNI was associated with inferior BFFS (P = 0.04) for high-risk patients and with both inferior BFFS (P = 0.01) and PCSS (P = 0.05) for low-risk patients. Biochemical failure occurred in 33% of low-risk men with PNI who did not receive ADT compared to 8% for low-risk men with PNI treated with ADT (P = 0.01). CONCLUSION: PNI was an independently significant predictor of adverse survival outcomes in this large institutional cohort, particularly for patients with NCCN low-risk disease. PNI should be carefully considered along with other standard prognostic factors when treating these patients with EBRT. Supplementing EBRT with ADT may be beneficial for select low-risk patients with PNI though independent validation with prospective studies is recommended.

Very High-Risk Localized Prostate Cancer: Outcomes Following Definitive Radiation.

PURPOSE: Existing definitions of high-risk prostate cancer consist of men who experience significant heterogeneity in outcomes. As such, criteria that identify a subpopulation of National Comprehensive Cancer Network (NCCN) high-risk prostate cancer patients who are at very high risk (VHR) for poor survival outcomes following prostatectomy were recently developed at our institution and include the presence of any of the following disease characteristics: multiple NCCN high-risk factors, primary Gleason pattern 5 disease and/or ≥5 biopsy cores with Gleason sums of 8 to 10. Whether these criteria also apply to men undergoing definitive radiation is unclear, as is the optimal treatment regimen in these patients. METHODS AND MATERIALS: All men consecutively treated with definitive radiation by a single provider from 1993 to 2006 and who fulfilled criteria for NCCN high-risk disease were identified (n=288), including 99 patients (34%) with VHR disease. Multivariate-adjusted competing risk regression models were constructed to assess associations between the VHR definition and biochemical failure (BF), distant metastasis (DM), and prostate cancer-specific mortality (PCSM). Multivariate-adjusted Cox regression analysis assessed the association of the VHR definition with overall mortality (OM). Cumulative incidences of failure endpoints were compared between VHR men and other NCCN high-risk men. RESULTS: Men with VHR disease compared to other NCCN high-risk men experienced a higher 10-year incidence of BF (54.0% vs 35.4%, respectively, P<.001), DM (34.9% vs 13.4%, respectively, P<.001), PCSM (18.5% vs 5.9%, respectively, P<.001), and OM (36.4% vs 27.0%, respectively, P=.04). VHR men with a detectable prostate-specific antigen (PSA) concentration at the end of radiation (EOR) remained at high risk of 10-year PCSM compared to VHR men with an undetectable EOR PSA (31.0% vs 13.7%, respectively, P=.05). CONCLUSIONS: NCCN high-risk prostate cancer patients who meet VHR criteria experience distinctly worse outcomes following definitive radiation and long-term androgen deprivation therapy, particularly if an EOR PSA is detectable. Optimal use of local therapies for VHR patients should be explored further, as should novel agents.

Evaluation of collaborative therapy review to improve care of heart failure patients.

OBJECTIVES: As more demands are placed on primary care providers, new innovative models are required to optimize heart failure (HF) care. The purpose of this study was to evaluate a collaborative therapy review (CTR) program that was implemented to improve guideline-based therapy among HF outpatients. STUDY DESIGN AND METHODS: We screened patient lists of 18 PCPs at the Portland Veterans Affairs Medical Center to identify patients with an ICD-9 code for HF. The charts of patients with ejection fractions (EFs) < 40% were then abstracted in more detail. The CTR team reviewed each patient and provided specific guideline-based recommendations. The team then gave specific recommendations to providers through the electronic medical record system. We categorized recommendations relating to drug or device therapies, or need for laboratory testing, and calculated provider acceptance rates by recommendation type. RESULTS: Of the 641 patients reviewed, 156 patients had detailed chart reviews. We found opportunities for improvement in care in 70 (45%) patients who received 100 recommendations. Among the 100 recommendations, 62 (55%) were for guideline-based drugs, 12 (17%) were for consideration of device therapy, and 26 (24%) were to update lab tests or echocardiograms. Eighty percent of the recommendations were acted on within 90 days. CONCLUSIONS: The CTR program was able to facilitate guideline-based management for HF patients by identifying treatment gaps and making specific guideline-based recommendations to PCPs. While further evaluations are needed, this approach may serve as an efficient method of leveraging the expertise of specialty-trained clinicians to optimize patient care.

Evidence behind FDA alerts for drugs with adverse cardiovascular effects: implications for clinical practice.

The U.S. Food and Drug Administration (FDA) periodically publishes Drug Safety Communications and Drug Alerts notifying health care practitioners and the general public of important information regarding drug therapies following FDA approval. These alerts can result in both positive and negative effects on patient care. Most clinical trials are not designed to detect long-term safety end points, and postmarketing surveillance along with patient reported events are often instrumental in signaling the potential harmful effect of a drug. Recently, many cardiovascular (CV) safety announcements have been released for FDA-approved drugs. Because a premature warning could discourage a much needed treatment or prompt a sudden discontinuation, it is essential to evaluate the evidence supporting these FDA alerts to provide effective patient care and to avoid unwarranted changes in therapy. Conversely, paying attention to these warnings in cases involving high-risk patients can prevent adverse effects and litigation. This article reviews the evidence behind recent FDA alerts for drugs with adverse CV effects and discusses the clinical practice implications.

Radiation induced bystander effects in mice given low doses of radiation in vivo.

The 'bystander effect' phenomenon has challenged the traditional framework for assessing radiation damage by showing radiation induced changes in cells which have not been directly targeted, but are neighbors to or receive medium from directly hit cells. Our group performed a range of single and serial low dose irradiations on two genetically distinct strains of mice. Bladder explants established from these mice were incubated in culture medium, which was used to measure death responses in a keratinocyte reporter system. The study revealed that the medium harvested from bladder tissues' (ITCM) from acutely irradiated C57BL6 but not Balb/c mice, was able to induce clonogenic death. Administration of a priming dose(s) before a challenge dose to both C57BL6 and Balb/c mice stimulated reporter cell survival irrespective of the time interval between dose(s) delivery. When ITCM corresponding to both strains of mice was measured for its calcium mobilization inducing ability, results showed an elevation in intracellular calcium levels that was strain dependent. This indicates that genotype determined the type of bystander signal/response that was produced after exposure to low and acute doses of radiation. However, serial exposure conditions modified bystander signal production to induce similar effects that were characterized by excessive growth.

Serum serotonin levels determine the magnitude and type of bystander effects in medium transfer experiments.

Serotonin has been shown to be involved in the production of bystander signals by irradiated cells. In this study we examined the levels of serotonin in 10 different batches of commercially available fetal calf serum and correlated the serotonin levels with the toxicity of medium harvested from irradiated cells (ICCM) using a standard medium transfer colony-forming assay. The serotonin levels in the serum varied widely between batches, and the levels correlated directly with the toxicity of the harvested ICCM. Three serum samples had levels of serotonin below 25 ng/ml, and these did not show medium transfer bystander effects. Exposure of serum samples to normal daylight reduced serotonin levels significantly. We suggest that serum batch variability may underlie much of the observed interlaboratory variation in the ability to produce bystander effects and further suggest that serum batches should be protected from light and prescreened for their ability to produce a bystander effect using a positive control cell line.

Genetic factors in drug metabolism.

Patients vary widely in their response to drugs. Having an understanding of the pharmacokinetic and pharmacodynamic properties of various medications is importantwhen assessing ethnic differences in drug response. Genetic factors can account for 20 to 95 percent of patient variability. Genetic polymorphisms for many drug-metabolizing enzymes and drug targets (e.g., receptors) have been identified. Although currently limited to a few pathways, pharmacogenetic testing may enable physicians to understand why patients react differently to various drugs and to make better decisions about therapy. Ultimately, this understanding may shift the medical paradigm to highly individualized therapeutic regimens.

Drug dosing adjustments in patients with chronic kidney disease.

Chronic kidney disease affects renal drug elimination and other pharmacokinetic processes involved in drug disposition (e.g., absorption, drug distribution, nonrenal clearance [metabolism]). Drug dosing errors are common in patients with renal impairment and can cause adverse effects and poor outcomes. Dosages of drugs cleared renally should be adjusted according to creatinine clearance or glomerular filtration rate and should be calculated using online or electronic calculators. Recommended methods for maintenance dosing adjustments are dose reductions, lengthening the dosing interval, or both. Physicians should be familiar with commonly used medications that require dosage adjustments. Resources are available to assist in dosing decisions for patients with chronic kidney disease.

Echocardiographic assessment of epicardial adipose tissue--a marker of visceral adiposity.

Visceral adipose tissue predicts an unfavorable cardiovascular and metabolic risk profile in humans. Existing methods to assess visceral adipose tissue have been limited. Thus, echocardiographic assessment of epicardial adipose tissue as a marker of visceral adiposity was suggested. The technique has been shown to be a very reliable method and an excellent measure of visceral adiposity. In this article, epicardial adipose tissue's localization on the heart, function, method of assessment and reliability as a marker of visceral adiposity is briefly reviewed. Areas of the technique requiring further study are identified.

The use of wireless laptop computers for computer-assisted learning in pharmacokinetics.

OBJECTIVE: To implement computer-assisted learning workshops into pharmacokinetics courses in a doctor of pharmacy (PharmD) program. DESIGN: Workshops were designed for students to utilize computer software programs on laptop computers to build pharmacokinetic models to predict drug concentrations resulting from various dosage regimens. In addition, students were able to visualize through graphing programs how altering different parameters changed drug concentration-time curves. Surveys were conducted to measure students' attitudes toward computer technology before and after implementation. Finally, traditional examinations were used to evaluate student learning. ASSESSMENT: Doctor of pharmacy students responded favorably to the use of wireless laptop computers in problem-based pharmacokinetic workshops. Eighty-eight percent (n = 61/69) and 82% (n = 55/67) of PharmD students completed surveys before and after computer implementation, respectively. Prior to implementation, 95% of students agreed that computers would enhance learning in pharmacokinetics. After implementation, 98% of students strongly agreed (p < 0.05) that computers enhanced learning. Examination results were significantly higher after computer implementation (89% with computers vs. 84% without computers; p = 0.01). CONCLUSION: Implementation of wireless laptop computers in a pharmacokinetic course enabled students to construct their own pharmacokinetic models that could respond to changing parameters. Students had greater comprehension and were better able to interpret results and provide appropriate recommendations. Computer-assisted pharmacokinetic techniques can be powerful tools when making decisions about drug therapy.

Likelihood and mechanisms of cross-allergenicity between sulfonamide antibiotics and other drugs containing a sulfonamide functional group.

Concerns about cross-allergenicity between sulfonamide antibiotics and nonantibiotic, sulfonamide-containing drugs persist and can complicate patients' drug therapy unnecessarily. No interaction between the human immune system and the sulfonamide functional group has been demonstrated. The immunologic determinant of type I, immediate hypersensitivity responses to sulfonamide antibiotics is the N1 heterocyclic ring. Nonantibiotic sulfonamides do not contain this structural feature. Non-type I hypersensitivity responses to sulfonamide antibiotics are largely attributable to reactive metabolites that may cause either direct cytotoxicity or immunologic response. Formation of these metabolites is a stereospecific process that occurs at the N4 amino nitrogen of the sulfonamide antibiotics, a structure also not found on any nonantibiotic sulfonamide drugs. The stereospecificity of these reactions implies that cross-reactivity with nonantibiotic sulfonamide-containing drugs is highly unlikely; this assertion is supported by recent literature. However, T-cell recognition of unmetabolized, nonhaptenated parent sulfonamide antibiotic appears to occur in a small subset of hypersensitive patients. Several of the severe cutaneous reactions associated with sulfonamide antibiotics are mediated by T cells. It is not known whether T-cell recognition of antibiotic is related to the sulfonamide functional group. Until the mechanism of this recognition is elucidated, cross-reactivity with nonantibiotic sulfonamides appears to remain at least theoretically possible.