Lindsay E. Calderon

Bromoenol Lactone Attenuates Nicotine-Induced Breast Cancer Cell Proliferation and Migration.

Objectives Calcium independent group VIA phospholipase A2 (iPLA2β) and Matrix Metalloproteinase-9 (MMP-9) are upregulated in many disease states; their involvement with cancer cell migration has been a recent subject for study. Further, the molecular mechanisms mediating nicotine-induced breast cancer cell progression have not been fully investigated. This study aims to investigate whether iPLA2β mediates nicotine-induced breast cancer cell proliferation and migration through both in-vitro and in-vivo techniques. Subsequently, the ability of Bromoenol Lactone (BEL) to attenuate the severity of nicotine-induced breast cancer was examined. Method and Results We found that BEL significantly attenuated both basal and nicotine-induced 4T1 breast cancer cell proliferation, via an MTT proliferation assay. Breast cancer cell migration was examined by both a scratch and transwell assay, in which, BEL was found to significantly decrease both basal and nicotine-induced migration. Additionally, nicotine-induced MMP-9 expression was found to be mediated in an iPLA2β dependent manner. These results suggest that iPLA2β plays a critical role in mediating both basal and nicotine-induced breast cancer cell proliferation and migration in-vitro. In an in-vivo mouse breast cancer model, BEL treatment was found to significantly reduce both basal (p<0.05) and nicotine-induced tumor growth (p<0.01). Immunohistochemical analysis showed BEL decreased nicotine-induced MMP-9, HIF-1alpha, and CD31 tumor tissue expression. Subsequently, BEL was observed to reduce nicotine-induced lung metastasis. Conclusion The present study indicates that nicotine-induced migration is mediated by MMP-9 production in an iPLA2β dependent manner. Our data suggests that BEL is a possible chemotherapeutic agent as it was found to reduce both nicotine-induced breast cancer tumor growth and lung metastasis.

Questionable validity of the catheter-associated urinary tract infection metric used for value-based purchasing

Catheter-associated urinary tract infections (CAUTIs) occur in 290,000 US hospital patients annually, with an estimated cost of

Viewpoint: A response to "Screening and isolation to control methicillin-resistant Staphylococcus aureus: Sense, nonsense, and evidence

290 million. Two different measurement systems are being used to track the US health care systems performance in lowering the rate of CAUTIs. Since 2010, the Agency for Healthcare Research and Quality (AHRQ) metric has shown a 28.2% decrease in CAUTI, whereas the Centers for Disease Control and Prevention metric has shown a 3%-6% increase in CAUTI since 2009. Differences in data acquisition and the definition of the denominator may explain this discrepancy. The AHRQ metric analyzes chart-audited data and reflects both catheter use and care. The Centers for Disease Control and Prevention metric analyzes self-reported data and primarily reflects catheter care. Because analysis of the AHRQ metric showed a progressive change in performance over time and the scientific literature supports the importance of catheter use in the prevention of CAUTI, it is suggested that risk-adjusted catheter-use data be incorporated into metrics that are used for determining facility performance and for value-based purchasing initiatives.

The incidence of MRSA infections in the United States: is a more comprehensive tracking system needed?

Surveillance and isolation for the prevention of methicillin-resistant Staphylococcus aureus (MRSA) has become a controversial topic, one that causes heated debate and appears to be surrounded by both politics and industrial conflicts-of-interest. There have been calls from numerous authors for a movement away from rigid mandates and toward an evidence-based medicine approach. However, much of the evidence can be viewed with an entirely different interpretation. Two major studies with negative findings have had an adverse impact on recommendations regarding active detection and isolation (ADI) for MRSA. However the negative findings in these studies can be explained by shortcomings in study implementation rather than the ineffectiveness of ADI. The use of daily chlorhexidine bathing has also been proposed as an alternative to ADI in ICU settings. There are shortcomings regarding the evidence in the literature concerning the effectiveness of daily chlorhexidine bathing. One of the major concerns with universal daily chlorhexidine bathing is the development of bacterial resistance. The use of surveillance and isolation to address epidemics and common dangerous pathogens should solely depend upon surveillance and isolation’s ability to prevent further spread to and infection of other patients through indirect contact. At present, there is a preponderance of evidence in the literature to support continuing use of surveillance and isolation to prevent the spread of MRSA.

The relationship between tort reform and medical utilization.

A review of epidemiological studies on the incidence of MRSA infections overtime was performed along with an analysis of data available for download from Hospital Compare (https://data.medicare.gov/data/hospital-compare). We found the estimations of the incidence of MRSA infections varied widely depending upon the type of population studied, the types of infections captured and in the definitions and terminology used to describe the results. We could not find definitive evidence that the incidence of MRSA infections in U.S. community or facilities is decreasing significantly. Of concern are recent data reported to the National Healthcare Safety Network (NHSN) on MRSA bloodstream infections which indicate that by the end of 2015 there had been little change in the average facility Standardized Infection Ratio (0.988), compared to a 2010–2011 baseline and is significantly increased compared to the previous year. This is in contradistinction to the recent Veterans Administration study which reported over an 80% reduction in MRSA infections. However, this discrepancy may be due to the inability to reconcile the baselines of the two data sets; and the observed increase may be artifactual due to aberrations in the NHSN tracking system. Our review supports the need for implementation of a comprehensive tracking and monitoring system involving all types of healthcare facilities for multi-drug resistant organisms, along with concomitant funding for both staff and infrastructure. Without such a system, determining the effectiveness of interventions such as antibiotic stewardship and chlorhexidine bathing will be hindered.

Much work still to be done to prevent central line-associated bloodstream infections.

Introduction The hidden cost of defensive medicine has been cited by policymakers as a significant driving force in the increase of our nation’s health-care costs. If this hypothesis is correct, one would expect that states with higher levels of tort reform will have a decrease in Medicare utilization and that medical utilization will decrease after tort reform is enacted. Methods State-level reimbursement data for years 1999 to 2010 (the last year available) was obtained from the Dartmouth Atlas of Health Care. Medical tort rankings for the 50 states were obtained from the Pacific Research Institute (PRI) and correlated with state medical utilization for the year 2010. In 3 states, Mississippi, Nevada, and Texas, data were available to make pretort and posttort reform comparisons. Results Data analysis between total state Medicare Reimbursements and the PRI’s tort rankings showed no significant observed correlation. In 6 Medicare utilization categories (total Medicare, hospital and skilled nursing facility, physician, home health agency, hospice, and durable medical equipment), a negative trend was observed when correlated with PRI tort rankings. This trend does not support the hypothesis that defensive medicine is a major driver of health-care expenditures. Tracking expenditures in the states of Texas, Nevada, and Mississippi, before and after passage of comprehensive medical tort reform gave inconsistent results and did not demonstrate substantial or meaningful total Medicare savings. In Mississippi, there was a trend of decreased expenditures after medical tort reform was passed. However, in Texas, where 80% of the analyzed enrollees resided, there was a trend of progressive increasing expenditures after tort reform was passed. Conclusion The comparison of the Dartmouth Atlas Medicare Reimbursement Data with Malpractice Reform State Rankings, which are used by the PRI, did not support the hypothesis that defensive medicine is a driver of rising health-care costs. Additionally, comparing Medicare reimbursements, premedical and postmedical tort reform, we found no consistent effect on health-care expenditures. Together, these data indicate that medical tort reform seems to have little to no effect on overall Medicare cost savings.

View point: gaps in the current guidelines for the prevention of Methicillin-resistant Staphylococcus aureus surgical site infections

Central Line Associated Bloodstream Infections (CLABSI) are all too common and often fatal events. To estimate the number of preventable CLABSIs, the authors analyzed SIR (Standardized Infection Ratio) and the number of CLABSI data from Hospital Compare. Several studies have suggested that an SIR of 0.35 may be achievable. If all institutions were able to perform at this level, then almost 50% of CLABSI would be prevented. Introduction: Central Line Associated Bloodstream Infections are all too common and often fatal events. Unfortunately using the latest available data, it can be argued that the medical industry has not done nearly enough to implement effective safety protocols and checklists designed to prevent these infections. A National Benchmark was set using CLABSI data gathered between 2006 and 2008 before prevention protocols were implemented in the vast majority of institutions. Using this data, the average performance was used to calculate Standardized Infection Ratio (SIR) and a National Benchmark was set which reflected average performance as a SIR of 1.0. Umscheild, et al. estimated in 2011 that as many as 65 to 70% of CLABSIs are preventable, which would define obtainable performance of facilities to have an SIR of between 0.30 to 0.35. Similar reductions were observed in the Keystone project. In a separate analysis, Saman, et al. used more recent CLABSI data and found the peak of the SIR distribution curve at 0.35 and advocated that this more accurately reflects the Obtainable SIR. Arguably, the current National Benchmark is an example of using old standards to define current performance. Methods: To estimate the number of preventable cases, a dataset was downloaded from Hospital Compare which was comprised of CLABSIs that occurred in Hospital ICUs during a data collection period of 7/1/2011 to 6/30/2012. To be included in the analysis a hospital had to have at least one predicted CLABSIs using the National Benchmark of 1.0. 1899 facilities were included in the analysis, 1135 had an SIR of greater than 0.35. The total number of Preventable Cases (PC) was then calculated from the number of Observed Cases (OC) in all facilities whose SIR was above that of the Obtainable SIR, using the following equation: PC = OC – [(Obtainable SIR/Facility’s SIR) * OC ] Three estimations of the obtainable SIR were used *Health Watch USA, Eastern Kentucky University, Essentia Institute of Rural Health, Corresponding Author: Kevin T Kavanagh, MD, MS Email: healthwatchusa@gmail.com Table 1: Estimation of the Number of Preventable Cases in Hospital ICUs out of the 10799 CLABSIs observed in ICUs between 7/1/2011 to 6/30/2012 Source of SIR SIR Preventable Cases National Benchmark Data – (2006 to 2008) 1.000 990 (9.2%) Average SIR 2011 Data (7/1/11 to 6/30/2012) 0.594 1128 (10.4%) Peak of the Curve SIR Data (1/1/11 to 12/1/2011) 0.350 5240 (48.5%) in this study. The first was the National Benchmark (SIR = 1.0), the average SIR of the Dataset (0.594) and the Obtainable SIR of 0.35. Results: The results shown in Table 1 revealed that almost 50% of the CLABSI could be prevented if facilities performed at the Obtainable SIR of 0.35. This represents 5240 patients and at a fatality rate up to 25%, or 1310 potential lives lost. Discussion: Wise, et al., estimated that in 2010 there were 15,000 CLABSIs in hospital ICUs, mainly at medium and large teaching hospitals. A targeted approach was suggested to achieve further reductions in central line infections. Our analysis also indicates that substantial improvement is still needed to prevent CLABSIs. In the 12 month period ending on June 30, 2012, there were 10799 CLABSIs in hospital ICUs that were reported to the National Healthcare Safety Network. It can be argued that almost half of these infections were preventable. Some in the healthcare industry have argued that this large variation is due to differences in reporting and definitions. However, this factor should be mitigated, since CLABSIs are now reported through the National Healthcare Safety Network, which has rigorous definitions and standards for how adverse events are reported. In addition, Saman, et al.(7) have shown that high SIRs for CLABSIs in Intensive Care Units are correlated with facility wide patient safety measures found on CMS’s Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) Survey, which may indicate problems in the culture of safety at the institution. In addition, over the last decade institutions have been treating and billing for these events, if there are existing problems with event diagnosis this would represent a significant failure of our healthcare system. The question which must be asked is can we do better and further improve our current results?

Pt-Mal-LHRH, a Newly Synthesized Compound Attenuating Breast Cancer Tumor Growth and Metastasis by Targeting Overexpression of the LHRH Receptor

The authors advocate the addition of two preventative strategies to the current United State’s guidelines for the prevention of surgical site infections. It is known that Staphylococcus aureus, including Methicillin-resistant Staphylococcus aureus (MRSA), carriers are at a higher risk for the development of infections and they can easily transmit the organism. The carriage rate of Staph. aureus in the general population approximates 33%. The CDC estimates the carriage rate of MRSA in the United States is approximately 2%. The first strategy is preoperative screening of surgical patients for Staph. aureus, including MRSA. This recommendation is based upon the growing literature which shows a benefit in both prevention of infections and guidance in preoperative antibiotic selection. The second is performing MRSA active surveillance screening on healthcare workers. The carriage rate of MRSA in healthcare workers approximates 5% and there are concerns of transmission of this pathogen to patients. MRSA decolonization of healthcare workers has been reported to approach a success rate of 90%. Healthcare workers colonized with dangerous pathogens, including MRSA, should be assigned to non-patient contact work areas. In addition, there needs to be implemented a safety net for both the worker’s economic security and healthcare. Finally, a reporting system for the healthcare worker acquisition and infections with dangerous pathogens needs to be implemented. These recommendations are needed because Staph. aureus including MRSA is endemic in the United States. Policies regarding endemic pathogens which are to be implemented only upon the occurrence of a facility defined “outbreak” have to be questioned, since absence of infections does not mean absence of transmission. Optimizing these policies will require further research but until then we should error on the side of patient safety.

The Cry of the Child and its Relationship to Hearing Loss in Parental Guardians and Health Care Providers

A new targeting chemotherapeutic agent, Pt-Mal-LHRH, was synthesized by linking activated cisplatin to luteinizing hormone releasing hormone (LHRH). The compounds efficacy and selectivity toward 4T1 breast cancer cells were evaluated. Carboplatin was selected as the comparative platinum complex, since the Pt-Mal-LHRH malonate linker chelates platinum in a similar manner to carboplatin. Breast cancer and normal cell viability were analyzed by an MTT assay comparing Pt-Mal-LHRH with carboplatin. Cells were also treated with either Pt-Mal-LHRH or carboplatin to evaluate platinum uptake by ICP-MS and cell migration using an in vitro scratch-migration assay. Tumor volume and metastasis were evaluated using an in vivo 4T1 mouse tumor model. Mice were administered Pt-Mal-LHRH (carboplatin molar equivalent dosage) through ip injection and compared to those treated with carboplatin (5 (mg/kg)/week), no treatment, and LHRH plus carboplatin (unbound) controls. An MTT assay showed a reduction in cell viability (p < 0.01) in 4T1 and MDA-MB-231 breast cancer cells treated with Pt-Mal-LHRH compared to carboplatin. Pt-Mal-LHRH was confirmed to be cytotoxic by flow cytometry using a propidium iodide stain. Pt-Mal-LHRH displayed a 20-fold increase in 4T1 cellular uptake compared to carboplatin. There was a decrease (p < 0.0001) in 4T1 cell viability compared to 3T3 normal fibroblast cells. Treatment with Pt-Mal-LHRH also resulted in a significant decrease in cell-migration compared to carboplatin. In vivo testing found a significant reduction in tumor volume (p < 0.05) and metastatic tumor colonization in the lungs with Pt-Mal-LHRH compared to carboplatin. There was a slight decrease in lung weight and no difference in liver weight between treatment groups. Together, our data indicate that Pt-Mal-LHRH is a more potent and selective chemotherapeutic agent than untargeted carboplatin.

Abstract LB-230: Pt-Mal-LHRH, a newly synthesized compound attenuating breast cancer tumor growth and metastasis by targeting overexpression of the LHRH receptor

In this study the authors investigate the sound pressure levels produced by crying children and discuss the possible adverse effects that direct exposure may impose on a tending guardian or healthcare professional. Sound intensity levels from various pediatric patients (N = 26) were measured under two segregate conditions, one imitating the exposure of an examining physician and the other resembling that of parental guardians. Interestingly, all of the recorded sound levels fell between 99–120 dB(A) of sound pressure; children presenting the greatest risk for intense cries with potentially harmful sound intensities were between the ages of 9 months and 6 years. The authors found that elevated noise levels produced from crying children can cause acute discomfort and mild pain to those exposed. In addition, there is a theoretical risk that chronic exposure to these intense sound pressures may result in noise-induced hearing loss in a parental guardian or an examining physician. Parents of young children may be more likely to succumb to impulsive reactions in attempting to arrest the crying, which could be a precipitating factor for child abuse, responding to physical stress as much as emotional stress. Social workers and medical personnel should consider suggesting the use of ear plugs by parental guardians of frequently crying children as a modality for the prevention of child abuse.