The Epidemiology and Incidence of Visual Deficits Following Ocular Trauma in Pediatric Patients

Ocular trauma has long been a significant disabling American health problem and a leading cause of unilateral visual loss in children. These injuries have many diverse costs including human suffering, long-term disabilities, loss of productivity, and economic hardship. Although several studies have evaluated the epidemiology of specific types or mechanisms of ocular trauma, there are few that describe the epidemiology and visual outcomes of a comprehensive set of ocular trauma diagnoses. The purpose of this thesis is to describe the incidence of significant deficits in visual acuity following pediatric ocular trauma and to describe the overall epidemiology of pediatric ocular trauma presenting to the Yale Eye Center or Yale Ophthalmology consult service between 1999 and 2006. A retrospective analysis of 396 cases of pediatric ocular trauma that presented to the Yale Eye Center or Yale Ophthalmology Consult Service between 1999 and 2006 was performed in which the study population was defined as children between 0 and 18 years of age with the following ICD-9 codes: 802.4-802.9 (malar, maxillary, orbital floor, and facial bone fractures), 870.0-870.9 (open wounds of the ocular adnexa), 871.0-871.9 (open wounds of the eyeball), 918.0-918.9 (superficial injury of the eye and adnexa), 921.0-921.9 (contusion of the eye and adnexa), 950.0-950.9 (injury to optic nerve and pathways), and 951.0-951.4 (injury to the other ocular cranial nerves). All data were examined for any correlation between parameters studied. Statistical significance for categorical data was performed using 2x2 contingency tables, Fishers exact test, and two-tailed P values. A total of 61 patients (15.4 %) had a final visual acuity with some degree of deficit. However, only a small proportion (7.3%) of children seen for an ocular injury was significantly visually impaired in the affected eye as a result of the injury. Males had a disproportionately large representation in the blindness category where they made up 77.3% compared to 65% of the overall patient population. Males in the 10-14 year age group were at the highest risk for eye injury (20.9%), and females in the 5-9 year age group were at the lowest risk (8.7%). The most common injuries were superficial injuries to the eye and ocular adnexa (33%) and contusions of the eye and adnexa (27.6%). In all age groups, the most common sites of injury were in the home (30.6%) and on streets/roads (30.6%). The data presented demonstrate a clear need for primary prevention and control of pediatric ocular trauma. Education targeting parents, school teachers, and children regarding hazardous objects, toys and the devastating consequences of seemingly innocuous actions is needed to reduce the incidence of ocular trauma and its consequences. It will also be important to continue to recognize the geographic variability, and dynamic changes throughout time in the epidemiology of ocular trauma

Fluoride Dose-Response of Human and Bovine Enamel Artificial Caries Lesions under pH-Cycling Conditions

Objectives This laboratory study aimed to (a) compare the fluoride dose-response of different caries lesions created in human and bovine enamel (HE/BE) under pH-cycling conditions and (b) investigate the suitability of Knoop and Vickers surface microhardness (K-SMH/V-SMH) in comparison to transverse microradiography (TMR) to investigate lesion de- and remineralization. Materials and methods Caries lesions were formed using three different protocols (Carbopol, hydroxyethylcellulose-HEC, methylcellulose-MeC) and assigned to 24 groups using V-SMH, based on a 2 (enamel types) × 3 (lesion types) × 4 (fluoride concentrations used during pH-cycling-simulating 0/250/1100/2800 ppm F as sodium fluoride dentifrices) factorial design. Changes in mineral content and structural integrity of lesions were determined before and after pH-cycling. Data were analyzed using three-way ANOVA. Results BE was more prone to demineralization than HE. Both enamel types showed similar responses to fluoride with BE showing more remineralization (as change in integrated mineral loss and lesion depth reduction), although differences between tissues were already present at lesion baseline. Carbopol and MeC lesions responded well to fluoride, whereas HEC lesions were almost inert. K- and V-SMH correlated well with each other and with the integrated mineral loss data, although better correlations were found for HE than for BE and for MeC than for Carbopol lesions. Hardness data for HEC lesions correlated only with surface zone mineral density data. Conclusion BE is a suitable surrogate for HE under pH-cycling conditions. Clinical relevance The in vitro modeling of dental caries is complex and requires knowledge of lesion behavior, analytical techniques, and employed hard tissues

Novel Biomarkers for the Diagnosis of Urinary Tract Infection—A Systematic Review

Urinary tract infections (UTIs) are associated with significant morbidity. We rely on clinical presentation, urinalysis, and urine culture to diagnose UTI. To differentiate between lower UTI and pyelonephritis, we depend on the clinical presentation. In the extremes of age and in immunocompromised individuals, clinical presentation is often atypical posing a challenge to diagnosis. In the elderly, the high prevalence of asymptomatic bacteriuria is another confounder. We conducted a search of publications to find novel biomarkers to diagnose UTI and to ascertain its severity. We searched PUBMED, MEDLINE and SCOPUS databases for studies pertaining to novel biomarkers and UTI. Two reviewers independently evaluated the methodology of the studies using the STARD (Standards for Reporting of Diagnostic Accuracy) criteria. We have identified procalcitonin as a biomarker to differentiate lower UTI from pyelonephritis in the pediatric age group. Elevated serum procalcitonin levels can result in early and aggressive treatment at the time of presentation. Interleukin 6 has also shown some promise in differentiating between lower UTI and pyelonephritis but needs further validation. Lastly, given the paucity of data in certain subgroups like diabetics, kidney transplant recipients, and individuals with spinal cord injury, further studies should be conducted in these populations to improve diagnostic criteria that will inform clinical management decisions

Scatterplot Variations Seen in Malaria Using Automated Hematological Analyzers: A Series of Ten Cases

Background: Malaria is a major health problem in India. Complete blood count and peripheral blood smear (PBS) is important for its diagnosis. Inter observer variation makes PBS fallible. Rapid diagnostic tests cannot detect low parasitemia and mixed infections. Scatterplot from automated analyzers have shown variations previously which might be exploited. Methods: Scatterplot patterns of ten samples of confirmed malaria and 100 control samples were derived and other infections ruled out by culture and serology as a part of descriptive study between July and August 2018. Each malarial scatterplot was compared with the control pattern for abnormalities and their frequency noted. Results: All the ten samples belonged to Plasmodium vivax species. Abnormalities detected included split in neutrophilic region, eosinophil-neutrophil merge, neutrophil graying, lymphopenia, ghost red blood cells (RBC), eosinophil split, reactive lymphocytes, monocytosis, pseudoeosinophilia, neutrophilic leukocytosis Conclusion: Variations in scatterplot patterns are seen in malaria and provide clues to the diagnosis of malaria

A Review of Organ/Tissue Donation in Out of Hospital Cardiac Arrest Patients at an Academic Community Hospital

A Review of Organ/Tissue Donation in Out of Hospital Cardiac Arrest Patients at an Academic Community Hospital Jordan Williams, Amanda Broderick, Alexandra Maryashina, James Wu, MD Department of Surgery, Division of Cardiothoracic Surgery Abstract Objective This study sought to review organ/tissue donation statistics in out of hospital cardiac arrest patients. Background While OHCA patients who are not revived in the emergency department are generally disqualified from donating organs, these patients are sometimes still able to donate tissue. However the fact remains that there is an organ shortage in the United States healthcare system as the need exceeds the donation rate, and thus other avenues to increase the donation rate need to be explored. Methods A retrospective chart review was performed on 378 patient records with OHCA from January 2011 to May 2015. From these records, the eligibility of the patients to donate, reasons behind their ineligibility, number of patients who donated, reasons for eligible patients who didn’t donate, and a comparison of number of arrests and number of donations by age were extracted. Results It was found that while 72% of patients were eligible to donate, only 41% of these patients went on to donate tissue and/or organs. For those patients that were ineligible the most common reason was being medically unsuitable, and for the eligible patients who didn’t donate the most common reason was their family withholding consent. In the age comparison of number of arrest and number of organ/tissue donations it was found that the rates by which these groups changed did not match, especially in patients over the age of 50. Conclusion While no formal conclusion can necessarily be drawn from this data, it does offer some suggestions and ideas for further research. One possible area of study could be increasing education about organ donation in the community surrounding the hospital. Another area of study could be in ways of lengthening organ viability time in OCHA patients that proceed to donate. Keywords Out of Hospital Cardiac Arrest, Organ Donation, ECMO, “Education in Organ Donation” Introduction The national survival to discharge rate in out of hospital cardiac arrest (OHCA) remains low, currently 9.5% as of 2013 according to the American Heart Association (American Heart Assocation, 2012). One potential solution to this problem might be extracorporeal membrane oxygenation (ECMO) for these patients assuming they match certain criteria such as age, comorbidities, presenting rhythm, time to advanced care, etc. However, another aspect of ECMO could be to prolong organ viability in potential organ donors (Magliocca, et al., 2005) (Munjal, et al., 2012). According to the US Organ Procurement and Transplantation Network, the percent of national eligible deaths that resulted in donation of at least one organ was 71.3% in 2013 (U.S. Department of Health and Human Services, 2015). However, the amount of organs available for transplant currently does not meet the demand. For example, at the end of 2013 there were 60,189 candidates on the waiting list for a kidney transplant, while there were only 17,654 transplants performed that year. Similar trends were noted for liver, heart, and lung donations (U.S. Department of Health and Human Services, 2015). Current US organ donation policy on deceased donors states that organ donation can only be considered when the potential donor has died from neurological death or controlled circulatory death (Wall, Plunkett, & Caplan, 2015). OHCA patients that are not successfully revived in the emergency department are considered to have died from an uncontrolled form of death, and thus many of these patients are only eligible to donate tissue (instead of organs). However, an OHCA patient could go on to become a donor if they are revived in the field, or in the emergency department, and are subsequently taken off life continuing measures such as ventilators, ECMO, etc., as this would now be considered a controlled form of circulatory death or neurological death if applicable. Even in a case where a patient has died from a controlled form of death, and is eligible to donate organs and/or tissue, a donation might not occur due to the family of the patient withholding consent. Legislation, such as the revised Uniformed Anatomical Gift Act of 2006, has been introduced which would eliminate the need to gain consent from the family, if the patient in question was listed in their state’s donation registry. However it has not been enacted in Pennsylvania, along with Delaware, Florida and New York (Uniform Law Commission, 2015). This study stands to serve as a review of organ/tissue donation information at an academic community hospital in order to generate interest for further research investigating ways to increase organ donation rates. Methods A retrospective chart review was utilized for patients with OHCA over the time period from January 2011 to May 2015. Patients were then sorted by age at time of admission, and were excluded if they were over the age of 70 or under 18, yielding 434 records. An arrest was classified as out of hospital if it occurred before arrival in the emergency department, or occurred in the emergency department. A database was created which encompassed many aspects of OHCA patients; however this study focused primarily on organ donation information. Specifically, the patients’ eligibility for organ/tissue donation was recorded, as well as the reason for their ineligibility, if applicable. The reasons for ineligibility were gained from the Gift of Life (our hospital’s organ procurement organization) form in the patient’s chart. Other data included were if the patient actually donated, reason(s) for not donating, and the specific tissue and/or organs donated. Based off of this information, patients were then excluded from the study if they did not have both eligibility data, and donation data. From this cohort of 378 patients, descriptive statistics were utilized to depict aspects of patient eligibility and donation information. Results Out of the 378 patients studied, 72% (272/378) were eligible to donate (see figure 1). For the other 28% (106/378), 33 patients survived to discharge, leaving 73 patients who were ineligible due to some other reason. The most common reason for their ineligibility was being medically unsuitable, with 48 out of the 73 falling into this category (figure 2). The next most common reason was that the medical examiner/coroner determined that they were ineligible (10/73). Finally being ineligible due to previous drug use (8/73), and being marked as ineligible without any reasoning (7/73) were the least common reasons. The next point viewed was the percent of eligible patients that actually went on to donate organs/tissue. Out of the 272 eligible patients, only 41% (112 patients) actually went on to donate, leaving 59% (160 patients), who, while eligible, didn’t donate (figure 3). The reason behind the lack of donation was then examined. The most frequent reason was family declining to give consent, with 91 of the 160 patients who were eligible but didn’t donate falling into this category (figure 4). For 65 of the 160 patients, the reasons for not donating were undocumented, 3 out of the 160 didn’t donate due to the hospital staff not gaining consent from the family within the organ viability timeframe, and 1 patient who was previously deemed eligible, was later deemed ineligible to donate. For those patients that were eligible and donated (112/378), the most common tissue donated was corneas, with 82 patients donating these, and the most common organ was the kidney, with 4 patients donating at least one of these (figure 5). An interesting trend to note is how the number of arrests for a given age group differs from the amount of organ donations in that category (figure 6). The number of arrests peak in the 59-62 years age range, while the number of donations peak in the 51-54 range. This would suggest that the rate at which organ/tissue donations are occurring differs from the rate that OHCA’s are occurring. Discussion Due to the fact that this study was done at one academic community hospital, formal conclusions cannot be drawn from this study. However, from this review of 378 OHCA patients, it can still be seen that the number of organ/tissue donations does not match the number of arrests. It can also be seen that the most common reason for eligible patients not donating is that their family did not give consent. While there is a law currently being introduced to the Pennsylvania state government that would remove the need to gain consent from the family if the patient was a known donor, other solutions should be pursued. It has been suggested that education on organ donation may serve to play an important role in increasing organ donation rates (Martinez, et al., 2001). Perhaps the families in this study might have benefited from more education on organ donation, before the sudden event of an OHCA in a loved one. This way they would be able to discuss with their loved one what their wishes were beforehand, to prevent the stressful decision from having to be made suddenly in the hospital setting. Considering that many of the patients in this study would not have been eligible to donate organs simply due to their death being classified as an uncontrolled form of death, further research in this hospital could be pursued in expanding organ donor criteria to include more OHCA patients. Along this line, research could be pursued in using ECMO or other organ preservation measures in OHCA patients in order to increase the rates of organ/tissue donation. Acknowledgements James Wu, MD Hope Kincaid, MPH, CPH Jane Scott Lynsey Biondi, MD Hubert Huang, PhD References American Heart Assocation. (2012, December 12). Heart Disease and Stroke Statistics-2013 Update. Dallas, Texas, United States. Retrieved from http://www.heart.org/HEARTORG/General/Cardiac-Arrest-Statistics_UCM_448311_Article.jsp Magliocca, J. F., Magee, J. C., Rowe, S. A., Gravel, M. T., Chenault, R. H., Merion, R. M., . . . Hemmila, M. R. (2005). Extracorporeal Support for Organ Donation after Cardiac Death Effectively Expands the Donor Pool. The Journal of Trauma: Injury, Infection and Critical Care, 1095-1102. Martinez, J. M., Lopez, J. S., Martin, A., Martin, M. J., Scandroglio, B., & Martin, J. M. (2001). Organ Donation and Family Decision-Making within the Spanish Donation System. Social Science and Medicine, 405-421. doi:10.1016/S0277-9536(00)00345-2 Munjal, K. G., Wall, S. P., Goldfrank, L. R., Gilbert, A., Kaufman, B. J., & Dubler, N. N. (2012). A Rationale in Support of Uncontrolled Donation After Circulatory Determination of Death. The Hastings Center Report , 19-26. U.S. Department of Health and Human Services. (2015, January ). OPTN/SRTR Annual Data Report 2013. American Journal of Transplantation, 15(S2), 1-13. doi:10.1111/ajt.13202 Uniform Law Commission. (2015). Anatomical Gift Act (2006). Retrieved from UniformLaws: http://uniformlaws.org/Act.aspx?title=Anatomical%20Gift%20Act%20%282006%29 Wall, S. P., Plunkett, C., & Caplan, A. (2015). A Potential Solution to the Shortage of Solid Organs for Transplantation. The Journal of the American Medical Assocation, 313(23). doi:doi:10.1001/jama.2015.5328 Appendix Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure

Review of In-Hospital and Out-of-Hospital Cardiac Arrests at a Tertiary Community Hospital for Potential ECPR Rescue

Review of In-Hospital and Out-of-Hospital Cardiac Arrests at a Tertiary Community Hospital for Potential ECPR Rescue Amanda Broderick1, Jordan Williams1, Alexandra Maryashina1, & James Wu, MD1 1 Department of Surgery, Division of Cardiothoracic Surgery Abstract This was a retrospective study on in and out-of-hospital cardiac arrest (IHCA and OHCA) patients at a tertiary community hospital. The aim of the study was to compare characteristics and outcomes of IHCA versus OHCA and evaluate those patients who might have been good candidates for more aggressive resuscitation like extracorporeal membrane oxygenation cardiopulmonary resuscitation (ECPR). The data suggests a strong correlation between an increased duration of cardiopulmonary resuscitation (CPR) and a decreased survival rate for both IHCA and OHCA. Overall survival to discharge rate for ICHA was found to be 30%, above the national average of 17%, and was 6.8% for OHCA, within the national average of around 5-10% (Peberdy et al. 2003; Abrams et al. 2013). Using specific inclusion and exclusion criteria suggested by recent research, 44 IHCA patients over 2 years and 133 OHCA patients over 4.5 years would have been potential candidates for ECPR. Though this study included only patients from a single institution, it highlights the possibility of improving patient outcomes by implementing a more aggressive resuscitation protocol for refractory cardiac arrest. It warrants further research into resuscitation protocols, specifically the addition of ECPR into the protocols at the Lehigh Valley Health Network for a specific cohort of patients. Introduction Cardiac arrest remains a major cause of death in United States despite changes in resuscitation protocols.1 Both in-hospital and out-of-hospital cardiac arrests still have very poor survival to discharge prognoses without any significant changes in recent years. In-hospital cardiac arrest (IHCA) survival rates are about 17% nationally while those for out-of-hospital cardiac arrest (OHCA) are even lower at 5-10% (Peberdy et al. 2003; Abrams et al. 2013). Previous studies have suggested significant differences in survival to discharge rates for those suffering witnessed versus unwitnessed arrests, for different initial cardiac rhythms (Ventricular tachycardia or ventricular fibrillation versus pulseless electrical activity (PEA) versus asystole), and for cardiopulmonary resuscitation (CPR) duration (Avalli et al. 2012). Within these categories there are additionally differences for those suffering IHCA versus OHCA (Peberdy et al. 2003). The current standard strategy for intervention of IHCA and OHCA is the advanced cardiac life support (ACLS) protocol. ACLS protocol includes performance of adequate chest compressions, airway management, defibrillation when appropriate, and administration of applicable drugs. The progression of cardiopulmonary resuscitation (CPR) for these arrests can vary greatly between patients. Many factors including initial cardiac rhythm, duration of CPR, quality of CPR, and cause of the arrest account for these differences and the end prognosis for the patient (Haneya et al. 2012). A more aggressive interventional strategy that is also currently available is extracorporeal membrane oxygenation cardiopulmonary resuscitation (ECPR), sometimes referred to as extracorporeal life support. ECPR is a technique and set of protocols to provide externally circulated blood to support cardiac and pulmonary function. The blood is drained from the patient and oxygenated outside of the body before it is returned to circulation. This temporarily allows for adequate bodily perfusion in patients whose hearts will not pump properly. ECMO is a transitory solution that offers valuable time for the pathologies behind the cardiac arrest to be evaluated and treated (Avalli et al. 2012; Haneya et al. 2012; Fagnoul et al. 2014). It is very resource intensive and invasive, so it is best used for patients in refractory cardiac arrest for which conventional CPR is futile. Survival rate for these patients would otherwise be about 0%. Recent studies have shown ECPR to improve survival rates of those with refractory cardiac arrest for both IHCA and OHCA up to 40-46% and 5-15% respectively (Avalli et al. 2012; Haneya et al. 2012; Fagnoul et al. 2014). Methods This was a retrospective study involving 169 patients between in 2011 and 2012 with IHCA and 425 patients in January 2011-May 2015 coming to the Emergency Department with OHCA. Data was examined for each patient from their medical charts, electronic medical records, and resuscitation records. The overall exclusion criterion was an age greater than 70 or less than 18 or an existing Do Not Resuscitate (DNR). All patients admitted to the hospital at the time of their first arrest were classified as IHCA while those with an arrest taking place prior to admittance were classified as OHCA. A database was made to compile to condense relevant information for the patients. The information looked at for this study included: demographics, medical history, if the arrest was witnessed, initial cardiac rhythm, duration of CPR, time from arrest to hospital (if OHCA), if there was a return of circulation (\u3e20minutes), and if the patient survived to discharger following the arrest. For OHCA this information included: When evaluating patients who may have benefited from ECPR, the inclusion criteria were: Patients with witnessed and non-traumatic arrests, CPR initiated within 5 minutes, no terminal malignancies, time from arrest to hospital less than 60 minutes or arrest in hospital. Exclusion criteria were survival or sustained ROSC from conventional CPR. Fischer’s Exact tests and t-tests were used to evaluate significance and p-values. Results A comparison of baseline characteristics, CPR variables, and outcomes of the IHCA versus OHCA patients is shown in Table 1 of Appendix 1. The IHCA cohort consisted of 169 patients (98 male, 71 female) with an average age of 55 (21-70) and the OHCA cohort consisted of 425 patients (305 male, 120 female) also with an average age of 55 (18-70). About 89.3% of IHCA patients suffered witnessed cardiac arrests while about 62.4% of OHCA were witnessed. The initial cardiac rhythm was ventricular fibrillation/tachycardia for about 25% of both IHCA and OHCA patients while it was pulseless electrical activity (PEA) for 49% and 26% and asystole 25% and 49% for IHCA and OHCA respectively. Additionally, about 59.2% of IHCA and 16.5% of OHCA patients had a return of spontaneous circulation greater than 20 minutes. Figure 1 shows the overall survival to discharge rates for IHCA to be 30.8% and 6.8% for OHCA. A statistically significant difference in mean total duration of CPR for index event was found. Mean duration for IHCA was 19.4±18.2 minutes with a range of 1-126 minutes and for OHCA was 47.3±25.7 minutes with a range of 1-330 minutes (p-value Based upon the inclusion and exclusion criteria for ECPR outlined in the methods, 44 of the 117 IHCA patients who did not survive could have potentially been candidates for ECPR. Additionally, 133 of the 396 OHCA patients who did not survive could have potentially been candidates for ECPR. Figure 4 illustrates the inclusion criteria and that when using ECPR survival rates given by recent studies, 17-20 additional IHCA patients could have potentially survived in 2 years and 13-26 additional OHCA patients could have potentially survived in 4.5 years. Conclusions A large correlation was found between decreasing survival rates with increasing total duration of CPR for both IHCA and OHCA, as shown in Figure 3. This finding is consistent with other research (Haneya et al. 2012). The small increase in survival rate for IHCA with a CPR duration of greater than 51 minutes is likely due to a small sample size. While the overall survival to discharge rate for IHCA is much greater than for OHCA, the survival rate for a CPR duration of 0-5 minutes is actually greater for OHCA as seen in Figure 3. This could again be due to a small sample size and/or because of the additional health issues present for many IHCA patients. Overall survival to discharge rates were found to be above the national average of 17% for IHCA at 30% and within the national average of 5-10% for OHCA at 6.8% (Peberdy et al. 2003; Abrams et al. 2013). The higher than average survival rate for IHCA is likely because those over the age of 70 were not included in this study. If ECPR protocols had been in place with the specific inclusion and exclusion criteria outlined, a cohort of IHCA and OHCA patients would have been good candidates and could have potentially survived. This study warrants further research into resuscitation protocols for those with prolonged or refractory cardiac arrests and into the implementation of and ECPR protocol in the LVHN. However, this study cannot be generalized to any population because it includes data from only one institution and a relatively small sample of patients. Acknowledgements James Wu, MD Jane Scott Hope Kincaid, MPH, CPH Hubert Huang Bryan Auvil, Alexandra Maryashina, Rosalie Mattiola, & Jordan Williams References 1 Avalli, L., Maggioni, E., Formica, F., Redaelli, G., Migliari, M., Scanziani, M., … Fumagalli, R. (2012). Favorable survival of in-hospital compared to out-of-hospital refractory cardiac arrest patients treated with extracorporeal membrane oxygenation: An Italian tertiary care centre experience. Reuscitation, 83, 579-583. 2 Fagnoul, D., Combes, A., & De Backer, D. (2014). Extracorporeal cardiopulmonary resuscitation. Current Opinion Critical Care, 20, 259-265. 3 Haneya, A., Philipp, A., Diez, C., Schopka, S., Bein, T., Zimmermann, M., … Muller, T. (2012). A 5-year experience with cardiopulmonary resuscitation using extracorporeal life support in non-postcardiotomy patients with cardiac arrest. Resuscitation, 83, 1331-1337. 4 Peberdy, M., Kaye, W., Ornato, J.P., Larkin, V.N., Mancini, M.E., Berg, R.A., … Lane-Trultt, T. (2003). Cardiopulmonary resuscitation of adults in the hospital: A report of 14720 cardiac arrests from the National Registry of Cardiopulmonary Resuscitation. Resuscitation, 58, 297-308. 5 Abrams, H, McNally, B., Ong, M., Moyer, P.H., & Dyer, KS. (2013). A composite model of survival from out-of-hospital cardiac arrest using the Cardiac Arrest Registry to Enhance Survival (CARES). Resuscitation, 84, 1093-1098. Appendix 1 Table 1 All patients (n=594) In-Hospital (n=169) Out-of-Hospital (n=425) p Value Age, years (range) 54.9 (18-70) 55.3 (21-70) 54.8 (18-70) Male, n (%) 403(67.8) 98 (58.0) 305 (71.8) .002 Medical history, n (%) Hypertension 308 (51.9) 87 (51.5) 221 (52.0) Diabetes mellitus 191 (32.1) 64 (37.8) 127 (29.9) Myocardial infarction 78 (13.1) 20 (11.8) 58 (13.6) Chronic heart failure 75 (12.6) 16 (9.5) 59 (13.9) Renal failure on dialysis 57 (9.6) 22 (13.0) 35 (8.2) Cancer 59 (9.9) 27 (16.0) 32 (7.5) Witnessed Arrest, n (%) 416 (70.0) 151 (89.3) 265 (62.4) \u3c.0001 Initial cardiac rhythm Ventricular fibrillation/Tachycardia Pulseless Electrical Activity Asystole 140 (23.6) 42 (24.9) 98 (24.8) 0.91 185 (31.1) 82 (48.5) 103 (26.1) \u3c.0001 206 (34.7) 42 (24.9) 194 (49.1) \u3c.0001 CPR Duration, min 39.4 19.4±18.2 47.3±25.7 \u3c.0001 Outcome, n (%) Return of Circulation \u3e20min 170 (28.6) 100 (59.2) 70 (16.5) \u3c.0001 Survival to Discharge 81 (13.6) 52 (30.8) 29 (6.8) \u3c.0001 Figure 1 Figure 2 Figure 3 Figure 4 17-20 Patients in 2 years 13-26 Patients in 4.5 year

PqqD is a novel peptide chaperone that forms a ternary complex with the radical S-adenosylmethionine protein PqqE in the pyrroloquinoline quinone biosynthetic pathway

Pyrroloquinoline quinone (PQQ) is a product of a ribosomally synthesized and post-translationally modified pathway consisting of five conserved genes, pqqA-E. PqqE is a radical S-adenosylmethionine (RS) protein with a C-terminal SPASM domain, and is proposed to catalyze the formation of a carbon-carbon bond between the glutamate and tyrosine side chains of the peptide substrate PqqA. PqqD is a 10-kDa protein with an unknown function, but is essential for PQQ production. Recently, in Klebsiella pneumoniae (Kp), PqqD and PqqE were shown to interact; however, the stoichiometry and KD were not obtained. Here, we show that the PqqE and PqqD interaction transcends species, also occurring in Methylobacterium extorquens AM1 (Me). The stoichiometry of the MePqqD and MePqqE interaction is 1:1 and the KD, determined by surface plasmon resonance spectroscopy (SPR), was found to be ∼12 μm. Moreover, using SPR and isothermal calorimetry techniques, we establish for the first time that MePqqD binds MePqqA tightly (KD ∼200 nm). The formation of a ternary MePqqA-D-E complex was captured by native mass spectrometry and the KD for the MePqqAD-MePqqE interaction was found to be ∼5 μm. Finally, using a bioinformatic analysis, we found that PqqD orthologues are associated with the RS-SPASM family of proteins (subtilosin, pyrroloquinoline quinone, anaerobic sulfatase maturating enzyme, and mycofactocin), all of which modify either peptides or proteins. In conclusion, we propose that PqqD is a novel peptide chaperone and that PqqD orthologues may play a similar role in peptide modification pathways that use an RS-SPASM protein

Outcomes of Patients on Extracorporeal Membrane Oxygenation (ECMO) for Periods of Time without Anticoagulation at LVHN in the Past 3 Years

Outcomes of Patients on Extracorporeal Membrane Oxygenation (ECMO) for Periods of Time Without Anticoagulation at LVHN in the Past 3 Years Bryan Auvil, Rosalie Mattiola, Rita Pechulis, MD, James Wu, MD Department of Surgery, Division of Cardiothoracic Surgery Lehigh Valley Health Network, Allentown, PA Abstract Extracorporeal membrane oxygenation (ECMO) is an aggressive life support technique that utilizes extracorporeal circuits and oxygenators to support severe lung injury such as acute respiratory distress syndrome (ARDS), as well as severe cardiac disorders like cardiogenic shock and cardiac arrest. Veno-Venous (VV) ECMO is primarily used in respiratory distress. Clots can form within the oxygenator or circuit, which can develop embolic complications or flow problems. To prevent this, patients are anticoagulated, usually with heparin. However patients can develop bleeding complications, and therefore must have their AC discontinued. A retrospective chart review was done on 57 VV ECMO patients, out of which 19 had their heparin held for at least one period of 24 hours or longer. Temporarily non-heparinized patients required far more oxygenator and circuit replacements than control (58% compared to 8% of patients), had more DVTs (37% compared to 21%), and had a higher mortality rate (47% compared to 29%), however the rates of DVT per day on ECMO were very similar. Patients in the non-heparinized cohort died when the families withdrew care because of prolonged ECMO without improvement, worsening sepsis, and/or severe bleeding complications. Based on these findings there is no direct evidence that temporarily discontinuing AC resulted in increased patient mortality. This was more likely due to increased severity of illness and bleeding complications, evidenced by the increased time on ECMO. Keywords Extracorporeal membrane oxygenation, ECMO, Veno-venous ECMO, VV ECMO, heparin, anticoagulation, DVT, thrombosis, thrombotic complication Introduction Extracorporeal membrane oxygenation (ECMO), also known as extracorporeal life support (ECLS) is a very aggressive technique that utilizes extracorporeal circuits and oxygenators to support severe lung injury such as acute respiratory distress syndrome (ARDS), as well as cardiac support for cardiogenic shock and cardiac arrest. There are two major categories of ECMO: Veno-Venous ECMO is primarily used in respiratory distress, using a right internal jugular vein access; and Veno-Arterial ECMO is primarily used for cardiac or cardiopulmonary support, using femoral vein and artery access1. Extra Corporeal Life Support (ECLS) is sometimes used synonymously. Blood that comes into contact with foreign surfaces tends to coagulate. Clots that form within the oxygenator and extracorporeal tubing can be pushed into the patient and ultimately cause a thrombus, or in severe cases, a stroke. Therefore, as part of the protocol for extracorporeal circuits, patients undergo anticoagulation (AC) therapy and are uniformly heparinized with a partial thromboplastin time (PTT) in the range of 50-70 seconds, and an activated clotting time (ACT) of 180-200 sec2. Some of these severely ill patients can develop bleeding complications involving the oral pharyngeal cavity, abdominal cavity, thoracic cavity, and cannulation sites. In these cases, because of ongoing bleeding and exploratory surgery, AC needs to be stopped, sometimes for prolonged periods of time. Other patients are coagulopathic due to their illness, and therefore don’t receive therapeutic AC. Major bleeding is defined as clinically overt bleeding associated with a hemoglobin (Hgb) fall of at least 2 g/dl in a 24 hour period, greater than 20 ml/kg over a 24 hour period, or a transfusion requirement of one or more 10 ml/kg packed red blood cell (PRBC) transfusions over that same time period. In addition, bleeding that is retroperitoneal, pulmonary or involves the central nervous system, or bleeding that requires surgical intervention would also be considered major bleeding. Minor bleeding would be considered less than 20 ml/kg/day and require transfusion of one 10 ml/kg PRBC transfusion, or less. This is significant, because hemorrhagic complications and the requirement for greater red blood cell transfusion volumes are associated with increased mortality in both cardiac and non-cardiac ECLS2. The ultimate goal of this project was to review the safety and outcome of patients on ECMO in whom therapeutic anticoagulation is held secondary to bleeding complications, as there is no significant body of literature regarding this topic. Methods This retrospective study involved 57 VV ECMO patients (47% male, average age: 48) selected from the hospital database. Patients were sorted based off of the following inclusion criteria: (1) Patient had to have been on VV ECMO at LVHN since 2013, and (2) Patient had to be at least 18 years old. Of the 57 patients, 19 had their heparin held for at least one period of 24 hours or longer. All patients’ electronic medical records (EHMR) were examined to determine incidence of upper extremity (UE) and lower extremity (LE) deep vein thrombosis (DVT), patient mortality, and possible link between thrombotic complications and patient outcomes. Thrombotic complications include stroke, ischemic limb, kidney and liver injury, and surgical procedures for bleeding from body cavities and insertion sites. Records were also examined to determine if/how many oxygenator or circuit changes were necessary. For patients whose heparin was held, the source of bleeding was determined. Incidence of DVT, as well as need for oxygenator/circuit changes were calculated both as a percentage of the population, and as a rate of total events per total days on ECMO for that group. This was done in an attempt to normalize the data to account for the large difference between groups in average time spent on ECMO. Results The 19 patients whose heparin was held for a period of at least 24 hours (non-heparinized patients) spent an average of 25 days on ECMO, with an average AC hold time of 175 hours, while the 38 control patients spent an average of 10 days on ECMO (Table 1). The non-heparinized group was 47% male, with an average age of 46, and the control group was 42% male with an average age of 49 (Table 1). 58% of non-heparinized patients required oxygenator or circuit changes, at a rate of 0.034 changes per total day on ECMO (16 changes/475 days), while only 7.8% of control patients required changes, at a rate of 0.0079 (3 changes/379 days) (Table 1). 26% of non-heparinized patients and 13% of control patients experienced a LE DVT, but the rates were more similar at 0.017 (8 DVTs/475 days) and 0.013 (5 DVTs/379 days), respectively (Table 1). This trend continued with UE DVTs; although 26% of non-heparinized patients experienced an UE DVT compared to 11% of control patients, non-heparinized patients’ rate of 0.017 (8 DVTs/475 days) was actually lower than control patients’ rate of 0.026 (10 DVTs/379 days) (Table 1). The mortality rate for non-heparinized patients was 47% (9/19), with 6 out of 9 patients’ families deciding to withdraw care. The mortality rate for control patients was 29% (11/38), with 7 out of 11 patients’ families deciding to withdraw care (Table 1). 11% (2/19) of non-heparinized patients were discharged home and 42% (8/19) were discharged to rehab facilities, while 18% (7/38) of control patients were discharged home and 55% (21/38) were discharged to rehab facilities (Table 1). Reasons for discontinuing heparin or other AC included hemoptysis (7/19) and oropharyngeal (5/19), tracheotomy site (6/19), and cannula site (6/19) bleeding. VV ECMO patient etiology included H1N1 (28%), pneumonia (16%), aspiration (14%), Legionella (9%), post-operative complications (7%), MI and cardiac arrest (5%), and other illnesses (9%). Etiology was unknown for 12% of patients (Figure 3). Non-heparinized patients died due to severe bleeding, sepsis, hypoxia-related brain death, and family withdrawing care due to prolonged ECMO treatment without improvement (Table 3). Conclusions Patients whose heparin was held for period(s) of at least 24 hours required oxygenator and circuit changes much more frequently. They also experienced more DVTs and had a higher mortality rate; however, their overall rate of DVTs per day on ECMO is similar that of the control group, indicating that the increased incidence of DVT is likely due to the significantly longer average amount of time those patients spent on ECMO relative to control patients. Patients in the non-heparinized cohort mostly died when the families withdrew care because of prolonged ECMO without improvement, worsening sepsis, and/or severe bleeding complications. There were no obvious systemic thrombotic complications. Based on these findings there is no direct evidence that temporarily discontinuing AC resulted in increased patient mortality. This was more likely due to increased severity of illness and bleeding complications, requiring more time on ECMO. The study has quite a few limitations. It cannot necessarily be broadly applied due to the small sample size of only 57 total patients over three years, with an experimental group of only 19 patients. Furthermore, only statistics from a single hospital system were examined. However, the findings indicate that at least in this patient cohort, there was no obvious link between withholding anticoagulation therapy while on ECMO and increased patient mortality. This suggests that in contrast to standard ECMO protocol, it might be reasonable to withhold heparin from ECMO patients - at least temporarily - in the case of moderate to severe bleeding2. Further study is indicated to determine whether the results of this study are generalizable to a wider patient population, and whether discontinuing AC therapy in ECMO patients does in fact affect patient mortality. Acknowledgements James Wu, MD, Rita Pechulis, MD, Hope Kincaid, MPH, CPH, Jane Scott, Hubert Huang, Ph. D., Jordan Williams, Amanda Broderick, Alex Maryshina, Joseph Napolitano, Ph.D. References D Brodie, M Bacchetta. Extracorporeal Membrane Oxygenation for ARDS in Adults. N Engl J Med 2011;365:1905-14. ELSO Anticoagulation Guideline 2014 Table 1: LVHN VV ECMO data 2013-2015 Table 2: Reasons for discontinuing heparin Figure 1: Etiology of LVHN VV ECMO patients 2013-2015 Table 3: Causes of death for heparin-held patients Figure 2: Patient complications and outcomes as percentage of total group Figure 3: Rate of patient complications (total # of events per total days on EC

Urine culture doubtful in determining etiology of diffuse symptoms among elderly individuals: a cross-sectional study of 32 nursing homes

Background: The high prevalence of bacteriuria in elderly individuals makes it difficult to know if a new symptom is related to bacteria in the urine. There are different views concerning this relationship and bacteriuria often leads to antibiotic treatments. The aim of this study was to investigate the relationship between bacteria in the urine and new or increased restlessness, fatigue, confusion, aggressiveness, not being herself/himself, dysuria, urgency and fever in individuals at nursing homes for elderly when statistically considering the high prevalence of asymptomatic bacteriuria in this population.\ud \ud Methods: In this cross-sectional study symptoms were registered and voided urine specimens were collected for urinary cultures from 651 elderly individuals. Logistic regressions were performed to evaluate the statistical correlation between bacteriuria and presence of a symptom at group level. To estimate the clinical relevance of statistical correlations at group level positive and negative etiological predictive values (EPV) were calculated.\ud \ud Results: Logistic regression indicated some correlations at group level. Aside from Escherichia coli in the urine and not being herself/himself existing at least one month, but less than three months, EPV indicated no clinically useful correlation between any symptoms in this study and findings of bacteriuria.\ud \ud Conclusions: Urinary cultures provide little or no useful information when evaluating diffuse symptoms among elderly residents of nursing homes. Either common urinary tract pathogens are irrelevant, or urine culture is an inappropriate test

Staphylococcus aureus Bloodstream Infections: The Association Between Age and Mortality and Functional Status

To assess the association between Staphylococcus aureus (S. aureus) blood stream infections (BSIs) and morbidity and mortality in older adults. DESIGN : Retrospective review. SETTING : Veterans Affairs Ann Arbor Healthcare System. PARTICIPANTS : All patients with S. aureus BSI during 2004/05. MEASUREMENTS : Outcomes included in-hospital and 6-month mortality, as well as need for subacute care. RESULTS : Sixty-eight patients with S. aureus BSI were identified (mean age 63.5±13.0). Outcomes of interest included in-hospital mortality (19.1%), 6-month mortality (33.8%), and need for subacute care (65.4%). Univariate analysis identified several predictors of death, including older age, chronic renal insufficiency, catheter-related infection, Charlson weighted index of comorbidity score, and infection with methicillin-resistant S. aureus (MRSA). Multivariable analysis demonstrated that older age (odds ratio (OR)=1.1, P <.01), chronic renal insufficiency (OR=16.6, P =.01), and MRSA infection (OR=5.1, P =.03) were independently associated with 6-month mortality. These results suggest that, for every decade increase in age, the odds of death within 6 months of S. aureus BSI doubles (OR=1.1). Chronic renal insufficiency was also independently associated with in-hospital mortality. Of the previously community-dwelling patients (n=50), 41 survived hospitalization, of whom 22 (53.7%) required subacute care after discharge. CONCLUSION : Better understanding of the epidemiology of S. aureus BSI in older patients and validation of risk factors for poor functional outcomes and death should be the focus of future prospective studies.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65795/1/j.1532-5415.2008.01823.x.pd