Advances in Neonatal Care

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ZAP-VAP: A Quality Improvement Initiative to Decrease Ventilator-Associated Pneumonia in the Neonatal Intensive Care Unit, 2012-2016 Background: Ventilator-associated pneumonia (VAP) is the second most frequent hospital-acquired infection in neonatal intensive care units (NICUs) and significantly affects neonatal morbidity and mortality. The population most at risk for VAP are extremely preterm infants. Purpose: The objectives of this quality improvement project were to create and evaluate the effectiveness of a VAP prevention bundle ("ZAP-VAP") in reducing VAP. Methods: The development of the ZAP-VAP bundle and creation of audit tools were documented. A targeted gestational age less than 29 weeks was selected for this study. Electronic medical record review was used to determine the preintervention baseline for patient outcomes. Patient medical record data were analyzed retrospectively to measure patient outcomes preimplementation. VAP rates (number of VAP cases per 1000 ventilator days) were calculated pre- and postintervention. After implementation, data were analyzed prospectively to measure patient outcomes between neonates who developed VAP and those who did not. Results: The VAP rate significantly decreased from 8.5 (2010-2011) to 2.5 (P= .0004) postintervention (2016). Median mechanical ventilation days decreased among VAP cases (47 vs 33 days) and slightly increased among non-VAP cases (19 vs 24 days) during the intervention period. Median length of stay decreased for VAP cases (136 vs 100 days) but remained unchanged for non-VAP cases (85 vs 84 days). Implications for Practice: The intervention was implemented from 2012 to 2016. The protocol was readily accepted by our neonatal intensive care unit (NICU) team through education and practice changes. ZAP-VAP is an effective and straightforward protocol that improved VAP outcomes in our level IIIB NICU. An interdisciplinary team successfully implemented this intervention for mechanically ventilated infants of all gestational ages in our unit and has been a model for these practice changes in other units and other hospitals. Implications for Research: Future studies should focus on how to create sustainable interventions to decrease VAP in NICUs and to expand the approaches to other units in our hospital and other hospitals in our city among patients at risk for VAP.

Successful Reduction in Electrode-Related Pressure Ulcers During EEG Monitoring in Critically Ill Neonates Background: Neonates are at a high risk for pressure ulcers (PU) due to skin immaturity and exposure to various medical devices. The prevalence of PU in the neonatal intensive care unit is estimated to be 23%, with 80% of those being related to medical devices, including electroencephalographic (EEG) electrodes. Proposed mechanisms involve prolonged pressure to the electrodes and chemical reactions to conductive agents. Purpose: The object of this quality improvement project was to reduce PU in neonates during continuous EEG (cEEG) monitoring by 50% within 12 months and 75% within 18 months. A secondary objective was to eliminate electrode-related infections by 12 months. Balancing measures included gestational age at the time of monitoring, integrity of the EEG setup, and cost effectiveness. The process measure was adherence to the skin-monitoring tool kit. Methods: A multiple Plan-Do-Study-Act cycle method was used. All neonates monitored with cEEG were included. The monitoring tool kit was used to document the condition of scalp and EEG electrodes before, during, and after cEEG. Results: In the preproject period, 8.5% (9/106) of monitored patients developed PU, and 22.2% (2/9) of those developed infections. During the project period, 3.5% (7/198) of monitored patients developed PU and no infections were observed. During monitoring, 21 patients showed skin irritation, and timely intervention resulted in resolution in more than 90% of the cases and prevented progression into PU. Silver/silver chloride–plated electrodes, when exposed to external heat sources, can cause burns, resembling PU. Implications for Practice: Intervention at the electrode level together with skin inspection successfully reduces PU in neonates. Silver/silver chloride–plated electrodes should be avoided in neonates. Implications for Research: Further research is needed to identify the optimal electrode for neonatal EEG.

Outcomes of Neonates With Complex Medical Needs Background: Children with complex medical needs (CMN) are high healthcare resource utilizers, have varying underlying diagnoses, and experience repeated hospitalizations. Outcomes on neonatal intensive care (NICU) patients with CMN are unknown. Purpose: The primary aim is to describe the clinical profile, resource use, prevalence, and both in-hospital and postdischarge outcomes of neonates with CMN. The secondary aim is to assess the feasibility of sustaining the use of the neonatal complex care team (NCCT). Methods: A retrospective cohort study was conducted after implementing a new model of care for neonates with CMN in the NICU. All neonates born between January 2013 and December 2016 and who met the criteria for CMN and were cared for by the NCCT were included. Results: One hundred forty-seven neonates with a mean (standard deviation) gestational age of 34 (5) weeks were included. The major underlying diagnoses were genetic/chromosomal abnormalities (48%), extreme prematurity (26%), neurological abnormality (12%), and congenital anomalies (11%). Interventions received included mechanical ventilation (69%), parenteral nutrition (68%), and technology dependency at discharge (91%). Mortality was 3% before discharge and 17% after discharge. Postdischarge hospital attendances included emergency department visits (44%) and inpatient admissions (58%), which involved pediatric intensive care unit admissions (26%). Implications for Practice: Neonates with CMN have multiple comorbidities, high resource needs, significant postdischarge mortality, and rehospitalization rates. These cohorts of NICU patients can be identified early during their NICU course and serve as targets for implementing innovative care models to meet their unique needs. Implications for Research: Future studies should explore the feasibility of implementing innovative care models and their potential impact on patient outcomes and cost-effectiveness.

Evaluating Teamwork in the Neonatal Intensive Care Unit: A Survey of Providers and Parents Background: A unified vision of team mission, psychologically safe practice environment, effective communication, and respect among team members are key characteristics of an effective interdisciplinary neonatal intensive care unit (NICU) team. Purpose: A quality improvement team in a quaternary NICU surveyed parents, physicians, and nurses on perceptions of teamwork to identify opportunities for improvement. Design/Methods: Parents and healthcare staff (n = 113) completed an anonymous survey from May to July of 2014 to assess team roles and membership, team qualities, shared mission, psychological safety, hierarchy, communications, and conflict awareness. An expert panel assigned questions into one or more characteristics of team intelligence. Results: Physicians, nurses, and parents perceive their roles and the composition of the healthcare team differently. Most providers reported a shared mission and having a cooperative spirit as their teams' best attributes. While most nurses chose safety as most important, the majority of doctors chose treatment plan. Parents consider tenderness toward their infant, providing medical care and answers to their questions important. All expressed varying concerns about psychological safety, conflict resolution, and miscommunications. Implications for Practice: This survey identifies strengths and gaps of teamwork in our NICU and provides insight on necessary changes that need to be made to improve collaboration among the interdisciplinary care team including parents. Implications for Research: This quality improvement report identifies aspects of team care delivery in NICUs that require further study. The concept of team intelligence and its impact on team effectiveness invites in-depth exploration.

What Are the Effects of the Maternal Voice on Preterm Infants in the NICU? Background/Significance: Premature infants often experience extended stays in the neonatal intensive care unit (NICU) as opposed to home with parents. This prolonged separation creates a strain for both parents and infants, decreasing attachment and parental caregiving. One strategy to combat this shared stress is increasing parental participation, particularly through the use of their voices whether parents are present or not. Purpose: This Evidence-Based Practice Brief column explores the connection between mother and child, specifically the effects of maternal voice on infant autonomic stability, weight gain, and behavioral states. Methods: A systematic search of CINAHL, PubMed, and PsycInfo was used to identify studies involving the use of maternal voice intervention with preterm infants in the NICU. Results: Fifteen studies were identified. Three intervention categories emerged: (1) live maternal speech, (2) recorded maternal speech (subcategories included whether intervention content was prescribed or not), and (3) recorded maternal speech that was combined with biological maternal sounds (heart rate). Within each category, studies were organized chronologically to reflect how knowledge has changed overtime. Implications for Practice: Maternal voice has physiological as well as behavioral and emotional effect on preterm infants. Several studies found that maternal voice increased autonomic stability improving (heart rate and respirations) as well as weight gain. No negative effects were identified. Given these findings, incorporating different types of maternal voice into routine care by the bedside nurse can assist the mother in feeling more involved in her infant's care without seemingly being a distraction or obstacle to providers. Implications for Research: A major limitation for generalizability was sample size; more research is needed with larger sample sizes replicating interventions types to discern best outcomes. Video Abstract available at https://journals.lww.com/advancesinneonatalcare/Pages/videogallery.aspx?videoId=31&autoPlay=true.

A Community Hospital NICU Developmental Care Partner Program: Feasibility and Association With Decreased Nurse Burnout Without Increased Infant Infection Rates Background: Volunteers can provide staff-directed sensory inputs to infants hospitalized in the NICU, but research on volunteer programs is limited. Purpose: To evaluate the feasibility of a developmental care partner (DCP) program in a level III NICU and determine its relationship with provider burnout and infant infection rates. Methods: DCPs were trained to provide sensory input to infants, based on the behavioral cues observed by the occupational therapists and nursing staff, in medically stable infants. Feasibility was assessed by documenting the process of training and utilizing volunteers, as well as tracking duration and frequency of DCP visits. Staff burnout measures were assessed using the Maslach Burnout Inventory Human Services Survey (MBI-HSS) before and after implementation. Infant infection rates before and after the introduction of volunteers were compared. Results: Seventy-two volunteers were interested, and 25 (35%) completed the DCP competencies and provided sensory exposures to 54 neonates, who were visited an average of 8 times (range 1-15). Twelve (48%) DCPs did once-per-week visits, and 9 (36%) did at least 50 contact hours. MBI-HSS scores for staff emotional exhaustion (P < .001) and depersonalization (P < .006) were lower after DCP implementation. There were no differences in infant infection rates before and after DCP implementation (Fisher exact P = 1.000). Implications for Practice: Volunteer-based DCP programs may be feasible to implement in community hospitals and could help reduce staff emotional exhaustion and depersonalization without increasing the incidence of infant infections. Implications for Research: Future research on NICU volunteer programs with larger sample sizes and different infant populations is warranted.

Relationship of Necrotizing Enterocolitis Rates to Adoption of Prevention Practices in US Neonatal Intensive Care Units Background: Applying quality improvement methods has reduced necrotizing enterocolitis (NEC) in some neonatal intensive care units (NICUs) by 40% to 90%. Purpose: This study was conducted to (1) examine relationships between adoption of prevention practices using the NEC-Zero adherence score and NEC rates, and (2) describe implementation strategies NICUs use to prevent NEC. Methods: A descriptive cross-sectional correlational study was completed among US quality improvement–focused NICUs. Relationships of the NEC-Zero adherence score to NEC rates were examined. Subgroup analyses explored relationships of a human milk adherence subscore and differences between high NEC rate (≥8%) and low NEC rate (≤2%) NICUs. Results: NICUs (N = 76) ranged in size from 18 to 114 beds. The mean adherence score was 7.3 (standard deviation = 1.7; range, 3-10). The 10-point adherence score was not related to the NEC rate. The human milk subscore related to lower NEC rates (Rho = −0.26, P = .049), as was colostrum for oral care (Rho = −0.27, P = .032). The units that used a feeding protocol showed higher NEC rates (Rho = 0.27, P = .03), although very few addressed the use of effective implementation strategies to track adherence or to ensure consistency among clinicians. The units that used colostrum for oral care were more likely to adopt strategies to limit inappropriate antibiotic exposure (Rho = 0.34, P = .003). Implications for Practice: Broader use of evidence-based implementation strategies could bolster delivery of NEC prevention practices. Maternal lactation support is paramount. Implications for Research: Future studies are needed to identify how individual clinicians deliver prevention practices, to find the extent to which this relates to overall delivery of prevention, and to study effects of bundles on NEC outcomes.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Trauma and Acute Care Surgery

Selective aortic arch perfusion with fresh whole blood or HBOC-201 reverses hemorrhage-induced traumatic cardiac arrest in a lethal model of noncompressible torso hemorrhage BACKGROUND Hemorrhage-induced traumatic cardiac arrest (HiTCA) has a dismal survival rate. Previous studies demonstrated selective aortic arch perfusion (SAAP) with fresh whole blood (FWB) improved the rate of return of spontaneous circulation (ROSC) after HiTCA, compared with resuscitative endovascular balloon occlusion of the aorta and cardiopulmonary resuscitation (CPR). Hemoglobin-based oxygen carriers, such as hemoglobin-based oxygen carrier (HBOC)-201, may alleviate the logistical constraints of using FWB in a prehospital setting. It is unknown whether SAAP with HBOC-201 is equivalent in efficacy to FWB, whether conversion from SAAP to extracorporeal life support (ECLS) is feasible, and whether physiologic derangement post-SAAP therapy is reversible. METHODS Twenty-six swine (79 ± 4 kg) were anesthetized and underwent HiTCA which was induced via liver injury and controlled hemorrhage. Following arrest, swine were randomly allocated to resuscitation using SAAP with FWB (n = 12) or HBOC-201 (n = 14). After SAAP was initiated, animals were monitored for a 20-minute prehospital period prior to a 40-minute damage control surgery and resuscitation phase, followed by 260 minutes of critical care. Primary outcomes included rate of ROSC, survival, conversion to ECLS, and correction of physiology. RESULTS Baseline physiologic measurements were similar between groups. ROSC was achieved in 100% of the FWB animals and 86% of the HBOC-201 animals (p = 0.483). Survival (t = 320 minutes) was 92% (11/12) in the FWB group and 67% (8/12) in the HBOC-201 group (p = 0.120). Conversion to ECLS was successful in 100% of both groups. Lactate peaked at 80 minutes in both groups, and significantly improved by the end of the experiment in the HBOC-201 group (p = 0.001) but not in the FWB group (p = 0.104). There was no significant difference in peak or end lactate between groups. CONCLUSION Selective aortic arch perfusion is effective in eliciting ROSC after HiTCA in a swine model, using either FWB or HBOC-201. Transition from SAAP to ECLS after definitive hemorrhage control is feasible, resulting in high overall survival and improvement in lactic acidosis over the study period.

Four-factor prothrombin complex concentrate is associated with improved survival in trauma-related hemorrhage: A nationwide propensity-matched analysis INTRODUCTION Post-traumatic hemorrhage is the most common preventable cause of death in trauma. Numerous small single-center studies have shown the superiority of four-factor prothrombin complex concentrate (4-PCC) along with fresh frozen plasma (FFP) over FFP alone in resuscitation of trauma patients. The aim of our study was to evaluate outcomes of severely injured trauma patients who received 4-PCC + FFP compared to FPP alone. METHODS Two-year (2015–2016) analysis of the American College of Surgeons-Trauma Quality Improvement Program database. All adult (age ≥18 years) trauma patients who received 4-PCC + FFP or FFP alone were included. We excluded patients who were on preinjury anticoagulants. Patients were stratified into two groups: 4-PCC + FFP versus FFP alone and were matched in a 1:1 ratio using propensity score matching for demographics, vitals, injury parameters, comorbidities, and level of trauma centers. Outcome measures were packed red blood cells, plasma and platelets transfused, complications, and mortality. RESULTS A total of 468 patients (4-PCC + FFP, 234; FFP alone, 234) were matched. Mean age was 50 ± 21 years; 70% were males; median injury severity score was 27 [20–36], and 86% had blunt injuries. Four-PCC + FFP was associated with a decreased requirement for packed red blood cells (6 units vs. 10 units; p = 0.02) and FFP (3 units vs. 6 units; p = 0.01) transfusion compared to FFP alone. Patients who received 4-PCC + FFP had a lower mortality (17.5% vs. 27.7%, p = 0.01) and lower rates of acute respiratory distress syndrome (1.3% vs. 4.7%, p = 0.04) and acute kidney injury (2.1% vs. 7.3%, p = 0.01). There was no difference in the rates of deep venous thrombosis (p = 0.11) and pulmonary embolism (p = 0.33), adverse discharge disposition (p = 0.21), and platelets transfusion (p = 0.72) between the two groups. CONCLUSIONS Our study demonstrates that the use of 4-PCC as an adjunct to FFP is associated with improved survival and reduction in transfusion requirements compared to FFP alone in resuscitation of severely injured trauma patients. Further studies are required to evaluate the role of addition of PCC to the massive transfusion protocol. LEVEL OF EVIDENCE Therapeutic studies, level III.

Effect of damage control laparotomy on major abdominal complications and lengths of stay: A propensity score matching and Bayesian analysis BACKGROUND In patients for whom surgical equipoise exists for damage control laparotomy (DCL) and definitive laparotomy (DEF), the effect of DCL and its associated resource utilization are unknown. We hypothesized that DEF would be associated with fewer abdominal complications and less resource utilization. METHODS In 2016, six US Level I trauma centers performed a yearlong, prospective, quality improvement project with the primary aim to safely decrease the use of DCL. From this cohort of patients undergoing emergent trauma laparotomy, those who underwent DCL but were judged by majority faculty vote at each center to have been candidates for potential DEF (pDEF) were prospectively identified. These pDEF patients were matched 1:1 using propensity scoring to the DEF patients. The primary outcome was the incidence of major abdominal complications (MAC). Deaths within 5 days were excluded. Outcomes were assessed using both Bayesian generalized linear modeling and negative binomial regression. RESULTS Eight hundred seventy-two total patients were enrolled, 639 (73%) DEF and 209 (24%) DCL. Of the 209 DCLs, 44 survived 5 days and were judged to be patients who could have safely been closed at the primary laparotomy. Thirty-nine pDEF patients were matched to 39 DEF patients. There were no differences in demographics, mechanism of injury, Injury Severity Score, prehospital/emergency department/operating room vital signs, laboratory values, resuscitation, or procedures performed during laparotomy. There was no difference in MAC between the two groups (31% DEF vs. 21% pDEF, relative risk 0.99, 95% credible interval 0.60–1.54, posterior probability 56%). Definitive laparotomy was associated with a 72%, 77%, and 72% posterior probability of more hospital-free, intensive care unit-free, and ventilator-free days, respectively. CONCLUSION In patients for whom surgeons have equipoise for DCL versus definitive surgery, definitive abdominal closure was associated with a similar probability of MAC, but a high probability of fewer hospital-free, intensive care unit-free, and ventilator-free days. LEVEL OF EVIDENCE Therapeutic/care management, level III.

Top-tier emergency general surgery hospitals: Good at one operation, good at them all BACKGROUND There is a longstanding interest in the field of management science to study high performance organizations. Applied to medicine, research on hospital performance indicates that some hospitals are high performing, while others are not. The objective of this study was to identify a cluster of high-performing emergency general surgery (EGS) hospitals and assess whether high performance at one EGS operation was associated with high performance on all EGS operations. METHODS Adult patients who underwent one of eight EGS operations were identified in the California State Inpatient Database (2010–2011), which we linked to the American Hospital Association database. Beta regression was used to estimate a hospital's risk-adjusted mortality, accounting for patient- and hospital-level factors. Centroid cluster analysis grouped hospitals by patterns of mortality rates across the eight EGS operations using z scores. Multinomial logistic regression compared hospital characteristics by cluster. RESULTS A total of 220 acute care hospitals were included. Three distinct clusters of hospitals were defined based on assessment of mortality for each operation type: high-performing hospitals (n = 66), average performing (n = 99), and low performing (n = 55). The mortality by individual operation type at the high-performing cluster was consistently at least 1.5 standard deviations better than the low-performing cluster (p < 0.001). Within-cluster variation was minimal at high-performing hospitals compared with wide variation at low-performing hospitals. A hospital's high performance in one EGS operation type predicted high performance on all EGS operation types. CONCLUSION High-performing EGS hospitals attain excellence across all types of EGS operations, with minimal variability in mortality. Poor-performing hospitals are persistently below average, even for low-risk operations. These findings suggest that top-performing EGS hospitals are highly reliable, with systems of care in place to achieve consistently superior results. Further investigation and collaboration are needed to identify the factors associated with high performance. LEVEL OF EVIDENCE Prognostic, level III.

Evaluating mortality outlier hospitals to improve the quality of care in emergency general surgery BACKGROUND Expected performance rates for various outcome metrics are a hallmark of hospital quality indicators used by Agency of Healthcare Research and Quality, Center for Medicare and Medicaid Services, and National Quality Forum. The identification of outlier hospitals with above- and below-expected mortality for emergency general surgery (EGS) operations is therefore of great value for EGS quality improvement initiatives. The aim of this study was to determine hospital variation in mortality after EGS operations, and compare characteristics between outlier hospitals. METHODS Using data from the California State Inpatient Database (2010–2011), we identified patients who underwent one of eight common EGS operations. Expected mortality was obtained from a Bayesian model, adjusting for both patient- and hospital-level variables. A hospital-level standardized mortality ratio (SMR) was constructed (ratio of observed to expected deaths). Only hospitals performing three or more of each operation were included. An "outlier" hospital was defined as having an SMR with 80% confidence interval that did not cross 1.0. High- and low-mortality SMR outliers were compared. RESULTS There were 140,333 patients included from 220 hospitals. Standardized mortality ratio varied from a high of 2.6 (mortality, 160% higher than expected) to a low of 0.2 (mortality, 80% lower than expected); 12 hospitals were high SMR outliers, and 28 were low SMR outliers. Standardized mortality was over three times worse in the high SMR outliers compared with the low SMR outliers (1.7 vs. 0.5; p < 0.001). Hospital-, patient-, and operative-level characteristics were equivalent in each outlier group. CONCLUSION There exists significant hospital variation in standardized mortality after EGS operations. High SMR outliers have significant excess mortality, while low SMR outliers have superior EGS survival. Common hospital-level characteristics do not explain the wide gap between underperforming and overperforming outlier institutions. These findings suggest that SMR can help guide assessment of EGS performance across hospitals; further research is essential to identify and define the hospital processes of care which translate into optimal EGS outcomes. LEVEL OF EVIDENCE Epidemiologic Study, level III.

Ventilator-associated events, not ventilator-associated pneumonia, is associated with higher mortality in trauma patients BACKGROUND Ventilator-associated events (VAE), using objective diagnostic criteria, are the preferred quality indicator for patients requiring mechanical ventilation (MV) for greater than 48 hours. We aim to identify the occurrence of VAE in our trauma population, the impact on survival, and length of stay, as compared to the traditional definition of ventilator-associated pneumonia (VAP). METHODS This retrospective review included adult trauma patients, who were Washington residents, admitted between 2012 and 2017, and required at least 3 days of MV. Exclusions included patients with Abbreviated Injury Scale head score greater than 4 and burn related mechanisms of injury. We matched trauma registry data with our institutional, physician-adjudicated, and culture-confirmed ventilator event database. We compared the clinical outcomes of ventilator-free days, intensive care unit length of stay, hospital length of stay, and likelihood of death between VAE and VAP. RESULTS One thousand five hundred thirty-three trauma patients met criteria; 124 (8.1%) patients developed VAE, 114 (7.4%) patients developed VAP, and 63 (4.1%) patients met criteria for both VAE and VAP. After adjusted analyses, patients with VAE were more likely to die (hazard ratio [HR], 2.86; 95% confidence interval [CI], 1.44–5.68), than those with VAP, as well those patients with neither diagnosis (HR, 2.83; 95% CI, 1.83–4.38). Patients with VAP were no more likely to die (HR, 1.55; 95% CI, 0.91–2.68) than those with neither diagnosis. Patients with VAE had fewer ventilator-free days than those with VAP (HR, −2.71; 95% CI, −4.74 to −0.68). CONCLUSION Critically injured trauma patients who develop VAE are three times more likely to die and utilize almost 3 days more MV than those that develop VAP. The objective criteria of VAE make it a promising indicator on which quality indicator efforts should be focused. Future studies should be aimed at identification of modifiable risk factors for VAE and their impact on outcome, as these patients are at high risk for death. LEVEL OF EVIDENCE Retrospective cohort study, level III.

Trauma system resource preservation: A simple scene triage tool can reduce helicopter emergency medical services overutilization in a state trauma system BACKGROUND Helicopter emergency medical services improve survival in some injured patients but current utilization leads to significant overtriage with considerable numbers of transported patients discharged home from the emergency department or found to have non–time-sensitive injuries. Current triage models for utilization are complex and untested. METHODS Data from a state trauma registry were reviewed from 1987 to 1993 and from 2013 to 2015 and compared. Data from 2013 to 2015 were analyzed for field information found to influence mortality and a model for low mortality-risk patients designed. RESULTS Indexed to population, a major increase in numbers of injured patients transported directly to designated trauma centers (39.849–167.626/100,000/year) occurred with an increased portion transported by helicopter emergency medical services from 7.28% to 9.26%. A simple triage tool to predict low mortality rates was designed utilizing results from logistic regression. Nongeriatric adult patients (age, 16.0–69.9 years) with a blunt injury mechanism, normal Glasgow Coma Scale motor score, pulse rate of 60 bpm to 120 bpm and respiratory rate of 10 breaths per minute to 29 breaths per minute are at low risk for mortality. Cost for helicopter transportation was substantially higher than ground transportation based on available data. Cost differentials in transport mode increased patient financial risk when helicopter transportation was utilized. CONCLUSION Implementing a simple decision tool designating nongeriatric adult patients with a blunt injury mechanism, normal Glasgow Coma Scale motor score, systolic blood pressure greater than 90 mm Hg, pulse rate of 60 bpm to 120 bpm, and respiratory rate of 10 breaths per minute to 29 breaths per minute to ground transportation would result in substantial savings without an increase in mortality and reduce risk of patient financial harm. LEVEL OF EVIDENCE Prognostic/Epidemiological study, level IV. Economic and value based evaluation, level IV.

Acute resuscitation with polyethylene glycol-20k: A thromboelastographic analysis BACKGROUND Previous ex vivo studies have shown that polyethylene glycol-20,000 Da (PEG-20k), a novel synthetic polymer that is highly effective for resuscitation, has a hypocoagulable effect on human blood. This study's objective was to determine the in vivo effects of PEG-20k-based resuscitation solutions on coagulation and platelet function in a porcine model of hemorrhagic shock. METHODS Anesthetized pigs underwent controlled hemorrhage until the lactate reached 7 mmol/L or 50% to 55% of their estimated blood volume was removed. A laparotomy was performed to simulate tissue injury. Low volume resuscitation (LVR) was given with fluorescein isothiocyanate-labeled 10% PEG-20k solution (100 mg/mL) or Lactated Ringers, both delivered at volumes equal to 10% of the estimated blood volume (n = 5). Thromboelastography was performed after surgery (baseline), after hemorrhage, and 15 minutes, 120 minutes, and 240 minutes postresuscitation. Hemoglobin was measured to determine changes in plasma volume. Plasma PEG-20k concentration was measured by indicator dilution. RESULTS Pigs given PEG-20k survived 2.6-fold longer than controls (p < 0.001) and had a significant increase in plasma volume demonstrated by the sustained drop in hemoglobin, relative to controls. Pigs resuscitated with LR died from hypotension an average of 90 minutes after resuscitation compared to the PEG-20k pigs, which all survived 240 minutes and were then euthanized with normal blood pressure and lactate. Administration of PEG-20k primarily decreased the thromboelastograph maximum amplitude, however this began to return toward baseline by 240 minutes. Peak plasma concentration of PEG-20k after LVR were 40% lower than predicted, based on simple dilution (5.7 mg/mL vs. 10 mg/mL) and the half-life was 59.6 minutes. CONCLUSION These data demonstrate that acute resuscitation with PEG-20k significantly improves tolerance to hypovolemia but also decreases platelet function in the coagulation cascade, which was due, in part, to its volume expanding effects.

Comparison of male and female victims of intimate partner homicide and bidirectionality—an analysis of the national violent death reporting system BACKGROUND Intimate partner violence (IPV) is a public health crisis, affecting at least 1:4 women and 1:9 men. A recent multicenter trial on universal screening in trauma patients showed similar rates of positive screens between men and women. Few studies have explored the bidirectional violence in opposite-sex or same-sex relationships. Our goal was to estimate prevalence and risk factors for the most severe manifestation of IPV: intimate partner homicide. METHODS This is a 2003–2015 retrospective review of the National Violent Death Reporting System, a Centers for Disease Control and Prevention database of surveillance data. Deaths were coded IPV if the primary relationship between the suspect and victim fell into the categories of current partner or ex-partner. Bivariable and multivariable analysis examined differences between groups for factors and circumstances. RESULTS A total of 6,131 persons in opposite-sex relationships and 181 in same-sex relationships were murdered as a result of IPV. Women and Black men were disproportionately affected, and alcohol and preceding arguments were a factor in a higher proportion of male victims. Abuse preceded homicide in many women with almost half of male suspects attempting or committing suicide at the time of intimate partner homicide. Women were more likely than men to use a stabbing instrument, although firearms were still the most common means for each group. In 46.5% of homicides of women, the male suspect attempted suicide (p < 0.001). Bidirectionality was highest in male victims of female perpetrators and in same-sex pairings regardless of sex of the victim. CONCLUSION Homicide caused by IPV is a significant public health crisis for both men and women, with women and Black men at particular risk. Firearms are the most commonly used weapon for homicide in both sexes, and mental illness is not a common risk factor. A staggering proportion of these homicides involve suicide of the suspect, suggesting that each potential incident has two victims to target for prevention and intervention. Interventional programs to prevent such bidirectional mortality are urgently needed. LEVEL OF EVIDENCE Retrospective secondary data analysis, level III.

Altered monocyte and NK cell phenotypes correlate with posttrauma infection BACKGROUND Trauma induces a complex immune response, requiring a systems biology approach to capture multicellular changes. Using mass cytometry by time-of-flight (CyTOF), we evaluated time-dependent changes in peripheral blood in trauma patients to identify changes correlated with infection. METHODS Total leukocytes were prepared via red blood cell lysis using peripheral blood samples from trauma patients with an Injury Severity Score greater than 20 at Days 1, 3, and 5 after injury, and from age- and sex-matched uninjured controls. Cells were stained using a 33-marker immunophenotyping CyTOF panel. Statistics were calculated using one-way analysis of variance with multiple comparisons. RESULTS The CyTOF staining demonstrated changes in many cell subsets. The mean expression intensity of CD86 on monocytes decreased significantly at all time points after injury. When the patients were stratified based on development of infection, there was a trend to decreased CD86 expression on monocytes of those patients that developed subsequent infection. Based on stratification, we identified significantly increased expression of CD39 on NK cells only in patients that developed an infection. CONCLUSION This study used a systems biology approach to identify novel changes in circulating immune cell subsets in trauma patients correlating with post-traumatic infection. Decreased expression of CD86, a costimulatory molecule, on monocytes demonstrates that trauma affects the innate system's ability to control T-cell immunity. We also found that CD39 expression on NK cells increased significantly in patients with subsequent infection. CD39 is a protein that generates adenosine, which has immunosuppressive effects on several immune cell types including NK cells. In summary, our results point to pathways that may be central to second-hit infections and further study to delineate these pathways could be key to generating clinical biomarkers or targeted immune therapies for trauma patients. LEVEL OF EVIDENCE Prognostic study, level II.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Advanced Emergency Nursing

AAENP and ACEP: Cultivating Interprofessionalism No abstract available

The Modified Valsalva Maneuver for Reversion of Stable Supraventricular Tachycardia: Lessons Learned From the REVERT Trial The REVERT trial was a randomized multicenter trial that investigated the efficacy of using a modified Valsalva maneuver for the reversion of stable supraventricular tachycardia back to a sinus rhythm. Although no improvement in discharge to home from the emergency department (ED) or ED length of stay was observed, the REVERT trial demonstrated that the modified Valsalva maneuver was superior to the standard Valsalva maneuver. The modified Valsalva maneuver should be considered first-line treatment for patients who present with a stable supraventricular tachycardia. A case presentation illustrates the methodology for utilizing the modified Valsalva maneuver to treat supraventricular tachycardia in a hemodynamically stable patient who presents to the ED.

Mallet Finger This article provides an overview of issues associated with traumatic injury to the distal finger that results in extensor tendon disruption or bony avulsion at the base of the distal phalanx. Commonly referred to as mallet finger, drop finger, or baseball finger, terminal extensor tendon injuries are a common presentation to the emergency department. Providers need to be advised of evidence-based management of these extensor tendon injuries in order to prevent decreased function and permanent deformity. Current evidence supports nonoperative interventions, but injuries need to be addressed in a timely manner in order to avoid poor outcomes.

Orolingual Angioedema After Tissue Plasminogen Activator Administration in Patients Taking Angiotensin-Converting Enzyme Inhibitors Orolingual angioedema is a rare adverse effect (1%–5%) of tissue plasminogen activator (tPA) that can lead to significant morbidity in patients with acute ischemic stroke. It is thought that increased levels of bradykinin and histamine resulting from tPA administration can result in angioedema. Angiotensin-converting enzyme (ACE) inhibitors can also lead to increased levels of bradykinin and appear to be a risk factor for tPA-associated angioedema. A literature review was conducted to examine previous cases of orolingual angioedema associated with tPA administration in patients also taking ACE inhibitors to better understand the relationship between ACE inhibitors and tPA-induced angioedema. Over a 20-year period, 27 patients who experienced angioedema with tPA while on ACE inhibitor therapy were identified. In this patient population, the onset of angioedema symptoms appeared as soon as 15 min after the tPA bolus and as late as 2 hr after the tPA infusion. Most patients required a combination of supportive medications such as corticosteroids (81.5%), antihistamines (74%), and epinephrine (18.5%) for the management of angioedema. Severe presentations of orolingual angioedema resulted in intubation for airway protection (26%). Symptom resolution ranged from shortly after the administration of supportive medications to 72 hr after symptom onset. Orolingual angioedema after tPA administration has the potential to cause significant morbidity, indicating patients should be monitored closely for a few hours after administration for the development of airway compromise. ACE inhibitors should not be the preferred antihypertensive agents for patients who require blood pressure lowering prior to tPA administration.

Orolingual Angioedema After Tissue Plasminogen Activator Administration in Patients Taking Angiotensin-Converting Enzyme Inhibitors No abstract available

An Atypical Case of Abdominal Pain in a Toddler: A Diagnostic Challenge Abdominal pain in the pediatric patient presents a unique diagnostic challenge for emergency department (ED) providers due to the wide range of possible etiologies and sequelae. The list of differential diagnoses is extensive and includes the spectrum of conditions that range from benign and self-limiting to those that are potentially life-threatening. This article describes a case of a young toddler with an acute appendicitis complicated by perforation and abscess formation. Although acute appendicitis is uncommon in infants and younger children, it does occur and, as this case illustrates, is often misdiagnosed, which leads to delayed treatment and a higher incidence of complications. This article includes a discussion of the challenges faced by ED providers in the clinical-decision making process when caring for a pediatric patient with abdominal pain due to an acute appendicitis. This discussion includes the age-associated epidemiology, pathophysiology, clinical presentation, and evidence-based recommendations for diagnosis and treatment.

Kawasaki Disease in Infancy Kawasaki disease (KD) is an acute vasculitis that primarily affects young children and, if untreated, is associated with development of coronary artery aneurysms in approximately 25% of those affected. Infants, especially those younger than 6 months, often have atypical (incomplete) presentations of KD and are most at risk for development of aneurysms. Identification of KD requires a careful and thorough history and physical examination because multiple other conditions cause similar findings. Providers in acute care settings need to have a high degree of suspicion for KD so that those affected may receive appropriate and timely treatment.

Dental Pain Relief in the Age of ALTO The opioid public health crisis necessitates that health care providers seek alternatives to opioid pain control. For patients presenting with dental pain, a dental nerve block provides effective, long-lasting pain relief without the use of opioid pain medications. This article presents the techniques required to safely and effectively administer 3 types of dental nerve blocks, allowing the emergency nurse practitioner to provide effective pain control to patients with dental pain.

Dental Pain Relief in the Age of ALTO No abstract available

Advanced Practice Provider Burnout in a Large Urban Medical Center Burnout is characterized by 3 facets: the presence of emotional exhaustion, depersonalization, and a lack of sense of personal accomplishment. It arises when stress becomes so severe relative to a person's own resources that he or she loses motivation to perform, and it is associated with many negative outcomes. Emergency medicine (EM) physicians ranked highest in a study of burnout rates among physician subspecialties. However, there is an overall lack of robust research examining the work-related psychological states in advanced practice providers (APPs). Because the utilization of APPs in emergency departments (EDs) is steadily increasing, we aimed to describe burnout in this understudied group. A sample of APPs employed in a large urban academic hospital was surveyed using 3 well-established questionnaires measuring burnout, resilience, and mindfulness. Responses were compared with a normative group of health care workers (HCWs). The respondents reported a significantly greater sense of personal accomplishment than other HCWs. This was greater with a perceived control over their work environment and if they self-identified as being nonjudgmental. The sense of accomplishment was less in the respondents of older age and for those with children. This group also reported an increased sense of depersonalization. Mindfulness traits of acting with awareness and having trust in their instincts were identified as potential protective factors against depersonalization. Although the respondents were not more emotionally exhausted than other HCWs, being more emotionally "reactive" did predict greater emotional exhaustion. This is an important finding for APPs working in affect-laden work environments such as EDs. These findings suggest that increasing control over the work environment, fostering trust of instincts, and reducing emotional reactiveness are prudent interventional targets for EM-APP leaders to prevent and reduce burnout in the workforce.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Cancer Research and Clinical Oncology

Correction to: Neoadjuvant chemoradiotherapy delivered with helical tomotherapy under daily image guidance for rectal cancer patients: efficacy and safety in a large, multi-institutional series The article "Neoadjuvant chemoradiotherapy delivered with helical tomotherapy under daily image guidance for rectal cancer patients: efficacy and safety in a large, multi-institutional series"

Low number of intrafollicular T cells may predict favourable response to rituximab-based immuno-chemotherapy in advanced follicular lymphoma: a secondary analysis of a randomized clinical trial Abstract Background First-line rituximab therapy together with chemotherapy is the standard care for patients with advanced follicular B-cell lymphoma, as rituximab together with chemotherapy prolongs progression-free and overall survival (Herold et al. 2007; Marcus et al. 2005). However, as not all patient subgroups benefit from combined immuno-chemotherapy, we asked whether the microenvironment may predict benefit from rituximab-based therapy. Design To address this question, we performed a retrospective immunohistochemical analysis on pathological specimens of 18 patients recruited into a randomized clinical trial, where patients with advanced follicular lymphoma were randomized into either chemotherapy or immuno-chemotherapy with rituximab (Herold et al. 2007). Results We show here that rituximab exerts beneficial effects, especially in the subgroup of follicular lymphoma patients with low intrafollicular CD3, CD5, CD8, and ZAP70 and high CD56 and CD68 expression. Conclusion Rituximab may overcome immune-dormancy in follicular lymphoma in cases with lower intrafollicular T-cell numbers and higher CD56 and CD68 cell counts. As this was a retrospective analysis on a small subgroup of patients, these data need to be corroborated in larger clinical trials.

A prognostic score system with lymph node ratio in stage IIIA-N2 NSCLC patients after surgery and adjuvant chemotherapy Abstract Purpose The survival of patients with IIIA-N2 non-small cell lung cancer after surgery followed by adjuvant chemotherapy is heterogeneous. The aim of this study is to form a prognostic system and a heat map method to visualize the overall survival rates in those patients. Methods Univariate and multivariate Cox hazards regression models and the associated Wald Chi square coefficient were used to form the prognostic score system. Recursive partitioning analysis was used to determine the cutoff values of lymph node ratio and prognostic score in SEER cohort and validated in FDUSCC cohort. Meanwhile, a heat map method was used to visualize the overall survival probabilities of 3, 5 and 10 years for individual patient of both cohorts. Results Lymph node ratio (with cutoff of 0.36) significantly correlates with overall survival of these patients. In addition, in patients with the same level of N2 disease, lymph node ratio still significantly affects survival. Also, after the multivariate analysis in SEER cohort, six factors were independent prognostic factors including age, sex, type of surgery, size, lymph node ratio and differentiation. A prognostic sore system with these factors (with cutoff of 12) was validated as a predictor for overall survival in FDUSCC cohort. Conclusions This prognostic score system including lymph node ratio can predict the survival rates of IIIA-N2 patient after surgery and post-operative chemotherapy. Lymph node ratio could be a useful supplementation in TNM stage classification for IIIA-N2 patients. The heat map method can visualize the predicted overall survival of an individual patient.

Genetic profiling as a clinical tool in advanced parathyroid carcinoma Abstract Context Parathyroid carcinoma (PC) is a rare endocrine malignancy with no approved systemic therapies for unresectable locally invasive or distant metastatic disease. Understanding the molecular changes in advanced PC can provide better understanding of this disease and potentially help directing targeted therapy. Objective To evaluate tumor-specific genetic changes using next-generation sequencing (NGS) panels. Design All patients with advanced PC were tested for hot-spot panels using NGS panels including a 50-gene panel, a 409-gene panel if the standard 50-gene panel (Ion Torrent, Life Technology) was negative or a FoundationOne panel. Setting The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Patients or other participants 11 patients with advanced PC were selected to undergo molecular testing. Main outcome measure(s) Genetic profiles of advanced PC. Results Among the 11 patients, 4 patients had the 50-gene panel only, 6 had 409-gene panel after a negative 50-gene panel and 1 had FoundationOne. One patient who had 50-gene panel only also had his metastatic site (esophagus) of his tumor tested with FoundationOne. The most common mutations identified were in the PI3 K (PIK3CA, TSC1 and ATM) (4/11 patients) and TP53 (3/11) pathways. Genes not previously reported to be mutated in PC included: SDHA, TERT promoter and DICER1. Actionable mutations were found in 54% (6/11) of the patients. Conclusions Mutational profiling using NGS panels in advanced PC has yielded important potentially targetable genetic alterations. Larger studies are needed to identify commonly mutated genes in advanced PC patients. Development of novel therapies targeting these cellular pathways should be considered.

Effect of age on the effectiveness of the first-line standard of care treatment in patients with metastatic colorectal cancer: systematic review of observational studies Abstract Purpose Most metastatic colorectal cancer (mCRC) patients are elderly. This systematic review identifies and describes observational studies evaluating the influence of age on first-line treatment effectiveness in real-world practice. Methods Medline and EMBASE were searched up to May 2016. The included studies were those that investigated first-line treatment of mCRC and reported age groups and overall survival (OS), progression-free survival (PFS) or overall response rate (ORR) were included. Studies published before 2008 were excluded. Study quality was assessed using the Newcastle–Ottawa Scale. Data were evaluated by age group (< 70 vs. ≥ 70 years; 65–75 vs. ≥ 75 years) and outcome. A pooled survival median was calculated for patients (cutoff = 70 years). Results In total, 11 articles with 11,063 patients were included. Four studies using a cutoff of 70 years of age reported OS and PFS, and two studies reported ORRs. In terms of OS, all studies showed a higher OS for those < 70 years of age than for those ≥ 70 years of age. PFS did not find differences by age. For ORRs, one study favoured the younger group, while the second study did not differ by age. Based on three studies, the pooled medians for  < 70 years of age and ≥ 70 years of age were the same for PFS (10.2) and were 27.0 and 22.9 for OS, respectively. All included studies were of high or acceptable quality. Conclusions The results suggest that age has no effect on PFS. For ORR, the results were inconsistent between studies. Younger patients in general had better OS, which might be partly explained by more aggressive treatment. This treatment seemed not to be guided by performance status or number of metastatic sites.

Targeting cathepsin K diminishes prostate cancer establishment and growth in murine bone Abstract Background The processes of prostate cancer (PCa) invasion and metastasis are facilitated by proteolytic cascade involving multiple proteases, such as matrix metalloproteinases, serine proteases and cysteine proteases including cathepsin K (CatK). CatK is predominantly secreted by osteoclasts and specifically degrades collagen I leading to bone destruction. PCa and breast cancer preferentially metastasize to the bone. Importantly, CatK expression level is greater in PCa bone metastatic sites compared to primary tumor and normal prostate tissues. However, the underlying mechanism of CatK during PCa metastases into the bone remains to be elucidated. We investigated the functional role of CatK during the PCa establishment and growth process in the murine bone. Methods CatK mRNA expression was validated by RT-PCR, protein expression by immunoblotting in PCa LNCaP, C4-2B, and PC3 cells as well as in PCa tissues. Its protein production was measured using ELISA assay. The effect of both knockdowns via siRNA and CatK inhibitor was compared in regard to PCa cell invasion. We further studied the dose-dependent CatK inhibitor effect on conditioned media-induced bone resorption. In setting up an animal model, C4-2B cells were injected into the tibiae of SCID mice. The animals treated with either vehicle or CatK inhibitor for 8 weeks at the time of tumor cell injection (tumor establishment model; protocol I) or 4 weeks after tumor cell injection (tumor progression model; protocol II) were applied to histological and histomorphometric analyses. Results We confirmed CatK expression in PCa LNCaP, C4-2B, and PC3 cells as well as in PCa tissues. Furthermore, we observed the inhibitory effects of a selective CatK inhibitor on PCa cell invasion. The CatK inhibitor dose-dependently inhibited PCa-conditioned media-induced bone resorption. Upon injection of C4-2B cells into the tibiae of SCID mice, the selective CatK inhibitor significantly prevented the tumor establishment in protocol I, and reduced the tumor growth in bone in protocol II. It also decreased serum PSA levels in both animal models. The inhibitory effects of the CatK inhibitor were enhanced in combination with zoledronic acid (ZA). Conclusion The selective CatK inhibitor may prevent the establishment and progression of PCa in bone, thus making it a novel therapeutic approach for advanced PCa.

Aberrant expression of Sec61α in esophageal cancers Abstract Introduction The heterotrimeric Sec61α translocon complex is topological located in the membrane of the endoplasmic reticulum (ER) and allows protein transport and calcium across the membrane. Recently, aberrant expression of Sec proteins was linked to carcinogenesis and prognosis of patients. Materials and methods Here, we analysed the role of Sec61α in esophageal cancer, and we analysed Sec61α staining on a tissue microarray containing more than 600 esophageal cancer specimens by immunohistochemistry. Results Sec61α staining was always strong in benign esophagus, but was only found in 5% of interpretable esophageal adenocarcinomas (EACs) and 14.5% of squamous cell carcinomas (ESCCs). Reduced Sec61α staining was not strongly linked to tumor phenotype in both subgroups of esophageal cancers and was unrelated to clinical outcome of patients (EACs: p = 0.8051 and ESCCs: p = 0.2751). Conclusions Thus, Sec61α measurement has not an additional prognostic benefit for the patients.

Association of glutathione- S -transferase p1 gene promoter methylation and the incidence of prostate cancer: a systematic review and meta-analysis Abstract Objective Some studies have shown that the methylation status of the GSTP1 gene promoter is related to the incidence of prostate cancer, but this finding is still controversial. The aim of this study was to evaluate the association between glutathione-S-transferase p1 (GSTP1) promoter methylation and the incidence of prostate cancer. Methods The Medline, Embase, Web of Science, and Cochrane CENTRAL databases were searched from their inception to February 22, 2019. According to the inclusion criteria, studies of the association between the methylation status of the GSTP1 gene promoter and prostate cancer were included. The difference in the incidence of GSTP1 promoter methylation in tissues, blood, or urine between patients with prostate cancer and those without prostate cancer were compared, and the results were expressed as the odds ratio (OR) and 95% confidence interval (CI). The pooled OR of each study was estimated using a fixed-effects model or a random-effects model to generate forest plots. Results Ultimately, 15 studies (1540 samples) were included. The estimated effect from our meta-analysis showed that the incidence of GSTP1 promoter methylation was higher in patients with prostate cancer than in those without prostate cancer (OR 18.58, 95% CI 9.60–35.95, P = 0.000). GSTP1 promoter methylation was highly correlated with the incidence of prostate cancer. Conclusions Methylation of the GSTP1 promoter may increase the risk of prostate cancer. This study may provide a strategic direction for prostate cancer research. Pending validation of these findings, the methylation of the GSTP1 promoter may be a potential biomarker to diagnose prostate cancer.

RRx-001 protects normal tissues but not tumors via Nrf2 induction and Bcl-2 inhibition Abstract Background RRx-001, a minimally toxic next-generation checkpoint inhibitor that targets myeloid suppressor cells in the tumor microenvironment, has also been shown to protect normal tissues from the cytotoxic effects of chemotherapy and radiation. The following experiments were carried out to determine whether the cytoprotective functions of RRx-001 in normal cells were operative in tumor cells. Design The effects of RRx-001 on normal cells, and ovarian cancer A2780 and UWB1 cells were evaluated with a colony-forming assay. Western blot densitometry was used to measure Nrf2 nuclear translocation in Caco2 cells after exposure to RRx-001. Following incubation with RRx-001, levels of the antioxidant, NQO1, were determined in Caco2 cells by measuring absorbance over 300 min at 440 nm. RRx-001-mediated cytotoxicity in HCT-116 colorectal cancer cells was evaluated with an MTT assay. In addition, the effect of RRx-001 incubation on the protein expression of Nrf2, PARP, cleaved PARP, procaspases 3, 8, and 9, Bcl-2, and Bax in HCT-116 colorectal cells was determined by western blot analysis. Results RRx-001 is demonstrated to induce Nrf2 in normal tissues, mediating protection, and to downregulate the Nrf2-controlled antiapoptotic target gene, B-cell lymphoma 2 (Bcl-2) in tumors, mediating cytotoxicity. Conclusion Through Nrf2 induction in normal cells and inhibition of Bcl-2 in tumor cells, RRx-001 selectively protects normal cells against lethality in normal cells, but induces apoptosis in tumor cells.

Human papillomavirus and lung cancer: an overview and a meta-analysis Abstract Purpose This review is devoted to assessing the prevalence of human papillomavirus (HPV) in lung cancer (LC) in the world. HPV is recognized as the etiological factor of cervical cancer, however, there is widespread evidence that this virus is detected not only in gynecological carcinomas, but also in tumors of other organs, in particular the upper respiratory tract and digestive tract. Materials and methods  A search was conducted to a depth of 29 years in the PubMed, Web of Science, Scopus, databases. The review includes 95 articles. Results Of all the analyzed studies (9195 patients), 12 works showed a complete absence of HPV in the biological material in patients with LC. The absence of a virus among lung cancer patients has been established for Canada, the Netherlands and Singapore. The highest average percent of occurrence of this virus is shown for such countries as: Brazil, Korea, Greece and Taiwan (more than 40%). But the highest percentage of HPV occurrence by region is observed in Latin America (33.5%), followed by the Asian countries (31%), in European countries the frequency is 18%. Interestingly, the highest occurrence of high oncogenic types (16 and 18) is observed in Asia (40.3%), then in Latin America (33.6%), Europe (25.6%) and North America (15.4%). Low-oncogenic types (6 and 11) are also predominantly observed in Asia (39.9%), while in Europe and North America 30% and 12.8%, respectively. A meta-analysis of the prevalence of HPV was conducted using Comprehensive Meta-Analysis 3.0. Program, which included 26 studies, the results of which revealed: the prevalence of HPV infection in tumor lung tissue was compared with normal lung tissue OR (95% CI) = 5.38 (3.21–9.00) p < 0.0001, significance was also found for Chinese studies OR = 6.3, 95% CI 3.42–11.53, p < 0.0001, I2 = 71.8% and for nine studies in Europe OR = 6.3, 95% CI 1.8–22.18, p = 0.004, I2 = 51.0%. However, given the fact that the frequency of occurrence of HPV in lung tumor tissue varies greatly, a question may arise about the real role of HPV in LC carcinogenesis, which makes further research relevant and promising.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Endocrine

LncRNA MCM3AP-AS1 promotes proliferation and invasion through regulating miR-211-5p/SPARC axis in papillary thyroid cancer Abstract Background Long non-coding RNAs (lncRNAs) are an emerging class of regulators in cancer. A lncRNA, MCM3AP-AS1, has been demonstrated as a versatile mediator in many cancers, except papillary thyroid cancer. The aim of this study is to investigate the role and mechanism of MCM3AP-AS1 in papillary thyroid cancer. Methods Quantitative real-time PCR was used to assess the level of MCM3AP-AS1 and miR-211-5p in papillary thyroid cancer tissues and cells. Western blot was used to detect E-cadherin and secreted protein acidic and cysteine rich (SPARC) protein levels. CCK-8, scratch wound assay, and transwell assay were used to evaluate papillary thyroid cancer cell proliferation, migration, and invasion, respectively. BLAST alignment and luciferase assay were used to explore the interaction among MCM3AP-AS1, mi/r-211, and SPARC. Results In papillary thyroid cancer, MCM3AP-AS1 was upregulated, while miR-211 was downregulated. MCM3AP-AS1 overexpression promoted papillary thyroid cancer proliferation, migration, and invasion. Further, MCM3AP-AS1 was shown to be negatively correlated with miR-211-5p. We next validated that miR-211-5p overexpression could reverse the promoting role of MCM3AP-AS1 in papillary thyroid cancer, whereby SPARC plays an important regulating role. In vivo, we confirmed the anti-tumor role of MCM3AP-AS1 silencing and the close relation among MCM3AP-AS1, miR-211-5p, and SPARC. Conclusions MCM3AP-AS1 promotes papillary thyroid cancer by regulating the MCM3AP-AS1/miR-211-5p/SPARC axis, which could potentially be a therapeutic target in papillary thyroid cancer.

Extended cycle streptozotocin/5-FU chemotherapy for maintenance therapy in pancreatic neuroendocrine tumors Abstract Purpose The standard of care treatment for patients with advanced pancreatic neuroendocrine tumors (pNET) is a combination of streptozotocin and 5-FU. Although widely used, little is known about the best long-term strategy with these substances. Methods We here report our experience of 28 patients treated with streptozotocin/5-FU for advanced pNET with special consideration for long-term management using an extended cycle protocol. Results Standard 6-weekly Moertel protocol resulted in a median progression-free survival of 21 months (range 3–128) and a median overall survival of 69 months (range 3–157+) in the whole cohort. Thirteen of the 28 patients were switched to an extended 3-month cycle protocol for maintenance therapy. Of these 13 patients, 2 achieved complete remission, 1 partial remission, and 8 stable disease as best response while 2 showed progressive disease following switch to the extended protocol, resulting in an additional median progression-free survival of 23 months. Median overall survival after the start of chemotherapy in this patient group was 69 months (21–157+). Patients benefitted from extended periods free of chemotherapy-associated side effects after switching to the extended cycle protocol. Conclusions Switching to an extended cycle protocol of 3 months for maintenance therapy following initial standard cycles may achieve long-term disease stabilization in selected patients with advanced pNET with good patient acceptance.

Impact of adrenomedullin blockage on lipid metabolism in female mice exposed to high-fat diet Abstract Purpose Adrenomedullin (ADM) levels are elevated in gestational and type 2 diabetic patients. ADM also stimulates lipolysis in vitro. Disturbed lipid metabolism has been implicated in the pathogenesis of diabetes. Here, we explore whether blockade of ADM is beneficial for metabolic homeostasis in a diabetic mouse model. Methods C57BL/6J female mice were placed on either a control or a high fat high sucrose (HFHS) diet for 8 weeks. At week 4, osmotic mini-pumps were implanted for constant infusion of either saline or ADM antagonist, ADM22–52. Glucose tolerance tests were performed prior to infusion and 4 weeks after infusion began. Animals were then sacrificed and visceral adipose tissue collected for further analysis. Results Mice fed HFHS displayed glucose intolerance, increased mRNA expressions in VAT for Adm and its receptor components, Crlr. HFHS fed mice also had increased basal and isoprenaline-induced glycerol release by VAT explants. ADM22–52 did not significantly affect glucose intolerance. ADM22–52 did suppress basal and isoprenaline-induced glycerol release by VAT explants. This alteration was associated with enhanced mRNA expression of insulin signaling factors Insr and Glut4, and adipogenic factor Pck1. Conclusions HFHS diet induces glucose intolerance and enhances ADM and its receptor expressions in VAT in female mice. ADM22–52 treatment did not affect glucose intolerance in HFHS mice, but reduced both basal and isoprenaline-induced lipolysis, which is associated with enhanced expression of genes involved in adipogenesis. These results warrant further research on the effects of ADM blockade in improving lipid homeostasis in diabetic patients.

Relationship between metabolic syndrome and thyroid nodules and thyroid volume in an adult population Abstract Purpose The effects of metabolic syndrome (MetS) on thyroid nodules (TN) and thyroid volume (TV), especially the related gender and age disparities, are controversial. In this study, we aimed to assess the relationships between MetS and TN and TV in an adult population. Methods This cross-sectional study was performed in an adult population in Tianjin. A total of 2606 subjects were enrolled. TV and TN were measured by thyroid ultrasonography. Blood samples were collected to measure biochemical and metabolic parameters. Results The prevalence of TN was significantly higher in the MetS (+) group than in the MetS (−) group (P < 0.0001). MetS was independently associated with increased TN risk (OR: 1.24, 95% CI: 1.01–1.51). When stratified by gender, MetS was associated with higher prevalence of TN in males (OR: 1.38, 95% CI: 1.05–1.81) compared with females (OR: 1.02, 95% CI: 0.75–1.39). However, the interaction effect of gender and MetS on TN was not statistically significant (Pfor interaction = 0.94). MetS was associated with the greater risks of TN in both the <60-year-old group (OR: 1.32, 95% CI: 1.05–1.68) and the ≥60-year-old group (OR: 1.84, 95% CI: 1.24–2.73), while the OR value was significantly higher in the elderly group (P for interaction = 0.03). Additionally, TV was significantly higher in subjects with TN (β = 1.94, P < 0.0001) and MetS (β = 0.94, P = 0.0037). Conclusions This study suggested positive relationships between MetS and an increased risk of TN and enlarged TV. Elderly people (≥60 years old) with MetS were associated with a higher risk of TN than younger people (<60 years old). The effect of MetS on TN was not significantly affected by gender.

SDHx -related pheochromocytoma/paraganglioma – genetic, clinical, and treatment outcomes in a series of 30 patients from a single center Abstract Purpose Germline mutations in the four genes that encode the succinate dehydrogenase complex (SDHx) are a risk factor for developing pheochromocytomas and/or paragangliomas. The precise genotype–phenotype correlations are still uncertain and the most common SDHx genetic defects in the Portuguese population are poorly described. The objectives of our study were to characterize the genetic alterations, clinical features, and treatment outcomes of a cohort of SDHx-related pheochromocytomas and/or paragangliomas patients. Methods Single center, retrospective analysis based on the presence of a SDHx mutation in cases diagnosed from 1986 until October 2016. Results Thirty cases were included. The mean age at diagnosis was 36.8 years (±15.4 years) and 53.3% were females. Remission was observed in 33.3% and stable disease (including partial responses) in 53.0%. SDHC and SDHD patients were prone to develop single and multiple head and neck paragangliomas, respectively. SDHB patients carried an increased risk of malignancy. Deletions in SDHB exon-1 and in SDHD exon-4 were the most common genetic findings. SDHB patients and head and neck paragangliomas had the worse prognosis, the former related to malignancy, and the latter to cranial nerve deficits, unresectable disease, and multimodality interventions. Peptide receptor radionuclide therapy and radioactive iodine MIBG therapy proved to be ineffective. Radiotherapy represented a good alternative in unresectable head and neck paragangliomas and in bone metastases. Conclusion This single center study is the most complete Portuguese cohort in the literature and helps to understand the behavior of tumors based on their genotype and anatomical location.

Genetic analysis of adult Slovenian patients with combined pituitary hormone deficiency Abstract Purpose Among genetic causes of combined pituitary hormone deficiency (CPHD), mutations of genes coding for transcription factors involved in pituitary development have been implicated. Congenital CPHD is a rare disease; therefore, it is important to expand the knowledge about incidence and regional distribution of specific mutations. The aim of this paper is to report results of genetic analyses of adult Slovenian patients with CPHD. Methods Twenty-three adult Slovenian patients with early childhood onset CPHD were included in the study. Blood samples were collected through the GENHYPOPIT network to assess possible mutations of six genes (PROP1/HESX1/LHX4/LHX3/POU1F1) involved in the pituitary development following an established algorithm. Results In seven out of 23 patients (30%) a specific mutation in genes encoding pituitary transcription factors was discovered. In five patients, two different mutations of the PROP1 gene (c.150delA and c.301-302delAG) were identified. One patient was heterozygous for a missense variant in the LHX4 gene. Additionally, one patient was positive for a mutation in the gene coding for prokineticin receptor-2. Conclusions Our study confirms that the two most common mutations of the PROP1 gene globally are also the most frequent mutations in the cohort of adult Slovenian patients with CHPD. Other mutations of pituitary transcription factor genes are extremely rare.

Copeptin relates to a fatty liver and measures of obesity in a South African population with mixed ethnicities Abstract Purpose Elevated copeptin, a vasopressin marker, is linked to metabolic disease, and obese rats with low-vasopressin concentration had a decreased risk of liver steatosis. We here investigated the association between copeptin and nonalcoholic fatty liver disease (NAFLD) and possible differences in copeptin concentration between ethnicities. Methods In this cross-sectional study of 361 South Africans (n = 172 African black, 189 = Caucasian) with a mean age of 45 years and 45% men, plasma copeptin was measured and associated with NAFLD according to a validated fatty liver index accounting for measures of BMI, waist, triglycerides, and gamma-glutamyltransferase. Results There was no significant difference in copeptin concentrations between ethnicities after age and gender adjustment (p = 0.24). Increasing copeptin tertile levels were significantly associated with obesity, overweight, and abdominal obesity, respectively, after multivariate adjustment for age, gender, ethnicity, and high HOMA-IR (p = 0.02 for all). Individuals in the second and third copeptin tertile had an increased odds (95% CI) of NAFLD of 1.77 (1.04–3.02) and 2.97 (1.74–5.06), respectively, compared to the bottom tertile (p < 0.001). The association between increasing copeptin tertile and NAFLD remained significant after adjustment for age, gender, ethnicity, high HOMA-IR, self-reported current alcohol intake, and statin treatment (p = 0.01). Conclusions Elevated plasma copeptin is independently associated with NAFLD in a population with mixed ethnicities, pointing at the pharmacologically modifiable vasopressin system as a new mechanism behind NAFLD.

True MEN1 or phenocopy? Evidence for geno-phenotypic correlations in MEN1 syndrome Abstract Purpose Multiple endocrine neoplasia type 1 is a rare tumor syndrome caused by germline mutations of MEN1 gene. Phenotype varies widely, and no definitive correlation with the genotype has been observed. Mutation-negative patients with MEN1-associated tumors represent phenocopies. By comparing mutation-positive and mutation-negative patients, we aimed to identify phenotype features predictive for a positive genetic test and to evaluate the role of MEN1mutations in phenotype modulation. Methods Mutation screeening of MEN1 gene by Sanger sequencing and assessment of clinical data of 189 consecutively enrolled probands and relatives were performed at our national and European Reference Center. Multiple ligation probe amplification analysis of MEN1 gene and Sanger sequencing of CDKN1B were carried out in clinically suspicious but MEN1-negative cases. Results Twenty-seven probands and twenty family members carried MEN1 mutations. Five mutations have not been described earlier. Pronouncedly high number of phenocopies (>70%) was observed. Clinical suspicion of MEN1 syndrome emerged at significantly earlier age in MEN1-positive compared to MEN1-negative probands. Gastroenteropancreatic neuroendocrine tumors developed significantly earlier and more frequently in carriers compared to non-carriers. Probands with high-impact (frameshift, nonsense, large deletions) mutations, predicted to affect menin function significantly, developed GEP-NETs more frequently compared to low-impact (inframe and missense) mutation carriers. Conclusions MEN1 phenocopy is common and represents a significant confounder for the genetic testing. GEP-NET under 30 years best predicted a MEN1 mutation. The present study thus confirmed a previous proposal and suggested that GEP-NET under 30 years should be considered as a part of the indication criteria for MEN1 mutational analysis.

High-intensity focused ultrasound (HIFU) for benign thyroid nodules: 2-year follow-up results Abstract Background High-intensity focused ultrasound (HIFU) is the last introduced thermal treatment of thyroid nodules. Here we evaluated the results at 24 months after HIFU. Methods Since 2016, HIFU was considered as a therapeutic option at our institute in patients with benign thyroid nodules presenting local symptoms. We searched in our database all patients who had undergone thyroid HIFU and selected for the study only cases followed-up for at least 24 months after the treatment. Volume reduction rate (VRR) was evaluated. A reduction above 50% defined the success of HIFU. Results Thirty-one nodules of 31 patients (24 females and 7 males, median age 67 years) with median major diameter from 17 to 34 mm and estimated nodule volume of 5.48 mL were included. HIFU was performed with median power of 42 W/site (interquartile range 25–45) and median energy of 263 J/site (interquartile range 225–273). Median duration of the procedure was 6 min (interquartile range 5–7). At 2 years after HIFU, nodule volume was significantly (p < 0.0001) lower (i.e., 3.40 mL) with VRR of 43.3%, and 26 (83.9%) lesions were reduced. A reduction by at least 50% was observed at 6, 12, and 24 months in 2 (6.4%), 5 (16.1%), and 7 (22.5%) nodules, respectively. Visual analog score showed a significant improvement (p < 0.0001). No complications were recorded. Conclusions A reduction of benign thyroid nodule by more than 40% could be reached within 1 year by HIFU. Given the non-significant size increase of some lesions later, a larger study with a longer follow-up is necessary.

Abnormal expression of Pappa2 gene may indirectly affect mouse hip development through the IGF signaling pathway Abstract Introduction Developmental dysplasia of the hip (DDH) is a major cause of disability in children, and the genetic mechanism of this disease remains unclear. In our previous study, we found that pregnancy-associated plasma protein-A2 (PAPP-A2) was associated with DDH significantly. Objectives The aim of this study was to investigate the insulin-like growth factor (IGF) expression and collagen synthesis as well as cartilage proliferation-related proteins in the case of abnormal expression of Pappa2 in mice to research the relationship between PAPP-A2 and the pathological changes of DDH. Methods In vivo animal experiments, the mice were directly injected with 50 µl of Cas9/PAPP-A2 sgRNA lentiviruses around the hip to downregulate the Pappa2 gene expression and injected with control lentiviruses on the other side, then to observe the expression and localization of related proteins. And in an in vitro experiment, mice fibroblasts and primary chondrocytes were cultured with insulin-like growth factor binding protein-5 (IGFBP-5) protein, PAPP-A2 protein and Cas9/PAPP-A2 sgRNA lentiviruses to detect of related proteins and mRNA expression. Results Cartilage proliferation-related proteins demonstrated a significant decrease in the PAPP-A2 knockdown hips acetabulum and femoral head cartilage, meanwhile the IGF expression was also downregulated in the soft tissue around the acetabulum compared with the control hips. Furthermore, the role PAPP-A2 played in chondrocytes and fibroblasts was the same as in the in vivo experiments, downregulation of PAPP-A2 expression or upregulation of IGFBP-5 expression can reduce collagen synthesis and cartilage proliferation. Conclusions PAPP-A2 may be involved in the development of the mouse hip joint by interfering the fibrous and cartilaginous metabolism via IGF pathway-associated proteins pathway.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com