Real-time performance improvement optimizes damage control resuscitation best practice adherence: Results of a pilot prospective observational study.

BACKGROUND: Maintaining balanced blood product ratios during damage control resuscitation (DCR) is independently associated with improved survival. We hypothesized that real-time performance improvement (RT-PI) would increase adherence to DCR best practice. STUDY DESIGN AND METHODS: From December 2020-August 2021, we prospectively used a bedside RT-PI tool to guide DCR in severely injured patients surviving at least 30 min. RT-PI study patients were compared to contemporary control patients at our institution and historic PROMMTT study patients. A subset of patients transfused ≥6 U red blood cells (RBC) in 6 h (MT+) was also identified. The primary endpoint was percentage time in a high ratio range (≥3:4) of plasma (PLAS):RBC and platelet (PLT):RBC over 6 h. Secondary endpoints included time to massive transfusion protocol activation, time to calcium and tranexamic acid (TXA) dosing, and cumulative 6-h ratios. RESULTS: Included patients (n = 772) were 35 (24-51) years old with an Injury Severity Score of 27 (17-38) and 42% had penetrating injuries. RT-PI (n = 10) patients spent 96% of the 6-h resuscitation in a high PLAS:RBC range, no different versus CONTROL (n = 87) (96%) but more than PROMMTT (n = 675) (25%, p < .001). In the MT+ subgroup, optimal PLAS:RBC and PLT:RBC were maintained for the entire 6 h in RT-PI (n = 4) versus PROMMTT (n = 391) patients for both PLAS (p < .001) and PLT ratios (p < .001). Time to TXA also improved significantly in RT-PI versus CONTROL patients (27 min [22-31] vs. 51 min [29-98], p = .035). CONCLUSION: In this prospective study, RT-PI was associated with optimized DCR. Multicenter validation of this novel approach to optimizing DCR implementation is warranted.

Hospital nurses' moral distress and mental health during COVID-19.

AIMS: To explore factors associated with nurses' moral distress during the first COVID-19 surge and their longer-term mental health. DESIGN: Cross-sectional, correlational survey study. METHODS: Registered nurses were surveyed in September 2020 about their experiences during the first peak month of COVID-19 using the new, validated, COVID-19 Moral Distress Scale for Nurses. Nurses' mental health was measured by recently experienced symptoms. Analyses included descriptive statistics and regression analysis. Outcome variables were moral distress and mental health. Explanatory variables were frequency of COVID-19 patients, leadership communication and personal protective equipment/cleaning supplies access. The sample comprised 307 nurses (43% response rate) from two academic medical centres. RESULTS: Many respondents had difficulty accessing personal protective equipment. Most nurses reported that hospital leadership communication was transparent, effective and timely. The most distressing situations were the transmission risk to nurses' family members, caring for patients without family members present, and caring for patients dying without family or clergy present. These occurred occasionally with moderate distress. Nurses reported 2.5 days each in the past week of feeling anxiety, withdrawn and having difficulty sleeping. Moral distress decreased with effective communication and access to personal protective equipment. Moral distress was associated with longer-term mental health. CONCLUSION: Pandemic patient care situations are the greatest sources of nurses' moral distress. Effective leadership communication, fewer COVID-19 patients, and access to protective equipment decrease moral distress, which influences longer-term mental health. IMPACT: Little was known about the impact of COVID-19 on nurses' moral distress. We found that nurses' moral distress was associated with the volume of care for infected patients, access to personal protective equipment, and communication from leaders. We found that moral distress was associated with longer-term mental health. Leaders should communicate transparently to decrease nurses' moral distress and the negative effects of global crises on nurses' longer-term mental health.

Systematic Debriefing for Critical Events Facilitates Team Dynamics, Education, and Process Improvement.

BACKGROUND: Debriefing is used in clinical settings to support interprofessional staff, improve processes, and identify educational needs. Nurses who lead debriefing sessions are empowered to improve processes. PROBLEM: Nurse leaders identified the need for debriefing outside the critical care areas due to the rising acuity levels. APPROACH: Two nurse leaders developed a debriefing initiative in one urban teaching hospital following rapid responses, codes, and stressful situations. Nurses developed a Debriefing Facilitation Guide to collect qualitative aspects of clinical emergencies to improve processes, education, and team dynamics. OUTCOMES: Following each debriefing session, we deductively purposively coded the qualitative data into 3 a priori themes: the American Heart Association's team dynamics, process improvement, and educational opportunities. We identified opportunities for improvement for these themes during our first 54 debriefing sessions. CONCLUSIONS: Following each debriefing session, the debriefing nurse leader intervened on all educational and process improvement opportunities identified and facilitated positive team dynamics.

Association of Nurse Engagement and Nurse Staffing on Patient Safety.

BACKGROUND: Nurse engagement is a modifiable element of the work environment and has shown promise as a potential safety intervention. PURPOSE: Our study examined the relationship between the level of engagement, staffing, and assessments of patient safety among nurses working in hospital settings. METHODS: A secondary analysis of linked cross-sectional data was conducted using survey data of 26 960 nurses across 599 hospitals in 4 states. Logistic regression models were used to examine the association between nurse engagement, staffing, and nurse assessments of patient safety. RESULTS: Thirty-two percent of nurses gave their hospital a poor or failing patient safety grade. In 25% of hospitals, nurses fell in the least or only somewhat engaged categories. A 1-unit increase in engagement lowered the odds of an unfavorable safety grade by 29% (P < .001). Hospitals where nurses reported higher levels of engagement were 19% (P < .001) less likely to report that mistakes were held against them. Nurses in poorly staffed hospitals were 6% more likely to report that important information about patients "fell through the cracks" when transferring patients across units (P < .001). CONCLUSIONS: Interventions to improve nurse engagement and adequate staffing serve as strategies to improve patient safety.

Increasing Research Capacity in a Safety Net Setting Through an Academic Clinical Partnership.

Safety net settings care for a disproportionate share of low-resource patients often have fewer resources to invest in nursing research. To address this dilemma, an academic-clinical partnership was formed in an effort to increase nursing research capacity at a safety net setting. Penn Presbyterian Medical Center and the Center for Health Outcomes and Policy Research located at the University of Pennsylvania partnered researchers and baccalaureate-prepared nurses in an 18-month research skill development program. This article describes the programmatic design, conceptual framework, resource requirements, and effect on the institutional partners and participants.

Unmet Nursing Care Linked to Rehospitalizations Among Older Black AMI Patients: A Cross-Sectional Study of US Hospitals.

BACKGROUND: Recent studies suggest that nurses may be unable to complete all aspects of necessary care due to a lack of time. Research is needed to determine whether unmet nursing care contributes to disparities in readmissions for vulnerable populations. OBJECTIVES: To examine differences in the relationship between nursing care left undone and acute myocardial infarction readmissions among older black patients compared with older white patients. RESEARCH DESIGN: Cross-sectional analysis of multiple datasets, including: 2006 to 2007 administrative discharge data, a survey of registered nurses, and the American Hospital Association Annual Survey. Risk-adjusted logistic regression models were used to estimate the association between care left undone and 30-day readmission. Interactions were used to examine the moderating effect of care left undone on readmission by race. RESULTS: The sample included 69,065 patients in 253 hospitals in California, New Jersey, and Pennsylvania. Older black patients were 18% more likely to experience a readmission after adjusting for patient and hospital characteristics and more likely to be in hospitals where nursing care was often left undone. Black patients were more likely to be readmitted when nurses were unable to talk/comfort patients [odds ratio (OR), 1.09; 95% confidence interval (CI), 1.01-1.19], complete documentation (OR, 1.16; 95% CI, 1.01-1.32), or administer medications in a timely manner (OR, 1.26; 95% CI, 1.09-1.46). CONCLUSIONS: Unmet nursing care is associated with readmissions for older black patients following acute myocardial infarction. Investment in nursing resources to improve the delivery of nursing care may decrease disparities in readmission.

Phenotypic heterogeneity is a selected trait in natural yeast populations subject to environmental stress.

Populations of genetically uniform microorganisms exhibit phenotypic heterogeneity, where individual cells have varying phenotypes. Such phenotypes include fitness-determining traits. Phenotypic heterogeneity has been linked to increased population-level fitness in laboratory studies, but its adaptive significance for wild microorganisms in the natural environment is unknown. Here, we addressed this by testing heterogeneity in yeast isolates from diverse environmental sites, each polluted with a different principal contaminant, as well as from corresponding control locations. We found that cell-to-cell heterogeneity (in resistance to the appropriate principal pollutant) was prevalent in the wild yeast isolates. Moreover, isolates with the highest heterogeneity were consistently observed in the polluted environments, indicating that heterogeneity is positively related to survival in adverse conditions in the wild. This relationship with survival was stronger than for the property of mean resistance (IC(50)) of an isolate. Therefore, heterogeneity could be the major determinant of microbial survival in adverse conditions. Indeed, growth assays indicated that isolates with high heterogeneities had a significant competitive advantage during stress. Analysis of yeasts after cultivation for ≥ 500 generations additionally showed that high heterogeneity evolved as a heritable trait during stress. The results showed that environmental stress selects for wild microorganisms with high levels of phenotypic heterogeneity.

Heterogeneous expression of the virulence-related adhesin Epa1 between individual cells and strains of the pathogen Candida glabrata.

We investigated the relevance of gene expression heterogeneity to virulence properties of a major fungal pathogen, Candida glabrata. The organism's key virulence-associated factors include glycosylphosphatidylinositol-anchored adhesins, encoded subtelomerically by the EPA gene family. Individual-cell analyses of expression revealed very striking heterogeneity for Epa1, an adhesin that mediates ∼95% of adherence to epithelial cells in vitro. The heterogeneity in Epa1 was markedly greater than that known for other yeast genes. Sorted cells expressing high or low levels of Epa1 exhibited high and low adherence to epithelial cells, indicating a link between gene expression noise and potential virulence. The phenotypes of sorted subpopulations reverted to mixed phenotypes within a few generations. Variation in single-cell Epa1 protein and mRNA levels was correlated, consistent with transcriptional regulation of heterogeneity. Sir-dependent transcriptional silencing was the primary mechanism driving heterogeneous Epa1 expression in C. glabrata BG2, but not in CBS138 (ATCC 2001). Inefficient silencing in the latter strain was not due to a difference in EPA1 sequence or (sub)telomere length and was overcome by ectopic SIR3 expression. Moreover, differences between strains in the silencing dependence of EPA1 expression were evident across a range of clinical isolates, with heterogeneity being the greatest in strains where EPA1 was subject to silencing. The study shows how heterogeneity can impact the virulence-related properties of C. glabrata cell populations, with potential implications for microbial pathogenesis more broadly.

The Lived Experience of Persons With Malignant Pleural Mesothelioma in the United States.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare but deadly cancer. Although there is an emerging picture of the individual MPM experience, the United States is underrepresented in this literature. With the United States contributing more deaths from MPM than any other country, findings from this study will enhance a global body of literature on the lived experience of this devastating cancer. OBJECTIVE: The aims of this descriptive phenomenological research study were to explore the lived experience of MPM in the United States and identify unmet patient needs. INTERVENTIONS/METHODS: This was a descriptive phenomenology study employing semi-structured individual interviews with persons with MPM. RESULTS: A total of 7 persons with MPM from a large northeastern US medical center participated. Three major themes about the MPM lived experience emerged: (1) uncertainty/worry about the future, (2) value in relationships, and (3) adapting to a new norm. CONCLUSIONS: Findings from this study are consistent with other MPM research, noting a high symptom burden, lifestyle changes, and feelings of uncertainty about the future. However, participants also expressed feelings of hope and optimism. Particularly salient to the MPM experience was the role of communication with the healthcare team as well as other persons with MPM. IMPLICATIONS FOR PRACTICE: Timely, coordinated, and personalized care as well as skilled communication should be the cornerstone of care for persons with MPM. Supportive care strategies that address uncertainty, the high symptom burden, feelings of isolation, and existential concerns are also integral to quality care.

Teaching Evidence-Based Sepsis Care: A Sepsis Escape Room.

BACKGROUND: Using evidence-based sepsis guidelines, nurse educators identified the nursing skills required to recognize and treat sepsis. METHOD: Nurse educators created an innovative, interactive sepsis escape room to provide sepsis education. The escape room included a manikin, puzzles, distractors, riddles, and props. Participants were given 20 minutes to solve four puzzles/riddles to treat the sepsis patient and escape the room. RESULTS: All but two (N = 16) groups solved the clues and riddles to prioritize treatment in the allotted time. Evaluations were excellent. Mean score (1 = poor to 5 = outstanding) for overall escape room experience was 4.92. Adherence data improved on the Surviving Sepsis Campaign sepsis performance measure intervention bundles (SEP 1-3 care bundles) 2 months following the escape room. Bundles are a group of interventions that improve care. CONCLUSION: The escape room engaged nurses in educational gaming, stimulating critical thinking and problem solving contributing to improved clinical outcomes. [J Contin Educ Nurs. 2021;52(5):217-225.].

Optimizing a decision support system for damage-control resuscitation using mixed methods human factors analysis.

BACKGROUND: Damage-control resuscitation (DCR) improves trauma survival; however, consistent adherence to DCR principles through multiple phases of care has proven challenging. Clinical decision support may improve adherence to DCR principles. In this study, we designed and evaluated a DCR decision support system using an iterative development and human factors testing approach. METHODS: The phases of analysis included initial needs assessment and prototype design (Phase 0), testing in a multidimensional simulation (Phase 1), and testing during initial clinical use (Phase 2). Phase 1 and Phase 2 included hands-on use of the decision support system in the trauma bay, operating room, and intensive care unit. Participants included trauma surgeons, trauma fellows, anesthesia providers, and trauma bay and intensive care unit nurses who provided both qualitative and quantitative feedback on the initial prototype and all subsequent iterations. RESULTS: In Phase 0, 14 (87.5%) of 16 participants noted that they would use the decisions support system in a clinical setting. Twenty-four trauma team members then participated in simulated resuscitations with decision support where 178 (78.1%) of 228 of tasks were passed and 27 (11.8%) were passed with difficulty. Twenty-three (95.8%) completed a postsimulation survey. Following iterative improvements in system design, Phase 2 evaluation included 21 trauma team members during multiple real-world trauma resuscitations. Of these, 15 (71.4%) completed a formal postresuscitation survey. Device-level feedback on a Likert scale (range, 0-4) confirmed overall ease of use (median score, 4; interquartile range, 4-4) and indicated the system integrated well into their workflow (median score, 3; interquartile range, 2-4). Final refinements were then completed in preparation for a pilot clinical study using the decision support system. CONCLUSIONS: An iterative development and human factors testing approach resulted in a clinically useable DCR decision support system. Further analysis will determine its applicability in military and civilian trauma care. LEVEL OF EVIDENCE: Therapeutic/Care Management, Level V.

Staying on target: Maintaining a balanced resuscitation during damage-control resuscitation improves survival.

BACKGROUND: Damage-control resuscitation (DCR) improves survival in severely bleeding patients. However, deviating from balanced transfusion ratios during a resuscitation may limit this benefit. We hypothesized that maintaining a balanced resuscitation during DCR is independently associated with improved survival. METHODS: This was a secondary analysis of the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study. Patients receiving >3 U of packed red blood cells (PRBCs) during any 1-hour period over the first 6 hours and surviving beyond 30 minutes were included. Linear regression assessed the effect of percent time in a high-ratio range on 24-hour survival. We identified an optimal ratio and percent of time above the target ratio threshold by Youden's index. We compared patients with a 6-hour ratio above the target and above the percent time threshold (on-target) with all others (off-target). Kaplan-Meier analysis assessed the combined effect of blood product ratio and percent time over the target ratio on 24-hour and 30-day survival. Multivariable logistic regression identified factors independently associated with 24-hour and 30-day survival. RESULTS: Of 1,245 PROMMTT patients, 524 met the inclusion criteria. Optimal targets were plasma/PRBC and platelet/PRBC of 0.75 (3:4) and ≥40% time spent over this threshold. For plasma/PRBC, on-target (n = 213) versus off-target (n = 311) patients were younger (median, 31 years; interquartile range, [22-50] vs. 40 [25-54]; p = 0.002) with similar injury burdens and presenting physiology. Similar patterns were observed for platelet/PRBC on-target (n = 116) and off-target (n = 408) patients. After adjusting for differences, on-target plasma/PRBC patients had significantly improved 24-hour (odds ratio, 2.25; 95% confidence interval, 1.20-4.23) and 30-day (odds ratio, 1.97; 95% confidence interval, 1.14-3.41) survival, while on-target platelet/PRBC patients did not. CONCLUSION: Maintaining a high ratio of plasma/PRBC during DCR is independently associated with improved survival. Performance improvement efforts and prospective studies should capture time spent in a high-ratio range. LEVEL OF EVIDENCE: Epidemiologic/prognostic study, level II; Therapeutic, level IV.

The development of a novel grip motion analysis technique using the Dartfish movement analysis software to evaluate hand movements during activities of daily living.

Individuals with hand osteoarthritis (OA) have impairments in grip strength and range of motion (ROM). Obtaining quantitative joint angle measures of the hand is difficult. Without a complete understanding of the kinematics of the hand, the assessment of hand OA when performing activities of daily living (ADL) and recreational activities is not fully understood. The objectives of this study were to establish a simple measurement technique (Grip Configuration Model) describing an individual's grip ROM using the Dartfish Movement Analysis Software, and compare the joint angle measures during maximum flexion/extension and five ADL in people with/without hand OA. Forty participants (20 without hand OA, 20 with hand OA) thumb CMC and MCP, and index MCP and PIP joint angles were evaluated for each activity using the Dartfish Software and Grip Configuration Model. Significant limitations of 17.2% (p < 0.001) and 12.7% (p = 0.01) were seen in the group with hand OA for maximum flexion/extension, respectively. The spray bottle task demonstrated a significant difference of 14.7% (p = 0.001) between the two test groups. Measurements using the Dartfish Software were compared against a manual goniometer and electromagnetic tracking system. This study demonstrated the weakened ROM in individuals with hand OA is translated to ADL and how the Grip Configuration Model simplifies the evaluation of how people grasp objects.

Wearable strain gauge-based technology measures manual tactile forces during the activities of daily living.

INTRODUCTION: Current methods of determining applied forces in the hand rely on grip dynamometers or force-measurement gloves which are limited in their ability to isolate individual finger forces and interfere with the sense of touch. The objective of this study was to develop an improved force measurement system that could be used during various activities of daily living. METHODS: Custom-made strain gauge sensors were secured to the fingernail of four fingers and two middle phalanges and calibrated to measure hand forces in eight healthy individuals during five activities of daily living. RESULTS: These sensors were capable of measuring forces as small as 0.17 N and did not saturate at high force tasks around 15 N, which is within the envelope of forces experienced during daily life. Preliminary data demonstrate the ability of these tactile sensors to reliably distinguish which fingers/segments were used in various tasks. CONCLUSIONS: Until now, there has been no method for real-time unobtrusive monitoring of force exposure during the tasks of daily life. The system used in this study provides a new type of low-cost wearable technology to monitor forces in the hands without interfering with the contact surface of the hand.

Evidence based practice translated through global nurse partnerships.

This paper highlights the impact of translating evidence into practice between two nursing leaders, one from the United States and one from Botswana, Africa to strengthen global nurse partnerships, and to propose a plan to enhance nursing knowledge and skills. One of the challenges nurses face in under-resourced countries is the ability to collaborate with nurses who have access to professional development, evidence based practice, and nursing education resources.

Mitochondrial Ferredoxin Determines Vulnerability of Cells to Copper Excess.

The essential micronutrient copper is tightly regulated in organisms, as environmental exposure or homeostasis defects can cause toxicity and neurodegenerative disease. The principal target(s) of copper toxicity have not been pinpointed, but one key effect is impaired supply of iron-sulfur (FeS) clusters to the essential protein Rli1 (ABCE1). Here, to find upstream FeS biosynthesis/delivery protein(s) responsible for this, we compared copper sensitivity of yeast-overexpressing candidate targets. Overexpression of the mitochondrial ferredoxin Yah1 produced copper hyper-resistance. 55Fe turnover assays revealed that FeS integrity of Yah1 was particularly vulnerable to copper among the test proteins. Furthermore, destabilization of the FeS domain of Yah1 produced copper hypersensitivity, and YAH1 overexpression rescued Rli1 dysfunction. This copper-resistance function was conserved in the human ferredoxin, Fdx2. The data indicate that the essential mitochondrial ferredoxin is an important copper target, determining a tipping point where plentiful copper supply becomes excessive. This knowledge could help in tackling copper-related diseases.

Novel, Synergistic Antifungal Combinations that Target Translation Fidelity.

There is an unmet need for new antifungal or fungicide treatments, as resistance to existing treatments grows. Combination treatments help to combat resistance. Here we develop a novel, effective target for combination antifungal therapy. Different aminoglycoside antibiotics combined with different sulphate-transport inhibitors produced strong, synergistic growth-inhibition of several fungi. Combinations decreased the respective MICs by ≥8-fold. Synergy was suppressed in yeast mutants resistant to effects of sulphate-mimetics (like chromate or molybdate) on sulphate transport. By different mechanisms, aminoglycosides and inhibition of sulphate transport cause errors in mRNA translation. The mistranslation rate was stimulated up to 10-fold when the agents were used in combination, consistent with this being the mode of synergistic action. A range of undesirable fungi were susceptible to synergistic inhibition by the combinations, including the human pathogens Candida albicans, C. glabrata and Cryptococcus neoformans, the food spoilage organism Zygosaccharomyces bailii and the phytopathogens Rhizoctonia solani and Zymoseptoria tritici. There was some specificity as certain fungi were unaffected. There was no synergy against bacterial or mammalian cells. The results indicate that translation fidelity is a promising new target for combinatorial treatment of undesirable fungi, the combinations requiring substantially decreased doses of active components compared to each agent alone.

Psychosocial and Adaptive Deficits Associated With Learning Disability Subtypes.

Children with specific learning disabilities (SLD) have deficits in the basic psychological processes that interfere with learning and academic achievement, and for some SLD subtypes, these deficits can also lead to emotional and/or behavior problems. This study examined psychosocial functioning in 123 students, aged 6 to 11, who underwent comprehensive evaluations for learning and/or behavior problems in two Pacific Northwest school districts. Using concordance-discordance model (C-DM) processing strengths and weaknesses SLD identification criteria, results revealed working memory SLD (n = 20), processing speed SLD (n = 30), executive SLD (n = 32), and no disability groups (n = 41). Of the SLD subtypes, repeated measures MANOVA results revealed the processing speed SLD subtype exhibited the greatest psychosocial and adaptive impairment according to teacher behavior ratings. Findings suggest processing speed deficits may be behind the cognitive and psychosocial disturbances found in what has been termed "nonverbal" SLD. Limitations, implications, and future research needs are addressed.

The essential iron-sulfur protein Rli1 is an important target accounting for inhibition of cell growth by reactive oxygen species.

Oxidative stress mediated by reactive oxygen species (ROS) is linked to degenerative conditions in humans and damage to an array of cellular components. However, it is unclear which molecular target(s) may be the primary "Achilles' heel" of organisms, accounting for the inhibitory action of ROS. Rli1p (ABCE1) is an essential and highly conserved protein of eukaryotes and archaea that requires notoriously ROS-labile cofactors (Fe-S clusters) for its functions in protein synthesis. In this study, we tested the hypothesis that ROS toxicity is caused by Rli1p dysfunction. In addition to being essential, Rli1p activity (in nuclear ribosomal-subunit export) was shown to be impaired by mild oxidative stress in yeast. Furthermore, prooxidant resistance was decreased by RLI1 repression and increased by RLI1 overexpression. This Rlip1 dependency was abolished during anaerobicity and accentuated in cells expressing a FeS cluster-defective Rli1p construct. The protein's FeS clusters appeared ROS labile during in vitro incubations, but less so in vivo. Instead, it was primarily (55)FeS-cluster supply to Rli1p that was defective in prooxidant-exposed cells. The data indicate that, owing to its essential nature but dependency on ROS-labile FeS clusters, Rli1p function is a primary target of ROS action. Such insight could help inform new approaches for combating oxidative stress-related disease.

Chromate toxicity and the role of sulfur.

The molecular mode(s)-of-action of the toxic metal chromium has yet to be fully resolved. This Mini review focuses on interactions between chromate and sulfur in biological systems. Cr binds sulfur ligands, with cysteine and glutathione having the capacity to aggravate or ameliorate Cr toxicity. Competition between chromate and sulfate for uptake and in metabolism provokes sulfur starvation, which can be growth limiting. Recent data indicate that sulfur deficiency determines protein damage-related Cr toxicity, due to mRNA mistranslation caused by Cr-induced S limitation. Sulfur deprivation could contribute to additional aspects of Cr toxicity, including oxidative DNA damage and Cr related disease.