Amyloid-ß and caspase-1 are indicators of sepsis and organ injury.

Background: Sepsis is a life-threatening condition that results from a dysregulated host response to infection, leading to organ dysfunction. Despite the prevalence and associated socioeconomic costs, treatment of sepsis remains limited to antibiotics and supportive care, and a majority of intensive care unit (ICU) survivors develop long-term cognitive complications post-discharge. The present study identifies a novel regulatory relationship between amyloid-ß (Aß) and the inflammasome-caspase-1 axis as key innate immune mediators that define sepsis outcomes. Methods: Medical ICU patients and healthy individuals were consented for blood and clinical data collection. Plasma cytokine, caspase-1 and Aß levels were measured. Data were compared against indices of multiorgan injury and other clinical parameters. Additionally, recombinant proteins were tested in vitro to examine the effect of caspase-1 on a functional hallmark of Aß, namely aggregation. Results: Plasma caspase-1 levels displayed the best predictive value in discriminating ICU patients with sepsis from non-infected ICU patients (area under the receiver operating characteristic curve=0.7080). Plasma caspase-1 and the Aß isoform Aßx-40 showed a significant positive correlation and Aßx-40 associated with organ injury. Additionally, Aß plasma levels continued to rise from time of ICU admission to 7 days post-admission. In silico, Aß harbours a predicted caspase-1 cleavage site, and in vitro studies demonstrated that caspase-1 cleaved Aß to inhibit its auto-aggregation, suggesting a novel regulatory relationship. Conclusions: Aßx-40 and caspase-1 are potentially useful early indicators of sepsis and its attendant organ injury. Additionally, Aßx-40 has emerged as a potential culprit in the ensuing development of post-ICU syndrome.

Key stakeholders' perspectives: A gap analysis of hospital-acquired pressure injuries.

INTRODUCTION: Hospital-acquired pressure injuries (HAPIs) are a global high-stakes patient safety issue. Key stakeholder perspectives regarding their role and experiences with pressure injuries is critical as part of the solution to minimizing HAPI occurrence and attain sustainability. DESIGN: A qualitative, descriptive approach provided multiple perspectives of key stakeholders to support the complexity of HAPI care. The qualitative data are a part of a mixed method convergent research study examining pressure injury prevention and management practices. METHODS: Nursing system theory, mixed method convergent design, and participatory action research methodologies were chosen to address both the gap analysis development and results, achieve collaborative comprehensiveness, and enable key stakeholder involvement throughout this HAPI prevention and management initiative. Participants were recruited and enrolled from a large Level I trauma hospital and the key stakeholders. Demographic information were collected prior to the individual interview. Focused interviews were conducted virtually using zoom technology. Qualitative data were analyzed using NVivo software and thematic analysis was confirmed across the co-investigators for congruence and applicability to the research questions. RESULTS: Qualitative interviews with 26 key stakeholders provided data to support and integrate a link with gap analysis results on the complex health issue of HAPIs. Specific barrier and recommendation themes identified interventions that could be prioritized. The 52 barrier and 52 recommendation themes/sub-theme(s) respectively were organized by Donabedian (structure, process, and outcome) with structure elements the majority. The top three structure barrier themes involved equipment and standards for use, staff prevention education, and specialized health professionals. The top three structure recommendation themes involved specialized health professionals, equipment and standards for use, and an educational plan for those at risk or with HAPIs. CONCLUSION: The article provides findings from the qualitative portion of a mixed method study related to HAPIs. The qualitative findings associated with the gap analysis quantitative results, achieved the goal of the participatory action research key stakeholders' input into HAPI care and can be replicated internationally. CLINICAL RELEVANCE: The benefit of key stakeholder's involvement in solving a clinical problem is sustainability. A quantitative approach and integrating qualitative stakeholders' perspectives provide an in-depth solution that will advance nursing capacity toward health care delivery and HAPI nursing science and policy development on a global level.

Arterial stiffness mediates the association between age and processing speed at low levels of microvascular function in humans across the adult lifespan.

The function of micro- and macrovessels within the peripheral vasculature has been identified as a target for the investigation of potential cardiovascular-based promoters of cognitive decline. However, little remains known regarding the interaction of the micro- and macrovasculature as it relates to cognitive function, especially in cognitively healthy individuals. Therefore, our purpose was to unravel peripheral factors that contribute to the association between age and processing speed. Ninety-nine individuals (51 men, 48 women) across the adult life span (19-81 yr) were used for analysis. Arterial stiffness was quantified as carotid-femoral pulse-wave velocity (cfPWV) and near-infrared spectroscopy assessed maximal tissue oxygenation (Sto2max) following a period of ischemia. Processing speed was evaluated with Trail Making Test (TMT) Parts A and B. Measures of central (cPP) and peripheral pulse pressure (pPP) were also collected. Moderated mediation analyses were conducted to determine contributions to the age and processing speed relation, and first-order partial correlations were used to assess associations while controlling for the linear effects of age. A P ≤ 0.05 was considered statistically significant. At low levels of Sto2max, there was a significant positive (b = 1.92; P = 0.005) effect of cfPWV on time to completion on TMT part A. In addition, cPP (P = 0.028) and pPP (P = 0.027) remained significantly related to part A when controlling for age. These results suggested that the peripheral microvasculature may be a valuable target for delaying cognitive decline, especially in currently cognitively healthy individuals. Furthermore, we reinforced current evidence that pulse pressure is a key endpoint for trials aimed at preventing or delaying the onset of cognitive decline.NEW & NOTEWORTHY Arterial stiffness partially mediates the association between age and processing speed in the presence of low microvascular function, as demarcated by maximum tissue oxygenation following ischemia. Central and peripheral pulse pressure remained associated with processing speed even after controlling for age. Our findings were derived from a sample that was determined to be cognitively healthy, which highlights the potential for these outcomes to be considered during trials aimed at the prevention of cognitive decline.

Women's perceptions of body mass graphics and their preferences for weight counselling.

Health care providers may lack data-driven guidance about best practises for discussing weight. We assessed women's self-perception of body mass index (BMI) and preferences for weight counselling by provider characteristics and the initiating question. A voluntary, anonymous survey was completed by 756 women (age ≥ 19 year) at our tertiary care obstetrics and gynaecology clinics in autumn 2021. The respondents' height and weight were collected before respondents selected graphics from a validated Body Image Scale that they felt best represented their current body size and which graphs should prompt weight loss or gain recommendations. Respondents were asked their preferences about provider characteristics for discussion about weight and to identify which of six initiating questions from a provider was most and least preferred. Blank responses were allowed. In 708 responses, 366 women (52%) selected the most accurate graphic that corresponded to their BMI; the selected graphic represented a lower than actual BMI in 268 women (38%) and higher in 74 women (10%). In 648 responses, 374 women (58%) preferred a female provider, but provider body shape, ethnicity/race and age were not important to most women. The most preferred question to initiate a discussion about weight was "A lot of women have trouble achieving or maintaining a healthy weight; is that something we can discuss?" in 181 of 555 women (33%), and the least preferred question was "Do you feel like you are at an appropriate weight?" in 172 of 554 women (31%). Provider knowledge about patient preferences regarding questions may facilitate the discussion about weight.

A Quality Improvement Project: Implementation of the Centers for Disease Control and Prevention's Hepatitis C Virus Treatment Guidelines at an Addiction Treatment Center.

PURPOSE: This quality improvement project was introduced at an addiction treatment center to implement the Centers for Disease Control and Prevention's (CDC's) hepatitis C virus (HCV) treatment guidelines and offer anticraving medications to patients to improve standards of care of patients with substance use disorders. LITERATURE REVIEW: Patients with opioid use disorders are at the highest risk of contracting HCV. More than 80% of people in the United States with opioid use disorders who use intravenous drugs have contracted HCV. Despite the high prevalence of HCV, patients at treatment centers are being screened only for HCV antibodies (HCV-AB) and are not receiving the CDC's HCV treatment guidelines. The CDC has treatment recommendations of hepatitis panels, full STD testing, and early follow-up care. METHOD: This quality improvement project utilized the Plan-Do-Study-Act tool. With the application of Plan-Do-Study-Act, for patients identified with HCV-AB, the established CDC HCV treatment guidelines were followed, and the clinical progress of the implementation of the guidelines was monitored. Chart reviews comparing compliance of guidelines before and after the study were implemented. PARTICIPANTS: A convenience sample of 125 patients were collected, and of these, 32 patients were found to be HCV-AB+. FINDINGS: The findings revealed that 18.75% of patients followed the CDC's HCV recommendations after the quality improvement project compared with 6.25% of patients before the intervention. The number of HIV testing offered increased by 40.00% as a result of the implementation of the project.

Effect of Bariatric Surgery on Plasma Cell-Free Mitochondrial DNA, Insulin Sensitivity and Metabolic Changes in Obese Patients.

While improvement of mitochondrial function after bariatric surgery has been demonstrated, there is limited evidence about the effects of bariatric surgery on circulatory cell-free (cf) mitochondrial DNA (mtDNA) and intracellular mtDNA abundance. Plasma and peripheral blood mononuclear (PBM) cells were isolated from healthy controls (HC) and bariatric surgery patients before surgery and 2 weeks, 3 months, and 6 months after surgery. At baseline, the plasma level of short cf-mtDNA (ND6, ~100 bp) fragments was significantly higher in obese patients compared to HC. But there was no significant variation in mean ND6 values post-surgery. A significant positive correlation was observed between preop plasma ND6 levels and HgbA1c, ND6 and HOMA-IR 2 weeks post-surgery, and mtDNA content 6 months post-surgery. Interestingly, plasma from both HC and obese groups at all time points post-surgery contains long (~8 kb) cf-mtDNA fragments, suggesting the presence of near-intact and/or whole mitochondrial genomes. No significant variation was observed in mtDNA content post-surgery compared to baseline data in both PBM and skeletal muscle samples. Overall, bariatric surgery improved insulin sensitivity and other metabolic parameters without significant changes in plasma short cf-mtDNA levels or cellular mtDNA content. Our study provides novel insights about possible molecular mechanisms underlying the metabolic effects of bariatric surgery and suggests the development of new generalized approaches to characterize cf-mtDNA.

Pressure Injury Prevention and Management: A Gap Analysis Using Key Stakeholder Engagement.

PURPOSE: The purpose of this study was to examine pressure injury prevention and management (PIPM) practices in an academic acute care setting. Specific aims were to (1) develop and examine key stakeholder engagement regarding PIPM practices, (2) develop a valid/reliable gap analysis instrument, and (3) conduct a gap analysis of current PIPM practices. DESIGN: Mixed-methods convergent design and participatory action research. SUBJECTS AND SETTING: A nurse-led council (Council) of key stakeholders from a large academic university healthcare setting was developed. The gap analysis was conducted in a southern gulf coast level I trauma academic acute care hospital in the Southeastern United States. METHODS: A multidisciplinary key stakeholder Council with 27 members was developed to accomplish study aims using the participatory action research approach to train, promote, and foster key stakeholder engagement in all aspects of the research process. The Pressure Injury Prevention Gap Analysis Instrument (PIPGAI) was developed and psychometrically tested. A gap analysis of PIPM practices across a level I trauma academic acute care hospital was conducted using the PIPGAI. RESULTS: The PIPGAI was developed using 2019 Pressure Ulcer/Injury Clinical Practice Guideline recommendations, an integrative literature review/appraisal, a concept map, and Council input. The overall PIPGAI content validity index of 0.95 demonstrated excellent content validity. The individual item content validity index scores ranged from 0.62 to1.0. Low-scoring items (0.62-0.75) were deleted or revised. Interrater reliability was demonstrated by percentage of agreement (62%-79%). Using a modified Delphi approach, items of disagreement were summarized and discussed until 100% consensus was achieved. A gap analysis of PIPM practices was conducted resulting in a cumulative score of 267/553 (48%), indicating gaps in PIPM practices. Fifty (73%) items had content present; 37 of 58 (64%) items had minimal detail, and 36 of 58 (62%) items were difficult or required notable effort to accomplish. Fifty items (63%) had a total score of 4 or less and were identified as a gap (range: 0-7). CONCLUSIONS: The main outcome of this study was an innovative and evidence-based gap analysis process. The study provides (1) a model for key stakeholder engagement, (2) a valid/reliable gap analysis instrument, and (3) a method to evaluate PIPM practices.

Pilot Study of Respiratory-Swallow Coordination in Amyotrophic Lateral Sclerosis.

PURPOSE: Amyotrophic lateral sclerosis (ALS) impacts bulbar and respiratory musculature, which may contribute to impaired swallow function (dysphagia) and respiratory-swallow coordination. The purpose of this pilot study was to examine if respiratory-swallow coordination in individuals with ALS was perturbed compared to healthy controls. We further explored relationships between measures of respiratory function and self-reported swallowing outcomes on respiratory-swallow coordination. METHOD: We employed a cross-sectional design with eight participants with ALS and eight age- and sex-matched healthy participants. Respiratory inductance plethysmography and a nasal cannula were used to capture respiratory-swallow phase patterns during a standardized clinical swallow examination. The advantageous respiratory-swallow phase pattern was defined if exhalation surrounded the swallow (E-E). Spirometry was used to capture indices of respiratory function (forced vital capacity % predicted, peak cough flow [PCF]). Validated questionnaires were used to collect information regarding ALS-related bulbar functional status and swallowing-related concerns. RESULTS: Compared to the matched healthy cohort, individuals with ALS demonstrated higher rates of non-E-E respiratory-swallow phase patterning and worse bulbar/swallow dysfunction. Group (ALS), swallow tasks, and PCF were significantly associated with respiratory-swallow phase pattern. CONCLUSIONS: These preliminary findings support altered respiratory-swallow phase patterning in ALS. Future work should employ an instrumental assessment to quantify swallowing physiology and elucidate the relationship between perturbed respiratory-swallow coordination and swallowing function.

Review of Outcomes of Low Verses Standard Pressure Pneumoperitoneum in Laparoscopic Surgery.

BACKGROUND: Carbon dioxide pneumoperitoneum during laparoscopy changes cardiorespiratory physiology and contributes to post-op pain. We studied outcomes before and after implementing low-pressure pneumoperitoneum QI project. METHODS: Forty-two patients were insufflated at standard pressures (15 mmHg) while 41 were insufflated using low (8-12 mmHg) during laparoscopic procedures. These variables were obtained from the patient chart: pain scores, intravenous morphine milligram equivalents (MME), peak inspiratory pressures (PIP), end-tidal CO2 (EtCO2), surgery duration, and patient demographics. The study was conducted after IRB approval. RESULTS: Low-pressure pneumoperitoneum is feasible and the surgeon can increase to 10-12 mmHg as needed. The mean post-op IV MME was significantly decreased in the low-pressure group (11.75 ± 10.41) compared to the standard pressure group (17.36 ± 18.1) (t-test, P = .047). Mean peak inspiratory pressures during insufflation were significantly higher for procedures conducted at standard pressure (31.40 ± 4.82) compared to the 8 mmHg (24.68 ± 4.19) and 12 mmHg (27.33± 3.85) low pressure groups (one-way ANOVA, P < .0001). During insufflation, there was a significant increase in the average EtCO2 in the standard pressure group (42.07 ± 5.60) compared to the 8 mmHg low pressure group (37.59 ± 5.05) (ANOVA, P = .0096). Constant flow insufflation was more likely to be performed at low pressure than demand mode (58% v. 33%). CONCLUSION: Low pressure pneumoperitoneum decreases PIP pressure and CO2 absorption evidenced by lower ETCO2 intra-operatively. Patients have significant improvement in postoperative pain evidenced by decreased narcotics needed. Low pressure pneumoperitoneum using a constant flow insufflator is safe and results in improved patient outcomes.

Ostomy Complications and Quality of Life of Ostomy Support Belt/Garment Wearers: A Web-Based Survey.

PURPOSE: The purpose of this study was to examine ostomy complications and health-related quality of life (QOL) in individuals with an ostomy who wear an ostomy support belt/garment. DESIGN: A mixed-methods descriptive study. SUBJECTS AND SETTING: Two hundred two community-living adults with an ostomy were recruited using an industry distribution list. The target sample had no geographic restrictions. METHODS: Descriptive analysis was conducted for all outcomes. Participants were separated into groups depending on type of ostomy belt or belt/garment worn or none. All categorical data were summarized using percentages and numerical data using mean ± standard deviation. Association between categorical factors was evaluated using a χ2 test and proportions of occurrences from 2 groups were compared using a 2-proportion z-test. The mean outcomes for 2 or more groups were compared using t tests or analysis of variance (ANOVA), respectively. If ANOVA showed difference among groups, post hoc analysis of group means was conducted using Tukey's Honestly Significant Difference (HSD) test. RESULTS: Two hundred two respondents completed the survey. Of the 174 participants who responded to the survey question on leakage, 157 (90%) reported experiencing leakage and 135 (77.59%) reported rash or skin irritation. Comparison of whether participants had ever experienced a leakage event was not significantly different across groups (P = .3663). Those who wore an ostomy support belt/garment reported leakage less often (less than once a month) versus respondents who wore other types of belts or no belt (n = 49, 73.13% vs n = 53, 59.55%; P = .0388). Of the 174 participants who responded to the peristomal skin question, 135 (77.59%) participants reported peristomal skin complications. Significantly fewer participants who wore an ostomy support belt/garment reported having peristomal skin irritation compared to those who wore other types of belts or no belt (69.01% vs 84.16%; P = .0080). The mean cumulative total City of Hope Quality of Life (COH QOL) Ostomy score for all participants was 6.45 ± 1.36 out of 10, with the psychosocial domain scoring the lowest at 5.67 ± 1.30 out of 10. No significant differences were observed in mean QOL domain and total scores by those who wore an ostomy support belt/garment, other type of belt/garment, and none. When comparing COH QOL mean scores and leakage frequency of more/less once a month, those who reported leakage more often had significantly worse QOL scores in all 4 domains as well as total scores: physical (P = .0008), psychological (P = .0154), social (P = .0056), spiritual (P = .0376), and total COH QOL score (P = .0018). CONCLUSION: This study provides important information related to ostomy complications and QOL associated with wearing an ostomy belt or belt/garment. The use of an ostomy support belt/garment may offer an additional intervention to decrease frequency of leakage and peristomal skin irritation and improve QOL.

The Influence of the Psychophysical Assessment Paradigm on Pitch Discrimination for Adults (and a Pilot Sample of Children).

Pitch discrimination ability has been of research interest due to its potential relationship to language and literacy. However, assessment protocols for pitch discrimination have varied widely. Prior studies with both children and adults have produced conflicting performance findings across different pitch discrimination research paradigms, though they have consistently shown that discrimination accuracy is based on the psychophysical assessment method applied. In the present study, we examined pitch discrimination performance among convenience samples of 19 adult women and ten female children across six different adaptive psychophysical measurement conditions. We found pitch discrimination performance in both groups to be impacted by the measurement paradigm such that, while adults exhibited significantly better discrimination thresholds than did children, the pattern of performance across the six conditions was similar for both the adults and the children.

Clinical and Hematological Predictors of High-Grade Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors.

BACKGROUND: Life-threatening immune-related adverse events (irAEs) that require hospital admission are not uncommon in patients treated with immune checkpoint inhibitors (ICIs). The clinical and hematological parameters are attractive biomarkers as potential predictors of irAE. METHODS: This is a retrospective study of patients with melanoma and lung cancer treated with ICIs between 2015 and 2019 at the University of South Alabama Mitchell Cancer Institute. Fisher's exact test, Pearson Chi-squared test, log-rank test, and Cox proportional hazard model were used to evaluate clinical and hematological parameters as possible predictors of irAE. RESULTS: The cohort consisted of 160 patients treated with at least two doses of ICI, of which 54 (33.8%) patients had melanoma and 106 (66.3%) had lung cancer. Incidence of irAE did not have any bearing on the overall survival (OS) or progression-free survival (PFS) of the cohort. The clinical factors associated with irAE were dual-agent therapy (ipilimumab/nivolumab combination) and high disease burden (≥ 2 metastatic sites). The irAE-group had a lower mean platelet-to-lymphocyte ration (PLR, 200 vs. 257, P = 0.04). Although not statistically significant at the level of 0.05, other factors such as type of cancer (lung cancer > melanoma (P = 0.06)), stage at treatment (stage IV > stage II and III disease (P = 0.06)), and higher absolute lymphocyte counts (P = 0.07) showed a considerable association with irAE and warrants further review with different patient data. CONCLUSIONS: Irrespective of ICI used to treat lung cancer and melanoma, patients with high disease burden and dual-agent ICI therapy were more prone to irAE. The only hematological parameter that may predict the incidence of irAE is low baseline PLR.

Effect of Covid-19 quarantine on diabetes Care in Children.

BACKGROUND: With the onset of the COVID-19 pandemic and state-mandated school closures in the spring of 2020, the management of type 1 diabetes in children underwent significant changes. The aim of our study was to assess the effect of stay-at-home orders on glycemic control in children. METHODS: We conducted a retrospective review of 238 children with type 1 and type 2 diabetes who were seen in the Pediatric Endocrinology Clinic at the University of South Alabama. Average Hemoglobin A1c (A1c) levels in the year prior to stay-at home orders (May 2019-April 2020) were compared with A1c values during the quarantine period (May 2020-July 2020) using a paired t-test. We also analyzed the change of A1c level with respect to sex, race, type of diabetes, type of insurance, and mode of insulin administration, using a 2-sample t-test. RESULTS: The average A1c significantly increased from 9.2% during the previous year to 9.5% during the quarantine period (p = 0.0097). The increase of A1c was significantly higher in public insurance patients (0.49% increase) compared to private insurance patients (0.03% increase), (p = 0.0137). We also observed a significant association between the direction of change and type of insurance. Forty-eight percent of public insurance patients had an A1c increase of > 0.5% while 54% of private insurance patients had no change or decrease in A1c (p = 0.0079). CONCLUSIONS: The COVID-19 pandemic resulted in worsening glycemic control in children with type 1 diabetes, with those on public insurance affected in greater proportion than those with private insurance.

Nurse's Achilles Heel: Using Big Data to Determine Workload Factors That Impact Near Misses.

PURPOSE: To explore how big data can be used to identify the contribution or influence of six specific workload variables: patient count, medication count, task count call lights, patient sepsis score, and hours worked on the occurrence of a near miss (NM) by individual nurses. DESIGN: A correlational and cross-section research design was used to collect over 82,000 useable data points of historical workload data from the three unique systems on a medical-surgical unit in a midsized hospital in the southeast United States over a 60-day period. Data were collected prior to the start of the Covid-19 pandemic in the United States. METHODS: Combined data were analyzed using JMP Pro version 12. Mean responses from two groups were compared using a t-test and those from more than two groups using analysis of variance. Logistic regression was used to determine the significance of impact each workload variable had on individual nurses' ability to administer medications successfully as measured by occurrence of NMs. FINDINGS: The mean outcome of each of the six workload factors measured differed significantly (p < .0001) among nurses. The mean outcome for all workload factors except the hours worked was found to be significantly higher (p < .0001) for those who committed an NM compared to those who did not. At least one workload variable was observed to be significantly associated (p < .05) with the occurrence or nonoccurrence of NMs in 82.6% of the nurses in the study. CONCLUSIONS: For the majority of the nurses in our study, the occurrence of an NM was significantly impacted by at least one workload variable. Because the specific variables that impact performance are different for each individual nurse, decreasing only one variable, such as patient load, will not adequately address the risk for NMs. Other variables not studied here, such as education and experience, might be associated with the occurrence of NMs. CLINICAL RELEVANCE: In the majority of nurses, different workload variables increase their risk for an NM, suggesting that interventions addressing medication errors should be implemented based on the individual's risk profile.

Efficacy and Safety of Full-thickness Resection Device (FTRD) for Colorectal Lesions Endoscopic Full-thickness Resection: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Endoscopic full-thickness resection (eFTR) is a field of increasing interest that offers a minimally invasive resection modality for lesions that are not amenable for resection by conventional methods. Full-thickness resection device (FTRD) is a new device that was developed for a single-step eFTR using an over-the scope-clip. In this meta-analysis, we aim to assess the efficacy and safety of FTRD for eFTR of colorectal lesions. METHODS: A Comprehensive literature review of different databases to identify studies reporting FTRD with outcomes of interest was performed. Studies with <10 cases were excluded. Rates of histologic complete resection (R0), technical success, and complications were extracted. Efficacy was assessed by using the technical and the R0 rates whereas safety was assessed by using the complications rates. Weighted pooled rates (WPRs) and the 95% confidence interval (CI) were calculated depending on the heterogeneity (I2 statistics). RESULTS: Nine studies including 551 patients with 555 lesions were included in this study. The WPR for overall R0 was 82.4% (95% CI: 79.0%-85.5%),with moderate heterogeneity (I2=34.8%). The WPR rate for technical success was 89.25% (95% CI: 86.4%-91.7%), with low heterogeneity (I2=23.7%). The WPR for total complications rate was 10.2% (7.8, 12.8%) with no heterogeneity. The pooled rate for minor bleeding, major bleeding, postpolypectomy syndrome, and perforation were 3.2%, 0.97%, 2.2%, and 1.2%, respectively. Of 44 periappendicular lesions, the pooled rate for acute appendicitis was 19.7%. CONCLUSIONS: FTRD seems to be effective and safe for eFTR of difficult colorectal lesions. Large prospective studies comparing FTRD with conventional resection techniques are warranted.

Enhanced Mitochondrial DNA Repair Resuscitates Transplantable Lungs Donated After Circulatory Death.

BACKGROUND: Transplantation of lungs procured after donation after circulatory death (DCD) is challenging because postmortem metabolic degradation may engender susceptibility to ischemia-reperfusion (IR) injury. Because oxidative mitochondrial DNA (mtDNA) damage has been linked to endothelial barrier disruption in other models of IR injury, here we used a fusion protein construct targeting the DNA repair 8-oxoguanine DNA glycosylase-1 (OGG1) to mitochondria (mtOGG1) to determine if enhanced repair of mtDNA damage attenuates endothelial barrier dysfunction after IR injury in a rat model of lung procurement after DCD. MATERIALS AND METHODS: Lungs excised from donor rats 1 h after cardiac death were cold stored for 2 h after which they were perfused ex vivo in the absence and presence of mt-OGG1 or an inactive mt-OGG1 mutant. Lung endothelial barrier function and mtDNA integrity were determined during and at the end of perfusion, respectively. RESULTS AND CONCLUSIONS: Mitochondria-targeted OGG1 attenuated indices of lung endothelial dysfunction incurred after a 1h post-mortem period. Oxidative lung tissue mtDNA damage as well as accumulation of proinflammatory mtDNA fragments in lung perfusate, but not nuclear DNA fragments, also were reduced by mitochondria-targeted OGG1. A repair-deficient mt-OGG1 mutant failed to protect lungs from the adverse effects of DCD procurement. CONCLUSIONS: These findings suggest that endothelial barrier dysfunction in lungs procured after DCD is driven by mtDNA damage and point to strategies to enhance mtDNA repair in concert with EVLP as a means of alleviating DCD-related lung IR injury.

Deficiency of tumor suppressor Merlin facilitates metabolic adaptation by co-operative engagement of SMAD-Hippo signaling in breast cancer.

The NF2 gene encodes the tumor and metastasis suppressor protein Merlin. Merlin exerts its tumor suppressive role by inhibiting proliferation and inducing contact-growth inhibition and apoptosis. In the current investigation, we determined that loss of Merlin in breast cancer tissues is concordant with the loss of the inhibitory SMAD, SMAD7, of the TGF-ß pathway. This was reflected as dysregulated activation of TGF-ß signaling that co-operatively engaged with effectors of the Hippo pathway (YAP/TAZ/TEAD). As a consequence, the loss of Merlin in breast cancer resulted in a significant metabolic and bioenergetic adaptation of cells characterized by increased aerobic glycolysis and decreased oxygen consumption. Mechanistically, we determined that the co-operative activity of the Hippo and TGF-ß transcription effectors caused upregulation of the long non-coding RNA Urothelial Cancer-Associated 1 (UCA1) that disengaged Merlin's check on STAT3 activity. The consequent upregulation of Hexokinase 2 (HK2) enabled a metabolic shift towards aerobic glycolysis. In fact, Merlin deficiency engendered cellular dependence on this metabolic adaptation, endorsing a critical role for Merlin in regulating cellular metabolism. This is the first report of Merlin functioning as a molecular restraint on cellular metabolism. Thus, breast cancer patients whose tumors demonstrate concordant loss of Merlin and SMAD7 may benefit from an approach of incorporating STAT3 inhibitors.