Graft dysfunction in compassionate use of genetically engineered pig-to-human cardiac xenotransplantation: a case report.

BACKGROUND: A genetically engineered pig cardiac xenotransplantation was done on Jan 7, 2022, in a non-ambulatory male patient, aged 57 years, with end-stage heart failure, and on veno-arterial extracorporeal membrane oxygenation support, who was ineligible for an allograft. This report details our current understanding of factors important to the xenotransplantation outcome. METHODS: Physiological and biochemical parameters critical for the care of all heart transplant recipients were collected in extensive clinical monitoring in an intensive care unit. To ascertain the cause of xenograft dysfunction, we did extensive immunological and histopathological studies, including electron microscopy and quantification of porcine cytomegalovirus or porcine roseolovirus (PCMV/PRV) in the xenograft, recipient cells, and tissue by DNA PCR and RNA transcription. We performed intravenous immunoglobulin (IVIG) binding to donor cells and single-cell RNA sequencing of peripheral blood mononuclear cells. FINDINGS: After successful xenotransplantation, the graft functioned well on echocardiography and sustained cardiovascular and other organ systems functions until postoperative day 47 when diastolic heart failure occurred. At postoperative day 50, the endomyocardial biopsy revealed damaged capillaries with interstitial oedema, red cell extravasation, rare thrombotic microangiopathy, and complement deposition. Increased anti-pig xenoantibodies, mainly IgG, were detected after IVIG administration for hypogammaglobulinaemia and during the first plasma exchange. Endomyocardial biopsy on postoperative day 56 showed fibrotic changes consistent with progressive myocardial stiffness. Microbial cell-free DNA testing indicated increasing titres of PCMV/PRV cell-free DNA. Post-mortem single-cell RNA sequencing showed overlapping causes. INTERPRETATION: Hyperacute rejection was avoided. We identified potential mediators of the observed endothelial injury. First, widespread endothelial injury indicates antibody-mediated rejection. Second, IVIG bound strongly to donor endothelium, possibly causing immune activation. Finally, reactivation and replication of latent PCMV/PRV in the xenograft possibly initiated a damaging inflammatory response. The findings point to specific measures to improve xenotransplant outcomes in the future. FUNDING: The University of Maryland School of Medicine, and the University of Maryland Medical Center.

Neurocognitive Dysfunction and Smaller Brain Volumes in Adolescents and Adults With a Fontan Circulation.

BACKGROUND: Neurocognitive outcomes beyond childhood in people with a Fontan circulation are not well defined. This study aimed to investigate neurocognitive functioning in adolescents and adults with a Fontan circulation and associations with structural brain injury, brain volumetry, and postnatal clinical factors. METHODS: In a binational study, participants with a Fontan circulation without a preexisting major neurological disability were prospectively recruited from the Australia and New Zealand Fontan Registry. Neurocognitive function was assessed by using Cogstate software in 107 participants with a Fontan circulation and compared with control groups with transposition of the great arteries (n=50) and a normal circulation (n=41). Brain MRI with volumetric analysis was performed in the participants with a Fontan circulation and compared with healthy control data from the ABIDE I and II (Autism Brain Imaging Data Exchange) and PING (Pediatric Imaging, Neurocognition, and Genetics) data repositories. Clinical data were retrospectively collected. RESULTS: Of the participants with a Fontan circulation who had a neurocognitive assessment, 55% were male and the mean age was 22.6 years (SD 7.8). Participants with a Fontan circulation performed worse in several areas of neurocognitive function compared with those with transposition of the great arteries and healthy controls (P<0.05). Clinical factors associated with worse neurocognitive outcomes included more inpatient days during childhood, younger age at Fontan surgery, and longer time since Fontan procedure (P<0.05). Adults with a Fontan circulation had more marked neurocognitive dysfunction than adolescents with a Fontan circulation in 2 domains (psychomotor function, P=0.01 and working memory, P=0.02). Structural brain injury was present in the entire Fontan cohort; the presence of white matter injury was associated with worse paired associate learning (P<0.001), but neither the presence nor severity of infarct, subcortical gray matter injury, and microhemorrhage was associated with neurocognitive outcomes. Compared with healthy controls, people with a Fontan circulation had smaller global brain volumes (P<0.001 in all regions) and smaller regional brain volumes in most cerebral cortical regions (P<0.05). Smaller global brain volumes were associated with worse neurocognitive functioning in several domains (P<0.05). A significant positive association was also identified between global brain volumes and resting oxygen saturations (P≤0.04). CONCLUSIONS: Neurocognitive impairment is common in adolescents and adults with a Fontan circulation and is associated with smaller gray and white matter brain volume. Understanding modifiable factors that contribute to brain injury to optimize neurocognitive function is paramount.

Management of People With a Fontan Circulation: a Cardiac Society of Australia and New Zealand Position statement.

The Fontan circulation describes the circulatory state resulting from an operation in congenital heart disease where systemic venous return is directed to the lungs without an intervening active pumping chamber. As survival increases, so too does recognition of the potential health challenges. This document aims to allow clinicians, people with a Fontan circulation, and their families to benefit from consensus agreement about management of the person with a Fontan circulation. The document was crafted with input from a multidisciplinary group of health care providers as well as individuals with a Fontan circulation and families. It is hoped that the shared common vision of long-term wellbeing will continue to drive improvements in care and quality of life in this patient population and eventually translate into improved survival. KEYPOINTS.

Definition of a COPD self-management intervention: International Expert Group consensus.

There is an urgent need for consensus on what defines a chronic obstructive pulmonary disease (COPD) self-management intervention. We aimed to obtain consensus regarding the conceptual definition of a COPD self-management intervention by engaging an international panel of COPD self-management experts using Delphi technique features and an additional group meeting.In each consensus round the experts were asked to provide feedback on the proposed definition and to score their level of agreement (1=totally disagree; 5=totally agree). The information provided was used to modify the definition for the next consensus round. Thematic analysis was used for free text responses and descriptive statistics were used for agreement scores.In total, 28 experts participated. The consensus round response rate varied randomly over the five rounds (ranging from 48% (n=13) to 85% (n=23)), and mean definition agreement scores increased from 3.8 (round 1) to 4.8 (round 5) with an increasing percentage of experts allocating the highest score of 5 (round 1: 14% (n=3); round 5: 83% (n=19)).In this study we reached consensus regarding a conceptual definition of what should be a COPD self-management intervention, clarifying the requisites for such an intervention. Operationalisation of this conceptual definition in the near future will be an essential next step.

Characteristics of effective self-management interventions in patients with COPD: individual patient data meta-analysis.

It is unknown whether heterogeneity in effects of self-management interventions in patients with chronic obstructive pulmonary disease (COPD) can be explained by differences in programme characteristics. This study aimed to identify which characteristics of COPD self-management interventions are most effective.Systematic search in electronic databases identified randomised trials on self-management interventions conducted between 1985 and 2013. Individual patient data were requested for meta-analysis by generalised mixed effects models.14 randomised trials were included (67% of eligible), representing 3282 patients (75% of eligible). Univariable analyses showed favourable effects on some outcomes for more planned contacts and longer duration of interventions, interventions with peer contact, without log keeping, without problem solving, and without support allocation. After adjusting for other programme characteristics in multivariable analyses, only the effects of duration on all-cause hospitalisation remained. Each month increase in intervention duration reduced risk of all-cause hospitalisation (time to event hazard ratios 0.98, 95% CI 0.97-0.99; risk ratio (RR) after 6 months follow-up 0.96, 95% CI 0.92-0.99; RR after 12 months follow-up 0.98, 95% CI 0.96-1.00).Our results showed that longer duration of self-management interventions conferred a reduction in all-cause hospitalisations in COPD patients. Other characteristics are not consistently associated with differential effects of self-management interventions across clinically relevant outcomes.

O2 pulse slope correlates with stroke volume during exercise in patients with a Fontan circulation.

BACKGROUND: Peak oxygen pulse (O2pulse=oxygen consumption/heart rate) is calculated by the product of stroke volume (SV) and oxygen extraction. It has been shown to be reduced in patients with a Fontan circulation. However, in the Fontan population, it may be a poor marker of SV. We propose that the slope of the O2 pulse curve may be more reflective of SV during exercise. METHODS: We analysed cardiopulmonary exercise test data in 22 subjects with a Fontan circulation (cohort A) and examined the association between peak SV during exercise (aortic flow measured on exercise cardiac MRI), and O2 pulse parameters (absolute O2 pulse and O2 pulse slopes up to anaerobic threshold (AT) and peak exercise). In a separate Fontan cohort (cohort B, n=131), associations between clinical characteristics and O2 pulse kinetics were examined. RESULTS: In cohort A, peak aortic flow was moderately and significantly associated with O2pulseslopePEAK (r=0.47, p=0.02). However, neither absolute O2pulseAT nor O2pulsePEAK was significantly associated with peak aortic flow. In cohort B, O2pulseslopePEAK and O2pulseslopeAT were not significantly associated with clinical parameters, apart from a weak association with forced vital capacity. CONCLUSION: The slope of the O2 pulse curve to peak exercise may be more reflective of peak SV in the Fontan population than a single peak O2 pulse value.

Overprediction of Carbapenemase-Containing Isolates by an Automated AST Instrument's Computer Algorithm.

BACKGROUND: The VITEK® 2 is generally accepted as a reliable method for predicting antibiotic resistance mechanisms including aminoglycoside phenotypes, beta lactam phenotypes, impermeability, and penicillinases. However, when it comes to predicting carbapenemases, the research that has been done is inconsistent in both methods and results. METHODS: We compared the predictions of the VITEK 2 and Advanced Expert System™ (AES) with the results of the modified carbapenemase inactivation method in an academic medical center lab to evaluate the clinical reliability of the VITEK 2 and AES in routine workflow for the detection of carbapenemases. RESULTS: Our findings show that the positive predictive value of carbapenemase detection on the VITEK2 and AES is 30.3% (91/300) in our patient population. CONCLUSIONS: In light of these results, we propose that the VITEK 2 and AES be used as a screening tool for carbapenemase-containing organisms rather than as a definitive test.

Adolescent individual, school, and neighborhood influences on young adult hypertension risk.

BACKGROUND: Geographic and contextual socioeconomic risk factors in adolescence may be more strongly associated with young adult hypertension than individual-level risk factors. This study examines the association between individual, neighborhood, and school-level influences during adolescence on young adult blood pressure. METHODS: Data were analyzed from the National Longitudinal Study of Adolescent to Adult Health (1994-1995 aged 11-18 and 2007-2008 aged 24-32). We categorized hypertension as systolic blood pressure ≥140 mm Hg and/or diastolic blood pressure ≥90 mm Hg. Secondary outcomes included continuous systolic and diastolic blood pressure. We fit a series of cross-classified multilevel models to estimate the associations between young adulthood hypertension with individual-level, school-level, and neighborhood-level factors during adolescence (i.e., fixed effects) and variance attributable to each level (i.e., random effects). Models were fit using Bayesian estimation procedures. For linear models, intra-class correlations (ICC) are reported for random effects. RESULTS: The final sample included 13,911 participants in 128 schools and 1,917 neighborhoods. Approximately 51% (7,111) young adults were hypertensive. Individual-level characteristics-particularly older ages, Non-Hispanic Black race, Asian race, male sex, BMI, and current smoking-were associated with increased hypertension. Non-Hispanic Black (OR = 1.21; 95% CI: 1.03-1.42) and Asian (OR = 1.28; 95% CI: 1.02-1.62) students had higher odds of hypertension compared to non-Hispanic White students. At the school level, hypertension was associated with the percentage of non-Hispanic White students (OR for 10% higher = 1.06; 95% CI: 1.01-1.09). Adjusting for individual, school, and neighborhood predictors attenuated the ICC for both the school (from 1.4 null to 0.9 fully-adjusted) and neighborhood (from 0.4 to 0.3). CONCLUSION: We find that adolescents' schools and individual-level factors influence young adult hypertension, more than neighborhoods. Unequal conditions in school environments for adolescents may increase the risk of hypertension later in life. Our findings merit further research to better understand the mechanisms through which adolescents' school environments contribute to adult hypertension and disparities in hypertension outcomes later in life.

Older age at Fontan completion is associated with reduced lung volumes and increased lung reactance.

BACKGROUND: Fontan patients have abnormal lung function, in particular restrictive lung disease and low diffusing capacity of carbon monoxide (DLCO). We sought to further characterise these abnormalities with detailed pulmonary function testing and examine associations with clinical parameters. METHODS: 132 Fontan patients across Australia and New Zealand underwent spirometry, with 126 subjects included in final analyses. Measurement of diffusion capacity (DLCO) including its components (alveolar volume (VA) and rate of uptake of CO (KCO)) and oscillometry (reactance (X5) and resistance (R5)) were assessed in a subset of Fontan patients (n = 44) and healthy controls (n = 12). Double diffusion (to assess diffusing capacity of nitric oxide (DLNO), capillary blood volume (Vc), alveolar capillary membrane function (DmCO)) was performed in Fontan patients (n = 18) and healthy controls (n = 12). RESULTS: FEV1 and FVC z-scores were low in Fontan subjects (mean - 1.67 ± 1.24 and - 1.61 ± 1.29, respectively) and correlated with exercise capacity. Compared to controls, z-scores for X5, DLCO, KCO, VA and DLNO were significantly lower in Fontan patients. R5, Vc and DmCO z-scores were preserved. X5 was associated with VA (r = 0.41,p = 0.009) and DmCO (r = 0.61,p = 0.008). Older age at Fontan completion was associated with lower z-scores for FEV1 (r = -0.46,p = 0.002), FVC (r = -0.47,p = 0.002), X5 (r = -0.32,p = 0.033) and VA (r = -0.36,p = 0.022). CONCLUSION: Fontan patients have a reduced DLCO which is largely driven by low VA. Lung stiffness (X5) is increased which is associated with VA and DmCO. These parameters negatively correlate with older age of Fontan completion suggesting that earlier Fontan completion may have a beneficial effect on lung function.

Postmortem Assessment of Olfactory Tissue Degeneration and Microvasculopathy in Patients With COVID-19.

Importance: Loss of smell is an early and common presentation of COVID-19 infection. Although it has been speculated that viral infection of olfactory neurons may be the culprit, it is unclear whether viral infection causes injuries in the olfactory bulb region. Objective: To characterize the olfactory pathology associated with COVID-19 infection in a postmortem study. Design, Setting, and Participants: This multicenter postmortem cohort study was conducted from April 7, 2020, to September 11, 2021. Deceased patients with COVID-19 and control individuals were included in the cohort. One infant with congenital anomalies was excluded. Olfactory bulb and tract tissue was collected from deceased patients with COVID-19 and appropriate controls. Histopathology, electron microscopy, droplet digital polymerase chain reaction, and immunofluorescence/immunohistochemistry studies were performed. Data analysis was conducted from February 7 to October 19, 2021. Main Outcomes and Measures: (1) Severity of degeneration, (2) losses of olfactory axons, and (3) severity of microvasculopathy in olfactory tissue. Results: Olfactory tissue from 23 deceased patients with COVID-19 (median [IQR] age, 62 [49-69] years; 14 men [60.9%]) and 14 control individuals (median [IQR] age, 53.5 [33.25-65] years; 7 men [50%]) was included in the analysis. The mean (SD) axon pathology score (range, 1-3) was 1.921 (0.569) in patients with COVID-19 and 1.198 (0.208) in controls (P < .001), whereas axon density was 2.973 (0.963) × 104/mm2 in patients with COVID-19 and 3.867 (0.670) × 104/mm2 in controls (P = .002). Concomitant endothelial injury of the microvasculature was also noted in olfactory tissue. The mean (SD) microvasculopathy score (range, 1-3) was 1.907 (0.490) in patients with COVID-19 and 1.405 (0.233) in control individuals (P < .001). Both the axon and microvascular pathology was worse in patients with COVID-19 with smell alterations than those with intact smell (mean [SD] axon pathology score, 2.260 [0.457] vs 1.63 [0.426]; P = .002; mean [SD] microvasculopathy score, 2.154 [0.528] vs 1.694 [0.329]; P = .02) but was not associated with clinical severity, timing of infection, or presence of virus. Conclusions and Relevance: This study found that COVID-19 infection is associated with axon injuries and microvasculopathy in olfactory tissue. The striking axonal pathology in some cases indicates that olfactory dysfunction in COVID-19 infection may be severe and permanent.

Disease management program for chronic obstructive pulmonary disease: a randomized controlled trial.

RATIONALE: The effect of disease management for chronic obstructive pulmonary disease (COPD) is not well established. OBJECTIVES: To determine whether a simplified disease management program reduces hospital admissions and emergency department (ED) visits due to COPD. METHODS: We performed a randomized, adjudicator-blinded, controlled, 1-year trial at five Veterans Affairs medical centers of 743 patients with severe COPD and one or more of the following during the previous year: hospital admission or ED visit for COPD, chronic home oxygen use, or course of systemic corticosteroids for COPD. Control group patients received usual care. Intervention group patients received a single 1- to 1.5-hour education session, an action plan for self-treatment of exacerbations, and monthly follow-up calls from a case manager. MEASUREMENTS AND MAIN RESULTS: We determined the combined number of COPD-related hospitalizations and ED visits per patient. Secondary outcomes included hospitalizations and ED visits for all causes, respiratory medication use, mortality, and change in Saint George's Respiratory Questionnaire. After 1 year, the mean cumulative frequency of COPD-related hospitalizations and ED visits was 0.82 per patient in usual care and 0.48 per patient in disease management (difference, 0.34; 95% confidence interval, 0.15-0.52; P < 0.001). Disease management reduced hospitalizations for cardiac or pulmonary conditions other than COPD by 49%, hospitalizations for all causes by 28%, and ED visits for all causes by 27% (P < 0.05 for all). CONCLUSIONS: A relatively simple disease management program reduced hospitalizations and ED visits for COPD. Clinical trial registered with www.clinicaltrials.gov (NCT00126776).

AccuO2 oximetry-driven oxygen-conserving device versus fixed-dose oxygen devices in stable COPD patients.

BACKGROUND: Because standard home oxygen (O2) systems deliver O2 at fixed rates, these systems are not designed to ensure optimal oxygen delivery based on physiologic need. We tested the ability of the AccuO2 (OptiSat Medical, Minneapolis, Minnesota), a portable, closed-loop, oximetry-driven, O2-conserving device to maintain SpO2 at ≥ 90%, compared to continuous-flow oxygen and a standard O2-conserving device (CR-50, Puritan-Bennett, Pleasanton, California). METHODS: We randomly assigned 28 patients who were on continuous home O2 for COPD to use each of 3 O2 delivery systems (continuous-flow O2, CR-50, and AccuO2) for 8 hours a day, for 2 consecutive days, at home, at their current O2 prescription. We recorded SpO2 and calculated the conservation ratio (duration of a given O2 supply with an O2-conserving device compared to continuous-flow O2). RESULTS: Twenty-two patients completed all 3 study arms; 2 additional patients completed the AccuO2 arm and the continuous-flow O2 arm. The mean ± SD SpO2 was 92 ± 4% with continuous-flow O2, 92 ± 4% with the CR-50, and 91 ± 2% with AccuO2 (P = .006 for the AccuO2 vs continuous-flow O2, P = .03 for the AccuO2 vs the CR-50). SpO2 variability was less with the AccuO2 (P < .001 vs continuous-flow O2 and vs the CR-50). The conservation ratios were 9.9 ± 7.3 for the AccuO2 and 2.6 ± 1.0 for the CR-50 (P < .001). CONCLUSIONS: Compared to continuous-flow O2 or the CR-50, the AccuO2 maintained SpO2 closer to the target, and AccuO2 had a higher conservation ratio than CR-50.

Economic evaluation of a disease management program for chronic obstructive pulmonary disease.

BACKGROUND: The data on cost savings with disease management (DM) in chronic obstructive pulmonary disease (COPD) is limited. A multicomponent DM program in COPD has recently shown in a large randomized controlled trial to reduce hospitalizations and emergency department visits compared to usual care (UC). The objectives of this study were to determine the cost of implementing the DM program and its impact on healthcare resource utilization costs compared to UC in high-risk COPD patients. MATERIALS AND METHODS: This study was a post-hoc economic analysis of a multicenter randomized, adjudicator-blinded, controlled, 1-year trial comparing DM and UC at 5 Midwest region Department of Veterans Affairs (VA) medical centers. Health-care costs (hospitalizations, ED visits, respiratory medications, and the cost of the DM intervention) were compared in the COPD DM intervention and UC groups. RESULTS: The composite outcome for all hospitalizations or ED visits were 27% lower in the DM group (123.8 mean events per 100 patient-years) compared to the UC group (170.5 mean events per 100 patient-years) (rate ratio 0.73; 0.56-0.90; p < 0.003). The cost of the DM intervention was $241,620 or $650 per patient. The total mean ± SD per patient cost that included the cost of DM in the DM group was 4491 ± 4678 compared to $5084 ± 5060 representing a $593 per patient cost savings for the DM program. CONCLUSIONS: The DM intervention program in this study was unique for producing an average cost savings of $593 per patient after paying for the cost of DM intervention.

Randomized trial of zileuton for treatment of COPD exacerbations requiring hospitalization.

RATIONALE: Leukotrienes have been implicated in the pathogenesis of acute exacerbations of COPD, but leukotriene modifiers have not been studied as a possible therapy for exacerbations. OBJECTIVE: We sought to test the safety and efficacy of adding oral zileuton (a 5-lipoxygenase inhibitor) to usual treatment for acute exacerbations of COPD requiring hospitalization. METHODS: Randomized double-blind, placebo-controlled, parallel group study of zileuton 600 mg orally, 4 times daily versus placebo for 14 days starting within 12 hours of hospital admission for COPD exacerbation. Primary outcome measure was hospital length of stay; secondary outcomes included treatment failure and biomarkers of leukotriene production. MAIN FINDINGS: Sixty subjects were randomized to zileuton and 59 to placebo (the study was stopped short of enrollment goals because of slow recruitment). There was no difference in hospital length of stay (3.75 +/- 2.19 vs. 3.86 +/- 3.06 days for zileuton vs. placebo, p = 0.39) or treatment failure (23% vs. 27% for zileuton vs. placebo, p = 0.63) despite a decline in urinary LTE(4) levels in the zileuton-treated group as compared to placebo at 24 hours (change in natural log-transformed ng/mg creatinine -1.38 +/- 1.19 vs. 0.14 +/- 1.51, p < 0.0001) and 72 hours (-1.32 +/- 2.08 vs. 0.26 +/- 1.93, p<0.006). Adverse events were similar in both groups. PRINCIPAL CONCLUSIONS: While oral zileuton during COPD exacerbations that require hospital admission is safe and reduces urinary LTE(4) levels, we found no evidence suggesting that this intervention shortened hospital stay, with the limitation that our sample size may have been insufficient to detect a modest but potentially meaningful clinical improvement.

Case report: echocardiographic detection of rare single coronary artery anomaly in a child with an atrial septal defect.

BACKGROUND: A single right coronary artery (RCA) with the left anterior descending (LAD) and circumflex coronary arteries located in the usual anatomic position and supplied by collaterals is the rarest variant of single RCA. CASE SUMMARY: We report a paediatric patient with an incidental finding of single RCA Lipton type RI pattern during assessment for transcatheter device closure of an ostium secundum atrial septal defect (secASD). Transthoracic echocardiography (TTE) revealed a dilated RCA, abnormal flow in the LAD, and no identifiable left main coronary artery. Diagnosis of a single RCA was confirmed with angiography. Dobutamine stress echocardiography revealed no inducible ischaemia. Transcatheter device closure of the secASD was subsequently successfully performed. DISCUSSION: TTE in paediatric patients can raise suspicion of coronary artery origin anomalies. Additional modalities, such as computed tomography and angiography, are required to comprehensively determine coronary artery anatomy. Functional assessment of ventricular function is also indicated. Coronary artery anatomy is important to delineate prior to transcatheter device closure of a secASD and should be part of the pre-procedure assessment.

Long-term outcomes of warfarin versus aspirin after Fontan surgery.

OBJECTIVES: Because of the nature of the Fontan physiology, patients are at an increased risk of thromboembolic complications. As such, warfarin or aspirin is generally prescribed lifelong for thromboprophylaxis. This study aimed to compare long-term rates of cerebrovascular injury, thrombosis, bleeding, bone mineral density, and quality of life in people living with Fontan circulation receiving warfarin compared with aspirin. METHODS: This was a multicenter study of a selected cohort from the Australia and New Zealand Fontan population. Participants underwent cerebral magnetic resonance imaging to detect the presence of cerebrovascular injury (n = 84) and dual-energy X-ray absorptiometry to assess bone mineral density (n = 120). Bleeding (n = 100) and quality of life (n = 90) were assessed using validated questionnaires: Warfarin and Aspirin Bleeding assessment tool and Pediatric Quality of Life Inventory, respectively. RESULTS: Stroke was detected in 33 participants (39%), with only 7 (6%) being clinically symptomatic. There was no association between stroke and Fontan type or thromboprophylaxis type. Microhemorrhage and white matter injury were detected in most participants (96% and 86%, respectively), regardless of thromboprophylaxis type. Bleeding rates were high in both groups; however, bleeding was more frequent in the warfarin group. Bone mineral density was reduced in our cohort compared with the general population; however, this was further attenuated in the warfarin group. Quality of life was similar between the warfarin and aspirin groups. Home international normalized ratio monitoring was associated with better quality of life scores in the warfarin group. CONCLUSIONS: Cerebrovascular injury is a frequent occurrence in the Australia and New Zealand Fontan population regardless of thromboprophylaxis type. No benefit of long-term warfarin prophylaxis could be demonstrated over aspirin; however, consideration must be given to important clinical features such as cardiac function and lung function. Furthermore, the association of reduced bone health in children receiving warfarin warrants further mechanistic studies.

Preoperative pulmonary function and mortality after cardiac surgery.

BACKGROUND: The aim of the study was to examine the relationship between preoperative pulmonary function and outcomes after cardiac surgery. METHODS: We performed preoperative pulmonary function tests (PFTs) in 1,169 patients undergoing cardiac surgery at the Minneapolis Veterans Affairs Medical Center. Airway obstruction was defined as forced expiratory volume in 1 minute (FEV(1)) to forced vital capacity ratio <0.7. RESULTS: Of the 1,169 patients, 483 (41%) had a prior history of chronic obstructive pulmonary disease (COPD). However, 178 patients with a history of COPD had no airway obstruction on PFT. Conversely, 186 patients without a COPD history had airway obstruction on PFT. Thus, PFT results helped reclassify the COPD status of 364 patients (31%). Operative mortality was 2% in patients with no or mild airway obstruction versus 6.7% in those with moderate or severe obstruction (ie, FEV(1) to forced vital capacity ratio <0.7 and FEV(1) <80% predicted). Postoperative mortality was higher (odds ratio 3.2, 95% CI 1.6-6.2, P = .001) in patients with moderate or severe airway obstruction and in patients with diffusing capacity of the lung for carbon monoxide <50% of predicted (odds ratio 4.9, 95% CI 2.3-10.8, P = .0001). Notably, mortality risk was 10x higher (95% CI 3.4-27.2, P = .0001) in patients with moderate or severe airway obstruction and diffusing capacity of the lung for carbon monoxide <50% of predicted. CONCLUSIONS: These data show that PFT before cardiac surgery reclassifies the COPD status of a substantial number of patients and provides important prognostic information that the current risk estimate models do not capture.

Does need for cognitive closure explain individual differences in lung cancer screening? A brief report.

The need for cognitive closure describes the extent to which a person, faced with a decision, prefers any answer in lieu of continued uncertainty. This construct may be relevant in lung cancer screening, which can both reduce and increase uncertainty. We examined whether individual differences in need for cognitive closure are associated with Veterans' completion of lung cancer screening using a self-administered survey (N = 361). We also assessed whether need for cognitive closure moderates an association between screening completion and lung cancer risk perception. Contrary to our main hypothesis, high need for cognitive closure Veterans were not more likely to complete lung cancer screening and need for cognitive closure did not have a moderating role.

Association of invitation to lung cancer screening and tobacco use outcomes in a VA demonstration project.

A potential unintended consequence of lung cancer screening (LCS) is an adverse effect on smoking behaviors. This has been difficult to assess in previous randomized clinical trials. Our goal was to determine whether cessation and relapse behaviors differ between Veterans directly invited (DI) to participate in LCS compared to usual care (UC). We conducted a longitudinal survey of tobacco use outcomes among Veterans (Minneapolis VA) from 2014 to 2015, randomized (2:1) to DI versus UC and stratified by baseline smoking status (current/former). Within the DI group, we explored differences between those who did and did not choose to undergo LCS. A total of 979 patients (n = 660 DI, n = 319 UC) returned the survey at a median of 484 days. Among current smokers (n = 488), smoking abstinence rates and cessation attempts did not differ between DI and UC groups. More baseline smokers in DI were non-daily smokers at follow-up compared to those in UC (25.3% vs 15.6%, OR 1.97 95%CI 1.15-3.36). A significant proportion of former smokers at baseline relapsed, with 17% overall indicating past 30-day smoking. This did not differ between arms. Of those invited to LCS, smoking outcomes did not significantly differ between those who chose to be screened (161/660) versus not. This randomized program evaluation of smoking behaviors in the context of invitation to LCS observed no adverse or beneficial effects on tobacco cessation or relapse among participants invited to LCS, or among those who completed screening. As LCS programs scale and spread nationally, effective cessation programs will be essential.

The FOXM1 Inhibitor RCM-1 Decreases Carcinogenesis and Nuclear ß-Catenin.

The oncogenic transcription factor FOXM1 has been previously shown to play a critical role in carcinogenesis by inducing cellular proliferation in multiple cancer types. A small-molecule compound, Robert Costa Memorial drug-1 (RCM-1), has been recently identified from high-throughput screen as an inhibitor of FOXM1 in vitro and in mouse model of allergen-mediated lung inflammation. In the present study, we examined antitumor activities of RCM-1 using tumor models. Treatment with RCM-1 inhibited tumor cell proliferation as evidenced by increased cell-cycle duration. Confocal imaging of RCM-1-treated tumor cells indicated that delay in cellular proliferation was concordant with inhibition of FOXM1 nuclear localization in these cells. RCM-1 reduced the formation and growth of tumor cell colonies in the colony formation assay. In animal models, RCM-1 treatment inhibited growth of mouse rhabdomyosarcoma Rd76-9, melanoma B16-F10, and human H2122 lung adenocarcinoma. RCM-1 decreased FOXM1 protein in the tumors, reduced tumor cell proliferation, and increased tumor cell apoptosis. RCM-1 decreased protein levels and nuclear localization of ß-catenin, and inhibited protein-protein interaction between ß-catenin and FOXM1 in cultured tumor cells and in vivo Altogether, our study provides important evidence of antitumor potential of the small-molecule compound RCM-1, suggesting that RCM-1 can be a promising candidate for anticancer therapy.