A systematic review of social classroom climate in online and technology-enhanced learning environments in primary and secondary school.

Although the significance of a positive social classroom climate in face-to-face learning has been established, its role within online and technology-enhanced learning environments is unclear. The central aim of this systematic review was to synthesize the findings of empirical studies which have examined any aspect of the social classroom climate in online and technology-enhanced learning environments in primary and secondary schools. Appropriate search terms were entered into ACM Digital Library, Web of Science, Scopus, and ERIC in November 2021. Articles were included if they were relevant for the aim, reported primary data, sampled primary/secondary school students and/or teachers, and were published in journals, conference proceedings, or book chapters in English. Furthermore, articles were excluded if they focused on the development/testing of measurement tools. The thematic narrative synthesis includes 29 articles, comprising of qualitative, quantitative, and mixed-method studies. A quality assessment checklist was completed for all. The findings encompass examinations of the social classroom climate in online learning before and during the Covid-19 pandemic, in blended learning environments and a comparison between them. Furthermore, associations between the online social classroom climate and academic variables is explored, as is the fostering thereof through synchronous/asynchronous discussion groups and social media. We discuss the theoretical framing of the studies, the impact of a positive classroom climate in online and technology-enhanced learning environments on students, as well as practical approaches and new opportunities in leveraging technologies. Based on the findings and the studies' limitations we outline implications and future research, such as the need to consider students' voices and diversity, technology perspectives, a transdiciplinary approach and the reconceptualization of boundaries.

National trends and outcomes of heart-kidney transplantation using hepatitis C positive donors.

BACKGROUND: This study evaluated the outcomes of combined heart-kidney transplantation in the United States using hepatitis C positive (HCV+) donors. METHODS: Adults undergoing combined heart-kidney transplantation from 2015 to 2020 were identified in the United Network for Organ Sharing registry. Patients were stratified by donor HCV status. Kaplan-Meier curves with multivariable Cox regression models were used for risk-adjustment in a propensity-matched cohort. RESULTS: A total of 950 patients underwent heart-kidney transplantation of which 7.8% (n = 75) used HCV+ donors; 68% (n = 51) were viremic and 32% (n = 24) were non-viremic donors. Unadjusted 1-year recipient survival was similar between HCV+ versus HCV- donors (84% vs 88%, respectively; P = .33). Risk-adjusted analysis in the propensity-matched cohort showed HCV+ donor use did not confer increased risk of 1-year mortality (hazard ratio .63, 95% CI .17-2.32; P = .49). Sub-group analysis showed viremic and non-viremic HCV+ donors had similar 1-year survival as well (84% vs 84%; P = .95). CONCLUSIONS: Compared with recipients of HCV- donor dual heart-kidney transplants, recipients of HCV+ organs had comparable 1-year survival and clinical outcomes after combined transplantation. Although future studies should evaluate other outcomes related to HCV+ donor use, this practice appears safe and should be expanded further in the heart-kidney transplant population.

HVAD versus heartmate III bridge to heart transplantation: Waitlist and posttransplant outcomes.

BACKGROUND: This study compared outcomes of patients bridged with either the Heartware HVAD or Heartmate 3 (HM3) device to orthotopic heart transplantation (OHT). METHODS: The United Network of Organ Sharing registry was queried to perform two separate analyses of adult, isolated OHT candidates bridged with HVAD or HM3. First, waitlist outcomes were compared among patients waitlisted 1/1/2015-3/20/2020. Second, posttransplant survival was compared among those transplanted 1/1/2015-3/20/2020. RESULTS: Two thousand two hundred fifty-five candidates were waitlisted within the study period, 1587 (70.4%) bridged with HVAD and 668 (29.6%) with HM3. At 1 year from waitlisting, cumulative incidence of OHT higher in the HVAD cohort (p < .001). During the same time period, 2643 patients underwent OHT, 2154 (81.5%) with prior HVAD and 489 (18.5%) with HM3. Yearly proportions of patients bridged with HM3 increased across the study period and decreased for HVAD (p < .001). HM3-bridged recipients had shorter waitlist times, longer graft cold ischemic times, and experienced a higher rate of posttransplant dialysis requirement. Unadjusted and risk-adjusted posttransplant mortality rates were similar between both groups. CONCLUSIONS: Posttransplant survival is equivalent regardless of device type used for bridging. However, HM3 patients had lower likelihood of reaching transplantation, which may be a reflection of the recent heart allocation policy changes.

The HeartMate 3 left ventricular assist device as a strategy to bridge to transplant.

PURPOSE: Recent changes in the market for left ventricular assist devices have resulted in the HeartMate 3 (HM3) being the only commercially-available device. This study evaluates the outcomes of patients with a HM3 waitlisted for and undergoing orthotopic heart transplantation (OHT). METHODS: Patients waitlisted for isolated OHT with a HM3 or undergoing OHT after bridge-to-transplant (BTT) with a HM3 between 2015 and 2021 were identified from the UNOS registry and included in this study. Propensity matching was used to compare outcomes of BTT-HM3 versus primary OHT. RESULTS: A total of 1321 patients supported with a HM3 underwent OHT during our study period. Unadjusted 30-day, 90-day, and 1-year survival following OHT in the BTT-HM3 cohort was 96.5%, 94.4%, and 90.7%, respectively. In propensity-matched analysis, 1103 BTT-HM3 patients were compared with 1103 primary OHT patients. Rates of post-OHT stroke were higher in the BTT-HM3 group (4.4% vs. 2.0%, p = .001). The BTT-HM3 group had lower 30-day survival (96.2% vs. 97.4%, p = .033) although 90-day (94.2% vs. 95.3%, p = .103) and 1-year survival (90.4% vs. 91.7%, p = .216) were comparable. A total of 1251 patients were supported with a HM3 at the time of OHT listing during the study period. At the time of this analysis, 60 (4.5%) remained on the waitlist, 991 (75.0%) underwent OHT, and 119 (9.0%) died or clinically deteriorated with waitlist removal. CONCLUSIONS: The HM3 is a viable method for BTT with acceptable waitlist outcomes. Although 1-year survival is comparable to primary OHT, early outcomes are worse, suggesting that refinement of patient selection and perioperative management is prudent to optimizing outcomes.

Native Coronary Artery Pseudoaneurysm after Coronary Artery Bypass Grafting.

Coronary artery pseudoaneurysms are extremely rare and most often occur after trauma or endovascular procedures [Aoki 2008; Kar 2017]. Delay in diagnosis or treatment may lead to coronary thrombosis with resultant ischemia or hemorrhage subsequent tamponade. Here, we present the case of a 66-year-old female who developed a coronary artery pseudoaneurysm of a non-grafted vessel three weeks after coronary artery bypass grafting. To avoid re-sternotomy, the pseudoaneurysm was successfully managed with a covered coronary stent and mini-left anterior thoracotomy to evacuate the hemopericardium and relieve tamponade.

ZFP148 (Zinc-Finger Protein 148) Binds Cooperatively With NF-1 (Neurofibromin 1) to Inhibit Smooth Muscle Marker Gene Expression During Abdominal Aortic Aneurysm Formation.

Objective- The goal of this study was to determine the role of ZFP148 (zinc-finger protein 148) in aneurysm formation. Approach and Results- ZFP148 mRNA expression increased at day 3, 7, 14, 21, and 28 after during abdominal aortic aneurysm formation in C57BL/6 mice. Loss of ZFP148 conferred abdominal aortic aneurysm protection using ERTCre+ ZFP148 flx/flx mice. In a third set of experiments, smooth muscle-specific loss of ZFP148 alleles resulted in progressively greater protection using novel transgenic mice (MYH [myosin heavy chain 11] Cre+ flx/flx, flx/wt, and wt/wt). Elastin degradation, LGAL3, and neutrophil staining were significantly attenuated, while α-actin staining was increased in ZFP148 knockout mice. Results were verified in total cell ZFP148 and smooth muscle-specific knockout mice using an angiotensin II model. ZFP148 smooth muscle-specific conditional mice demonstrated increased proliferation and ZFP148 was shown to bind to the p21 promoter during abdominal aortic aneurysm formation. ZFP148 smooth muscle-specific conditional knockout mice also demonstrated decreased apoptosis as measured by decreased cleaved caspase-3 staining. ZFP148 bound smooth muscle marker genes via chromatin immunoprecipitation analysis mediated by NF-1 (neurofibromin 1) promote histone H3K4 deacetylation via histone deacetylase 5. Transient transfections and chromatin immunoprecipitation analyses demonstrated that NF-1 was required for ZFP148 protein binding to smooth muscle marker genes promoters during aneurysm formation. Elimination of NF-1 using shRNA approaches demonstrated that NF-1 is required for binding and elimination of NF-1 increased BRG1 recruitment, the ATPase subunit of the SWI/SWF complex, and increased histone acetylation. Conclusions- ZFP148 plays a critical role in multiple murine models of aneurysm formation. These results suggest that ZFP148 is important in the regulation of proliferation, smooth muscle gene downregulation, and apoptosis in aneurysm development.

Redirecting photosynthetic electron flux in the cyanobacterium Synechocystis sp. PCC 6803 by the deletion of flavodiiron protein Flv3.

BACKGROUND: Oxygen-evolving photoautotrophic organisms, like cyanobacteria, protect their photosynthetic machinery by a number of regulatory mechanisms, including alternative electron transfer pathways. Despite the importance in modulating the electron flux distribution between the photosystems, alternative electron transfer routes may compete with the solar-driven production of CO2-derived target chemicals in biotechnological systems under development. This work focused on engineered cyanobacterial Synechocystis sp. PCC 6803 strains, to explore possibilities to rescue excited electrons that would normally be lost to molecular oxygen by an alternative acceptor flavodiiron protein Flv1/3-an enzyme that is natively associated with transfer of electrons from PSI to O2, as part of an acclimation strategy towards varying environmental conditions. RESULTS: The effects of Flv1/3 inactivation by flv3 deletion were studied in respect to three alternative end-products, sucrose, polyhydroxybutyrate and glycogen, while the photosynthetic gas fluxes were monitored by Membrane Inlet Mass Spectrometry (MIMS) to acquire information on cellular carbon uptake, and the production and consumption of O2. The results demonstrated that a significant proportion of the excited electrons derived from photosynthetic water cleavage was lost to molecular oxygen via Flv1/3 in cells grown under high CO2, especially under high light intensities. In flv3 deletion strains these electrons could be re-routed to increase the relative metabolic flux towards the monitored target products, but the carbon distribution and the overall efficiency were determined by the light conditions and the genetic composition of the respective pathways. At the same time, the total photosynthetic capacity of the Δflv3 strains was systematically reduced, and accompanied by upregulation of oxidative glycolytic metabolism in respect to controls with the native Flv1/3 background. CONCLUSIONS: The observed metabolic changes and respective production profiles were proposedly linked with the lack of Flv1/3-mediated electron transfer, and the associated decrease in the intracellular ATP/NADPH ratio, which is bound to affect the metabolic carbon partitioning in the flv3-deficient cells. While the deletion of flv3 could offer a strategy for enhancing the photosynthetic production of desired chemicals in cyanobacteria under specified conditions, the engineered target pathways have to be carefully selected to align with the intracellular redox balance of the cells.

Novel Role of IL (Interleukin)-1ß in Neutrophil Extracellular Trap Formation and Abdominal Aortic Aneurysms.

OBJECTIVE: Neutrophils promote experimental abdominal aortic aneurysm (AAA) formation via a mechanism that is independent from MMPs (matrix metalloproteinases). Recently, we reported a dominant role of IL (interleukin)-1ß in the formation of murine experimental AAAs. Here, the hypothesis that IL-1ß-induced neutrophil extracellular trap formation (NETosis) promotes AAA was tested. APPROACH AND RESULTS: NETs were identified through colocalized staining of neutrophil, Cit-H3 (citrullinated histone H3), and DNA, using immunohistochemistry. NETs were detected in human AAAs and were colocalized with IL-1ß. In vitro, IL-1RA attenuated IL-1ß-induced NETosis in human neutrophils. Mechanistically, IL-1ß treatment of isolated neutrophils induced nuclear localization of ceramide synthase 6 and synthesis of C16-ceramide, which was inhibited by IL-1RA or fumonisin B1, an inhibitor of ceramide synthesis. Furthermore, IL-1RA or fumonisin B1 attenuated IL1-ß-induced NETosis. In an experimental model of murine AAA, NETs were detected at a very early stage-day 3 of aneurysm induction. IL-1ß-knockout mice demonstrated significantly lower infiltration of neutrophils to aorta and were protected from AAA. Adoptive transfer of wild-type neutrophils promoted AAA formation in IL-1ß-knockout mice. Moreover, treatment of wild-type mice with Cl-amidine, an inhibitor NETosis, significantly attenuated AAA formation, whereas, treatment with deoxyribonuclease, a DNA digesting enzyme, had no effect on AAA formation. CONCLUSIONS: Altogether, the results suggest a dominant role of IL-1ß-induced NETosis in AAA formation.

D-series resolvins inhibit murine abdominal aortic aneurysm formation and increase M2 macrophage polarization.

The role of resolvins in abdominal aortic aneurysm (AAA) has not been established. We hypothesized that treatment with D-series resolvins (RvD2 or RvD1) would attenuate murine AAA formation through alterations in macrophage polarization and cytokine expression. Male C57/B6 mice (n = 9 per group) 8 to 12 wk old received RvD2 (100 ng/kg/treatment), RvD1 (100 ng/kg/treatment), or vehicle only every third day beginning 3 d before abdominal aortic perfusion with elastase as prevention. Aortas were collected 14 d after elastase perfusion. Cytokine analysis (n = 5 per group) or confocal microscopy (n = 4 per group) was performed. In a separate experiment, RvD2 was provided to mice with small AAAs 3 d after elastase treatment (n = 8 per group). Additionally, apolipoprotein E knockout mice treated with angiotensin II (1000 ng/kg) were treated with RvD2 or vehicle alone (n = 10 per group) in a nonsurgical model of AAA. To determine the effect of RvD2 on macrophage polarization, confocal staining for macrophages, M1 and M2 macrophage subtypes, α-actin, and DAPI was performed. Mean aortic dilation was 96 ± 13% for vehicle-treated mice, 57 ± 9.7% for RvD2-treated mice, and 61 ± 11% for RvD1-treated mice (P < 0.0001). Proinflammatory cytokines macrophage chemotactic protein 1, C-X-C motif ligand 1, and IL-1ß were significantly elevated in control animals compared to RvD2- and RvD1-treated animals (P < 0.05), resulting in a reduction of matrix metalloproteinase 2 and 9 activity in resolvin-treated mice in both elastase and angiotensin II models. Treatment of existing small AAAs with RvD2 demonstrated a 25% reduction in aneurysm size at d 14 compared to vehicle alone (P = 0.018). Confocal histology demonstrated a prevalence of M2 macrophages within the aortic medium in mice treated with RvD2. Resolvin D2 exhibits a potent protective effect against experimental AAA formation. Treatment with RvD2 significantly influences macrophage polarization and decreases several important proinflammatory cytokines. Resolvins and the alteration of macrophage polarization represent potential future targets for prevention of AAA.-Pope, N. H., Salmon, M., Davis, J. P., Chatterjee, A., Su, G., Conte, M. S., Ailawadi, G., Upchurch, G. R., Jr. D-series resolvins inhibit murine abdominal aortic aneurysm formation and increase M2 macrophage polarization.

Mesenchymal Stem Cells Attenuate NADPH Oxidase-Dependent High Mobility Group Box 1 Production and Inhibit Abdominal Aortic Aneurysms.

OBJECTIVE: Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, smooth muscle activation, and matrix degradation. This study tests the hypothesis that macrophage-produced high mobility group box 1 (HMGB1) production is dependent on nicotinamide adenine dinucleotide phosphate oxidase (Nox2), which leads to increase in interleukin (IL)-17 production resulting in AAA formation and that treatment with human mesenchymal stem cells (MSCs) can attenuate this process thereby inhibiting AAA formation. APPROACH AND RESULTS: Human aortic tissue demonstrated a significant increase in HMGB1 expression in AAA patients when compared with controls. An elastase-perfusion model of AAA demonstrated a significant increase in HMGB1 production in C57BL/6 (wild-type [WT]) mice, which was attenuated by MSC treatment. Furthermore, anti-HMGB1 antibody treatment of WT mice attenuated AAA formation, IL-17 production, and immune cell infiltration when compared with elastase-perfused WT mice on day 14. Elastase-perfused Nox2(-/y) mice demonstrated a significant attenuation of HMGB1 and IL-17 production, cellular infiltration, matrix metalloproteinase activity, and AAA formation when compared with WT mice on day 14. In vitro studies showed that elastase-treated macrophages from WT mice, but not from Nox2(-/y) mice, produced HMGB1, which was attenuated by MSC treatment. The production of macrophage-dependent HMGB1 involved Nox2 activation and superoxide anion production, which was mitigated by MSC treatment. CONCLUSIONS: These results demonstrate that macrophage-produced HMGB1 leads to aortic inflammation and acts as a trigger for CD4(+) T-cell-produced IL-17 during AAA formation. HMGB1 release is dependent on Nox2 activation, which can be inhibited by MSCs leading to attenuation of proinflammatory cytokines, especially IL-17, and protection against AAA formation.

Pharmacologic blockade and genetic deletion of androgen receptor attenuates aortic aneurysm formation.

BACKGROUND: Testosterone is theorized to play a major role in the pathophysiology of abdominal aortic aneurysms (AAAs) because this disease occurs primarily in men. The role of the androgen receptor (AR) in the formation of AAAs has not been well elucidated, and therefore, it is hypothesized that androgen blockade will attenuate experimental aortic aneurysm formation. METHODS: Aortas of 8- to 12-week-old male C57Bl/6 wild-type (WT) mice or male AR knockout (AR(-/-)) mice were perfused with purified porcine pancreatic elastase (0.35 U/mL) to induce AAA formation. Two groups of WT male mice were treated with the AR blockers flutamide (50 mg/kg) or ketoconazole (150 mg/kg) twice daily by intraperitoneal injection. Aortas were harvested on day 14 after video micrometry was used to measure AAA diameter. Cytokine arrays and histologic analysis were performed on aortic tissue. Groups were compared using an analysis of variance and a Tukey post hoc test. RESULTS: Flutamide and ketoconazole treatment (mean ± standard error of the mean) attenuated AAA formation in WT mice (84.2% ± 22.8% [P = .009] and 91.5% ± 18.2% [P = .037]) compared with WT elastase (121% ± 5.23%). In addition, AR(-/-) mice showed attenuation of AAA growth (64.4% ± 22.7%; P < .0001) compared with WT elastase. Cytokine arrays of aortic tissue revealed decreased levels of proinflammatory cytokines interleukin (IL)-α, IL-6, and IL-17 in flutamide-treated and AR(-/-) groups compared with controls. CONCLUSIONS: Pharmacologic and genetic AR blockade cause attenuation of AAA formation. Therapies for AR blockade used in prostate cancer may provide medical treatment to halt progression of AAAs in humans.

Inhibition of interleukin-1ß decreases aneurysm formation and progression in a novel model of thoracic aortic aneurysms.

BACKGROUND: Thoracic aortic aneurysms (TAAs) are common, but experimental TAA models are limited and the role of interleukin-1ß (IL-1ß) is undetermined. METHODS AND RESULTS: IL-1ß protein was measured in human TAAs and control aortas, and IL-1ß protein was increased ≈20-fold in human TAAs. To develop an experimental model of TAAs, 8- to 10-week-old male C57Bl/6 mice (wild type [WT]) underwent thoracotomy with application of periadventitial elastase (WT TAA) or saline (WT control; n=30 per group). Elastase treatment to thoracic aortas resulted in progressive dilation until day 14 with maximal dilation of 99.6±24.7% compared with 14.4±8.2% for WT saline control (P<0.0001). WT TAAs demonstrated elastin fragmentation, smooth muscle cell loss, macrophage infiltration, and increased IL-1ß expression. Next, TAAs were induced in mice deficient of IL-1ß (IL-1ß knockout) or IL-1 receptor (IL-1R knockout; n=10 each). Genetic deletion of IL-1ß and IL-1R significantly decreased thoracic aortic dilation (IL-1ß knockout=54.2±16.8% and IL-1R knockout=62.6±17.2% versus WT TAA=104.7±23.8%; P<0.001for both). IL-1ß knockout and IL-1R knockout aortas demonstrated preserved elastin and smooth muscle cells with fewer inflammatory cells. Correspondingly, IL-1ß and IL-1R knockout aortas had decreased inflammatory cytokine and matrix metalloproteinase 9 expression. Separately, WT mice pretreated with either IL-1R antagonist anakinra (100 mg/kg per day) or vehicle alone (control) underwent elastase treatment. Pretreatment of WT mice with anakinra attenuated TAA formation (control: 99.2±15.5% versus anakinra: 68.3±19.2%; P<0.005). Finally, to investigate treatment of small TAAs, WT mice were treated with anakinra 3 days after TAA induction. Anakinra treatment in WT mice with small TAAs reduced aortic dilation on day 14 (control treatment: 89.1±18.6% versus anakinra treatment: 59.7±25.7%; P=0.01). CONCLUSIONS: Periadventitial application of elastase to murine thoracic aortas reproducibly produced aneurysms with molecular and histological features consistent with TAA disease. Genetic and pharmacological inhibition of IL-1ß decreased TAA formation and progression, indicating that IL-1ß may be a potential target for TAA treatment.

B2 cells suppress experimental abdominal aortic aneurysms.

Recent reports of rupture in patients with abdominal aortic aneurysm (AAA) receiving B-cell depletion therapy highlight the importance of understanding the role of B cells (B1 and B2 subsets) in the development of AAA. We hypothesized that B2 cells aggravate experimental aneurysm formation. The IHC staining revealed infiltration of B cells in the aorta of wild-type (C57BL/6) mice at day 7 after elastase perfusion and persisted through day 21. Quantification of immune cell types using flow cytometry at day 14 showed significantly greater infiltration of mononuclear cells, including B cells (B2: 93% of total B cells) and T cells in elastase-perfused aortas compared with saline-perfused or normal aortas. muMT (mature B-cell deficient) mice were prone to AAA formation similar to wild-type mice in two different experimental AAA models. Contradicting our hypothesis, adoptive transfer of B2 cells suppressed AAA formation (102.0% ± 7.3% versus 75.2% ± 5.5%; P < 0.05) with concomitant increase in the splenic regulatory T cell (0.24% ± 0.03% versus 0.92% ± 0.23%; P < 0.05) and decrease in aortic infiltration of mononuclear cells. Our data suggest that B2 cells constitute the largest population of B cells in experimental AAA. Furthermore, B2 cells, in the absence of other B-cell subsets, increase splenic regulatory T-cell population and suppress AAA formation.

Attenuation of aortic aneurysms with stem cells from different genders.

BACKGROUND: No medical therapies are yet available to slow abdominal aortic aneurysm (AAA) growth. This study sought to investigate the effect of different genders of bone marrow-derived mesenchymal stem cells (MSC) on AAA growth in a murine AAA model. Given the decreased rate of AAA in women, it is hypothesized that female MSC would attenuate AAA growth more so than male MSC. MATERIALS AND METHODS: Aortas of 8-10-wk-old male C57Bl/6 mice were perfused with purified porcine pancreatic elastase to induce AAA formation. Bone marrow-derived MSC from male and female mice were dosed via tail vein injection (3 million cells per dose, 500 µL of volume per injection) on postaortic perfusion days 1, 3, and 5. Aortas were harvested after 14 d. RESULTS: Mean aortic dilation in the elastase group was 121 ± 5.2% (mean ± standard error of the mean), while male MSC inhibited AAA growth (87.8 ± 6.9%, P = 0.008) compared with that of elastase. Female MSC showed the most marked attenuation of AAA growth (75.2 ± 8.3% P = 0.0004). Proinflammatory cytokines tumor necrosis factor α, interleukin 1ß, and monocyte chemotactic protein-1 (MCP-1) were only decreased in tissues treated with female MSC (P = 0.017, P = 0.001, and P < 0.0001, respectively, when compared with elastase). CONCLUSIONS: These data exhibit that female MSC more strongly attenuate AAA growth in the murine model. Furthermore, female MSC and male MSC inhibit proinflammatory cytokines at varying levels. The effects of MSC on aortic tissue offer a promising insight into biologic therapies for future medical treatment of AAAs in humans.

KLF4 regulates abdominal aortic aneurysm morphology and deletion attenuates aneurysm formation.

BACKGROUND: KLF4 mediates inflammatory responses after vascular injury/disease; however, the role of KLF4 in abdominal aortic aneurysms (AAAs) remains unknown. The goals of the present study were to (1) determine the role of KLF4 in experimental AAA; and (2) determine the effect of KLF4 on smooth muscle (SM) cells in AAAs. METHODS AND RESULTS: KLF4 expression progressively increased at days 3, 7, and 14 after aortic elastase perfusion in C57BL/6 mice. Separately, loss of a KLF4 allele conferred AAA protection using ERTCre+ KLF4 flx/wt mice in the elastase AAA model. In a third set of experiments, SM-specific loss of 1 and 2 KLF4 alleles resulted in progressively greater protection using novel transgenic mice (MYHCre+ flx/flx, flx/wt, and wt/wt) in the elastase AAA model compared with control. Elastin degradation, MAC2, and cytokine production (MCP1, tumor necrosis factor-α, and interleukin-23) were significantly attenuated, whereas α-actin staining was increased in KLF4 knockout mice versus controls. Results were verified in global KLF4 and SM-specific knockout mice using an angiotensin II model of aneurysm formation. KLF4 inhibition with siRNA attenuated downregulation of SM gene expression in vitro, whereas in vivo studies demonstrated that KLF4 binds to promoters of SM genes by chromatin immunoprecipitation analysis. Finally, human aortic aneurysms demonstrated significantly higher KLF4 expression that was localized to SM cells. CONCLUSIONS: KLF4 plays a critical role in aortic aneurysm formation via effects on SM cells. These results suggest that KLF4 regulates SM cell phenotypic switching and could be a potential therapeutic target for AAA disease.

Changes in heart transplant outcomes of elderly patients in the new allocation era.

OBJECTIVE: Studies demonstrate that heart transplantation can be performed safely in septuagenarians. We evaluate the outcomes of septuagenarians undergoing heart transplantation after the US heart allocation change in 2018. METHODS: The United Network for Organ Sharing registry was used to identify heart transplant recipients aged 70 years or more between 2010 and 2021. Primary outcomes were 90-day and 1-year mortality. Kaplan-Meier, multivariable Cox proportional hazards, and accelerated failure time models were used for unadjusted and risk-adjusted analyses. RESULTS: A total of 27,403 patients underwent heart transplantation, with 1059 (3.9%) aged 70 years or more. Patients aged 70 years or more increased from 3.7% before 2018 to 4.5% after 2018 (P = .003). Patients aged 70 years or more before 2018 had comparable 90-day and 1-year survivals relative to patients aged less than 70 years (90 days: 93.8% vs 94.2%, log-rank P = .650; 1 year: 89.4% vs 91.1%, log-rank P = .130). After 2018, septuagenarians had lower 90-day and 1-year survivals (90 days: 91.4% vs 95.0%, log-rank P = .021; 1 year: 86.5% vs 90.9%, log-rank P = .018). Risk-adjusted analysis showed comparable 90-day mortality (hazard ratio, 1.29; 0.94-1.76, P = .110) but worse 1-year mortality (hazard ratio, 1.32; 1.03-1.68, P = .028) before policy change. After policy change, both 90-day and 1-year mortalities were higher (90 days: HR, 1.99; 1.23-3.22, P = .005; 1 year: hazard ratio, 1.71; 1.14-2.56, P = .010). An accelerated failure time model showed comparable 90-day (0.42; 0.16-1.44; P = .088) and 1-year (0.48; 0.18-1.26; P = .133) survival postallocation change. CONCLUSIONS: Septuagenarians comprise a greater proportion of heart transplant recipients after the allocation change, and their post-transplant outcomes relative to younger recipients have worsened.

Prolonged Ischemia Times for Heart Transplantation: Impact of the 2018 Allocation Change.

BACKGROUND: In 2018, the United Network for Organ Sharing implemented a change in heart allocation policy resulting in increased organ ischemia times in early analyses. This study evaluated the effect of ischemia time on 1-year mortality in the context of allocation policy changes implemented in 2006 and 2018. METHODS: The United Network for Organ Sharing registry was used to identify adults undergoing heart transplantation from 2000 to 2020. Patients were stratified by the allocation policy era in which they received a transplant (2000-June 2006, July 2006-October 2018, October 2018-2020) and by ischemia time, defined as normal (≤4 hours) and prolonged (>4 hours). One-year survival was estimated using Kaplan-Meier analysis. Cox regression was used to determine risk-adjusted hazards for ischemia time on 1-year mortality. RESULTS: There were 40 052 patients included for analysis. Ischemia times were normal in 32 585 (81.36%) and prolonged in 7467 (18.64%) patients. The proportion of transplantations with prolonged ischemia times increased with each subsequent policy era. After the 2018 policy change, 1-year survival was 90.92% with normal ischemia times vs 87.52% with prolonged ischemia times (P < .001). Ischemia time independently predicted 1-year mortality in each era with a hazard ratio of 1.20 per hour (P = .004) in the current era. CONCLUSIONS: Prolonged ischemia times occur in a minority of cases but are increasing in frequency. The independent risk of prolonged ischemia time on 1-year mortality persists despite advances in storage technology and should remain a consideration in donor-recipient matching.

Heart Transplantation for Peripartum Cardiomyopathy: Outcomes Over 3 Decades.

BACKGROUND: This study evaluated trends and outcomes of patients undergoing heart transplantation for peripartum cardiomyopathy (PPCM) over the past 3 decades. METHODS: The United Network for Organ Sharing registry was used to identify patients undergoing isolated heart transplantation between 1987 and 2020. Patients were stratified by the decade of transplantation. Overall survival was compared using Kaplan-Meier analysis, and risk-adjustment was performed using Cox proportional hazards modeling. RESULTS: A total of 76 009 heart transplantations occurred in the study period, including 20 352 female patients and 809 female patients with PPCM. The frequency of transplantation for PPCM increased over the study period (P = .015). Among female patients, PPCM was significantly associated with 1-year mortality compared with nonischemic cardiomyopathy (hazard ratio, 1.38; 95% CI, 1.11-1.69; P = .004). Among patients with PPCM, Black and Hispanic heart transplant recipients had increased 1-year posttransplant mortality risk compared with White recipients. On Kaplan-Meier survival analysis, early and midterm survival was significantly worse in patients with PPCM compared with other female patients. The 5-, 10-, and 15-year survivals in patients with PPCM were 66.5%, 49.0%, and 40.2% compared with 74.3%, 56.0%, and 37.5% in female heart transplant recipients with other heart failure diagnoses, respectively (P < .001). Survival improved significantly in patients who underwent heart transplantation for PPCM in the latest decade from 2010 to 2020 compared with earlier decades (P < .001), and this improvement was most marked for Black recipients. CONCLUSIONS: Patients who underwent heart transplantation for PPCM have a significantly elevated risk for 1-year mortality compared with other female transplant recipients. However, survival among these patients has improved in the last decade, particularly for Black transplant recipients.

Conversion of the HVAD Left Ventricular Assist Device to the Centrimag Using a Customized Apical Plug.

Left ventricular assist device thrombosis is a potentially life-threatening complication often managed acutely with device exchange. In the absence of modifiable risk factors recurrent thrombosis can occur. Recent changes in the heart allocation policy have reduced left ventricular assist device complications from top priority to status 3. In this report we present a patient with recurrent left ventricular assist device thrombosis. Given no modifiable risk factors and recurrence of thrombosis, the HeartWare HVAD ((Medtronic, Minneapolis, MN)) was converted to a temporary Centrimag device device (Abbott, Abbott Park, IL) using a novel plug through the existing sewing ring. With status 2 listing the patient was successfully transplanted on postoperative day 3.