Single-Cell Map of Diverse Immune Phenotypes in the Breast Tumor Microenvironment.

Knowledge of immune cell phenotypes in the tumor microenvironment is essential for understanding mechanisms of cancer progression and immunotherapy response. We profiled 45,000 immune cells from eight breast carcinomas, as well as matched normal breast tissue, blood, and lymph nodes, using single-cell RNA-seq. We developed a preprocessing pipeline, SEQC, and a Bayesian clustering and normalization method, Biscuit, to address computational challenges inherent to single-cell data. Despite significant similarity between normal and tumor tissue-resident immune cells, we observed continuous phenotypic expansions specific to the tumor microenvironment. Analysis of paired single-cell RNA and T cell receptor (TCR) sequencing data from 27,000 additional T cells revealed the combinatorial impact of TCR utilization on phenotypic diversity. Our results support a model of continuous activation in T cells and do not comport with the macrophage polarization model in cancer. Our results have important implications for characterizing tumor-infiltrating immune cells.

Novel gene-intergenic fusion involving ubiquitin E3 ligase UBE3C causes distal hereditary motor neuropathy.

Distal hereditary motor neuropathies (dHMNs) are a group of inherited diseases involving the progressive, length-dependent axonal degeneration of the lower motor neurons. There are currently 29 reported causative genes and four disease loci implicated in dHMN. Despite the high genetic heterogeneity, mutations in the known genes account for less than 20% of dHMN cases, with the mutations identified predominantly being point mutations or indels. We have expanded the spectrum of dHMN mutations with the identification of a 1.35 Mb complex structural variation (SV) causing a form of autosomal dominant dHMN (DHMN1 OMIM %182906). Given the complex nature of SV mutations and the importance of studying pathogenic mechanisms in a neuronal setting, we generated a patient-derived DHMN1 motor neuron model harbouring the 1.35 Mb complex insertion. The DHMN1 complex insertion creates a duplicated copy of the first 10 exons of the ubiquitin-protein E3 ligase gene (UBE3C) and forms a novel gene-intergenic fusion sense transcript by incorporating a terminal pseudo-exon from intergenic sequence within the DHMN1 locus. The UBE3C intergenic fusion (UBE3C-IF) transcript does not undergo nonsense-mediated decay and results in a significant reduction of wild-type full-length UBE3C (UBE3C-WT) protein levels in DHMN1 iPSC-derived motor neurons. An engineered transgenic Caenorhabditis elegans model expressing the UBE3C-IF transcript in GABA-ergic motor neurons shows neuronal synaptic transmission deficits. Furthermore, the transgenic animals are susceptible to heat stress, which may implicate defective protein homeostasis underlying DHMN1 pathogenesis. Identification of the novel UBE3C-IF gene-intergenic fusion transcript in motor neurons highlights a potential new disease mechanism underlying axonal and motor neuron degeneration. These complementary models serve as a powerful paradigm for studying the DHMN1 complex SV and an invaluable tool for defining therapeutic targets for DHMN1.

Sex-related Outcomes after Thoracic Endovascular Repair for intact isolated Descending Thoracic Aortic Aneurysm: A Retrospective Cohort Study.

OBJECTIVE: To evaluate the association between sex and outcomes following TEVAR for intact isolated descending thoracic aortic aneurysms (iiDTAA). SUMMARY BACKGROUND DATA: Data regarding sex-related long-term outcomes after TEVAR for iiDTAA are limited and conflicting results regarding perioperative outcomes have been reported. METHODS: We included all TEVAR for iiDTAA between 2014-2019 in the Vascular Quality Initiative linked to Medicare claims, allowing reliable assessment of long-term outcome data. Primary outcomes included 5-year mortality, reinterventions, and ruptures of the thoracic aorta. Secondarily we assessed perioperative outcomes. RESULTS: We identified 685 patients, of which 54% were females. Females had higher aortic size index (females vs. males: 3.31 [IQR, 2.81-3.85] cm/m2 vs. 2.93 [IQR, 2.42-3.36] cm/m2; P<.001), were more frequently symptomatic (31% vs. 20%; P=.001), had longer procedure time (111 [IQR, 72-165] min vs. 97 [IQR, 70-146] min) and more iliac procedures (16% vs. 7.6%; P=.001). Compared with males, females had similar rates of 5-year mortality (58% vs. 53%; HR, 0.93; 95%CI 0.71-1.22; P=.61), reinterventions (39% vs. 30%; HR, 1.12; 95%CI 0.73-1.73; P=.60) and late ruptures (0.6% vs. 1.2%; HR, 0.87; 95%CI 0.12-6.18; P=.89). After adjustment, these outcomes remained similar through 5-years. Furthermore, perioperative mortality was not significantly different between sexes (4.1% vs. 2.2%; P=.25), as were rates of any complication as a composite outcome (16% vs. 21%; P=.16), as well as of individual complications (all P>.05). CONCLUSIONS: Our findings suggest that females who undergo TEVAR for iiDTAA have similar 5-year and perioperative outcomes as compared with males.

Light-Activated Vascular Anastomosis.

Background. There have been few advances in technique since vascular anastomosis was performed with silk suture on a curved needle in 1902. This technique results in disruption of the endothelium with exposed intraluminal suture, both of which may lead to thrombocyte aggregation, intimal hyperplasia, and vascular stenosis. A variety of alternative techniques have been explored, with limited success. Photochemical tissue bonding (PTB) is a light-activated methodology of rapidly cross-linking tissue interfaces at the molecular level. Herein, we describe a new technique for anastomosis of venous interposition graft in an ovine model of femoral artery bypass utilizing PTB. Methods. Polypay specific pathogen free sheep (n = 5; 40-45 kg) underwent femoral artery bypass utilizing saphenous vein. The femoral artery was transected and reversed saphenous vein was implanted as an interposition graft. The proximal anastomosis was created as a vein-over-artery cuff utilizing PTB, and the distal anastomosis was created with standard interrupted 8-0 polypropylene suture. Four weeks post-index operation, femoral angiogram was performed to evaluate patency, tortuosity, and luminal diameter. All bypass grafts were harvested and longitudinal and transverse histological sections from the proximal anastomosis were analyzed. Results. The PTB anastomoses (n = 5) were immediately watertight and patent. All animals survived the 28-day study duration. Angiography revealed patent grafts with no aneurysm or stenosis (n = 5). Histologic examination revealed integration of the venous endothelium with the arterial adventitia. Conclusion. Photochemical tissue bonding creates an immediate strong, watertight vascular anastomosis that can withstand physiologic arterial pressure and remains patent at 28 days without the need for intraluminal suture.

In-hospital outcomes after upper extremity versus transfemoral and transcarotid access for carotid stenting in the Vascular Quality Initiative.

OBJECTIVE: Carotid artery stenting (CAS) is frequently used for patients at high risk for carotid endarterectomy. However, there are limited data comparing transradial or transbrachial (tr/tbCAS) access with more established CAS approaches. Therefore, we examined the effect of a tr/tbCAS approach versus a transfemoral (tfCAS) or transcarotid (TCAR) approach on outcomes after CAS. METHODS: We identified all patients undergoing CAS in the Vascular Quality Initiative registry from January 2016 to December 2021. We compared outcomes across 1:3 propensity score-matched cohorts of patients who underwent tr/tbCAS versus tfCAS or tr/tbCAS versus TCAR. As a secondary analysis, we assessed outcomes stratified by carotid symptom status. Our primary outcome was a composite end point of in-hospital stroke/death. RESULTS: Among 40,835 CAS patients, 962 (2.4%) underwent tr/tbCAS, 18,840 (46%) underwent tfCAS, and 21,033 (52%) underwent TCAR. Among matched patients who underwent tr/tbCAS versus tfCAS, there was no significant difference in the risk of stroke/death (4.1% vs 2.9%; relative risk [RR] 1.4; 95% confidence interval [CI], 0.95-2.1), but tr/tbCAS was associated with a higher risk of death (2.4% vs 1.3%; RR, 1.8; 95% CI, 1.1-3.1). In the symptomatic subgroup, tr/tbCAS was associated with a higher risk of stroke/death (6.1% vs 3.9%; RR, 1.6; 95% CI, 1.0-2.4) and death (3.6% vs 1.7%; RR, 2.1; 95% CI, 1.2-3.7), but there were no differences in asymptomatic patients. After adjustment for mRS in patients with preoperative stroke, there were no significant differences in stroke/death (RR, 1.1; 95% CI, 0.66-1.9) or death (RR, 1.6; 95% CI, 0.81-3.3) between groups. In matched patients who underwent tr/tbCAS versus TCAR, tr/tbCAS was associated with a higher risk of stroke/death (4.2% vs 2.3%; RR, 1.8; 95% CI, 1.2-2.7) and death (2.4% vs 0.5%; RR, 4.8; 95% CI, 2.4-9.5). In the symptomatic subgroup, tr/tbCAS remained associated with a higher risk of stroke/death (6.2% vs 2.4%; RR, 2.6; 95% CI, 1.6-4.2) and death (3.7% vs 0.7%; RR, 5.6; 95% CI, 2.6-12), but there were no differences in asymptomatic patients. After adjustment for Modified Rankin Scale in patients with preoperative stroke, there were no significant differences in stroke/death (RR, 1.4; 95% CI, 0.79-2.6) or death (RR, 2.3; 95% CI, 0.95-5.7) between groups. CONCLUSIONS: Compared with tfCAS or TCAR, tr/tbCAS was associated with a higher risk of in-hospital stroke/death in symptomatic patients, which was driven primarily by a higher risk of death. These inferior outcomes were partly attributable to more severe preoperative neurologic disability in tr/tbCAS patients. In contrast, there were no differences in outcomes in asymptomatic patients. Overall, our findings highlight the importance of guideline-directed patient selection in tr/tbCAS.

Disparities in reporting and representation by sex, race, and ethnicity in endovascular aortic device trials.

OBJECTIVE: Vulnerable populations, including women and racial and ethnic minorities, have been historically underrepresented in clinical trials. We, therefore, studied the demographics of patients enrolled in pivotal endovascular aortic device trials in the United States. METHODS: We queried the Food and Drug Administration (FDA) medical devices database for all FDA-approved endografts for the treatment of aortic aneurysms, transections, and dissections from September 1999 to November 2021. These included abdominal endovascular aortic repair (EVAR), thoracic EVAR (TEVAR), fenestrated EVAR (FEVAR) devices, and dissection stents. Multiple cases of approval for expanded indications were included separately. The primary outcomes included the proportion of trials reporting participant sex, race, and ethnicity and the proportion of enrolled participants across sex, racial, and ethnic groups. RESULTS: The FDA provided 29 approvals from 29 trials of 24 devices: 15 EVAR devices (52%), 12 TEVAR devices (41%), 1 FEVAR device (3.4%), and 1 dissection stent (3.4%). These trials had included 4046 patients. Of the 29 trials, all had reported on the sex of the participants, and the median female enrollment was 21% (interquartile range [IQR], 11%-34%). The EVAR trials had the lowest female enrollment (11%; IQR, 8.7%-13%) compared with 41% (IQR, 27%-45%) in the TEVAR trials, 21% in the FEVAR trial, and 34% in the dissection stent trial (P < .01 for the difference). Only 52% of the trials had reported the three most common racial groups (White, Black, Asian), and only 48% had reported Hispanic ethnicity. The TEVAR trials were the most likely to report all three racial groups and Hispanic ethnicity (92% and 75%, respectively), while the EVAR trials had the lowest reporting rates (13% and 20%, respectively). Where reported, the median enrollment of racial and ethnic groups across the trials was as follows: Black patients, 9.8% (FEVAR, 0%; EVAR, 1.9%; TEVAR, 12%; dissection stent, 25%; P = .01); Asian patients, 2.4% (EVAR, 0.6%; FEVAR, 2.4%; TEVAR, 2.5%; dissection stent, 11%; P = .24); and Hispanic patients, 3.8% (EVAR, 1.3%; FEVAR, 2.4%; TEVAR, 3.9%; dissection stent, 4.1%; P = .75). CONCLUSIONS: Racial and ethnic minority groups were underrepresented and underreported in pivotal aortic device trials that led to FDA approval. Female patients were also underrepresented in these aortic trials, especially for EVAR. These data suggest the need for standardization of reporting practices and minimum thresholds for minority and female participation in pivotal trials to promote equitable representation.

Transcriptome analysis of islets from diabetes-resistant and diabetes-prone obese mice reveals novel gene regulatory networks involved in beta-cell compensation and failure.

The mechanisms underpinning beta-cell compensation for obesity-associated insulin resistance and beta-cell failure in type 2 diabetes remain poorly understood. We used a large-scale strategy to determine the time-dependent transcriptomic changes in islets of diabetes-prone db/db and diabetes-resistant ob/ob mice at 6 and 16 weeks of age. Differentially expressed genes were subjected to cluster, gene ontology, pathway and gene set enrichment analyses. A distinctive gene expression pattern was observed in 16 week db/db islets in comparison to the other groups with alterations in transcriptional regulators of islet cell identity, upregulation of glucose/lipid metabolism, and various stress response genes, and downregulation of specific amino acid transport and metabolism genes. In contrast, ob/ob islets displayed a coordinated downregulation of metabolic and stress response genes at 6 weeks of age, suggestive of a preemptive reconfiguration in these islets to lower the threshold of metabolic activation in response to increased insulin demand thereby preserving beta-cell function and preventing cellular stress. In addition, amino acid transport and metabolism genes were upregulated in ob/ob islets, suggesting an important role of glutamate metabolism in beta-cell compensation. Gene set enrichment analysis of differentially expressed genes identified the enrichment of binding motifs for transcription factors, FOXO4, NFATC1, and MAZ. siRNA-mediated knockdown of these genes in MIN6 cells altered cell death, insulin secretion, and stress gene expression. In conclusion, these data revealed novel gene regulatory networks involved in beta-cell compensation and failure. Preemptive metabolic reconfiguration in diabetes-resistant islets may dampen metabolic activation and cellular stress during obesity.

Response to 'The essential role of dermatology publications in enhancing professional diversity, equity and inclusion'.

LINKED ARTICLE: Burgin et al. Br J Dermatol 2021; 185:473-4.

Light-activated photosealing with human amniotic membrane strengthens bowel anastomosis in a hypotensive, trauma-relevant swine model.

BACKGROUND: Gastrointestinal anastomotic leakage is a dreaded complication despite advancements in surgical technique. Photochemical tissue bonding (PTB) is a method of sealing tissue surfaces utilizing photoactive dye. We evaluated if crosslinked human amniotic membrane (xHAM) photosealed over the enteroenterostomy would augment anastomotic strength in a trauma-relevant swine hemorrhagic shock model. METHODS: Yorkshire swine (40-45 kg, n = 14) underwent midline laparotomy and sharp transection of the small intestine 120 cm proximal to the ileocecal fold. Immediately following intestinal transection, a controlled arterial bleed was performed to reach hemorrhagic shock. Intestinal repair was performed after 60 minutes and autotransfusion of the withdrawn blood was performed for resuscitation. Animals were randomized to small intestinal anastomosis by one of the following methods (seven per group): suture repair (SR), or SR with PTB augmentation. Animals were euthanized at postoperative Day 28 and burst pressure (BP) strength testing was performed on all excised specimens. RESULTS: Mean BP for SR, PTB, and native tissue groups were 229 ± 40, 282 ± 21, and 282 ± 47 mmHg, respectively, with the SR group statistically significantly different on analysis of variance (p = 0.02). Post-hoc Tukey all-pairs comparison demonstrated a statistically significant difference in burst pressure strength between the SR only and the PTB group (p = 0.04). All specimens in SR group ruptured at the anastomosis upon burst pressure testing, while all specimens in the PTB group ruptured at least 2.5 cm from the anastomosis. CONCLUSION: Photosealing with xHAM significantly augments the strength of small intestinal anastomosis performed in a trauma porcine model.

Vascular transcriptome landscape of Trail-/- mice: Implications and therapeutic strategies for diabetic vascular disease.

Circulating plasma TRAIL levels are suppressed in patients with cardiovascular and diabetic diseases. To identify novel targets in vascular metabolic diseases, genome-wide transcriptome of aortic tissue from Trail-/- versus Trail+/+ mice were interrogated. We found 861 genes differentially expressed with TRAIL deletion. Gene enrichment analyses showed many of these genes were related to inflammation, cell-to-cell cytoskeletal interactions, and transcriptional modulation. We identified vascular protective and pathological gene clusters, with Ifi205 as the most significantly reduced vascular protective gene, whereas Glut1, the most significantly increased pathological gene with TRAIL deletion. We hypothesized that therapeutic targets could be devised from such integrated analysis and validated our findings from vascular tissues of diabetic mice. From the differentially expressed gene targets, enriched transcription factor (TF) and microRNA binding motifs were identified. The top two TFs were Elk1 and Sp1, with enrichment to eight gene targets common to both. miR-520d-3p and miR-377-3p were the top enriched microRNAs with TRAIL deletion; with four overlapping genes enriched for both microRNAs. Our findings offer an alternate in silico approach for therapeutic target identification and present a deeper understanding of gene signatures and pathways altered with TRAIL suppression in the vasculature.

Familization risks, defamilization risks and older women.

This article is about the familization and defamilization risks faced by older women. Such risks are generated by the lack of one or both of two conditions: the freedom to choose whether or not to perform certain family roles; and the capacity to maintain a reasonable standard of living. Examples are drawn from findings of a qualitative study in Hong Kong, in which 40 older women aged 65 or above were interviewed to discuss their experiences of issues relating to the risks and their diverse preferences of how these issues should be handled.

Digital conversations about suicide among teenagers and adults with epilepsy: A big-data, machine learning analysis.

OBJECTIVE: Digital media conversations can provide important insight into the concerns and struggles of people with epilepsy (PWE) outside of formal clinical settings and help generate useful information for treatment planning. Our study aimed to explore the big data from open-source digital conversations among PWE with regard to suicidality, specifically comparing teenagers and adults, using machine learning technology. METHODS: Advanced machine-learning empowered methodology was used to mine and structure open-source digital conversations of self-identifying teenagers and adults who endorsed suffering from epilepsy and engaged in conversation about suicide. The search was limited to 12 months and included only conversations originating from US internet protocol (IP) addresses. Natural language processing and text analytics were employed to develop a thematic analysis. RESULTS: A total of 222 000 unique conversations about epilepsy, including 9000 (4%) related to suicide, were posted during the study period. The suicide-related conversations were posted by 7.8% of teenagers and 3.2% of adults in the study. Several critical differences were noted between teenagers and adults. A higher percentage of teenagers are: fearful of "the unknown" due to seizures (63% vs 12% adults), concerned about social consequences of seizures (30% vs 21%), and seek emotional support (29% vs 19%). In contrast, a significantly higher percentage of adults show a defeatist ("given up") attitude compared to teenagers (42% vs 4%). There were important differences in the author's determined sentiments behind the conversations among teenagers and adults. SIGNIFICANCE: In this first of its kind big data analysis of nearly a quarter-million digital conversations about epilepsy using machine learning, we found that teenagers engage in an online conversation about suicide more often than adults. There are some key differences in the attitudes and concerns, which may have implications for the treatment of younger patients with epilepsy.

Magnetite and Green Rust: Synthesis, Properties, and Environmental Applications of Mixed-Valent Iron Minerals.

Mixed-valent iron [Fe(II)-Fe(III)] minerals such as magnetite and green rust have received a significant amount of attention over recent decades, especially in the environmental sciences. These mineral phases are intrinsic and essential parts of biogeochemical cycling of metals and organic carbon and play an important role regarding the mobility, toxicity, and redox transformation of organic and inorganic pollutants. The formation pathways, mineral properties, and applications of magnetite and green rust are currently active areas of research in geochemistry, environmental mineralogy, geomicrobiology, material sciences, environmental engineering, and environmental remediation. These aspects ultimately dictate the reactivity of magnetite and green rust in the environment, which has important consequences for the application of these mineral phases, for example in remediation strategies. In this review we discuss the properties, occurrence, formation by biotic as well as abiotic pathways, characterization techniques, and environmental applications of magnetite and green rust in the environment. The aim is to present a detailed overview of the key aspects related to these mineral phases which can be used as an important resource for researchers working in a diverse range of fields dealing with mixed-valent iron minerals.

Differences in BMI between Mexican and Colombian patients receiving antipsychotics: results from the International Study of Latinos on Antipsychotics (ISLA).

Objective: The objective of this study is to examine the association of country of residence with body mass index (BMI) between Mexican and Colombian patients exposed to antipsychotics. We hypothesize that there will be a significant association between country of residence and BMI and that Mexican patients will have higher BMI than their Colombian counterparts.Design: The International Study of Latinos on Antipsychotics (ISLA) is a multisite, international, cross sectional study of adult Latino patients exposed to antipsychotics in two Latin American Countries (i.e. Mexico and Colombia). Data were collected from a total of 205 patients (149 from Mexico and 56 from Colombia). The sites in Mexico included outpatient clinics in Mexicali, Monterrey and Tijuana. In Colombia, data were collected from outpatient clinics in Bogotá. For this study we included patients attending outpatient psychiatric community clinics that received at least one antipsychotic (new and old generation) for the last 3 months. A linear regression model was used to determine the association of country of residence with BMI for participants exposed to an antipsychotic.Results: After controlling for demographics, behaviors, biological and comorbid psychiatric variables, there was a significant difference between Colombia vs. Mexico in the BMI of patients exposed to antipsychotics (ß = 4.9; p < 0.05).Conclusion: Our hypotheses were supported. These results suggest that differences in BMI in patients exposed to antipsychotics in Mexico and Colombia may reflect differences in prevalence of overweight/obesity at the population level in the respective countries, and highlights the involvement of other risk factors, which may include genetics.

In-hospital versus postdischarge major adverse events within 30 days following lower extremity revascularization.

OBJECTIVE: Studies using hospital discharge data likely underestimate postoperative morbidity and mortality after lower extremity revascularization because they fail to capture postdischarge events. However, the degree of underestimation and the timing of postdischarge complications are not well-characterized. METHODS: We used the American College of Surgeons National Surgical Quality Improvement Program procedure-targeted vascular databases from 2011 to 2015 to tabulate 30-day adverse events (in hospital and after discharge) for lower extremity bypass (LEB) and percutaneous vascular interventions (PVIs) performed for claudication and chronic limb-threatening ischemia (CLTI). RESULTS: A total of 14,125 patients underwent lower extremity revascularization, 8909 patients (63%) with LEB and 5216 (37%) with PVI. For CLTI, total 30-day mortality was similar between PVI and LEB (2.3% vs 2.1%; P = .61), but in-hospital deaths only accounted for 43% of PVI mortality and only 65% of LEB mortality (P ≤ .001). Major adverse cardiac events occurred in 2.9% of PVI patients and 4.6% of LEB patients (P < .001), with postdischarge events accounting for 37% of PVI events and 18% of LEB (P ≤ .001). Although the 30-day reoperation rates were 14% for PVI and 18% for LEB (P < .001), almost one-half occurred after discharge (PVI 46% vs LEB 44%; P = .55). Any postoperative major adverse events (MAEs) occurred in 22% of patients after PVI and 31% after LEB, with more than one-half occurring after discharge (PVI 56% vs LEB 53%; P = .17). For claudicants, total 30-day mortality was 0.4% for PVI and 0.7% for LEB (P = .32), with the vast majority of events occurring after discharge (PVI 90% vs LEB 50%; P = .049). The 30-day reoperation rates were 5.2% for PVI and 8.0% for LEB (P < .001), with more than one-half occurring after discharge (PVI 63% vs LEB 53%; P = .09). Any MAEs occurred in 7.0% of patients after PVI and 17% after bypass, with the majority occurring after discharge (PVI 65% vs LEB 63%; P = .66). CONCLUSIONS: Most MAEs occur less frequently after PVI than LEB. However, a significant number of major of adverse events after lower extremity revascularization occur after leaving the hospital, especially after PVI, which may overestimate its benefits compared with LEB if only in-hospital data are evaluated. These data demonstrate the importance of reporting 30-day rather than in-hospital outcomes when evaluating postoperative adverse events.

Sex differences in mortality and morbidity following repair of intact abdominal aortic aneurysms.

OBJECTIVE: Medicare studies have shown increased perioperative mortality in women compared with men following endovascular and open abdominal aortic aneurysm (AAA) repair. However, a recent regional study of high-volume centers, adjusting for anatomy but limited in sample size, did not show sex to be predictive of worse outcomes. This study aimed to evaluate sex differences after intact AAA repair in a national clinical registry. METHODS: The targeted vascular module of the National Surgical Quality Improvement Program was queried to identify patients undergoing endovascular aneurysm repair (EVAR) or open repair for intact, infrarenal AAA from 2011 to 2014. Univariate analysis was performed using the Fisher exact test and Mann-Whitney test. Multivariable logistic regression was used to account for differences in comorbidities, aneurysm details, and operative characteristics. RESULTS: We identified 6611 patients (19% women) who underwent intact AAA repair (87% EVAR; 83% women vs 88% men; P < .001). Women were older (median age, 76 vs 73 years; P < .001), had smaller aneurysms (median, 5.4 vs 5.5 cm; P < .001), and had more chronic obstructive pulmonary disease (22% vs 17%; P < .001). Among patients undergoing EVAR, women had longer operative times (median, 138 [interquartile range, 103-170] vs 131 [106-181] minutes; P < .01) and more often underwent renal (6.3% vs 4.1%; P < .01) and lower extremity (6.6% vs 3.8%; P < .01) revascularization. After open repair, women had shorter operative time (215 [177-304] vs 226 [165-264] minutes; P = .02), but women less frequently underwent lower extremity revascularization (3.1% vs 8.2%; P = .03). Thirty-day mortality was higher in women after EVAR (3.2% vs 1.2%; P < .001) and open repair (8.0% vs 4.0%; P = .04). After adjusting for repair type, age, aneurysm diameter, and comorbidities, female sex was independently associated with mortality (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.1-2.6; P = .02) and major complications (OR, 1.4; CI, 1.1-1.7; P < .01) after intact AAA repair. However, after adjusting for aortic size index rather than for aortic diameter, the association between female sex and mortality (OR, 1.5; CI, 0.98-2.4; P = .06) and major complications (OR, 1.1; CI, 0.9-1.4; P = .24) was reduced. CONCLUSIONS: Women were at higher risk for 30-day death and major complications after intact AAA repair. Some of this disparity may be explained by differences in aortic size index, which should be further evaluated to determine the ideal threshold for repair.

Identification of miR-34 regulatory networks in settings of disease and antimiR-therapy: Implications for treating cardiac pathology and other diseases.

Expression of the miR-34 family (miR-34a, -34b, -34c) is elevated in settings of heart disease, and inhibition with antimiR-34a/antimiR-34 has emerged as a promising therapeutic strategy. Under chronic cardiac disease settings, targeting the entire miR-34 family is more effective than targeting miR-34a alone. The identification of transcription factor (TF)-miRNA regulatory networks has added complexity to understanding the therapeutic potential of miRNA-based therapies. Here, we sought to determine whether antimiR-34 targets secondary miRNAs via TFs which could contribute to antimiR-34-mediated protection. Using miRNA-Seq we identified differentially regulated miRNAs in hearts from mice with cardiac pathology due to transverse aortic constriction (TAC), and focused on miRNAs which were also regulated by antimiR-34. Two clusters of stress-responsive miRNAs were classified as "pathological" and "cardioprotective," respectively. Using ChIPBase we identified 45 TF binding sites on the promoters of "pathological" and "cardioprotective" miRNAs, and 5 represented direct targets of miR-34, with the capacity to regulate other miRNAs. Knockdown studies in a cardiomyoblast cell line demonstrated that expression of 2 "pathological" miRNAs (let-7e, miR-31) was regulated by one of the identified TFs. Furthermore, by qPCR we confirmed that expression of let-7e and miR-31 was lower in hearts from antimiR-34 treated TAC mice; this may explain why targeting the entire miR-34 family is more effective than targeting miR-34a alone. Finally, we showed that Acsl4 (a common target of miR-34, let-7e and miR-31) was increased in hearts from TAC antimiR-34 treated mice. In summary, antimiR-34 regulates the expression of other miRNAs and this has implications for drug development.

Trends in Treatment and Mortality for Mesenteric Ischemia in the United States from 2000 to 2012.

BACKGROUND: It is unknown whether increased endovascular treatment of chronic mesenteric ischemia has led to decreases in open surgery, acute mesenteric ischemia, or overall mortality. The present study evaluates the trends in endovascular and open treatment over time for chronic and acute mesenteric ischemia. METHODS: We identified patients with chronic or acute mesenteric ischemia in the Nationwide Inpatient Sample and Center for Disease Control and Prevention database from 2000 to 2012. Trends in revascularization, mortality, and total deaths were evaluated over time. Data were adjusted to account for population growth. RESULTS: There were 14,810 revascularizations for chronic mesenteric ischemia (10,453 endovascular and 4,358 open) and 11,294 revascularizations for acute mesenteric ischemia (4,983 endovascular and 6,311 open). Endovascular treatment increased for both chronic (0.6-4.5/million, P < 0.01) and acute mesenteric ischemia (0.6-1.8/million, P < 0.01). However, concurrent declines in open surgery did not occur (chronic: 1-1.1/million, acute: 1.8-1.7/million). Among patients with acute mesenteric ischemia, the proportion with atrial fibrillation (18%) and frequency of embolectomy (1/million per year) remained stable. In-hospital mortality rates decreased for both endovascular (chronic: 8-3%, P < 0.01; acute: 28-17%, P < 0.01) and open treatment (chronic: 21-9%, P < 0.01; acute: 40-25%, P < 0.01). Annual population-based mortality remained stable for chronic mesenteric ischemia (0.7-0.6 deaths per million/year), but decreased for acute mesenteric ischemia (12.9-5.3 deaths per million/year, P < 0.01). CONCLUSIONS: Population mortality from acute mesenteric ischemia declined from 2000 to 2012, correlated with dramatic increases in endovascular intervention for chronic mesenteric ischemia, and in spite of a stable rate of embolization. However, open surgery for both chronic and acute ischemia remained stable.

The effects of defamilization and familization measures on the accumulation of retirement income for women in the UK.

This article is concerned with the link between the effects of pro-market pension reforms on women and familization/defamilization measures. It aims to contribute to the study of this link in three ways. Firstly, it identifies defamilization/familization measures that have the potential to reduce negative effects of pro-market pension measures on women. Secondly, based on the examples from the United Kingdom, it shows that the government's willingness to provide sufficient defamilization/familization measures to assist women to deal with the negative effects of the pro-market pension measures should not be taken for granted. Thirdly, it suggests ways for tackling this problem.