The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair.

Macrophage plasticity is critical for normal tissue repair to ensure transition from the inflammatory to the proliferative phase of healing. We examined macrophages isolated from wounds of patients afflicted with diabetes and of healthy controls and found differential expression of the methyltransferase Setdb2. Myeloid-specific deletion of Setdb2 impaired the transition of macrophages from an inflammatory phenotype to a reparative one in normal wound healing. Mechanistically, Setdb2 trimethylated histone 3 at NF-κB binding sites on inflammatory cytokine gene promoters to suppress transcription. Setdb2 expression in wound macrophages was regulated by interferon (IFN) ß, and under diabetic conditions, this IFNß-Setdb2 axis was impaired, leading to a persistent inflammatory macrophage phenotype in diabetic wounds. Setdb2 regulated the expression of xanthine oxidase and thereby the uric acid (UA) pathway of purine catabolism in macrophages, and pharmacologic targeting of Setdb2 or the UA pathway improved healing. Thus, Setdb2 regulates macrophage plasticity during normal and pathologic wound repair and is a target for therapeutic manipulation.

Single-Nuclei RNA-Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease.

BACKGROUND: Lower extremity peripheral artery disease (PAD) is a growing epidemic with limited effective treatment options. Here, we provide a single-nuclei atlas of PAD limb muscle to facilitate a better understanding of the composition of cells and transcriptional differences that comprise the diseased limb muscle. METHODS: We obtained gastrocnemius muscle specimens from 20 patients with PAD and 12 non-PAD controls. Nuclei were isolated and single-nuclei RNA-sequencing was performed. The composition of nuclei was characterized by iterative clustering via principal component analysis, differential expression analysis, and the use of known marker genes. Bioinformatics analysis was performed to determine differences in gene expression between PAD and non-PAD nuclei, as well as subsequent analysis of intercellular signaling networks. Additional histological analyses of muscle specimens accompany the single-nuclei RNA-sequencing atlas. RESULTS: Single-nuclei RNA-sequencing analysis indicated a fiber type shift with patients with PAD having fewer type I (slow/oxidative) and more type II (fast/glycolytic) myonuclei compared with non-PAD, which was confirmed using immunostaining of muscle specimens. Myonuclei from PAD displayed global upregulation of genes involved in stress response, autophagy, hypoxia, and atrophy. Subclustering of myonuclei also identified populations that were unique to PAD muscle characterized by metabolic dysregulation. PAD muscles also displayed unique transcriptional profiles and increased diversity of transcriptomes in muscle stem cells, regenerating myonuclei, and fibro-adipogenic progenitor cells. Analysis of intercellular communication networks revealed fibro-adipogenic progenitors as a major signaling hub in PAD muscle, as well as deficiencies in angiogenic and bone morphogenetic protein signaling which may contribute to poor limb function in PAD. CONCLUSIONS: This reference single-nuclei RNA-sequencing atlas provides a comprehensive analysis of the cell composition, transcriptional signature, and intercellular communication pathways that are altered in the PAD condition.

Chemical imaging of cellular ultrastructure by null-deflection infrared spectroscopic measurements.

Nearfield spectroscopic imaging techniques can be a powerful tool to map both cellular ultrastructure and molecular composition simultaneously but are currently limited in measurement capability. Resonance enhanced (RE) atomic force microscopy infrared (AFM-IR) spectroscopic imaging offers high-sensitivity measurements, for example, but probe-sample mechanical coupling, nonmolecular optical gradient forces, and noise overwhelm recorded chemical signals. Here, we analyze the key factors limiting AFM-IR measurements and propose an instrument design that enables high-sensitivity nanoscale IR imaging by combining null-deflection measurements with RE sensitivity. Our developed null-deflection scanning probe IR (NDIR) spectroscopic imaging provides ∼24× improvement in signal-to-noise ratio (SNR) compared with the state of the art, enables optimal signal recording by combining cantilever resonance with maximum laser power, and reduces background nonmolecular signals for improved analytical accuracy. We demonstrate the use of these properties for high-sensitivity, hyperspectral imaging of chemical domains in 100-nm-thick sections of cellular acini of a prototypical cancer model cell line, MCF-10A. NDIR chemical imaging enables facile recording of label-free, chemically accurate, high-SNR vibrational spectroscopic data from nanoscale domains, paving the path for routine studies of biomedical, forensic, and materials samples.

A patient-centered textbook outcome measure effectively discriminates contemporary elective open abdominal aortic aneurysm repair quality.

BACKGROUND: There is persistent controversy surrounding the merit of surgical volume benchmarks being used solely as a sufficient proxy for assessing the quality of open abdominal aortic aneurysm (AAA) repair. Importantly, operative volume quotas may fail to reflect a more nuanced and comprehensive depiction of surgical outcomes most relevant to patients. Accordingly, we herein propose a patient-centered textbook outcome (TO) for AAA repair that is analogous to other large magnitude extirpative operations performed in other surgical specialties, and test its feasibility to discriminate hospital performance using Society for Vascular Surgery (SVS) volume guidelines. METHODS: All elective open infrarenal AAA repairs (OAR) in the SVS-Vascular Quality Initiative were examined (2009-2022). The primary end point was a TO, defined as a composite of no in-hospital complication or reintervention/reoperation, length of stay of ≤10 days, home discharge, and 1-year survival rates. The discriminatory ability of the TO measure was assessed by comparing centers that did or did not meet the SVS annual OAR volume threshold recommendation (high volume ≥10 OARs/year; low volume <10 OARs/year). Logistic regression and multivariable models adjusted for patient and procedure-related differences. RESULTS: A total of 9657 OARs across 198 centers were analyzed (mean age, 69.5 ± 8.4 years; female, 26%; non-White, 12%). A TO was identified in 44% (n = 4293) of the overall cohort. The incidence of individual TO components included no in-hospital complication (61%), no in-hospital reintervention or reoperation (92%), length of stay of ≤10 days (78%), home discharge (76%), and 1-year survival (91%). Median annual center volume was 6 (interquartile range, 3-10) and a majority of centers did not meet the SVS volume suggested threshold (<10 OARs/year, n = 148 [74%]). However, most patients (6265 of 9657 [65%]) underwent OAR in high-volume hospitals. When comparing high- and low-volume centers, a TO was more likely to occur in high-volume institutions: ≥10 OARs/year (46%) vs <10 OARs/year (42%; P = .0006). The association of a protective effect for higher center volume remained after risk adjustment (odds ratio, 1.1; 95% confidence interval, 1.05-1.26; P = .003). CONCLUSIONS: TOs for elective OAR reflect a more nuanced and comprehensive patient centered proxy to measure care delivery, consistent with other surgical specialties. Surprisingly, a TO was achieved in <50% of elective AAA cases nationally. Although the likelihood of a TO seems to correlate with SVS center volume recommendations, it more importantly reflects elements which may be prioritized by patients and thus offers insights into further improving real-world AAA care.

Changing patterns of nest predation and predator communities along a tropical elevation gradient.

Tropical montane communities host the world's highest beta diversity of birds, a phenomenon usually attributed to community turnover caused by changes in biotic and abiotic factors along elevation gradients. Yet, empirical data on most biotic factors are lacking. Nest predation is thought to be especially important because it appears to be common and can change selective pressures underlying life history traits, which can alter competitive interactions. We monitored 2538 nests, 338 of which had known nest predators, to evaluate if nest predation changes along a tropical elevational gradient. We found that nest predation decreased with elevation, reflecting the loss of lowland predators that do not tolerate colder climates. We found different "super" nest predators at each elevation that accounted for a high percentage of events, suggesting that selection pressures exerted by nest predator communities may be less diffuse than has been hypothesized, at least for birds nesting in the understory.

The structure and organisation of an Amazonian bird community remains little changed after nearly four decades in Manu National Park.

Documenting patterns of spatiotemporal change in hyper-diverse communities remains a challenge for tropical ecology yet is increasingly urgent as some long-term studies have shown major declines in bird communities in undisturbed sites. In 1982, Terborgh et al. quantified the structure and organisation of the bird community in a 97-ha. plot in southeastern Peru. We revisited the same plot in 2018 using the same methodologies as the original study to evaluate community-wide changes. Contrary to longitudinal studies of other neotropical bird communities (Tiputini, Manaus, and Panama), we found little change in community structure and organisation, with increases in 5, decreases in 2 and no change in 7 foraging guilds. This apparent stability suggests that large forest reserves such as the Manu National Park, possibly due to regional topographical influences on precipitation, still provide the conditions for establishing refugia from at least some of the effects of global change on bird communities.

N-acetylcysteine treatment attenuates hemodialysis access-related limb pathophysiology in mice with chronic kidney disease.

The objective of the present study was to determine if treatment with N-acetylcysteine (NAC) could reduce access-related limb dysfunction in mice. Male and female C57BL6J mice were fed an adenine-supplemented diet to induce chronic kidney disease (CKD) prior to the surgical creation of an arteriovenous fistula (AVF) in the iliac vascular bundle. AVF creation significantly increased peak aortic and infrarenal vena cava blood flow velocities, but NAC treatment had no significant impact, indicating that fistula maturation was not impacted by NAC treatment. Hindlimb muscle and paw perfusion recovery and muscle capillary density in the AVF limb were unaffected by NAC treatment. However, NAC treatment significantly increased the mass of the tibialis anterior (P = 0.0120) and soleus (P = 0.0452) muscles post-AVF. There was a significant main effect of NAC treatment on hindlimb grip strength at postoperative day 12 (POD 12) (P = 0.0003), driven by significantly higher grip strength in both male (P = 0.0273) and female (P = 0.0031) mice treated with NAC. There was also a significant main effect of NAC treatment on the walking speed at postoperative day 12 (P = 0.0447), and post hoc testing revealed an improvement in NAC-treated male mice (P = 0.0091). The area of postsynaptic acetylcholine receptors (P = 0.0263) and motor endplates (P = 0.0240) was also increased by NAC treatment. Interestingly, hindlimb skeletal muscle mitochondrial oxidative phosphorylation trended higher in NAC-treated female mice but was not statistically significant (P = 0.0973). Muscle glutathione levels and redox status were not significantly impacted by NAC treatment in either sex. In summary, NAC treatment attenuated some aspects of neuromotor pathology in mice with chronic kidney disease following AVF creation.NEW & NOTEWORTHY Hemodialysis via autogenous arteriovenous fistula (AVF) is the preferred first-line modality for renal replacement therapy in patients with end-stage kidney disease. However, patients undergoing AVF surgery frequently experience a spectrum of hand disability symptoms postsurgery including weakness and neuromotor dysfunction. Unfortunately, no treatment is currently available to prevent or mitigate these symptoms. Here, we provide evidence that daily N-acetylcysteine supplementation can attenuate some aspects of limb neuromotor function in a preclinical mouse model of AVF.

Clinical and Economic Outcomes in Patients With Metastatic Urothelial Carcinoma Receiving First-Line Systemic Treatment (the IMPACT UC I Study).

BACKGROUND: The IMPACT UC I study assessed real-world treatment patterns, outcomes, healthcare resource utilization (HCRU), and costs in patients with metastatic urothelial carcinoma (mUC) receiving first-line (1L) systemic treatment after the FDA approval of 1L immune checkpoint inhibitor (ICI) monotherapy. PATIENTS AND METHODS: This retrospective study used 100% Medicare fee-for-service claims from 1/1/2015 to 6/30/2019 to identify patients aged ≥18 years diagnosed with UC with evidence of metastatic disease, continuously enrolled for 6 months before and after initial diagnosis. Patients were grouped by 1L treatment: cisplatin-containing chemotherapy, carboplatin-containing chemotherapy, ICI monotherapy, or nonplatinum-containing therapy. Unadjusted time on 1L treatment (TOT), overall survival (OS), HCRU, and total healthcare costs were analyzed. RESULTS: Of 18 888 patients with mUC, 8630 (45.7%) had received identified 1L systemic treatment; platinum-containing chemotherapy was the most common (cisplatin-containing chemotherapy, 37.6%; carboplatin-containing chemotherapy, 30.2%). Cisplatin- and carboplatin-containing chemotherapy had the shortest time-to-treatment initiation (median, 1.7-3.0 months) and longest TOT (median, 4.0-4.3 months). Median OS was longest with cisplatin-containing chemotherapy (20.0 months) and shortest with ICI monotherapy (7.6 months). Cisplatin- and carboplatin-containing chemotherapy were associated with highest HCRU; total healthcare costs were approximately 2-fold higher with ICI monotherapy vs other 1L treatments ($10 359 vs $5042-$5709 per patient per month). CONCLUSION: 1L platinum-containing chemotherapy resulted in the longest median OS and highest HCRU, whereas 1L ICI treatment had the shortest median OS and the highest costs. Over 50% of patients diagnosed with advanced UC (aUC) received no systemic therapy, highlighting the importance of optimal 1L treatment decisions in aUC.

Wet and dry extremes reduce arthropod biomass independently of leaf phenology in the wet tropics.

Warming temperatures are increasing rainfall extremes, yet arthropod responses to climatic fluctuations remain poorly understood. Here, we used spatiotemporal variation in tropical montane climate as a natural experiment to compare the importance of biotic versus abiotic drivers in regulating arthropod biomass. We combined intensive field data on arthropods, leaf phenology and in situ weather across a 1700-3100 m elevation and rainfall gradient, along with desiccation-resistance experiments and multi-decadal modelling. We found limited support for biotic drivers with weak increases in some herbivorous taxa on shrubs with new leaves, but no landscape-scale effects of leaf phenology, which tracked light and cloud cover. Instead, rainfall explained extensive interannual variability with maximum biomass at intermediate rainfall (130 mm month-1 ) as both 3 months of high and low rainfall reduced arthropods by half. Based on 50 years of regional rainfall, our dynamic arthropod model predicted shifts in the timing of biomass maxima within cloud forests before plant communities transition to seasonally deciduous dry forests (mean annual rainfall 1000-2500 mm vs. <800 mm). Rainfall magnitude was the primary driver, but during high solar insolation, the 'drying power of air' (VPDmax ) reduced biomass within days contributing to drought related to the El Niño-Southern Oscillation (ENSO). Highlighting risks from drought, experiments demonstrated community-wide susceptibility to desiccation except for some caterpillars in which melanin-based coloration appeared to reduce the effects of evaporative drying. Overall, we provide multiple lines of evidence that several months of heavy rain or drought reduce arthropod biomass independently of deep-rooted plants with the potential to destabilize insectivore food webs.

El aumento de las temperaturas está incrementando los extremos de precipitación, pero las respuestas de los artrópodos a las fluctuaciones climáticas siguen siendo poco conocidas. Aquí, utilizamos la variación espaciotemporal en el clima montano tropical como un experimento natural para comparar la importancia de los factores bióticos versus abióticos en la regulación de la biomasa de artrópodos. Combinamos datos de campo intensivos de artrópodos, fenología de las hojas y clima in situ a lo largo de un gradiente altitudinal de 1700 a 3100 m y un gradiente de precipitación, junto con experimentos de resistencia a la desecación y modelos multi-decenales. Encontramos evidencia limitada para los factores bióticos con aumentos débiles en algunos taxones de herbívoros en arbustos con hojas nuevas, pero no hubo efectos a escala de paisaje en la fenología de la hoja, que rastreaba la luz y la cubierta de nubes. En cambio, las precipitaciones explicaron la amplia variabilidad interanual con una biomasa máxima en precipitaciones intermedias (130 mm mes−1 ), ya que los tres meses de precipitaciones altas y bajas redujeron los artrópodos a la mitad. Basándose en 50 años de precipitación regional, nuestro modelo dinámico de artrópodos predijo cambios en el momento de los máximos de biomasa dentro del bosque nuboso antes de que las comunidades de plantas hicieran la transición al bosque seco estacional caducifolio (precipitación media anual 1000-2500 mm vs. <800 mm). La magnitud de las lluvias fue el principal factor, pero durante la alta insolación solar, el "poder de secado del aire" (VPDmax ) redujo la biomasa en cuestión de días, lo que contribuyó a la sequía relacionada con El Niño-Southern Oscillation (ENSO). Destacando los riesgos de la sequía, los experimentos demostraron la susceptibilidad de toda la comunidad a la desecación, excepto en el caso de algunas orugas en las que la coloración a base de melanina parece reducir los efectos de la desecación por evaporación. En resumen, proporcionamos múltiples líneas de evidencia de que varios meses de fuertes lluvias o sequías reducen la biomasa de artrópodos independientemente de las plantas de raíces profundas con el potencial de desestabilizar las redes alimentarias de los insectívoros.

Sensitivity of tropical montane birds to anthropogenic disturbance and management strategies for their conservation in agricultural landscapes.

Tropical montane bird communities are hypothesized to be highly sensitive to anthropogenic disturbance because species are adapted to a narrow range of environmental conditions and display high rates of endemism. We assessed avian sensitivity at regional and continental scales for a global epicenter of montane bird biodiversity, the tropical Andes. Using data from an intensive field study of cloud forest bird communities across 7 landscapes undergoing agricultural conversion in northern Peru (1800-3100 m, 2016-2017) and a pan-Andean synthesis of forest bird sensitivity, we developed management strategies for maintaining avian biodiversity in tropical countrysides and examined how environmental specialization predicts species-specific sensitivity to disturbance. In Peru, bird communities occupying countryside habitats contained 29-93% fewer species compared with those in forests and were compositionally distinct due to high levels of species turnover. Fragments of mature forest acted as reservoirs for forest bird diversity, especially when large or surrounded by mixed successional vegetation. In high-intensity agricultural plots, an addition of 10 silvopasture trees or 10% more fencerows per hectare increased species richness by 18-20%. Insectivores and frugivores were most sensitive to disturbance: abundance of 40-70% of species declined in early successional vegetation and silvopasture. These results were supported by our synthesis of 816 montane bird species studied across the Andes. At least 25% of the species declined due to all forms of disturbance, and the percentage rose to 60% in agricultural landscapes. The most sensitive species were those with narrow elevational ranges and small global range sizes, insectivores and carnivores, and species with specialized trophic niches. We recommend protecting forest fragments, especially large ones, and increasing connectivity through the maintenance of early successional vegetation and silvopastoral trees that increase avian diversity in pastures. We provide lists of species-specific sensitivities to anthropogenic disturbance to inform conservation status assessments of Andean birds.

Sensibilidad de aves montanas a perturbaciones antropogénicas y estrategias de manejo para su conservación en paisajes agrícolas Resumen Se ha hipotetizado que las comunidades de aves tropicales montanas son sumamente sensibles a la perturbación antropogénica porque las especies están adaptadas a una reducida gama de condiciones ambientales y tienen altas tasas de endemismo. Evaluamos la sensibilidad aviar a escalas regional y continental para un epicentro global de biodiversidad de aves montanas, los Andes tropicales. Utilizando datos de un estudio intensivo de campo de comunidades de aves de bosques nublados en 7 paisajes bajo conversión agrícola en el norte de Perú (1800 - 3100 m, 2016-2017) y una síntesis pan-Andina de sensibilidad de aves de bosque, desarrollamos estrategias de manejo para el mantenimiento de la biodiversidad de aves en campiñas tropicales y examinamos cómo la especialización ambiental predice la sensibilidad de cada especie a la perturbación. Las comunidades de aves ocupando hábitats campestres tropicales en Perú contenían 29 - 93% menos especies en comparación con las de bosques y tuvieron una composición distinta debido a los altos niveles de recambio de especies. Los fragmentos de bosque maduro fungieron como reservorios para la diversidad de aves de bosque, especialmente cuando eran extensos y estaban rodeados por vegetación secundaria mixta. En las parcelas con actividad agrícola intensiva, la adición de 10 árboles silvopastoriles o 10% más de cercos por hectárea incrementó la riqueza de especies en 18 - 20%. Las insectívoras y frugívoras fueron más sensibles a la perturbación: la abundancia de 40 - 70% de especies declinó en la vegetación secundaria temprana y en la silvopastura. Estos resultados fueron sustentados por nuestra síntesis de 816 especies de aves montanas estudiadas en los Andes. Por lo menos 25% de estas especies declinaron debido a todas las formas de perturbación, y el porcentaje incrementó a 60% en paisajes agrícolas. Las especies más sensibles fueron aquellas con rangos altitudinales estrechos y extensiones de distribución pequeñas, las insectívoras y carnívoras y las especies con nichos tróficos especializados. Recomendamos la protección de fragmentos de bosque, especialmente los extensos, y el incremento de la conectividad mediante el mantenimiento de vegetación secundaria temprana y árboles silvopastoriles que incrementan la diversidad de aves en los pastizales. Proporcionamos listas de la sensibilidad de cada especie a la perturbación antropogénica para contribuir a las evaluaciones del estatus de conservación de aves Andinas.

Gahvora cradling in Tajikistan: Cultural practices and associations with motor development.

In Tajikistan, infants are bound supine in a "gahvora" cradle that severely restricts movement. Does cradling affect motor development and body growth? In three studies (2013-2018), we investigated associations between time in the gahvora (within days and across age) and motor skills and flattened head dimensions in 8-24-month-old Tajik infants (N = 269, 133 girls, 136 boys)) and 4.3-5.1-year-old children (N = 91, 53 girls, 38 boys). Infants had later motor onset ages relative to World Health Organization standards and pronounced brachycephaly; cradling predicted walk onset age and the proficiency of sitting, crawling, and walking. By 4-5 years, children's motor skills were comparable with US norms. Cultural differences in early experiences offer a unique lens onto developmental processes and equifinality in development.

The clinical and molecular spectrum of QRICH1 associated neurodevelopmental disorder.

De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity.

Pressurized DNA state inside herpes capsids-A novel antiviral target.

Drug resistance in viruses represents one of the major challenges of healthcare. As part of an effort to provide a treatment that avoids the possibility of drug resistance, we discovered a novel mechanism of action (MOA) and specific compounds to treat all nine human herpesviruses and animal herpesviruses. The novel MOA targets the pressurized genome state in a viral capsid, "turns off" capsid pressure, and blocks viral genome ejection into a cell nucleus, preventing viral replication. This work serves as a proof-of-concept to demonstrate the feasibility of a new antiviral target-suppressing pressure-driven viral genome ejection-that is likely impervious to developing drug resistance. This pivotal finding presents a platform for discovery of a new class of broad-spectrum treatments for herpesviruses and other viral infections with genome-pressure-dependent replication. A biophysical approach to antiviral treatment such as this is also a vital strategy to prevent the spread of emerging viruses where vaccine development is challenged by high mutation rates or other evasion mechanisms.

Outcomes of endovascular abdominal aortic aneurysm repair conversion in octogenarians treated at a high-volume aorta center.

BACKGROUND: Endovascular abdominal aortic aneurysm repair (EVAR) has become the dominant treatment strategy for infrarenal abdominal aortic aneurysms but has been especially preferred for octogenarian (age ≥80 years) patients because of concerns surrounding comorbidity severity and physiologic frailty. However, EVAR failure resulting in subsequent open conversion (EVAR-c) has been increasingly reported in older patients, although a paucity of literature focusing on the outcomes in this subgroup is available. The purpose of the present analysis was to evaluate our experience with EVAR-c for octogenarians (age ≥80 years) compared with that for younger patients (age <80 years). METHODS: A retrospective review of all nonmycotic EVAR-c procedures (2002-2020) at a single high-volume academic hospital with a dedicated aorta center (available at: https://www.uf-health-aortic-disease-center) was performed. A total of 162 patients were categorized into octogenarian (age ≥80 years; n = 43) and nonoctogenarian (age <80 years; n = 119) cohorts and compared. The primary end point was 30-day mortality. The secondary end points included complications, 90-day mortality, and overall survival. Cox regression was used to determine the effects of selected covariates on mortality risk. The Kaplan-Meier method was used to estimate survival. RESULTS: No differences in the preadmission EVAR reintervention rates were present (octogenarians, 42%; nonoctogenarians, 43%; P = 1.00) although the interval to the first reintervention was longer for the octogenarians (41 months) than for the nonoctogenarians (15 months; P = .01). In addition, the time to EVAR-c was significantly longer for the octogenarian patients (61 months) than for the nonoctogenarian patients (39 months; P < .01). No difference in rupture presentation was evident (14% vs 10%; P = .6). However, elective EVAR-c occurred less frequently for octogenarians (42%) than for nonoctogenarians (59%; P = .07). The abdominal aortic aneurysm diameter was significantly larger for elective octogenarian EVAR-c (7.8 ± 1.9 cm) than for nonoctogenarian EVAR-c (7.0 ± 1.5 cm; P = .02), and the presence of a type Ia endoleak was the most common indication overall (58%; n = 91). A trend toward greater 30-day mortality was evident for octogenarian patients (16%) compared with nonoctogenarian patients (7%; P = .06). Similarly, the 90-day mortality was greater for the octogenarian patients (26%) than for the nonoctogenarian patients (10%; P = .02). However, the incidence of any complication (56% vs 49%; P = .5), readmission rate (12% vs 6%; P = .3), unplanned reoperation rate (10% vs 5%; P = .5), and length of stay (11 days vs 9 days; P = .3) were not significantly different between the two groups. Age ≥80 years was predictive of short-term mortality after nonelective but not after elective surgery. However, increasing comorbidities, nonelective admission, and renal or mesenteric revascularization showed the strongest association with mortality risk. Survival at 1 and 3 years was not different between the two groups when comparing all patients after the first 90 days postoperatively. CONCLUSIONS: Although the unadjusted perioperative mortality was greater for octogenarian patients, the risk-adjusted elective outcomes were comparable to those for younger EVAR-c patients when treated at a high-volume aortic surgery center. This finding underscores the importance of appropriate patient selection and modulation of operative complexity when feasible to achieve optimal results. Providers caring for octogenarian patients with EVAR failure should consider timely elective referral to high-volume aorta centers to reduce resource usage and the frequency of nonelective presentations.

Functional response traits and altered ecological niches drive the disassembly of cloud forest bird communities in tropical montane countrysides.

Anthropogenic disturbance contributes to global change by reshaping the ecological niche space available to biological communities. Quantifying the range of functional response traits required for species persistence is central towards understanding the mechanisms underlying community disassembly in disturbed landscapes. We used intensive field surveys of cloud forest bird communities across seven replicate landscapes undergoing agricultural conversion in the Peruvian Andes to examine how a suite of 16 functional response traits related to morphology, diet, foraging behaviour and environmental niche breadth predict (1) species-specific abundance changes in countryside habitats compared to forest and (2) differential changes to the ecological niche space occupied by communities. Our analyses relied on (1) hierarchical distance sampling models to examine the functional predictors of abundance change across the agricultural land use gradient while accounting for imperfect detection and (2) n-dimensional hypervolumes to quantify the expansion and contraction of ecological niche space in countryside habitats. Key traits related to increased abundance in early successional and mixed-intensity agricultural areas included (1) morphological adaptations to dense understorey habitats, (2) plant-based diets (flowers, fruit and seeds) and (3) broad elevational range limits and habitat breadth. Species occupying mixed and high-intensity agricultural land use regimes had mean elevational range limits 20%-60% wider than species found within forests. Collectively, ecological niche space expanded within agricultural habitats for traits related to diet and environmental niche breadth, while contracting for foraging and dispersal traits. Such changes were driven by species with unique functional trait combinations. Our results reveal the dynamic changes to ecological niche space that underly community structure in disturbed landscapes and highlight how increased niche breadth can ameliorate disturbance sensitivity for generalist species. We emphasize that functional traits can be used to predict changes in community structure across disturbance gradients, allowing insights into specific mechanisms underlying community disassembly beyond emergent patterns of functional diversity. By identifying key functional trait groups that align with different countryside habitats, we demonstrate how conservation practitioners can contribute to the retention of avian functional diversity in agricultural landscapes throughout the world.

La perturbación antropogénica contribuye al cambio global al remodelar el espacio de nicho ecológico disponible para las comunidades biológicas. Cuantificar la gama de rasgos de respuesta funcional requeridos para la persistencia de las especies es fundamental para comprender los mecanismos que subyacen al desensamble de la comunidad en los paisajes perturbados. Utilizamos muestreos de campo intensivos de las comunidades de aves del bosque nublado en siete paisajes replicados convertidos a uso agrícola en los Andes peruanos para examinar cómo un conjunto de 16 rasgos de respuesta funcional relacionados con la morfología, dieta, comportamiento de forrajeo, y la amplitud del nicho ambiental predicen (1) cambios en las abundancias de especies específicas en paisajes agrícolas ("countrysides") en comparación con el bosque y (2) cambios diferenciales en el espacio del nicho ecológico ocupado por las comunidades. Nuestros análisis se basaron en (1) modelos jerárquicos de muestreo por la distancia para examinar los predictores funcionales del cambio de abundancia a través del gradiente de uso de suelo para agricultura teniendo en cuenta la detección imperfecta, y (2) "n-dimensional hypervolumes" para cuantificar la expansión y contracción del espacio de nicho ecológico en los hábitats agrícolas. Los rasgos clave relacionados con el aumento de la abundancia en áreas agrícolas de sucesión temprana y de intensidad mixta incluyeron (1) adaptaciones morfológicas a hábitats de sotobosque denso, (2) dietas basadas en plantas (flores, frutas y semillas), y (3) amplios límites de rango de elevación y amplitud de hábitat. Las especies que ocupan regímenes de suelo agrícola mixto y de alta intensidad tenían límites de rango de elevación promedio 20%-60% más amplios que las especies que se encuentran en los bosques. En conjunto, el espacio del nicho ecológico se expandió dentro de los hábitats agrícolas para los rasgos relacionadas con la dieta y la amplitud del nicho ambiental, mientras que se contrajo para los rasgos de forrajeo y dispersión. Dichos cambios fueron impulsados por especies con combinaciones de rasgos funcionales únicos. Nuestros resultados revelan los cambios dinámicos en el espacio del nicho ecológico que subyacen a la estructura de la comunidad en los paisajes perturbados y destacan cómo una mayor amplitud del nicho puede mejorar la sensibilidad a las perturbaciones para las especies generalistas. Enfatizamos que los rasgos funcionales pueden utilizarse para predecir los cambios en la estructura de la comunidad a través de gradientes de perturbación, lo que permite comprender los mecanismos específicos que subyacen al desensamble de la comunidad más allá de los patrones emergentes de diversidad funcional. Al identificar grupos de rasgos funcionales claves que se alinean con diferentes hábitats agrícolas como en "countrysides" demostramos cómo los profesionales de la conservación pueden contribuir a la retención de la diversidad funcional de las aves en los paisajes agrícolas en todo el mundo.

Clinical and genomic characterization of 8p cytogenomic disorders.

PURPOSE: To provide a detailed clinical and cytogenomic summary of individuals with chromosome 8p rearrangements of invdupdel(8p), del(8p), and dup(8p). METHODS: We enrolled 97 individuals with invdupdel(8p), del(8p), and dup(8p). Clinical and molecular data were collected to delineate and compare the clinical findings and rearrangement breakpoints. We included additional 5 individuals with dup(8p) from the literature for a total of 102 individuals. RESULTS: Eighty-one individuals had recurrent rearrangements of invdupdel(8p) (n = 49), del(8p)_distal (n = 4), del(8p)_proximal (n = 9), del(8p)_proximal&distal (n = 12), and dup(8p)_proximal (n = 7). Twenty-one individuals had nonrecurrent rearrangements. While all individuals had neurodevelopmental features, the frequency and severity of clinical findings were higher in individuals with invdupdel(8p), and with larger duplications. All individuals with GATA4 deletion had structural congenital heart defects; however, the presence of structural heart defects in some individuals with normal GATA4 copy number suggests there are other potentially contributing gene(s) on 8p. CONCLUSION: Our study may inform families and health-care providers about the associated clinical findings and severity in individuals with chromosome 8p rearrangements, and guide researchers in investigating the underlying molecular and biological mechanisms by providing detailed clinical and cytogenomic information about individuals with distinct 8p rearrangements.

In-Hospital Mortality in Patients with Idiopathic Pulmonary Fibrosis: A US Cohort Study.

PURPOSE: In patients with idiopathic pulmonary fibrosis (IPF), hospitalizations are associated with high mortality. We sought to determine in-hospital mortality rates and factors associated with in-hospital mortality in patients with IPF. METHODS: Patients with IPF were identified from the Premier Healthcare Database, a representative administrative dataset that includes > 20% of hospital discharges in the US, using an algorithm based on diagnostic codes and billing data. We used logistic regression to analyze associations between patient-, hospital-, and treatment-related characteristics and a composite primary outcome of death during the index visit, lung transplant during the index visit and > 1 day after admission, or death during a readmission within 90 days. RESULTS: The cohort comprised 6665 patients with IPF hospitalized between October 2011 and October 2014. A total of 963 (14.4%) met the primary outcome. Factors significantly associated with a higher risk of the primary outcome included mechanical ventilation [odds ratio 4.65 (95% CI 3.73, 5.80)], admission to the intensive care unit [1.83 (1.52, 2.21)], treatment with opioids (3.06 [2.57, 3.65]), and a diagnosis of pneumonia [1.44 (1.21, 1.71)]. Factors significantly associated with a lower risk included concurrent chronic obstructive pulmonary disease [0.65 (0.55, 0.77)] and female sex [0.67 (0.57, 0.79)]. CONCLUSIONS: Patients with IPF, particularly those receiving mechanical ventilation or intensive care, are at substantial risk of death or lung transplant during hospitalization or death during a readmission within 90 days.

Use it or lose it? Effects of age, experience, and disuse on crawling.

What happens to early acquired but later abandoned motor skills? To investigate effects of disuse on early-developing motor skills, we examined crawling in two groups of habitual crawlers (34 6-12-month-old infants and five adults with Uner Tan Syndrome) and two groups of rusty crawlers (27 11-12-year-old children and 13 college-aged adults). Habitual crawlers showed striking similarities in gait patterns, limbs supporting the body, and crawling speed, despite dramatic differences in crawling practice, posture, and body size. Habitual crawlers trotted predominantly, whereas rusty crawlers showed a variety of gait patterns. Within sequences, habitual crawlers and children showed more switches in gait patterns than young adults. Children crawled faster and kept fewer limbs on the grounds than the other groups. Old crawling patterns were retained despite disuse, but new ones were also added. Surprisingly, results indicate that nothing was lost with disuse, but some features of crawling were gained or altered.

Reversible secretome and signaling defects in diabetic mesenchymal stem cells from peripheral arterial disease patients.

OBJECTIVE: Regenerative medicine seeks to stall or to reverse the pathologic consequences of chronic diseases. Many people with diabetes have peripheral arterial disease (PAD), which increases their already high risk of major amputation. Cellular therapies are a promising regenerative medicine approach to PAD that can be used to focally inject regenerative cells to endangered tissue beds. Mesenchymal stem cells (MSCs) are known to promote tissue regeneration through stromal support and paracrine stimulation of new blood vessels (angiogenesis). Whereas little is known about human diabetic MSCs (dMSCs), particularly those from patients with PAD, dMSCs have a limited expansion capacity but can be improved with human platelet lysate (PL) supplementation. PL is rich in many growth factors, including epidermal growth factor (EGF), which is known to be important to cell proliferation and survival signaling pathways. We hypothesize that dMSCs have a reversible defect in EGF receptor pathways. The objective of this work was to test this hypothesis using dMSCs from PAD patients. METHODS: The secretome expression of EGF and prominent angiogens was characterized from bone marrow (BM)-derived and adipose tissue-derived (ATD) dMSCs from five patients (six limbs) undergoing major amputation. Western blot was used to characterize the AKT and extracellular signal-regulated protein kinases 1 and 2 expression in dMSCs under standard culture (5% fetal bovine serum plus fibroblast growth factor 2 [FGF2]), 5% human PL, or 5% fetal bovine serum plus EGF. Healthy donor MSCs were control cells. The angiogenic activity of BM- and ATD-dMSCs was tested on human umbilical vein endothelial cells (ECs). Paired t-test, analysis of variance, and Kruskal-Wallis tests were used as appropriate. RESULTS: Both BM- and ATD-dMSCs had typical MSC surface marker expression and similar expansion profiles, and they did not express EGF in their secretome. PL supplementation of dMSCs improved AKT signaling, but they were resistant to FGF2 activation of extracellular signal-regulated protein kinases 1 and 2. EGF supplementation led to similar AKT expression as with PL, but PL had greater phosphorylation of AKT at 30 and 60 minutes. The conditioned media from both BM- and ATD-dMSCs had robust levels of prominent angiogens (vascular endothelial growth factor, monocyte chemoattractant protein 1, hepatocyte growth factor), which stimulated EC proliferation and migration, and the co-culture of dMSCs with ECs led to significantly longer EC sprouts in three-dimensional gel than EC-alone pellets. CONCLUSIONS: PL and EGF supplementation improves AKT expression in dMSCs over that of FGF2, but PL improved pAKT over that of EGF. Thus, PL supplementation strategies may improve AKT signaling, which could be important to MSC survival in cellular therapies. Furthermore, BM- and ATD-dMSCs have similar secretomes and robust in vitro angiogenic activity, which supports pursuing dMSCs from both reservoirs in regenerative medicine strategies.