Peripheral artery disease (PAD) stems from atherosclerosis of lower extremity arteries with resultant arterial narrowing or occlusion. The most severe form of PAD is termed chronic limb-threatening ...ischemia and carries a significant risk of limb loss and cardiovascular mortality. Diabetes mellitus is known to increase the incidence of PAD, accelerate disease progression, and increase disease severity. Patients with concomitant diabetes mellitus and PAD are at high risk for major complications, such as amputation. Despite a decrease in the overall number of amputations performed annually in the United States, amputation rates among those with both diabetes mellitus and PAD have remained stable or even increased in high-risk subgroups. Within this cohort, there is significant regional, racial/ethnic, and socioeconomic variation in amputation risk. Specifically, residents of rural areas, African-American and Native American patients, and those of low socioeconomic status carry the highest risk of amputation. The burden of amputation is severe, with 5-year mortality rates exceeding those of many malignancies. Furthermore, caring for patients with PAD and diabetes mellitus imposes a significant cost to the healthcare system-estimated to range from $84 billion to $380 billion annually. Efforts to improve the quality of care for those with PAD and diabetes mellitus must focus on the subgroups at high risk for amputation and the disparities they face in the receipt of both preventive and interventional cardiovascular care. Better understanding of these social, economic, and structural barriers will prove to be crucial for cardiovascular physicians striving to better care for patients facing this challenging combination of chronic diseases.
Harnessing the potential of human stem cells for modeling the physiology and diseases of cortical circuitry requires monitoring cellular dynamics in vivo. We show that human induced pluripotent stem ...cell (iPSC)-derived cortical neurons transplanted into the adult mouse cortex consistently organized into large (up to ~100 mm
) vascularized neuron-glia territories with complex cytoarchitecture. Longitudinal imaging of >4000 grafted developing human neurons revealed that neuronal arbors refined via branch-specific retraction; human synaptic networks substantially restructured over 4 months, with balanced rates of synapse formation and elimination; and oscillatory population activity mirrored the patterns of fetal neural networks. Lastly, we found increased synaptic stability and reduced oscillations in transplants from two individuals with Down syndrome, demonstrating the potential of in vivo imaging in human tissue grafts for patient-specific modeling of cortical development, physiology, and pathogenesis.
Executive control processes, such as sustained attention, response inhibition, and error monitoring, allow humans to guide behavior in appropriate, flexible, and adaptive ways. The consequences of ...executive dysfunction for humans can be dramatic, as exemplified by the large range of both neurologic and neuropsychiatric disorders in which such deficits negatively affect outcome and quality of life. Much evidence suggests that many clinical disorders marked by executive deficits are highly heritable and that individual differences in quantitative measures of executive function are strongly driven by genetic differences. Accordingly, intense research effort has recently been directed toward mapping the genetic architecture of executive control processes in both clinical (e.g., attention-deficit/hyperactivity disorder) and nonclinical populations. Here we review the extant literature on the molecular genetic correlates of three exemplar but dissociable executive functions: sustained attention, response inhibition, and error processing. Our review focuses on monoaminergic gene variants given the strong body of evidence from cognitive neuroscience and pharmacology implicating dopamine, noradrenaline, and serotonin as neuromodulators of executive function. Associations between DNA variants of the dopamine beta hydroxylase gene and measures of sustained attention accord well with cognitive-neuroanatomical models of sustained attention. Equally, functional variants of the dopamine D2 receptor gene are reliably associated with performance monitoring, error processing, and reinforcement learning. Emerging evidence suggests that variants of the dopamine transporter gene (DAT1) and dopamine D4 receptor gene (DRD4) show promise for explaining significant variance in individual differences in both behavioral and neural measures of inhibitory control.
Eosinophils play a central role in asthma. The present study was performed to investigate the effect of tumour necrosis factor-α (TNF-α) on longevity of isolated human eosinophils. In contrast to ...Fas, TNF-α inhibited eosinophil apoptosis as evidenced by a combination of flow cytometry, DNA fragmentation assay and morphological analyses. The effect of TNF-α on eosinophil apoptosis was reversed by a TNF-α neutralising antibody. The anti-apoptotic effect of TNF-α was not due to autocrine release of known survival-prolonging cytokines interleukins 3 and 5 or granulocyte-macrophage-colony-stimulating factor as their neutralisation did not affect the effect of TNF-α. The anti-apoptotic signal was mediated mainly by the TNF-receptor 1. TNF-α induced phosphorylation and degradation of IκB and an increase in NF-κB DNA-binding activity. The survival-prolonging effect of TNF-α was reversed by inhibitors of NF-κB pyrrolidinedithiocarbamate and gliotoxin and by an inhibitor of IκB kinase, BMS-345541. TNF-α induced also an increase in AP-1 DNA-binding activity and the antiapoptotic effect of TNF-α was potentiated by inhibitors of AP-1, SR 11302 and tanshinone IIA and by an inhibitor of c-jun-N-terminal kinase, SP600125, which is an upstream kinase activating AP-1. Our results thus suggest that TNF-α delays human eosinophil apoptosis via TNF-receptor 1 and the resulting changes in longevity depend on yin-yang balance between activation of NF-κB and AP-1.
Environmental DNA (eDNA) surveillance holds great promise for improving species conservation and management. However, few studies have investigated eDNA dynamics under natural conditions, and ...interpretations of eDNA surveillance results are clouded by uncertainties about eDNA degradation. We conducted a literature review to assess current understanding of eDNA degradation in aquatic systems and an experiment exploring how environmental conditions can influence eDNA degradation. Previous studies have reported macrobial eDNA persistence ranging from less than 1 day to over 2 weeks, with no attempts to quantify factors affecting degradation. Using a SYBR Green quantitative PCR assay to observe Common Carp ( Cyprinus carpio ) eDNA degradation in laboratory mesocosms, our rate of Common Carp eDNA detection decreased over time. Common Carp eDNA concentration followed a pattern of exponential decay, and observed decay rates exceeded previously published values for aquatic macrobial eDNA. Contrary to our expectations, eDNA degradation rate declined as biochemical oxygen demand, chlorophyll, and total eDNA (i.e., from any organism) concentration increased. Our results help explain the widely divergent, previously published estimates for eDNA degradation. Measurements of local environmental conditions, consideration of environmental influence on eDNA detection, and quantification of local eDNA degradation rates will help interpret future eDNA surveillance results.
This study illustrates the use of logistic regression and machine learning methods, specifically random forest models, in health services research by analyzing outcomes for a cohort of patients with ...concomitant peripheral artery disease and diabetes mellitus.
Cohort study using fee-for-service Medicare beneficiaries in 2015 who were newly diagnosed with peripheral artery disease and diabetes mellitus. Exposure variables include whether patients received preventive measures in the 6 months following their index date: HbA1c test, foot exam, or vascular imaging study. Outcomes include any reintervention, lower extremity amputation, and death. We fit both logistic regression models as well as random forest models.
There were 88,898 fee-for-service Medicare beneficiaries diagnosed with peripheral artery disease and diabetes mellitus in our cohort. The rate of preventative treatments in the first six months following diagnosis were 52% (n = 45,971) with foot exams, 43% (n = 38,393) had vascular imaging, and 50% (n = 44,181) had an HbA1c test. The directionality of the influence for all covariates considered matched those results found with the random forest and logistic regression models. The most predictive covariate in each approach differs as determined by the t-statistics from logistic regression and variable importance (VI) in the random forest model. For amputation we see age 85 + (t = 53.17) urban-residing (VI = 83.42), and for death (t = 65.84, VI = 88.76) and reintervention (t = 34.40, VI = 81.22) both models indicate age is most predictive.
The use of random forest models to analyze data and provide predictions for patients holds great potential in identifying modifiable patient-level and health-system factors and cohorts for increased surveillance and intervention to improve outcomes for patients. Random forests are incredibly high performing models with difficult interpretation most ideally suited for times when accurate prediction is most desirable and can be used in tandem with more common approaches to provide a more thorough analysis of observational data.
The accumulation of soluble and cell‐wall bound UV‐absorbing compounds (i.e., flavonoids) in the epidermis and the mesophyll of leaves is a response of plants to UV exposure. These compounds are ...known to function in UV screening, but they are also of potential value for food quality. One way to non‐destructively monitor UV screening in leaves is by optical methods, from which UVA‐PAM and Dualex instruments stand out. The degree and rapidity to which plants can modulate UV screening in response to fluctuating solar UV conditions is poorly understood. In this study, okra plants were exposed to two solar radiation treatments (near‐ambient UV +UV and attenuated UV −UV) and the epidermal UV transmittance (TUV; UVA‐PAM) and flavonoid index (Dualex) were measured in the youngest and second youngest mature leaves over three consecutive days and within an individual day. The day‐to‐day (measured near solar noon) and diurnal (over the course of a day) measurements of leaf optical properties indicated that TUV decreased and flavonoid index increased in the adaxial epidermis ~50% until 15:00 CDT then returned close to morning values later in the day. Correlations between UV‐B radiation and TUV and flavonoid index revealed highest values 30 min to 1 h prior to the measurements. These findings indicate that plants can respond quickly to fluctuating solar UV conditions and underlines the importance of the harvest‐time point for health‐promoting compounds in fruit and vegetables. Our findings also indicate that the UVA‐PAM and the Dualex instruments are both suitable instruments to monitor rapid changes in UV screening in plants.
Highly transmissible Omicron variants of SARS-CoV-2 currently dominate globally. Here, we compare neutralization of Omicron BA.1, BA.1.1, and BA.2. BA.2 RBD has slightly higher ACE2 affinity than ...BA.1 and slightly reduced neutralization by vaccine serum, possibly associated with its increased transmissibility. Neutralization differences between sub-lineages for mAbs (including therapeutics) mostly arise from variation in residues bordering the ACE2 binding site; however, more distant mutations S371F (BA.2) and R346K (BA.1.1) markedly reduce neutralization by therapeutic antibody Vir-S309. In-depth structure-and-function analyses of 27 potent RBD-binding mAbs isolated from vaccinated volunteers following breakthrough Omicron-BA.1 infection reveals that they are focused in two main clusters within the RBD, with potent right-shoulder antibodies showing increased prevalence. Selection and somatic maturation have optimized antibody potency in less-mutated epitopes and recovered potency in highly mutated epitopes. All 27 mAbs potently neutralize early pandemic strains, and many show broad reactivity with variants of concern.
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•Potent RBD antibodies from Omicron breakthrough vaccinees broadly neutralize VoC•These, possible recall antibodies, are focused in two main clusters•Somatic maturation adapts public antibodies to recover potency•BA.2 > BA.1 ACE2 affinity. BA.2 < BA.1 neutralization by vaccine serum and Vir-S309
Analysis of antibodies from SARS-CoV-2 Omicron breakthrough infections reveals their structural and functional properties as well as ability to neutralize different pandemic strains.
•Stigma-based bullying occurs frequently and harms the wellbeing of youth.•Unique approaches are needed to address stigma-based bullying.•Twenty-one stigma-based bullying interventions were published ...in 2000–2015.•Interventions are increasing, yet vary greatly in focus, approach, and evaluation.•Multicomponent, theory-based, rigorously evaluated interventions are needed.
Youth living with socially devalued characteristics (e.g., minority sexual orientation, race, and/or ethnicity; disability; obesity) experience frequent bullying. This stigma-based bullying undermines youths’ wellbeing and academic achievement, with lifelong consequences. The National Academies of Sciences, Engineering, and Medicine recommends developing, implementing, and evaluating evidence-based interventions to address stigma-based bullying. To characterize the existing landscape of these interventions, we conducted a systematic review of stigma-based bullying interventions targeting youth in any country published in the peer-reviewed literature between 2000 and 2015. Our analysis was guided by a theoretical framework of stigma-based bullying, which describes stigma-related factors at the societal, structural, interpersonal, and individual levels that lead to stigma-based bullying. We screened 8,240 articles and identified 22 research studies describing 21 interventions addressing stigma-based bullying. We found that stigma-based bullying interventions are becoming more numerous, yet are unevenly distributed across stigmas, geographic locations, and types of organizations. We further found that these interventions vary in the extent to which they incorporate theory and have been evaluated with a wide range of research designs and types of data. We recommend that future work address stigma-based bullying within multicomponent interventions, adopt interdisciplinary and theory-based approaches, and include rigorous and systematic evaluations. Intervening specifically on stigma-related factors is essential to end stigma-based bullying and improve the wellbeing of youth living with socially devalued characteristics.
Parasitic helminth infections can be associated with lifelong morbidity such as immune-mediated organ failure. A better understanding of the host immune response to helminths could provide new ...avenues to promote parasite clearance and/or alleviate infection-associated morbidity. Murine resistin-like molecules (RELM) exhibit pleiotropic functions following helminth infection including modulating the host immune response; however, the relevance of human RELM proteins in helminth infection is unknown. To examine the function of human resistin (hResistin), we utilized transgenic mice expressing the human resistin gene (hRetnTg+). Following infection with the helminth Nippostrongylus brasiliensis (Nb), hResistin expression was significantly upregulated in infected tissue. Compared to control hRetnTg- mice, hRetnTg+ mice suffered from exacerbated Nb-induced inflammation characterized by weight loss and increased infiltration of inflammatory monocytes in the lung, along with elevated Nb egg burdens and delayed parasite expulsion. Genome-wide transcriptional profiling of the infected tissue revealed that hResistin promoted expression of proinflammatory cytokines and genes downstream of toll-like receptor signaling. Moreover, hResistin preferentially bound lung monocytes, and exogenous treatment of mice with recombinant hResistin promoted monocyte recruitment and proinflammatory cytokine expression. In human studies, increased serum resistin was associated with higher parasite load in individuals infected with soil-transmitted helminths or filarial nematode Wuchereria bancrofti, and was positively correlated with proinflammatory cytokines. Together, these studies identify human resistin as a detrimental factor induced by multiple helminth infections, where it promotes proinflammatory cytokines and impedes parasite clearance. Targeting the resistin/proinflammatory cytokine immune axis may provide new diagnostic or treatment strategies for helminth infection and associated immune-mediated pathology.
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