In the last 20 years, research focused on developing retinal imaging as a source of potential biomarkers for Alzheimer's disease and other neurodegenerative diseases, has increased significantly. The ...Alzheimer's Association and the Alzheimer's & Dementia: Diagnosis, Assessment, Disease Monitoring editorial team (companion journal to Alzheimer's & Dementia) convened an interdisciplinary discussion in 2019 to identify a path to expedite the development of retinal biomarkers capable of identifying biological changes associated with AD, and for tracking progression of disease severity over time. As different retinal imaging modalities provide different types of structural and/or functional information, the discussion reflected on these modalities and their respective strengths and weaknesses. Discussion further focused on the importance of defining the context of use to help guide the development of retinal biomarkers. Moving from research to context of use, and ultimately to clinical evaluation, this article outlines ongoing retinal imaging research today in Alzheimer's and other brain diseases, including a discussion of future directions for this area of study.
Human activity can degrade ecosystem function by reducing species number (richness) and by skewing the relative abundance of species (evenness). Conservation efforts often focus on restoring or ...maintaining species number, reflecting the well-known impacts of richness on many ecological processes. In contrast, the ecological effects of disrupted evenness have received far less attention, and developing strategies for restoring evenness remains a conceptual challenge. In farmlands, agricultural pest-management practices often lead to altered food web structure and communities dominated by a few common species, which together contribute to pest outbreaks. Here we show that organic farming methods mitigate this ecological damage by promoting evenness among natural enemies. In field enclosures, very even communities of predator and pathogen biological control agents, typical of organic farms, exerted the strongest pest control and yielded the largest plants. In contrast, pest densities were high and plant biomass was low when enemy evenness was disrupted, as is typical under conventional management. Our results were independent of the numerically dominant predator or pathogen species, and so resulted from evenness itself. Moreover, evenness effects among natural enemy groups were independent and complementary. Our results strengthen the argument that rejuvenation of ecosystem function requires restoration of species evenness, rather than just richness. Organic farming potentially offers a means of returning functional evenness to ecosystems.
BACKGROUND—This randomized controlled trial evaluated clinical durability of Zilver PTX, a paclitaxel-coated drug-eluting stent (DES), for femoropopliteal artery lesions. Outcomes compare primary DES ...versus percutaneous transluminal angioplasty (PTA), overall DES (primary and provisional) versus standard care (PTA and provisional Zilver bare metal stent BMS), and provisional DES versus provisional BMS.
METHODS AND RESULTS—Patients with symptomatic femoropopliteal artery disease were randomly assigned to DES (n=236) or PTA (n=238). Approximately 91% had claudication; 9% had critical limb ischemia. Patients experiencing acute PTA failure underwent secondary randomization to provisional BMS (n=59) or DES (n=61). The 1-year primary end points of event-free survival and patency showed superiority of primary DES in comparison with PTA; these results were sustained through 5 years. Clinical benefit (freedom from persistent or worsening symptoms of ischemia; 79.8% versus 59.3%, P<0.01), patency (66.4% versus 43.4%, P<0.01), and freedom from reintervention (target lesion revascularization, 83.1% versus 67.6%, P<0.01) for the overall DES group were superior to standard care in nonrandomized comparisons. Similarly, clinical benefit (81.8% versus 63.8%, P=0.02), patency (72.4% versus 53.0%, P=0.03), and freedom from target lesion revascularization (84.9% versus 71.6%, P=0.06) with provisional DES were improved over provisional BMS. These results represent >40% relative risk reduction for restenosis and target lesion revascularization through 5 years for the overall DES in comparison with standard care and for provisional DES in comparison with provisional BMS.
CONCLUSIONS—The 5-year results from this large study provide long-term information previously unavailable regarding endovascular treatment of femoropopliteal artery disease. The Zilver PTX DES provided sustained safety and clinical durability in comparison with standard endovascular treatments.
CLINICAL TRIAL REGISTRATION—URLhttp://www.clinicaltrials.gov. Unique identifierNCT00120406.
Infectious disease modeling has played a prominent role in recent outbreaks, yet integrating these analyses into public health decision-making has been challenging. We recommend establishing ...‘outbreak science’ as an inter-disciplinary field to improve applied epidemic modeling.
Tissues and organs are composed of distinct cell types that must operate in concert to perform physiological functions. Efforts to create high-dimensional biomarker catalogs of these cells have been ...largely based on single-cell sequencing approaches, which lack the spatial context required to understand critical cellular communication and correlated structural organization. To probe in situ biology with sufficient depth, several multiplexed protein imaging methods have been recently developed. Though these technologies differ in strategy and mode of immunolabeling and detection tags, they commonly utilize antibodies directed against protein biomarkers to provide detailed spatial and functional maps of complex tissues. As these promising antibody-based multiplexing approaches become more widely adopted, new frameworks and considerations are critical for training future users, generating molecular tools, validating antibody panels, and harmonizing datasets. In this Perspective, we provide essential resources, key considerations for obtaining robust and reproducible imaging data, and specialized knowledge from domain experts and technology developers.
There has been interest in the function of adult neurogenesis since its discovery, by Joseph Altman, nearly 60 years ago. While controversy curtailed follow up studies, in the 1990s a second wave of ...research validated many of Altman’s original claims and revealed that factors such as stress and environmental stimulation altered the production of new neurons in the hippocampus. However, only with the advent of tools for manipulating neurogenesis did it become possible to perform causal tests of the function of newborn neurons. Here, we identify approximately 100 studies in which adult neurogenesis was manipulated to study its function. A majority of these studies demonstrate functions for adult neurogenesis in classic hippocampal behaviors such as context learning and spatial memory, as well as emotional behaviors related to stress, anxiety and depression. However, a closer look reveals a number of other, arguably understudied, functions in decision making, temporal association memory, and addiction. In this special issue, we present 16 new studies and review articles that continue to address and clarify the function of adult neurogenesis in behaviors as diverse as memory formation and consolidation, pattern separation and discrimination behaviors, addiction, and attention. Reviews of stem cell dynamics and regenerative properties provide insights into the mechanisms by which neurogenesis may be controlled to offset age- and disease-related brain injury. Finally, translation-oriented reviews identify next steps for minimizing the gap between discoveries made in animals and applications for human health. The articles in this issue synthesize and extend what we have learned in the last half century of functional neurogenesis research and identify themes that will define its future.
A prospective, multinational randomized controlled trial (RCT) and a complementary single-arm study evaluated the 2-year safety and effectiveness of a paclitaxel-coated drug-eluting stent (DES) in ...patients with superficial femoral artery lesions. The RCT compared the DES with percutaneous transluminal angioplasty (PTA) and provisional bare-metal stent (BMS) placement.
Local drug delivery for superficial femoral artery lesions has been investigated with the intent of limiting restenosis similarly to DES for the coronary arteries. One-year outcomes of DES in the superficial femoral artery are promising, but longer-term benefits have not been established.
In the RCT, patients were randomly assigned to primary DES implantation (n = 236) or PTA (n = 238). Acute PTA failure occurred in 120 patients, who underwent secondary randomization to DES (n = 61) or BMS (n = 59) placement. The single-arm study enrolled 787 patients with DES treatment.
Compared with the control group, the primary DES group demonstrated significantly superior 2-year event-free survival (86.6% vs. 77.9%, p = 0.02) and primary patency (74.8% vs. 26.5%, p < 0.01). In addition, the provisional DES group exhibited superior 2-year primary patency compared with the provisional BMS group (83.4% vs. 64.1%, p < 0.01) and achieved higher sustained clinical benefit (83.9% vs. 68.4%, p = 0.05). Two-year freedom from target lesion revascularization with primary DES placement was 80.5% in the single-arm study and 86.6% in the RCT.
Two-year outcomes with the paclitaxel-eluting stent support its sustained safety and effectiveness in patients with femoropopliteal artery disease, including the long-term superiority of the DES to PTA and to provisional BMS placement. (Evaluation of the Zilver PTX Drug-Eluting Stent in the Above-the-Knee Femoropopliteal Artery; NCT00120406; Zilver(®) PTX™ Global Registry; NCT01094678).
The primary goals of this interdisciplinary consensus statement are to define the eligibility criteria for outpatient thyroidectomy and to explore preoperative, intraoperative, and postoperative ...factors that should be considered in order to optimize the safe and efficient performance of ambulatory surgery.
A series of criteria was developed that may represent relative contraindications to outpatient thyroidectomy, and these fell into the following broad categories: clinical, social, and procedural issues. Intraoperative factors that bear consideration are enumerated, and include choice of anesthesia, use of nerve monitoring, hemostasis, management of the parathyroid glands, wound closure, and extubation. Importantly, postoperative factors are described at length, including suggested discharge criteria and recognition of complications, especially bleeding, airway distress, and hypocalcemia.
Outpatient thyroidectomy may be undertaken safely in a carefully selected patient population provided that certain precautionary measures are taken to maximize communication and minimize the likelihood of complications.
Macrophages are activated during microbial infection to coordinate inflammatory responses and host defense. Here we find that in macrophages activated by bacterial lipopolysaccharide (LPS), ...mitochondrial glycerol 3-phosphate dehydrogenase (GPD2) regulates glucose oxidation to drive inflammatory responses. GPD2, a component of the glycerol phosphate shuttle, boosts glucose oxidation to fuel the production of acetyl coenzyme A, acetylation of histones and induction of genes encoding inflammatory mediators. While acute exposure to LPS drives macrophage activation, prolonged exposure to LPS triggers tolerance to LPS, where macrophages induce immunosuppression to limit the detrimental effects of sustained inflammation. The shift in the inflammatory response is modulated by GPD2, which coordinates a shutdown of oxidative metabolism; this limits the availability of acetyl coenzyme A for histone acetylation at genes encoding inflammatory mediators and thus contributes to the suppression of inflammatory responses. Therefore, GPD2 and the glycerol phosphate shuttle integrate the extent of microbial stimulation with glucose oxidation to balance the beneficial and detrimental effects of the inflammatory response.
Abstract
Context
Studies of the possible cardiovascular risk of testosterone treatment are inconclusive.
Objective
To determine the effect of testosterone treatment on cardiovascular biomarkers in ...older men with low testosterone.
Design
Double-blind, placebo-controlled trial.
Setting
Twelve academic medical centers in the United States.
Participants
In all, 788 men ≥65 years old with an average of two serum testosterone levels <275 ng/dL who were enrolled in The Testosterone Trials.
Intervention
Testosterone gel, the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months.
Main Outcome Measures
Serum markers of cardiovascular risk, including lipids and markers of glucose metabolism, fibrinolysis, inflammation, and myocardial damage.
Results
Compared with placebo, testosterone treatment significantly decreased total cholesterol (adjusted mean difference, −6.1 mg/dL; P < 0.001), high-density lipoprotein cholesterol (adjusted mean difference, −2.0 mg/dL; P < 0.001), and low-density lipoprotein cholesterol (adjusted mean difference, −2.3 mg/dL; P = 0.051) from baseline to month 12. Testosterone also slightly but significantly decreased fasting insulin (adjusted mean difference, −1.7 µIU/mL; P = 0.02) and homeostatic model assessment‒insulin resistance (adjusted mean difference, −0.6; P = 0.03). Testosterone did not change triglycerides, d-dimer, C-reactive protein, interleukin 6, troponin, glucose, or hemoglobin A1c levels more than placebo.
Conclusions and Relevance
Testosterone treatment of 1 year in older men with low testosterone was associated with small reductions in cholesterol and insulin but not with other glucose markers, markers of inflammation or fibrinolysis, or troponin. The clinical importance of these findings is unclear and requires a larger trial of clinical outcomes.
Compared with placebo, testosterone treatment of older men with low testosterone was associated with small reductions in total, HDL, and LDL cholesterol and in insulin and HOMA-IR but not glucose.
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