Paravascular drainage of solutes, including β-amyloid (Aβ), appears to be an important process in brain health and diseases such as Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). ...However, the major driving force for clearance remains largely unknown. Here we used in vivo two-photon microscopy in awake head-fixed mice to assess the role of spontaneous vasomotion in paravascular clearance. Vasomotion correlated with paravascular clearance of fluorescent dextran from the interstitial fluid. Increasing the amplitude of vasomotion by means of visually evoked vascular responses resulted in increased clearance rates in the visual cortex of awake mice. Evoked vascular reactivity was impaired in mice with CAA, which corresponded to slower clearance rates. Our findings suggest that low-frequency arteriolar oscillations drive drainage of solutes. Targeting naturally occurring vasomotion in patients with CAA or AD may be a promising early therapeutic option for prevention of Aβ accumulation in the brain.
•Spontaneous low-frequency oscillations can be observed in arterioles in awake mice•Vasomotion drives paravascular clearance of solutes from the brain•Paravascular clearance is impaired in the context of cerebral amyloid angiopathy
van Veluw et al. demonstrate that vasomotion is a major driving force for paravascular clearance of solutes from the brain. Loss of vascular smooth muscle cells and reduced vasomotion in the context of amyloid deposition is associated with impaired clearance.
The polymeric ionomer plays a vital role in PEM fuel cell device technology, not simply as the membrane that transports protons and water from one electrode to another but as the binder and transport ...medium responsible for electrochemical activity within the catalyst layer. This perspective examines critical features of the catalyst layer ionomer. It highlights the current understanding of interactions of ionomer in catalyst inks, where the microstructure of the catalyst layer is largely formed, and in the catalyst layer itself. Properties important to the design and function of next generation ionomers and the challenges faced in replacing PFSA ionomers with hydrocarbon-based analogues are closely examined.
Purpose
Social determinants of health that have been examined in relation to breast cancer incidence, stage at diagnosis, and survival include socioeconomic status (income, education), neighborhood ...disadvantage, unemployment, racial discrimination, social support, and social network. Other social determinants of health include medical distrust, immigration, status, inadequate housing, food insecurity, and geographic factors such as neighborhood access to health services. Socioeconomic factors influence risk of breast cancer. For all racial/ethnic groups, breast cancer incidence rates tend to be positively associated with socioeconomic status. On the other hand, low socioeconomic status is associated with increased risk of aggressive premenopausal breast cancers as well as late stage of diagnosis and poorer survival. There are well-documented disparities in breast cancer survival by socioeconomic status, race, education, census-tract-level poverty, and access to health insurance and preventive care. Poverty is associated with other factors related to late stage at breast cancer diagnosis and poorer survival such as inadequate health insurance, lack of a primary care physician and poor access to health care.
Results
The results of this review indicate that social determinants such as poverty, lack of education, neighborhood disadvantage, residential segregation by race, racial discrimination, lack of social support, and social isolation play an important role in breast cancer stage at diagnosis and survival.
Conclusion
To address these social determinants and eliminate cancer disparities, effective interventions are needed that account for the social and environmental contexts in which cancer patients live and are treated.
Approximately 20% of women with advanced-stage ovarian cancer survive beyond 12 years after treatment and are effectively cured. Initial therapy for ovarian cancer comprises surgery and chemotherapy, ...and is given with the goal of eradicating as many cancer cells as possible. Indeed, the three phases of therapy are as follows: debulking surgery to remove as much of the cancer as possible, preferably to a state of no visible residual disease; chemotherapy to eradicate any microscopic disease that remains present after surgery; and second-line or maintenance therapy, which is given to delay disease progression among patients with tumour recurrence. If no cancer cells remain after initial therapy is completed, a cure is expected. By contrast, if residual cancer cells are present after initial treatment, then disease recurrence is likely. Thus, the probability of cure is contingent on the combination of surgery and chemotherapy effectively eliminating all cancer cells. In this Perspectives article, I present the case that the probability of achieving a cancer-free state is maximized through a combination of maximal debulking surgery and intraperitoneal chemotherapy. I discuss the evidence indicating that by taking this approach, cures could be achieved in up to 50% of women with advanced-stage ovarian cancer.
Machine Learning for Fluid Mechanics Brunton, Steven L; Noack, Bernd R; Koumoutsakos, Petros
Annual review of fluid mechanics,
01/2020, Letnik:
52, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The field of fluid mechanics is rapidly advancing, driven by unprecedented volumes of data from experiments, field measurements, and large-scale simulations at multiple spatiotemporal scales. Machine ...learning (ML) offers a wealth of techniques to extract information from data that can be translated into knowledge about the underlying fluid mechanics. Moreover, ML algorithms can augment domain knowledge and automate tasks related to flow control and optimization. This article presents an overview of past history, current developments, and emerging opportunities of ML for fluid mechanics. We outline fundamental ML methodologies and discuss their uses for understanding, modeling, optimizing, and controlling fluid flows. The strengths and limitations of these methods are addressed from the perspective of scientific inquiry that considers data as an inherent part of modeling, experiments, and simulations. ML provides a powerful information-processing framework that can augment, and possibly even transform, current lines of fluid mechanics research and industrial applications.
This study was designed to examine the prospective relations of perceived racial discrimination with allostatic load (AL), along with a possible buffer of the association. A sample of 331 African ...Americans in the rural South provided assessments of perceived discrimination from ages 16 to 18 years. When youth were 18 years, caregivers reported parental emotional support and youth assessed peer emotional support. AL and potential confounder variables were assessed when youth were 20. Latent growth mixture modeling identified two perceived discrimination classes: high and stable, and low and increasing. Adolescents in the high and stable class evinced heightened AL even with confounder variables controlled. The racial discrimination to AL link was not significant for young adults who received high emotional support.
HIV-1 reservoirs preclude virus eradication in patients receiving highly active antiretroviral therapy (HAART). The best characterized reservoir is a small, difficult-to-quantify pool of resting ...memory CD4(+) T cells carrying latent but replication-competent viral genomes. Because strategies targeting this latent reservoir are now being tested in clinical trials, well-validated high-throughput assays that quantify this reservoir are urgently needed. Here we compare eleven different approaches for quantitating persistent HIV-1 in 30 patients on HAART, using the original viral outgrowth assay for resting CD4(+) T cells carrying inducible, replication-competent viral genomes as a standard for comparison. PCR-based assays for cells containing HIV-1 DNA gave infected cell frequencies at least 2 logs higher than the viral outgrowth assay, even in subjects who started HAART during acute/early infection. This difference may reflect defective viral genomes. The ratio of infected cell frequencies determined by viral outgrowth and PCR-based assays varied dramatically between patients. Although strong correlations with the viral outgrowth assay could not be formally excluded for most assays, correlations achieved statistical significance only for integrated HIV-1 DNA in peripheral blood mononuclear cells and HIV-1 RNA/DNA ratio in rectal CD4(+) T cells. Residual viremia was below the limit of detection in many subjects and did not correlate with the viral outgrowth assays. The dramatic differences in infected cell frequencies and the lack of a precise correlation between culture and PCR-based assays raise the possibility that the successful clearance of latently infected cells may be masked by a larger and variable pool of cells with defective proviruses. These defective proviruses are detected by PCR but may not be affected by reactivation strategies and may not require eradication to accomplish an effective cure. A molecular understanding of the discrepancy between infected cell frequencies measured by viral outgrowth versus PCR assays is an urgent priority in HIV-1 cure research.
While spreading the gospel around the world through his signature crusades, internationally renowned evangelist Billy Graham maintained a visible and controversial presence in his native South, a ...region that underwent substantial political and economic change in the latter half of the twentieth century. In this period Graham was alternately a desegregating crusader in Alabama, Sunbelt booster in Atlanta, regional apologist in the national press, and southern strategist in the Nixon administration.Billy Graham and the Rise of the Republican Southconsiders the critical but underappreciated role of the noted evangelist in the creation of the modern American South. The region experienced two significant related shifts away from its status as what observers and critics called the "Solid South": the end of legalized Jim Crow and the end of Democratic Party dominance. Author Steven P. Miller treats Graham as a serious actor and a powerful symbol in this transition-an evangelist first and foremost, but also a profoundly political figure. In his roles as the nation's most visible evangelist, adviser to political leaders, and a regional spokesperson, Graham influenced many of the developments that drove celebrants and detractors alike to place the South at the vanguard of political, religious, and cultural trends. He forged a path on which white southern moderates could retreat from Jim Crow, while his evangelical critique of white supremacy portended the emergence of "color blind" rhetoric within mainstream conservatism. Through his involvement in the Eisenhower and Nixon administrations, as well as his deep social ties in the South, the evangelist influenced the decades-long process of political realignment. Graham's public life sheds new light on recent southern history in all of its ambiguities, and his social and political ethics complicate conventional understandings of evangelical Christianity in postwar America. Miller's book seeks to reintroduce a familiar figure to the narrative of southern history and, in the process, examine the political and social transitions constitutive of the modern South.
The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and ...adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs).
Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols.
The Executive Summary of this 2020 updated guideline contains 52 recommendations: 21 Grade A (40%), 24 Grade B (46%), 7 Grade C (14%), and no Grade D (0%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 368 citations: 123 (33.5%) evidence level (EL) 1 (highest), 132 (36%) EL 2 (intermediate), 20 (5.5%) EL 3 (weak), and 93 (25%) EL 4 (lowest). New or updated topics in this CPG include: clarification of the diagnosis of osteoporosis, stratification of the patient according to high-risk and very-high-risk features, a new dual-action therapy option, and transitions from therapeutic options.
This guideline is a practical tool for endocrinologists, physicians in general, regulatory bodies, health-related organizations, and interested laypersons regarding the diagnosis, evaluation, and treatment of post-menopausal osteoporosis.
= 25-hydroxyvitamin D;
= American Association of Clinical Endocrinologists;
= American College of Endocrinology;
= atypical femoral fracture;
= American Society for Bone and Mineral Research;
= best evidence level;
= bone mineral density;
= bone turnover marker;
= confidence interval;
= clinical practice guideline;
= C-terminal telopeptide type-I collagen;
= dual-energy X-ray absorptiometry;
= evidence level;
= U.S. Food and Drug Administration;
= Fracture Risk Assessment Tool;
= gastrointestinal;
= Health Outcomes and Reduced Incidence with Zoledronic acid ONce yearly Pivotal Fracture Trial (zoledronic acid and zoledronate are equivalent terms);
= International Society for Clinical Densitometry;
= international units;
= intravenous;
= least significant change;
= National Osteoporosis Foundation;
= osteonecrosis of the jaw;
= serum amino-terminal propeptide of type-I collagen;
= parathyroid hormone;
= recommendation;
= region of interest;
= relative risk;
= standard deviation;
= trabecular bone score;
= vertebral fracture assessment;
= World Health Organization.
Latently-infected CD4+ T cells are widely considered to be the major barrier to a cure for HIV. Much of our understanding of HIV latency comes from latency models and blood cells, but most ...HIV-infected cells reside in lymphoid tissues such as the gut. We hypothesized that tissue-specific environments may impact the mechanisms that govern HIV expression. To assess the degree to which different mechanisms inhibit HIV transcription in the gut and blood, we quantified HIV transcripts suggestive of transcriptional interference (U3-U5; "Read-through"), initiation (TAR), 5' elongation (R-U5-pre-Gag; "Long LTR"), distal transcription (Nef), completion (U3-polyA; "PolyA"), and multiple splicing (Tat-Rev) in matched peripheral blood mononuclear cells (PBMCs) and rectal biopsies, and matched FACS-sorted CD4+ T cells from blood and rectum, from two cohorts of ART-suppressed individuals. Like the PBMCs, rectal biopsies showed low levels of read-through transcripts (median = 23 copies/106 cells) and a gradient of total (679)>elongated(75)>Nef(16)>polyadenylated (11)>multiply-spliced HIV RNAs(<1) p<0.05 for all, demonstrating blocks to HIV transcriptional elongation, completion, and splicing. Rectal CD4+ T cells showed a similar gradient of total>polyadenylated>multiply-spliced transcripts, but the ratio of total to elongated transcripts was 6-fold lower than in blood CD4+ T cells (P = 0.016), suggesting less of a block to HIV transcriptional elongation in rectal CD4+ T cells. Levels of total transcripts per provirus were significantly lower in rectal biopsies compared to PBMCs (median 3.5 vs. 15.4; P = 0.008) and in sorted CD4+ T cells from rectum compared to blood (median 2.7 vs. 31.8; P = 0.016). The lower levels of HIV transcriptional initiation and of most HIV transcripts per provirus in the rectum suggest that this site may be enriched for latently-infected cells, cells in which latency is maintained by different mechanisms, or cells in a "deeper" state of latency. These are important considerations for designing therapies that aim to disrupt HIV latency in all tissue compartments.
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