Diabetic kidney disease and diabetic nephropathy are the leading cause of end-stage kidney disease in the United States and most developed countries. Diabetes accounts for 30% to 50% of the incident ...cases of end-stage kidney disease in the United States. Although this represents a significant public health concern, it is important to note that only 30% to 40% of patients with diabetes develop diabetic nephropathy. Specific treatment of patients with diabetic nephropathy can be divided into 4 major arenas: cardiovascular risk reduction, glycemic control, blood pressure control, and inhibition of the renin-angiotensin system (RAS). Recommendations for therapy include targeting a hemoglobin A1c concentration < 7% and blood pressure < 140/90mmHg with therapy anchored around the use of a RAS-blocking agent. The single best evidence-based therapy for diabetic nephropathy is therapy with a RAS-blocking medication. This Core Curriculum outlines and discusses in detail the epidemiology, pathophysiology, diagnosis, and management of diabetic nephropathy.
A recent manuscript (Ferguson et al. in Impact of non-pharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand, Imperial College COVID-19 Response Team, London, 2020.
...https://www.imperial.ac.uk/media/imperial-college/medicine/sph/ide/gida-fellowships/Imperial-College-COVID19-NPI-modelling-16-03-2020.pdf
) from Imperial College modelers examining ways to mitigate and control the spread of COVID-19 has attracted much attention. In this paper, we will discuss a coarse taxonomy of models and explore the context and significance of the Imperial College and other models in contributing to the analysis of COVID-19.
This Review summarizes advances in fluorination by C(sp2)−H and C(sp3)−H activation. Transition‐metal‐catalyzed approaches championed by palladium have allowed the installation of a fluorine ...substituent at C(sp2) and C(sp3) sites, exploiting the reactivity of high‐oxidation‐state transition‐metal fluoride complexes combined with the use of directing groups (some transient) to control site and stereoselectivity. The large majority of known methods employ electrophilic fluorination reagents, but methods combining a nucleophilic fluoride source with an oxidant have appeared. External ligands have proven to be effective for C(sp3)−H fluorination directed by weakly coordinating auxiliaries, thereby enabling control over reactivity. Methods relying on the formation of radical intermediates are complementary to transition‐metal‐catalyzed processes as they allow for undirected C(sp3)−H fluorination. To date, radical C−H fluorinations mainly employ electrophilic N−F fluorination reagents but a unique MnIII‐catalyzed oxidative C−H fluorination using fluoride has been developed. Overall, the field of late‐stage nucleophilic C−H fluorination has progressed much more slowly, a state of play explaining why C−H 18F‐fluorination is still in its infancy.
The direct fluorination of C−H bonds has emerged as a powerful method for accessing functional molecules such as pharmaceuticals or PET radiotracers. This Review provides an overview of the state of play of this field with an emphasis on the advantages and limitations of the main activation modes exploited to date. The discussion brings to light the importance of the fluorination reagent, and the challenges associated with nucleophilic C−H fluorination methods.
We demonstrate the coherent creation of a single NaCs molecule in its rotational, vibrational, and electronic (rovibronic) ground state in an optical tweezer. Starting with a weakly bound Feshbach ...molecule, we locate a two-photon transition via the |c^{3}Σ_{1},v^{'}=26⟩ excited state and drive coherent Rabi oscillations between the Feshbach state and a single hyperfine level of the NaCs rovibronic ground state |X^{1}Σ,v^{''}=0,N^{''}=0⟩ with a binding energy of D_{0}=h×147044.63(11) GHz. We measure a lifetime of 3.4±1.6 s for the rovibronic ground state molecule, which possesses a large molecule-frame dipole moment of 4.6D and occupies predominantly the motional ground state. These long-lived, fully quantum-state-controlled individual dipolar molecules provide a key resource for molecule-based quantum simulation and information processing.
Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants of concern (VOCs) have prolonged coronavirus disease 2019 (COVID‐19) pandemic by escaping pre‐existing immunity acquired by ...natural infection or vaccination. Elucidation of VOCs' mutation trends and evasion of neutralization is required to update current control measures. Mutations and the prevalence of VOCs were analyzed in the global immunization coverage rate context. Lentivirus‐based pseudovirus neutralization analysis platforms for SARS‐CoV‐2 prototype strain (PS) and VOCs, containing Alpha, Beta, Gamma, Delta, and Omicron, were constructed based on the spike protein of each variant and HEK 293T cell line expressing the human angiotensin‐converting enzyme 2 (hACE2) receptor on the surface, and an enhanced green fluorescent protein reporter. Serum samples from 65 convalescent individuals and 20 WIBP‐CorV vaccine recipients and four therapeutic monoclonal antibodies (mAbs) namely imdevimab, casirivimab, bamlanivimab, and etesevimab were used to evaluate the neutralization potency against the variants. Pseudovirus‐based neutralization assay platforms for PS and VOCs were established, and multiplicity of infection (MOI) was the key factor influencing the assay result. Compared to PS, VOCs may enhance the infectivity of hACE2‐293T cells. Except for Alpha, other VOCs escaped neutralization to varying degrees. Attributed to favorable and emerging mutations, the current pandemic Omicron variant of all VOCs demonstrated the most significant neutralization‐escaping ability to the sera and mAbs. Compared with the PS pseudovirus, Omicron had 15.7‐ and 3.71‐fold decreases in the NT50 value (the highest serum dilution corresponding to a neutralization rate of 50%); and correspondingly, 90% and 43% of immunization or convalescent serum samples lost their neutralizing activity against the Omicron variant, respectively. Therefore, SARS‐CoV‐2 has evolved persistently with a strong ability to escape neutralization and prevailing against the established immune barrier. Our findings provide important clues to controlling the COVID‐19 pandemic caused by new variants.
Histological atlases of the cerebral cortex, such as those made famous by Brodmann and von Economo, are invaluable for understanding human brain microstructure and its relationship with functional ...organization in the brain. However, these existing atlases are limited to small numbers of manually annotated samples from a single cerebral hemisphere, measured from 2D histological sections. We present the first whole-brain quantitative 3D laminar atlas of the human cerebral cortex. It was derived from a 3D histological atlas of the human brain at 20-micrometer isotropic resolution (BigBrain), using a convolutional neural network to segment, automatically, the cortical layers in both hemispheres. Our approach overcomes many of the historical challenges with measurement of histological thickness in 2D, and the resultant laminar atlas provides an unprecedented level of precision and detail. We utilized this BigBrain cortical atlas to test whether previously reported thickness gradients, as measured by MRI in sensory and motor processing cortices, were present in a histological atlas of cortical thickness and which cortical layers were contributing to these gradients. Cortical thickness increased across sensory processing hierarchies, primarily driven by layers III, V, and VI. In contrast, motor-frontal cortices showed the opposite pattern, with decreases in total and pyramidal layer thickness from motor to frontal association cortices. These findings illustrate how this laminar atlas will provide a link between single-neuron morphology, mesoscale cortical layering, macroscopic cortical thickness, and, ultimately, functional neuroanatomy.
Are patient decision aids (PtDAs) associated with (1) improved decision quality defined as a decision informed by the evidence and a value-based decision; (2) improved decision-making processes ...defined as feeling informed, defining clear values related to the decision, and active participation in making the decision; and (3) better patient and health system outcomes compared with either usual care or a non-PtDA intervention?
Patient decision aids are associated with improved decision quality and decision-making processes without worse patient or health system outcomes.
The development and propagation of seizure-related activity was studied in piriform cortex (PC) and areas in the medial temporal lobe to which it projects. In the urethane anesthetized adult rat at ...normal body temperature, tiny injections of convulsants in anterior PC (APC) generate an epileptogenic zone (focus) that can recruit electrographic seizures in untreated posterior PC (PPC) when bursts in the focus are paced at delta frequency (1–4 Hz) by stimulating the lateral olfactory tract. Epileptiform activity initiated by this ‘paced-recruitment’ procedure propagates throughout PPC and into other areas involved in mesial temporal lobe epilepsy (mTLE) at an exceedingly low velocity (< 1 mm/sec) as reported for focal seizures in human cortex. Proconvulsants increased the probability of recruiting electrographic seizures relative to disinhibiting agents that typically recruited interictal discharges. Through methods including realtime recording of current source-density (CSD) with vertical 22-site silicon-based electrodes, and membrane potential with transmembrane microelectrode pairs, insights were gained into mechanisms for epileptogenesis from PC. These findings also may apply to seizure initiation from epileptogenic zones in other areas that project to PPC in addition to APC. Findings from surgical studies indicating that PC plays a critical role in mTLE suggest that the results may be relevant to finding new approaches for blocking seizures from this common, virulent form of epilepsy. Immediate implications for treatment include the optimal placement and patterning of deep brain stimulation to increase its effectiveness for blocking seizures from mTLE while reducing the risk to vasculature from direct stimulation of PC.
•New in vivo model for mesial temporal lobe epilepsy (mTLE) in the adult rat.•Physiological study of the role of piriform (olfactory) cortex in mTLE.•Delta-rate bursts in association fibers initiate seizures in piriform cortex.•Realtime CSD analysis of electrographic seizures in piriform cortex.•Seizure-like activity in piriform ctx propagates widely in the medial temporal lobe.
Chaga, a sclerotia formed by the Inonotus obliquus fungus, has been widely recognized for a number of medicinal properties. Although numerous scientific investigations have been published describing ...various biological activities of chaga from different geographical locations, little work has focused on chaga harvested in the USA or extraction techniques to maximize anti-inflammatory properties. The aim of this study was to investigate the anti-inflammatory properties of chaga collected in Maine (USA) extracted using traditional aqueous (hot water steeping) methods against lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Chaga extracts obtained from both conventional (ethanol/water) extraction methods and an accelerated solvent extraction method (ASE) at optimized conditions were compared to aqueous extracts (tea) obtained from chaga in the powder form (P) and powder form in tea bags (B) based on their effect on both nitric oxide (NO) production and pro-inflammatory cytokine expression, in particular, the expression of TNF-α, interleukin-6 (IL-6), and interleukin-β (IL-1β). Phenolic acid extracts from chaga and individual phenolic acid standards were also investigated for their effect on the same parameters. Results indicated that various chaga extracts have significant anti-inflammatory activity on LPS-stimulated RAW 264.7 cells. The inhibitory effect was through a decrease in the production of NO and the downregulation of TNF-α, IL-6, and IL-1β in RAW 264.7 macrophages. ASE1 (novel, optimized ethanol/water extraction) and P6 (six-minute steeping of powder in 100 °C water) extracts showed the highest inhibitory activity on NO production and on the expression of the inflammatory cytokines, compared to extracts obtained by conventional extraction methods.
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