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Objective Recent policy making aims to prevent health systems, lectronic health record (EHR) vendors, and others from blocking the electronic sharing of patient data necessary for clinical care. We sought to assess the prevalence of information blocking prior to enforcement of these rules. Materials and Methods We conducted a national survey of health information exchange organizations (HIEs) to measure the prevalence of information blocking behaviors observed by these third-party entities. Eighty-nine of 106 HIEs (84%) meeting the inclusion criteria responded. Results The majority (55%) of HIEs reported that EHR vendors at least sometimes engage in information blocking, while 30% of HIEs reported the same for health systems. The most common type of information blocking behavior EHR vendors engaged in was setting unreasonably high prices, which 42% of HIEs reported routinely observing. The most common type of information blocking behavior health systems engaged in was refusing to share information, which 14% of HIEs reported routinely observing. Reported levels of vendor information blocking was correlated with regional competition among vendors and information blocking was concentrated in some geographic regions. Discussion Our findings are consistent with early reports, revealing persistently high levels of information blocking and important variation by actor, type of behavior, and geography. These trends reflect the observations and experiences of HIEs and their potential biases. Nevertheless, these data serve as a baseline against which to measure the impact of new regulations and to inform policy makers about the most common types of information blocking behaviors. Conclusion Enforcement aimed at reducing information blocking should consider variation in prevalence and how to most effectively target efforts.

We report the transient intersegmental plane formed by circulation single-blocking, which is consistent with the true intersegmental plane, and its formation principles, characteristics and potential applications.

SUMMARYUpon cooling, most rocks acquire a thermoremanent magnetization (TRM); the cooling rate at which this happens not only affects palaeointensity estimates, but also their unblocking temperatures in stepwise thermal demagnetization experiments, which is important, for example, to estimate volcanic emplacement temperatures. Traditional single-domain (SD) theory of magnetic remanence relates relaxation times to blocking temperatures— the blocking temperature is the temperature at which the relaxation time becomes shorter than the experimental timescale—and therefore strictly only applies to remanence acquisition mechanisms at constant temperatures (i.e. viscous remanent magnetizations, VRMs). A theoretical framework to relate (constant) blocking temperatures to (time-varying) cooling rates exists, but this theory has very limited experimental verification—partly due to the difficulty of accurately knowing the cooling rates of geological materials. Here we present an experimental test of this ‘cooling rate effect on blocking temperatures’ through a series of demagnetization experiments of laboratory-induced TRMs with controlled cooling rates. The tested cooling rates span about 1 order of magnitude and are made possible through (1) extremely accurate demagnetization experiments using a low-temperature magnetic properties measurement system (MPMS) and (2) the use of a ‘1-step-only’ stepwise thermal demagnetization protocol where the relaxation process is measured over time. In this way the relaxation time corresponding to the blocking temperature is measured, which can be done to much higher accuracy than measuring the blocking temperature directly as done in traditional stepwise thermal demagnetization experiments. Our experiments confirm that the cooling rate relationship holds to high accuracy for ideal magnetic recorders, as shown for a synthetic weakly interacting SD magnetoferritin sample. A SD-dominated low-Ti titanomagnetite Tiva Canyon Tuff sample, however, showed that natural samples are unlikely to be sufficiently ‘ideal’ to meet the theoretical predictions to high accuracy—the experimental data agrees only approximately with the theoretical predictions, which may potentially affect blocking temperature estimates in stepwise thermal demagnetization experiments. Moreover, we find a strongly enhanced cooling rate effect on palaeointensities for even marginally non-ideal samples (up to 43 per cent increase in pTRM for a halving of the cooling rate).

Background and Aims Interstitial fibrosis, characterised by the accumulation of extracellular matrix in the cortical interstitium, is directly correlated with progressive chronic kidney disease secondary to inflammatory, immunologic, obstructive or metabolic causes. An invariant histologic marker of this progression is the accumulation of fibroblasts, with the phenotypic appearance of activated myofibroblasts expressing alpha smooth muscle actin (αSMA) within intracellular contractile stress fibres. Once present, these myofibroblasts are prognostic indicators of expansion of fibrotic matrix and progressive tubular atrophy, leading towards end-stage disease. The Receptor Tyrosine Kinase AXL is involved in a range of kidney pathologies, with increased activity associated with Epithelial to Mesenchymal Transition (EMT) and tubular proliferation following podocyte loss. In mice treated with an angiotensin-converting enzyme (ACE) inhibitor, enhancement of AXL expression is localised to tubular segments within the medulla and there is evidence of parallel regulatory control of ACE and AXL. We have demonstrated enhanced expression of AXL and the mesenchymal marker, vimentin in diseased human kidney tissue secondary to diabetes or hypertension. Targeting AXL with a small-molecule inhibitor has previously been reported to attenuate fibrosis and reduce inflammation in the unilateral ureteric-outflow obstruction (UUO) model of kidney fibrosis in mice (Landolt et al., 2019). Tilvestamab is a novel function blocking humanized anti-AXL antibody. Tilvestamab blocks GAS6-mediated AXL receptor activation in fibroblasts and renal tubule epithelial cells and mediates AXL receptor internalization and degradation. In this study we aimed to further characterise AXL as a target in CKD and to investigate anti-fibrotic efficacy of tilvestamab. Method Eight weeks old male C57BL/6 mice underwent UUO operation. After 15 days, kidneys were dissociated and stained with a high dimensional single cell mass cytometry 33 markers antibody panel. Data were analysed using JMP Genomics (v.8.2). Precision Cut Kidney Slices (PCKSs) from explanted human kidney tissue were propagated in a bioreactor (Paish et al., 2019, FibroFind, UK). PCKS were incubated for 72hrs in the presence of investigational drugs. Secreted collagen1a1 were quantified by ELISA. RNA was reverse transcribed to cDNA and used in qPCRs to measure Col1a1 and αSMA. FFPE sections were stained for αSMA. High magnification images were taken of each slide and analysed for surface area covered by the stain. Results Expression pattern of AXL during development of kidney fibrosis in the UUO model was investigated using a mass cytometry antibody panel designed for identifying subpopulations of immune cells as well as cell populations of the fibrotic stroma. Two predominant cell populations were affected by ligation; the mesenchymal and the immune island. AXL was a marker characterising several of the key populations that expanded upon ligation supporting a role for AXL in kidney fibrosis pathogenesis. In an ex vivo model of human PCKS, tilvestamab dose-dependently reduced the levels of αSMA. When combined with the lower of two doses of the ACE inhibitor enalapril, the lowest dose of tilvestamab synergized to reduce αSMA levels further as well as reducing secreted Collagen 1a1. Conclusion AXL expression is induced in key cell populations during development of kidney fibrosis supporting AXL as a novel target in CKD. Tilvestamab represents a promising strategy for the pharmacologic intervention of kidney fibrosis, and the potential synergy with current reno-protective therapies warrants further exploration.

Background Clinical hypertension is associated with renal inflammation and elevated circulating levels of proinflammatory cytokines. IL-1 receptor antagonist (IL-1Ra) is one of the most important anti-inflammatory cytokines and plays a crucial role in inflammation. Inhibition of IL-1 may contribute to modulation of the Angiotensin II (AngII)-induced hypertension response. This study aimed to elucidate the effects of IL-1Ra and anti-IL-1beta antibody (01BSUR) on AngII-induced hypertension and renal inflammation. Methods and results To determine the contribution of IL-1Ra to AngII-induced renal inflammation, male wild-type (WT) and IL-1Ra-deficient (IL-1Ra−/−) mice were infused with AngII (1000ng/kg/min) using subcutaneous osmotic pumps for 14 days. We checked blood pressure, histological change, and several mRNA expressions 14 days after infusion. Fourteen days after infusion, systolic blood pressure (197±5 vs 169±9 mmHg, p Conclusions Inhibition of interleukin-1 by both endogenous IL-1Ra and exogenous 01BSUR decreased AngII-induced hypertension and renal damage in mice, suggesting suppression of IL-1 may provide an additional strategy to protect against renal damage in hypertensive patients. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): JSPS KAKENHI

Discussion on the flexible kink produced in the β2-integrin transmembrane domain blocking mechanotransduction of signals necessary for neutrophil arrest and spreading.

Introduction Blue-blocking glasses are increasingly used as an intervention for jet-lag and other situations where an individual wishes to promote a “dark” signal despite the presence of ambient light. However, most studies on blue-blockers are done under controlled laboratory settings using emissions generated from electric light sources. The present study evaluated the performance of commercially available blue-blockers under daytime sunlight conditions. Methods A calibrated spectroradiometer (Ocean Insight), cosine corrector, optic fiber, and software package were used to measure the absolute irradiance (uW/cm^2/nm) available midday in a standardized location that received direct sunlight. Thirty-one commercially available blue-blockers were individually placed in front of the cosine corrector and intensity was measured and analyzed. Each lens was tested for its ability to block visible light, as well as light within the 440-530nm range. Lenses were evaluated individually and grouped by lens type: red-tinted lenses (RTL), orange-tinted lenses (ORL), orange-tinted lenses with blue reflectivity (OBL), brown-tinted lenses (BTL), yellow-tinted lenses (YTL), and clear lenses with blue reflectivity (RBL). Results Across the full spectrum, RTL blocked 66% of the light, OTL blocked 60%, OBL blocked 43%, BTL blocked 56%, YTL blocked 28%, and RBL blocked 20%. When the range was restricted to 440-530nm, RTL blocked 99%, OTL blocked 96%, OBL blocked 90%, BTL blocked 66%, YTL blocked 38%, and RBL blocked 17% of the light. Variation across lens types was significant for the full spectrum (one-way ANOVA, p < 0.0001) as well as the 440-530nm range (one-way ANOVA, p < 0.0001). Individual lenses showed variability in performance, though this variability was smaller than the between-group differences. Conclusion Under daylight conditions, red and orange lenses (RTL, OTL, and OBL) blocked at least 90% of the light in the 440-530nm range. Notably, RBL lenses restricted the most short-wavelength light as a proportion of the total light blocked. These data suggest that RTL, OTL, and OBL are effective at blocking the most circadian photosensitive components of daylight at the cost of reducing total illumination. Support (if any) R01MD011600, R01DA051321

Bell Media Inc. v GoldTV.Biz (2019) FC 1432, 15 November 2019 On 15 November 2019, the Federal Court of Canada issued Canada’s first website blocking order in a copyright case.

Background The pathogenesis of inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), has not been fully elucidated, but a strong correlation between IBD and the immune dysregulation of the host has been persistently detected. Sirtuin 2 (SIRT2), a histone deacetylase, has recently been found to play an important role in inflammation, infection and immunomodulatory. As a potent SIRT2-specific inhibitor, thiomyristoyl (TM) has an extensive anticancer activity, but its anti-inflammatory property remains unclear. Methods Human peripheral blood mononuclear cells (PBMC) were differentiated into T helper 17 (Th17) cells in vitro and were treated with TM simultaneously. Interleukin (IL)-17A in the culture supernatant, the ratio of T cells, the levels of phosphorylated-signal transducer and activator of transcription (p-stat3) and phosphorylated-nuclear factor kappa-B (p-NF κB) were determined by enzyme-linked immunosorbent assay (ELISA), flow cytometry or western blotting, respectively. Then, colitis C57BL/6J mice induced by 2.5% dextran sulphate sodium salt (DSS) were treated with TM, and were evaluated by disease activity index (DAI) and haematoxylin-eosin (HE) staining. T-cell subsets in the mice spleen, IL-6, IL-10 and IL-17A in serum, related factors retinoic acid receptor-related orphan receptor-γ t (ROR-γt), forkhead box protein P3 (FOXP3), IL-17A, interferon γ γ (IFN-γ), IL-23, IL-10 and hypoxia-inducible factor (HIF)-1α in mice colon were measured by flow cytometry, ELISA, quantitative real-time polymerase chain reaction (Q-PCR) and western blotting, respectively. Results Compared with the positive control group, the levels of IL-17A in culture supernatant, the percentage of Th17, the levels of p-stat3 and p-NF kappa B in cell lysate were lower in the TM group. Compared with PBS-treated colitis mice, TM-treated colitis mice had longer colons, fewer weight-losses, lower DAI and histopathologic scores. Interestingly, although the expression of IFN-γ, IL-17A, and ROR-γt was inhibited in the colons of TM-treated mice, the level of FOXP3 did not change. Consistently, the percentage of spleen Th17 cells was decreased in the TM group while the percentage of Treg cells was not affected. In addition, the TM group had reduced levels of IL-23 and HIF-1α, and an increased level of IL-10 in the colon, compared with colitis group. Conclusion TM ameliorates DSS-induced experimental colitis by blocking the differentiation of Th17 cells, which may be associated with the STAT3/IL-6 signal pathway. SIRT2 may represent a potential target for the treatment of IBD.

Introduction Blue blocking glasses are often marketed to promote relaxation, sleep, and circadian health by attenuating melatonin-suppressing light exposure. But these glasses represent a wide range of tint and other lens properties. Further, the utility of these glasses under ecologically valid indoor conditions (where light is typically generated from overhead broadspectrum fluorescent lamps) is still unclear, especially across various products. Methods A calibrated spectroradiometer (Ocean Insight), cosine corrector, optic fiber, and software package were used to measure the absolute irradiance (uW/cm^2/nm) emitted from overhead fluorescent lighting in a closeted dark room. Thirty-one commercially available blue blockers were individually placed between the cosine corrector and the luminaire, at a standardized distance and angle, where intensity was measured and analyzed. Each lens was evaluated individually relative to the light source under identical conditions. Then, lenses were collapsed by type into the following groups: red-tinted lenses (RTL), orange-tinted lenses (OTL), orange-tinted lenses with blue reflectivity (OBL), brown-tinted lenses (BTL), yellow-tinted lenses (YTL), and clear reflective blue lenses (RBL). Results There was significant variation in light-blocking across lens types (one-way ANOVA, p < 0.0001). On average, RTL and BTL restricted 59% of the visible light measured from 380-780nm. OTL blocked 47% of the light in this range, while OBL blocked 29%. Both YTL and RBL blocked 14% of the exposure. When narrowing the range of light to 440-530nm (the part of the spectrum most likely to produce a response from melanopsin-expressing retinal ganglion cells), we estimated the following performance: the RTL and OTL blocked close to 100% of the light, OBL blocked 98%, BTL blocked 80%, YTL blocked 33%, and RBL blocked 15%. These differences were statistically significant (one-way ANOVA, p < 0.0001). Individual lenses performed variably within groups, but these differences were small. Conclusion Focusing on the portion of the visible spectrum most likely to suppress melatonin secretion, RTL and OTL blocked exposure the best, followed by OBL, BTL, YTL, and (lastly) RBL. Support (if any) R01MD011600, R01DA051321

Discussion of the unique role of galectin-12 in regulating the response of APL to all ATRA.

Modulation of tumor-associated macrophages and microglia (TAMs) in glioblastoma (GBM) is a promising anti-tumor strategy. However, little is known about the phenotypic organization of the TAM-pool and the role of GBM subtypes in shaping their specific immunologic environment. Therefore, we sought to model the composition of microglia and peripheral macrophages within the GBM-TAM-pool. Further, we aimed at assessing the response of the TAM pool to CD47-Sirpα blockade. Using novel orthotopically xenografted, immunodeficient mice with genetically color-coded macrophages and microglia, termed NSG-Ccr2RFP/+Cx3cr1GFP/+ mice, we found that the TAM composition was dependent on the rate of tumor growth. While microglia dominated TAMs in slow growing tumors, high passaged cell lines induced a more mixed pool of both microglia and macrophages. Blockade of the “don’t eat me” signal CD47 by anti-CD47 antibodies prompted both macrophage and microglial-induced phagocytosis in vivo and led to marked microglial morphological changes assessed by intracranial in vivo imaging. The therapeutic efficacy of anti-CD47 treatment was preserved in mice lacking Ccr2, which limits macrophage recruitment to the brain. Anti-CD47-induced microglial phagocytosis alone was sufficient to reduce tumor burden. Under anti-CD47 treatment, macrophages changed their transcriptional profile towards a more pro-inflammatory, “M1”-polarized signature, whereas the microglial transcriptome remained unchanged as assessed by RNAseq analysis. These results emphasize the importance of both resident microglia and infiltrating macrophages in GBM progression and potential of GBM control. Moreover, CD47-Sirpα disruption promotes important phenotypic and functional status changes of resident microglia, which has critical implications for central nervous system (CNS) immunotherapies in the future.

Aldosterone has an important role in end-organ damage in hypertension, post-MI-cardiac remodelling, and heart failure. Accordingly blockers of the aldosterone receptor such as spironolactone and eplerenone have gained widespread use in the treatment of (post-MI) heart failure. The article outlines the clinical evidence on the efficacy of aldosterone blocking agents in heart failure and hypertension and outlines clinical perspectives for their use.

As more and more devices are equipped with multiple network interfaces, the multihomed technology is becoming an important technology that can provide more reliable connection against the network failure and higher data transmission rate. Concurrent Multipath Transfer (CMT), which is based on SCTP, is devised for multihomed networks. CMT can transmit data over all paths to maximize the data transmission speed. One of the main concerns of CMT is the receiver buffer blocking issue, especially in multihomed wireless mobile networks. Receiver buffer blocking is mainly caused by lost data. In this paper, we propose mobile CMT (mCMT) over wireless networks to deal with the receiver buffer blocking caused by error loss and handoff loss. mCMT has the features of (i) path-oriented multistreaming, (ii) MIH-assisted handoff mechanism, in which MIH denotes Media Independent Handover and (iii) association resume. Path-oriented multistreaming can reduce the receiver buffer blocking caused by error loss. MIH-assisted a handoff can reduce the amount of packet loss during a handoff, which may lead to receiver buffer blocking. Moreover, mCMT introduces the concept of association resume to recover the disconnected association. Simulation results show that mCMT can reduce the effect of the receiver buffer blocking effectively for devices that have smaller buffer size.

Higher order nonlinear effects of the site blocking induced oscillations in the Monte Carlo simulations of CO oxidation are outlined. It is shown that the rate equations accounting for these effects display a supercritical Hopf bifurcation.

The beta-adrenergic blockade as a therapeutic approach first emerged in the 1950s. During the past five decades, the total number of indications that have been suggested, and the remarkable number approved by regulatory agencies, places beta-blockade far ahead of all competing treatments, not only in the cardiovascular area, but in all of therapeutics. Differentiation of beta-adrenergic blocking agents has been made on the basis of beta1 selectivity, duration of action, intrinsic sympathomimetic activity, lipophilicity, and whether or not the beta-adrenergic blocking action is accompanied by an alpha-adrenergic blocking action. With the development of nebivolol, a beta-adrenergic blocking agent that also activates nitric oxide synthase in blood vessels, comes a new therapeutic option. Endothelial dysfunction with loss of nitric oxide production is a common feature in many cardiovascular diseases. This fascinating class of drugs continues to provide us with new and important therapeutic opportunities.

Spam—unsolicited commercial e-mail—is a complex and growing problem, and threatens to derail the internet revolution. Joshua Goodman and David Heckerman of Microsoft Research describe some statistics-based methods for blocking spam, first by distinguishing it from wanted mail, and then by constructing puzzles they propose to use to challenge suspected spammers.

The inhibitory effects of glibenclamide on the levcromakalim-induced ATP-sensitive K+ (KATP) channels were investigated with cell-attached configuration in pig proximal urethra. Application of 10 μm glibenclamide reversibly inhibited the activity of the 100 μm levcromakalim-induced KATP channel, decreasing not only the channel open probability but also the amplitude of unitary current. The inhibitory concentration-response curve of the glibenclamide-induced sublevel conductance of KATP channel was shifted to the right (IC50=4.7 μm), compared with the levcromakalim-induced KATP channel (full conductance, IC50=0.5 μm). Glibenclamide is the first reported sulphonylurea to selectively block KATP channel, not only by decreasing the channel activity but also by reducing the unitary amplitude in smooth muscle.

Proponents of personalized medicine met January 18–19 in Mountain View, California, to discuss emerging technologies and new business models and commiserate over the regulations and economics that seem to be blocking the translation of science to practice. The regulatory roadblock for

Factors driving the development of neuromuscular blocking agents are discussed. The goal of recent development of neuromuscular blocking agents is to develop agents with fewer adverse effects than succinylcholine and greater control. Greater control can be achieved through a short duration of action and a fast onset, similar to that found with succinylcholine. Duration control can be achieved through rapid, reliable metabolism that is organ independent, as with cisatracurium, or that occurs in the liver, because this will fail only in patients with severe hepatic disease. Rapid onset can be achieved by giving higher doses of drugs that have a fast, reliable metabolism or a rapid distribution to tissue. This has been done with succinylcholine, cisatracurium, and mivacurium. It has been shown that a low-potency drug has a faster onset than a higher-potency drug, even at the same relative dose. Rocuronium was the first neuromuscular blocking agent marketed that was developed specifically as a low-potency drug for achieving a rapid onset. In a comparison with two other intermediate-duration neuromuscular blocking agents at equipotent doses, rocuronium's onset was about one minute, which was two minutes faster than that of either vecuronium or atracurium. Rapacuronium is an investigational intermediate-duration agent and is even less potent than rocuronium. Clinical studies have shown it to have a very rapid onset (about 50 seconds) and a short duration of action (15-25 minutes, depending on the dose). Its short duration of action will make it potentially useful for short surgical procedures and procedures in which nerve integrity must be monitored. At the same time, its onset time approaches that of succinylcholine. Recent advances have made the administration of neuromuscular blocking agents much easier because the newer nondepolarizing relaxants offer faster onset and greater control.