Notes

Improved Sentinel Surveillance Program pertaining to COVID-19 Episode Forecast in the Huge European Dialysis Hospitals Community.
In our cohort, patients ventilated up to 12 h/d progressed not gradually, but abruptly, to ≥16 h/d. CONCLUSIONS Shortened endpoint-free survival is an important characteristic of SMA types 1 and 2a, but not types 2b, 3, and 4. For SMA types 1c and 2a, the age at which initiation of mechanical ventilation is necessary may be a more suitable endpoint than the arbitrarily set 16 h/d. © 2020 American Academy of Neurology.OBJECTIVE To investigate the clinicopathologic features of eosinophilic granulomatosis with polyangiitis (EGPA)-associated neuropathy with a focus on the presence or absence of anti-neutrophil cytoplasmic antibodies (ANCAs). METHODS We examined the clinical features and pathologic findings of sural nerve biopsy specimens from 82 patients with EGPA-associated neuropathy. Of these patients, 32.9% were myeloperoxidase (MPO)-ANCA positive, and 67.1% were MPO-ANCA negative. PR3-ANCA was negative in all of 78 examined patients. RESULTS Upper limb symptoms were more frequently reported as initial neuropathic manifestations in the MPO-ANCA-positive group than in the MPO-ANCA-negative group (44.4% vs 14.6%, p less then 0.01). The serum levels of C-reactive protein were significantly higher in the MPO-ANCA-positive group than in the MPO-ANCA-negative group (p less then 0.05). Sural nerve biopsy specimens showed findings suggestive of vasculitis (i.e., destruction of vascular structures) in epineurial vessels; these results were seen more frequently in the MPO-ANCA-positive group than in the MPO-ANCA-negative group (p less then 0.0001). Conversely, the numbers of eosinophils in the lumen of the epineurial vessels (p less then 0.01) and epineurial vessels occluded by intraluminal eosinophils (p less then 0.05) were higher in the MPO-ANCA-negative group than in the MPO-ANCA-positive group. Furthermore, the incidence of eosinophil infiltration in the endoneurium was higher in the MPO-ANCA-negative group than in the MPO-ANCA-positive group (p less then 0.01). CONCLUSIONS This study suggests that the pathogenesis of EGPA comprises at least 2 distinct mechanisms ANCA-associated vasculitis resulting in ischemic effects and inflammation, which is prominent in MPO-ANCA-positive patients, and eosinophil-associated vascular occlusion leading to ischemia and eosinophil-associated tissue damage, which is conspicuous in MPO-ANCA-negative patients. © 2020 American Academy of Neurology.OBJECTIVE To assess whether informant-reported apneas during sleep (witnessed apneas) in cognitively unimpaired (CU) elderly persons are associated with higher levels of brain tau. METHODS From the population-based Mayo Clinic Study of Aging, we identified 292 CU elderly ≥65 years of age with both AV-1451 tau-PET and Pittsburgh compound B (PiB)-PET scans and whose bed partners and close relatives had completed a questionnaire that assessed whether participants had witnessed apneas during sleep. For this cross-sectional analysis, we selected the entorhinal and inferior temporal cortices as our regions of interest (ROIs) because they are highly susceptible to tau accumulation. PET signal was scaled to the cerebellum crus to calculate standardized uptake value ratio (SUVR). We fit linear models to assess the association between regional tau and witnessed apneas while controlling for age, sex, years of education, body mass index, hypertension, hyperlipidemia, diabetes, reduced sleep, excessive daytime sleepiness, and global PiB. RESULTS Forty-three participants (14.7%) were found to have witnessed apneas during sleep. The report of witnessed apneas was associated with higher tau-PET SUVR elevation in our ROIs 0.049 SUVR (95% confidence interval [CI] 0.010-0.087, p = 0.015) in the entorhinal cortex and 0.037 SUVR (95% CI 0.006-0.067, p = 0.019) in the inferior temporal cortex after controlling for confounders. CONCLUSION We identified a significant association between witnessed apneas in CU elderly and elevated tau-PET signal in tau-susceptible brain regions. These results suggest a plausible mechanism that could contribute to cognitive impairment and the development of Alzheimer disease. Longitudinal observations are necessary to determine direction of causality. © 2020 American Academy of Neurology.OBJECTIVE To assess relative rates and clinical features of patients with genetic generalized epilepsy (GGE), focal epilepsy (FE), and developmental encephalopathic epilepsy (DEE) in the North American SUDEP Registry (NASR). METHODS We identified all adjudicated definite, definite plus, and probable sudden unexpected death in epilepsy (SUDEP) cases (n = 262) and determined epilepsy type (GGE, FE, or DEE) from medical record review including history, imaging and EEG results, genetics, and next-of-kin interviews. RESULTS Of the 262 SUDEP cases, 41 occurred in GGE, 95 in FE, 24 in DEE, and 102 were unclassifiable. GGE cases comprised 26% of NASR cases with an epilepsy syndrome diagnosis. The relative frequency of FEGGE was slightly lower (2.31) than in population cohorts (2.1-61). Compared to patients with FE, patients with GGE had similar (1) ages at death and epilepsy onset and rates of (2) terminal and historical antiseizure medication adherence; (3) abnormal cardiac pathology; (4) illicit drug/alcohol use histories; and (5) sleep state when SUDEP occurred. CONCLUSIONS GGE cases were relatively overrepresented in NASR. Because GGEs are less often treatment-resistant than FE or DEE, seizure type rather than frequency may be critical. Many people with GGE predominantly have generalized tonic-clonic seizures (GTCS) when they have uncontrolled or breakthrough seizures, whereas patients with FE more commonly experience milder seizures. Future mechanistic SUDEP studies should assess primary and focal-to-bilateral GTCS to identify potential differences in postictal autonomic and arousal disorders and to determine the differential role that lifestyle factors have on breakthrough seizures and seizure types in GGE vs FE to effectively target SUDEP mechanisms and prevention. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.BACKGROUND Youth and young adults frequently use social media and are susceptible to tobacco use. This study is the first to provide a systematic overview of how leading tobacco product brands use popular social media platforms. METHODS We identified 112 leading brands of e-cigarettes, hookah, cigars, cigarettes and smokeless tobacco based on sales and self-report user data. We searched for each brand on six platforms Instagram, Facebook, Twitter, YouTube, Pinterest and Tumblr. In early 2019, we conducted a content analysis of each page, coding age restrictions, warning display, page characteristics and post characteristics. RESULTS Cigarette brands were generally not present. Most e-cigarettes, hookah and cigar brands had pages on at least two platforms. One-third of smokeless brands had pages on at least one platform. Few brands had pages on Pinterest and Tumblr. Most pages had existed for 3-5 years. Overall, brand pages rarely used age gating, did not display health warnings, generally posted images of a product alone and often used hashtags unrelated to tobacco. Brands commonly used special features like ephemeral posts on Instagram and pop-up chat windows on Facebook. Many pages displayed images of young people and mentioned flavour. Median followers per brand ranged from about 1 000-10 000, and total followers summed across brands reached over 5 million on Facebook and Instagram alone. CONCLUSIONS Leading brands of most tobacco product types use social media extensively. Several findings identify issues related to youth exposure to and appeal of tobacco social media marketing. Findings can inform tobacco education efforts and regulation. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.An orally available and novel small molecule, ONO-7579 (N-2-[4-(2-amino-5-chloropyridin-3-yl)phenoxy]pyrimidin-5-yl-N'-[2-(methanesulfonyl)-5-(trifluoromethyl)phenyl]urea), is a highly potent and selective pan-tropomyosin receptor kinase (TRK) inhibitor. The objective of the present study was to characterize the pharmacokinetic (PK), pharmacodynamic (PD), and antitumor efficacy relationships of ONO-7579 in mice xenografted with a human colorectal cancer cell line, KM12 (harboring the TPM3-NTRK1 fusion gene), via a PK/PD modeling approach. Plasma and tumor concentrations of ONO-7579, tumor levels of phosphorylated TPM3-TRKA (pTRKA), and tumor volumes in the murine model were measured with a single or multiple dose of ONO-7579 0.06-0.60 mg/kg administered once daily. The PK/PD/efficacy models were developed in a sequential manner. Changes in plasma concentrations of ONO-7579 were described with an oral one-compartment model. Tumor concentrations of ONO-7579 were higher than plasma concentrations, and changes for explaining the antitumor efficacy of TRK inhibitors using a PK/PD modeling approach in xenograft mice. This finding suggests a rational dosing regimen in early-stage clinical studies for ONO-7579 , a novel pan-TRK inhibitor. Cobimetinib purchase The American Society for Pharmacology and Experimental Therapeutics.Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) have become a promising cell source for cardiovascular research. The electrophysiological characteristic of hESC-CMs has been generally studied, but little is known about electrophysiological response to adrenergic adrenoreceptor (AR) activation. This study aims to characterize electrophysiological responses of hESC-CMs to adrenergic stimulation, in terms of the conduction velocity (CV) and action potential (AP) shape. The H9 hESC-CMs were acquired by a classical differentiation protocol and cultured to achieve confluent cell monolayers. The AP shape and CV among the monolayers were recorded using optical mapping during electrophysiological and pharmacological stimulation experiments. RT-qPCR and Western blot were adopted to determine the expression levels of connexin and ion channel gene and protein. Chronic β-AR stimulation by isoproterenol for 24h in hESC-CMs monolayers increased CV by approximately 50%, while a-AR or acute β-AR stimulation had noncise signaling pathway in the ARs regulation of action potential shape and electrical propagation across hESCs-CMs monolayer. It is β1-AR, not β2-AR contributing to the modification of conduction velocity in hESC-CMs and accelerates conduction velocity by up-regulating Cx43 via PKA/MEK/MAPK pathway. The American Society for Pharmacology and Experimental Therapeutics.Loss-of-function of voltage-gated potassium (Kv) channels is linked to a range of lethal or debilitating channelopathies. New pharmacological approaches are warranted to isoform-selectively activate specific Kv channels. One example is KCNA1 (Kv1.1), an archetypal Shaker-type Kv channel, loss-of-function mutations in which cause Episodic Ataxia Type 1 (EA1). EA1 causes constant myokomia, episodic bouts of ataxia and may associate with epilepsy and other disorders. We previously found that the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and modified versions of glycine directly activate Kv channels within the KCNQ subfamily, a characteristic favored by strong negative electrostatic surface potential near the neurotransmitter carbonyl group. Here, we report that adjusting the number and positioning of fluorine atoms within the fluorophenyl ring of glycine derivatives produces isoform-selective KCNA1 channel openers that are inactive against KCNQ2/3 channels, or even KCNA2, the closest relative of KCNA1.
Homepage: https://www.selleckchem.com/products/cobimetinib-gdc-0973-rg7420.html