Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Back When Tigers Used to Smoke

Entry for the 9th Annual Baker & Whitehill Student Artists\u27 Book Contest. Opening Reception Thursday, March 02, 2023, Fleet Library, Main Reading Room. Juror: Andre Lee Bassuet.https://digitalcommons.risd.edu/specialcollections_bookcontest9th2023/1026/thumbnail.jp

Rab GTPase Expression Changes in α-Synucleinopathy and Tauopathy Disorders (P3.8-041)

Objective: Determine Rab GTPase expression changes in α-synucleinopathy and tauopathy disorders. Background: Alterations in Rab GTPase function are increasingly implicated in neurodegenerative disease pathology. In Lewy body disorders, Rab proteins interact with α-synuclein and several are substrates of PINK1 and LRRK2 kinases, supporting a potential role in Parkinson disease (PD). Expression of specific Rabs (e.g., Rab1, 3a, 8a) rescues α-synuclein associated trafficking deficits, vesicle accumulation, and toxicity. Rab proteins have similarly been linked to tau disorders such as Alzheimer disease (AD). However, little is known about the role of Rab GTPases in other tau disorders and expression patterns in neurodegenerative disease. Design/Methods: We examined expression levels of several Rab GTPase proteins (Rab 3a, 5, 7, 8a, 10, 11a, and 35) in postmortem human brain samples from multiple tauopathy (AD, PSP, CBD), Lewy body (α-synucleinopathy) disorders (PD, DLB, MSA), and matched controls. Tissues from select brain regions including frontal and temporal cortex, striatum, cerebellum, and white matter were analyzed. Frozen brain samples were homogenized in high salt buffer and analyzed by Western blot with specific Rab antibodies. Results: Rab3a expression was significantly increased in the striatum of DLB and MSA, but not PD. Rab8a levels were decreased in frontal and temporal cortex in atypical parkinsonian disorders (APD) compared to control. Rab11a was similarly decreased in frontal cortex in APD’s, but increased in the striatum and white matter of PSP and CBD. Rab35, recently implicated as potential PD biomarker, appeared unchanged in PD but was significantly decreased in the striatum in APD’s. Conclusions: These findings represent the first comprehensive analysis of Rab GTPase expression in neuropathological tissues and demonstrate differential expression patterns for Rab proteins in disease-affected regions of tau and α-synuclein disorders. Further studies are needed to determine the potential impact and role of Rab proteins in neurodegenerative disease pathology

Rab GTPase Protein Expression Changes in alpha-Synucleinopathy and Tauopathy Disorders

Objective: Determine Rab GTPase expression changes in α-synucleinopathy and tauopathy disorders. Background: Alterations in Rab GTPase function are increasingly implicated in neurodegenerative diseases. In Lewy body disorders, Rab proteins interact with α-synuclein, supporting a potential role in Parkinson disease (PD). Expression of specific Rabs (e.g., Rab1, 8a) rescues α-synuclein associated trafficking deficits. Rab proteins have similarly been linked to Alzheimer disease (AD). However, little is known about the role of Rab GTPases in tau disorders and expression patterns in neurodegenerative disease. Design/Methods: We examined expression levels of several Rab GTPase proteins (Rab 3a, 5, 7, 8a, 10, 11a, and 35) in postmortem human brain regions from multiple tauopathy (AD, PSP, CBD), Lewy body (α-Synucleinopathy) disorders (PD, DLB, MSA), and matched controls. Frozen brain samples were homogenized in high salt buffer and analyzed by Western blot with specific Rab antibodies. Results: Rab3a expression was significantly increased in the striatum of DLB and MSA, but not PD. Rab8a levels were decreased in frontal and temporal cortex in atypical parkinsonian disorders (APD) compared to control. Rab11a was similarly decreased in frontal cortex in APD’s but increased in the striatum and white matter of PSP and CBD. Rab35 appeared unchanged in PD but was significantly decreased in the striatum in APD’s. Conclusions: These findings represent the first comprehensive analysis of Rab GTPase expression and demonstrate differential expression patterns for Rab proteins in disease-affected regions of tau and α-synuclein disorders. Grant: Supported by the Allen-Simmons Atypical Parkinsonism Fellowship. Work performed at the University of Florida by Dr. Parmar under the mentorship of Dr. McFarland

Rab GTPase Proteins in Tauopathy (5236)

Objective: To elucidate the role of specific Rab GTPase proteins, Rab8a or Rab35, in tau accumulation and aggregate formation. Background: Alzheimer disease (AD) is characterized by the abnormal deposition of amyloid-beta (Aβ) plaques and tau tangles in neurons and glia. Although Aβ correlates well with disease, abnormal, tau accumulation is thought to be a major factor contributing to neurodegeneration in AD. Increasing data indicate that that specific Rab proteins malfunction in affected brain regions in AD. Nearly 70 Rab GTPase proteins have been identified in humans. Rab proteins play an important role in intracellular trafficking, endocytosis, and exocytosis/secretion; and may contribute to clearance of abnormally aggregated proteins including tau. Altered Rab function may be a precursor to tau protein accumulation, aggregation, and associated AD and AD-related pathology. Among several Rab proteins, both Rab8a and Rab35 have emerging roles in Parkinson disease (PD) and AD pathophysiology. In PD Rab35 levels are high in serum and in brain regions affected by disease, implying a role in disease pathology. Design/Methods: Human neuroglioma H4 cells were co-transfected with 4R0N wild type or self-aggregating mutant tau[P301L/S320F] and Rab8a/35 (and functional mutants). Total tau pathological phospho-tau levels were analyzed by Western blot, and aggregate formation with ThioS. The results were compared to a proteomics dataset and Rab expression analyses in postmortem tissue from from AD, PSP (progressive supranuclear palsy) and CBD (corticobasal degeneration). Results: In contrast to PD, Rab35 expression is decreased in postmortem brain tissues from AD, PSP and CBD, whereas Rab8a appears increased, especially in white mater. Both Rab8a and Rab35 overexpression in H4 cells resulted in a marked reduction of total and phosphor-tau. Further, Rab8a and Rab35 reduced ThioS positive tau inclusions in vitro. Conclusions: These data provide the first evidence that Rab8a and Rab35 may regulate tau levels and associated pathology

Diagnosis of Eosinophilic Otitis Media Using Blood Eosinophil Levels

Eosinophilic otitis media (EOM) is a rare middle ear disease with unfavorable outcomes. Under the current diagnostic criteria of EOM, it is challenging to suspect EOM before tympanostomy. Therefore, this study attempted to use blood eosinophil levels for the differential diagnosis of EOM from other conditions. Three disease groups with features of recurrent otorrhea were categorized, which included the following: EOM (n = 9), granulomatosis with polyangiitis (GPA, n = 12), and primary ciliary dyskinesia (PCD, n = 6). Clinical and radiological characteristics were analyzed in the three groups. Patients who underwent ventilation tube insertion due to serous otitis media were enrolled as the control group (n = 225) to evaluate the diagnostic validity of blood eosinophilia. The EOM group showed a significantly higher blood eosinophil concentration (p p < 0.001) compared to the GPA and PCD groups. The estimated sensitivity and specificity for diagnosing EOM from OME patients who underwent ventilation tube insertion were 100% and 95.6%, respectively. In addition, EOM tended to have protympanic space soft tissue density and a relatively clear retrotympanic space in temporal bone computerized tomography. Blood eosinophil evaluation is a significant clinical indicator of EOM. Furthermore, the assessment of exclusive protympanic soft tissue density can provide an additional diagnostic clue

Behemoth: A flash-centric training accelerator for extreme-scale DNNs

© 2021 by The USENIX Association.The explosive expansion of Deep Neural Networks (DNN) model size expedites the need for larger memory capacity. This movement is particularly true for models in natural language processing (NLP), a dominant application of AI along with computer vision. For example, a recent extreme-scale language model GPT-3 from OpenAI has over 175 billion parameters. Furthermore, such a model mostly consists of FC layers with huge dimensions, and thus has a relatively high arithmetic intensity. In that sense, an extreme-scale language model does not suit well to the conventional HBM DRAM-based memory system that lacks capacity and offers extremely high bandwidth. For this reason, we propose to pair the neural network training accelerator with the flash-based memory system instead of the HBM DRAM-based memory system. To design the effective flash-based memory system, we optimize the existing SSD design to improve the SSD bandwidth as well as endurance. Finally, we evaluate our proposed platform, and show that Behemoth achieves 3.65× cost saving over TPU v3 and 2.05× training throughput improvement over the accelerator attached to a commercial SSD.N

Effect of Dexamethasone Combination with Gentamicin in Chemical Labyrinthectomy on Hearing Preservation and Vertigo Control in Patients with Unilateral Meniere’s Disease: A Randomized Controlled Clinical Trial

Chemical labyrinthectomy using gentamicin is a popular method for treating intractable vertigo attacks in Meniere’s disease. However, the risk of hearing loss remains a major concern for clinicians. We investigated the effect of simultaneous dexamethasone and gentamicin application on hearing preservation and vertigo control in patients with intractable unilateral Meniere’s disease. A single-institutional, prospective, single-blinded, randomized clinical trial was conducted. Gentamicin-soaked Gelfoam® was directly applied on the oval window following middle ear exploration. On the round window, dexamethasone-soaked Gelfoam® was applied in the gentamicin with dexamethasone group (GD group, n = 18), and saline-soaked Gelfoam® was applied in the gentamicin with sham reagent group (GO group, n = 19). The hearing change 8 weeks after the procedure and vertigo control 2–12 months after the procedure were investigated. The high-frequency hearing threshold was significantly increased in the GO group (p = 0.005 and 0.012 for 4 and 8 kHz, respectively), but not in the GD group. The short-term (2–6 months) vertigo control was more successful in the GD group (57.89% vs. 94.44%, p = 0.019), but long-term control (6–12 months) was insignificant. In conclusion, the combined application of gentamicin and dexamethasone in chemical labyrinthectomy is an effective method for protecting high-frequency hearing and vertigo control

Bypass of hexavalent chromium-induced growth arrest by a protein tyrosine phosphatase inhibitor: Enhanced survival and mutagenesis

Although the consequences of genotoxic injury include cell cycle arrest and apoptosis, cell survival responses after genotoxic injury can produce intrinsic death-resistance and contribute to the development of a transformed phenotype. Protein tyrosine phosphatases (PTPs) are integral components of key survival pathways, and are responsible for their inactivation, while PTP inhibition is often associated with enhanced cell proliferation. Our aim was to elucidate signaling events that modulate cell survival after genotoxin exposure. Diploid human lung fibroblasts (HLF) were treated with Cr(VI) (as Na2CrO4), the soluble oxyanionic dissolution product of certain particulate chromates, which are well-documented human respiratory carcinogens. In vitro soluble Cr(VI) induces a wide spectrum of DNA damage, in both the presence and absence of a broad-range PTP inhibitor, sodium orthovanadate (SOV). Notably, SOV abrogated Cr(VI)-induced clonogenic lethality. The enhanced survival of Cr(VI)-exposed cells after SOV treatment was predominantly due to a bypass of cell cycle arrest, as there was no effect of the PTP inhibitor on Cr-induced apoptosis. Moreover, the SOV effect was not due to decreased Cr uptake as evidenced by unchanged Cr-DNA adduct burden. Additionally, the bypass of Cr-induced growth arrest by SOV was accompanied by a decrease in Cr(VI)-induced expression of cell cycle inhibiting genes, and an increase in Cr(VI)-induced expression of cell cycle promoting genes. Importantly, SOV resulted in an increase in forward mutations at the HPRT locus, supporting the hypothesis that PTP inhibition in the presence of certain types of DNA damage may lead to increased genomic instability, via bypass of cell cycle checkpoints. © 2008 Elsevier B.V. All rights reserved

Increasing the Coverage of Clarification Responses for a Cooking Assistant

In conversation genres like instruction, clarification questions asked by a user may either relate to the task at hand or to common-sense knowledge about the task domain, whereas most conversational agents focus on only one of these types. To learn more about the best approach and feasibility of integrating both types of questions, we experimented with different approaches for modelling and distinguishing between task-specific and common sense questions in the context of a cooking assistant. We subsequently integrated the best ones in a conversational agent, which we tested in a study with six users cooking a recipe. Even though the three elements functioned well on their own and all participants completed the recipe, question-answering accuracy was relatively low (66%). We conclude with a discussion of the aspects that need to be improved upon to cope with the diverse information need in task-based conversational agents