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Background The cholinesterase inhibitor therapeutics (CI) approved for use in Alzheimer's disease (AD) are palliative for a limited time. Objective To examine the outcome of AD patients with add-on therapy of the omega-3 fatty acid drink Smartfish. Methods We performed a prospective study using Mini-Mental State Examination, amyloid-β (Aβ) phagocytosis blood assay, and RNA-seq of peripheral blood mononuclear cells in 28 neurodegenerative patients who had failed their therapies, including 8 subjective cognitive impairment (SCI), 8 mild cognitive impairment (MCI), 2 AD dementia, 1 frontotemporal dementia (FTD), 2 vascular cognitive impairment, and 3 dementia with Lewy bodies (DLB) patients. Results MCI, FTD, and DLB patients patients volunteered for the addition of a ω-3 fatty acid drink Smartfish protected by anti-oxidants to failing CI therapy. On this therapy, all MCI patients improved in the first year energy transcripts, Aβ phagocytosis, cognition, and activities of daily living; in the long term, they remained in MCI status two to 4.5 years. All FTD and DLB patients rapidly progressed to dementia. On in vivo or in vitroω-3 treatments, peripheral blood mononuclear cells of MCI patients upregulated energy enzymes for glycolysis and citric acid cycle, as well as the anti-inflammatory circadian genes CLOCK and ARNTL2. Conclusion Add-on ω-3 therapy to CI may delay dementia in certain patients who had failed single CI therapy.

Background To describe the effect of the COVID-19 pandemic on emergency general surgery operative volumes during governmental shutdowns secondary to the pandemic and characterize differences in disease severity, morbidity, and mortality during this time compared to previous years. Methods This retrospective cohort study compares patients who underwent emergency general surgery operations at a tertiary hospital from March 1st to May 31st of 2020 to 2019. Average emergent cases per day were analyzed, comparing identical date ranges between 2020 (pandemic group) and 2019 (control group). Secondary analysis was performed analyzing disease severity, morbidity, and mortality. Results From March 1st to May 31st, 2020, 2.5 emergency general surgery operations were performed on average daily compared to 3.0 operations on average daily in 2019, a significant decrease ( P = .03). No significant difference was found in presenting disease severity, morbidity, or mortality between the pandemic and control groups. Discussion This study demonstrates a decrease of 65% in emergency general surgery operations during governmental restrictions secondary to the COVID-19 pandemic. This decrease in operations was not associated with worse disease severity, morbidity, or mortality.

Artificial intelligence (AI) and digital twin models of various systems have long been used in industry to test products quickly and efficiently. Use of digital twins in clinical medicine caught attention with the development of Archimedes, an AI model of diabetes, in 2003. More recently, AI models have been applied to the fields of cardiology, endocrinology, and undergraduate medical education. The use of digital twins and AI thus far has focused mainly on chronic disease management, their application in the field of critical care medicine remains much less explored. In neurocritical care, current AI technology focuses on interpreting electroencephalography, monitoring intracranial pressure, and prognosticating outcomes. AI models have been developed to interpret electroencephalograms by helping to annotate the tracings, detecting seizures, and identifying brain activation in unresponsive patients. In this mini-review we describe the challenges and opportunities in building an actionable AI model pertinent to neurocritical care that can be used to educate the newer generation of clinicians and augment clinical decision making.

BACKGROUND: Progressive apraxia of speech (PAOS) is a neurodegenerative disorder of speech programming distinct from aphasia and dysarthria, most commonly associated with a 4-repeat tauopathy. Our objective was to better understand the reasons for possible delays or diagnostic errors for patients with PAOS. METHODS: Seventy-seven consecutive PAOS research participants from the Neurodegenerative Research Group were included in this study. The medical records for these patients were reviewed in detail. For each speech-related visit, data such as the chief complaint, clinical findings, and neuroimaging findings were recorded. RESULTS: Apraxia of speech was the initial diagnosis in 20.1% of participants at first evaluation noted in the historical record. Other common diagnoses included primary progressive aphasia (PPA) (20.1%), dysarthria (18.18%), MCI/Dementia (6.5%), and motor neuron disease (3.9%). It took a median of 2.02 (Range: 0.16–8.18) years from symptoms onset for participants to receive an initial diagnosis and 3.00 (Range: 0.49–9.42) years to receive a correct diagnosis. Those who were seen by a speech-language pathologist (SLP) during their first documented encounter were more likely to be correctly diagnosed with PAOS (37/48) after SLP consultation than those who were not seen by an SLP on initial encounter (5/29) (p

Alteration in cellular prion protein (PrPC) localization on the cell surface through mediation of the glycosylphosphatidylinositol (GPI) anchor has been reported to dramatically affect the formation and infectivity of its pathological isoform (PrPSc). A patient with Gerstmann-Sträussler-Scheinker (GSS) syndrome was previously found to have a nonsense heterozygous PrP-Q227X mutation resulting in an anchorless PrP. However, the allelic origin of this anchorless PrPSc and cellular trafficking of PrPQ227X remain to be determined. Here, we show that PrPSc in the brain of this GSS patient is mainly composed of the mutant but not wild-type PrP (PrPWt), suggesting pathological PrPQ227X is incapable of recruiting PrPWt in vivo. This mutant anchorless protein, however, is able to recruit PrPWt from humanized transgenic mouse brain but not from autopsied human brain homogenates to produce a protease-resistant PrPSc-like form in vitro by protein misfolding cyclic amplification (PMCA). To further investigate the characteristics of this mutation, constructs expressing human PrPQ227X or PrPWt were transfected into neuroblastoma cells (M17). Fractionation of the M17 cells demonstrated that most PrPWt is recovered in the cell lysate fraction, while most of the mutant PrPQ227X is recovered in the medium fraction, consistent with the results obtained by immunofluorescence microscopy. Two-dimensional gel-electrophoresis and Western blotting showed that cellular PrPQ227X spots clustered at molecular weights of 22–25 kDa with an isoelectric point (pI) of 3.5–5.5, whereas protein spots from the medium are at 18–26 kDa with a pI of 7–10. Our findings suggest that the role of GPI anchor in prion propagation between the anchorless mutant PrP and wild-type PrP relies on the cellular distribution of the protein.

Sporadic late-onset Alzheimer disease (LOAD) preceded by mild cognitive impairment (MCI) is the most common type of dementia. Long-term studies of immunity to pathogenic amyloid-β (Aβ) in LOAD are lacking. Innate immunity of LOAD patients is malfunctioning in phagocytosis and degradation of Aβ and LOAD patients' macrophage transcriptome and metabolome are deregulated. We previously showed omega-3 fatty acid (ω-3)-mediated repair of unfolded protein response and here we show much broader transcriptomic effects. ω-3 treatment in vitro and ω-3 supplementation by the drink Smartfish (SMF) in vivo increased the transcripts of the genes and pathways of immunity, glycolysis, tricarboxylic acid cycle, OX-PHOS, nicotinamide dinucleotide (NAD+ ) synthesis, and reversed the defects in Aβ phagocytosis. In both peripheral blood mononuclear cells (PBMC) and macrophages, ω-3 increased ATP-linked oxygen consumption rate (OCR) and ω-3 with carnitine was superior to ω-3. ω-3 treatment in vitro and supplementation by the ω-3 drink SMF in vivo rescued macrophage phagocytosis when glycolysis or glycosylation were blocked. ω-3 provide flexible energy for immune clearance of the brain throughout the diurnal cycle, even in hypo- or hyper-glycemia. In certain LOAD patients, ω-3 may delay progression to dementia.

Macrophages (Mϕs) of patients with Alzheimer’s disease and mild cognitive impairment (MCI) are defective in amyloid-β1-42 (Aβ) phagocytosis and have low resistance to apoptosis by Aβ. Omega-3 fatty acids (ω-3s) in vitro and in vivo and the ω-3 mediator, resolvin D1, in vitro increase Aβ phagocytosis by Mϕs of patients with MCI. We have investigated the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress by Mϕs in a longitudinal study of fish-derived, ω-3–supplemented patients with MCI. Patients in the apolipoprotein E (ApoE)e3/e3 subgroup over time exhibited an increase of protein kinase RNA-like ER kinase (PERK) expression, Aβ phagocytosis, intermediate M1-M2 Mϕ type, and a Mini-Mental State Examination (MMSE) rate of change of +1.8 points per year, whereas patients in the ApoEe3/e4 subgroup showed individually divergent results with an MMSE rate of change of −3.2 points per year. In vitro treatment of Mϕs by fish-derived ω-3 emulsion increased Aβ phagocytosis, PERK expression, and UPR RNA signature, and decreased ER stress signature. Augmented genes in the UPR signature included chaperones, lectins, foldases, and N-linked glycosylation enzymes. In summary, fish-derived ω-3s increase cytoprotective genes and decrease proapoptotic genes, improve immune clearance of Aβ, and are associated with an improved MMSE rate of change in ApoEe3/e3 vs. ApoEe3/e4 patients.—Olivera-Perez, H. M., Lam, L., Dang, J., Jiang, W., Rodriguez, F., Rigali, E., Weitzman, S., Porter, V., Rubbi, L., Morselli, M., Pellegrini, M., Fiala, M. Omega-3 fatty acids increase the unfolded protein response and improve amyloid-β phagocytosis by macrophages of patients with mild cognitive impairment.

// Xiangzhu Xiao 1,* , Pingping Shen 1,2,* , Zerui Wang 1,2,* , Johnny Dang 1 , Alise Adornato 1 , Lewis S. Zou 1 , Zhiqian Dong 1 , Jue Yuan 1 , Jiachun Feng 2 , Li Cui 2 and Wen-Quan Zou 1,2,3 1 Department of Pathology, Case Western Reserve University, Cleveland, OH, USA 2 Institute of Neuroscience Center and Neurology Department, The First Hospital of Jilin University, Changchun, Jilin, China 3 State Key Laboratory for Infectious Disease Prevention and Control, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China * These authors have Contributed equally to this study Correspondence to: Li Cui, email: // Wen-Quan Zou, email: // Keywords : caveolin-1, human brain, prion disease, solubility, aggregation, Gerotarget Received : June 02, 2017 Accepted : July 12, 2017 Published : July 21, 2017 Abstract Caveolin-1 is a major component protein of the caveolae—a type of flask shaped, 50-100 nm, nonclathrin-coated, microdomain present in the plasma membrane of most mammalian cells. Caveolin-1 functions as a scaffolding protein to organize and concentrate signaling molecules within the caveolae, which may be associated with its unique physicochemical properties including oligomerization, acquisition of detergent insolubility, and association with cholesterol. Here we demonstrate that caveolin-1 is detected in all brain areas examined and recovered in both detergent-soluble and -insoluble fractions. Surprisingly, the recovered molecules from the two different fractions share a similar molecular size ranging from 200 to 2,000 kDa, indicated by gel filtration. Furthermore, both soluble and insoluble caveolin-1 molecules generate a proteinase K (PK)-resistant C-terminal core fragment upon the PK-treatment, by removing ~36 amino acids from the N-terminus of the protein. Although it recognizes caveolin-1 from A431 cell lysate, an antibody against the C-terminus of caveolin-1 fails to detect the brain protein by Western blotting, suggesting that the epitope in the brain caveolin-1 is concealed. No significant differences in the physicochemical properties of caveolin-1 between uninfected and prion-infected brains are observed.

Tumor lysis syndrome (TLS) is a life-threatening disorder that is an oncologic emergency. Risk factors for TLS are well-known, but the current literature shows case descriptions of unexpected acute TLS. Solid tumors and untreated hematologic tumors can lyse under various circumstances in children and adults. International guidelines and recommendations, including the early involvement of the critical care team, have been put forward to help clinicians properly manage the syndrome. Advanced practice nurses may be in the position of triaging and initiating treatment of patients with TLS, and need a thorough understanding of the syndrome and its treatment.

Drug-induced skin reactions are common, but only a small portion (10%) are attributed to a vasculitic mechanism. Small-vessel vasculitis (SVV) with leukocytoclastic histopathology is usually described in drug-induced vasculitis; however, given the shared histopathologic features between drug-induced vasculitis and other SVV, it is crucial to rule out infectious or other autoimmune etiologies underlying the clinical presentation. We hereby sought to present a case of sulfonamide-induced leukocytoclastic vasculitis, limited to the skin, in a patient with Ehlers-Danlos syndrome in order to emphasize the need for a broad diagnostic and clinical exclusion workup.

International audience; The original version of this article unfortunately contained a mistake. The email address Dr. Wen-Quan Zou, one of the corresponding authors should be written as wxz6@case.edu instead of wxz@case.edu.

Both sporadic variably protease-sensitive prionopathy (VPSPr) and familial Creutzfeldt-Jakob disease linked to the prion protein (PrP) V180I mutation (fCJDV180I) have been found to share a unique pathological prion protein (PrPSc) that lacks the protease-resistant PrPSc glycosylated at residue 181 because two of four PrP glycoforms are apparently not converted into the PrPSc from their cellular PrP (PrPC). To investigate the seeding activity of these unique PrPSc molecules, we conducted in vitro prion conversion experiments using serial protein misfolding cyclic amplification (sPMCA) and real-time quaking-induced conversion (RT-QuIC) assays with different PrPC substrates. We observed that the seeding of PrPSc from VPSPr or fCJDV180I in the sPMCA reaction containing normal human or humanized transgenic (Tg) mouse brain homogenates generated PrPSc molecules that unexpectedly exhibited a dominant diglycosylated PrP isoform along with PrP monoglycosylated at residue 181. The efficiency of PrPSc amplification was significantly higher in non-CJDMM than in non-CJDVV human brain homogenate, whereas it was higher in normal TgVV than in TgMM mouse brain homogenate. PrPC from the mixture of normal TgMM and Tg mouse brain expressing PrPV180I mutation (Tg180) but not TgV180I alone was converted into PrPSc by seeding with the VPSPr or fCJDV180I. The RT-QuIC seeding activity of PrPSc from VPSPr and fCJDV180I was significantly lower than that of sCJD. Our results suggest that the formation of glycoform-selective prions may be associated with an unidentified factor in the affected brain and the glycoform-deficiency of PrPSc does not affect the glycoforms of in vitro newly amplified PrPSc. Electronic supplementary material The online version of this article (10.1007/s12035-018-1459-0) contains supplementary material, which is available to authorized users.

Tumor lysis syndrome (TLS) is a life-threatening disorder that is an oncologic emergency. Risk factors for TLS are well-known, but the current literature shows case descriptions of unexpected acute TLS. Solid tumors and untreated hematologic tumors can lyse under various circumstances in children and adults. International guidelines and recommendations, including the early involvement of the critical care team, have been put forward to help clinicians properly manage the syndrome. Advanced practice nurses may be in the position of triaging and initiating treatment of patients with TLS, and need a thorough understanding of the syndrome and its treatment.

QR Chem is a free resource that enables teachers and researchers to link audiences directly to three-dimensional renderings of molecules.

International audience; Prions are infectious proteins that cause a group of fatal transmissible diseases in animals and humans. The scrapie isoform (PrPSc) of the cellular prion protein (PrPC) is the only known component of the prion. Several lines of evidence have suggested that the formation and molecular features of PrPSc are associated with an abnormal unfolding/refolding process. Quiescin-sulfhydryl oxidase (QSOX) plays a role in protein folding by introducing disulfides into unfolded reduced proteins. Here we report that QSOX inhibits human prion propagation in protein misfolding cyclic amplification reactions and murine prion propagation in scrapie-infected neuroblastoma cells. Moreover, QSOX preferentially binds PrPSc from prion-infected human or animal brains, but not PrPC from uninfected brains. Surface plasmon resonance of the recombinant mouse PrP (moPrP) demonstrates that the affinity of QSOX for monomer is significantly lower than that for octamer (312 nM vs 1.7 nM). QSOX exhibits much lower affinity for N-terminally truncated moPrP (PrP89-230) than for the full-length moPrP (PrP23-231) (312 nM vs 2 nM), suggesting that the N-terminal region of PrP is critical for the interaction of PrP with QSOX. Our study indicates that QSOX may play a role in prion formation, which may open new therapeutic avenues for treating prion diseases.

Prions are infectious proteins that cause a group of fatal transmissible diseases in animals and humans. The scrapie isoform (PrPSc) of the cellular prion protein (PrPC) is the only known component of the prion. Several lines of evidence have suggested that the formation and molecular features of PrPSc are associated with an abnormal unfolding/refolding process. Quiescin-sulfhydryl oxidase (QSOX) plays a role in protein folding by introducing disulfides into unfolded reduced proteins. Here we report that QSOX inhibits human prion propagation in protein misfolding cyclic amplification reactions and murine prion propagation in scrapie-infected neuroblastoma cells. Moreover, QSOX preferentially binds PrPSc from prion-infected human or animal brains, but not PrPC from uninfected brains. Surface plasmon resonance of the recombinant mouse PrP (moPrP) demonstrates that the affinity of QSOX for monomer is significantly lower than that for octamer (312 nM vs 1.7 nM). QSOX exhibits much lower affinity for N-terminally truncated moPrP (PrP89-230) than for the full-length moPrP (PrP23-231) (312 nM vs 2 nM), suggesting that the N-terminal region of PrP is critical for the interaction of PrP with QSOX. Our study indicates that QSOX may play a role in prion formation, which may open new therapeutic avenues for treating prion diseases.

Monocyte/macrophages of patients with mild cognitive impairment (MCI) and Alzheimer disease (AD) are defective in phagocytosis and degradation amyloid β1-42 (Aβ1-42), but are improved by ω-3 fatty acids (ω-3s). The hypothesis of this study was that active Aβ1-42 phagocytosis by macrophages prevents brain amyloidosis and thus maintains cognition. We studied the effects of self-supplementation with a drink with ω-3s, antioxidants, and resveratrol on Mini-Mental State Examination (MMSE) scores, macrophage M1M2 phenotype [the ratio of inflammatory cluster of differentiation (CD)54+CD80 and proresolution markers CD163+CD206], and Aβ1-42 phagocytosis in patients initially diagnosed as having MCI or subjective cognitive impairment (SCI). At baseline, the median MMSE score in patients in both the apolipoprotein E (ApoE) e3/e3 and ApoE e3/e4 groups was 26.0 and macrophage Aβ1-42 phagocytosis was defective. The MMSE rate of change increased in the ApoE e3/e3 group a median 2.2 points per year (P = 0.015 compared to 0) but did not change in the ApoE e3/e4 group (P = 0.014 between groups). In the ApoE e3/e3 group, all patients remained cognitively stable or improved; in the ApoE e3/e4 group, 1 recovered from dementia, but 3 lapsed into dementia. The macrophage phenotype polarized in patients bearing ApoE e3/e3 to an intermediate (green zone) M1-M2 type at the rate of 0.226 U/yr, whereas in patients bearing ApoE e3/e4, polarization was negative (P = 0.08 between groups). The baseline M1M2 type in the extreme M1 (red zone) or M2 (white zone) was unfavorable for cognitive outcome. Aβ1-42 phagocytosis increased in both ApoE groups (P = 0.03 in each groups). In vitro, the lipidic mediator resolvin D1 (RvD1) down regulated the M1 type in patients with ApoE e3/e3 but in some patients with e3/e4, paradoxically up-regulated the M1 type. Antioxidant/ω-3/resveratrol supplementation was associated with favorable immune and cognitive responses in ApoE e3/e3 and individual patients bearing ApoE e3/e4, and brings into personalized clinical practice the immune benefits expected from ω-3 mediators called resolvins. The validity of this study is limited by its small size and uncontrolled design.-Famenini, S., Rigali, E. A., Olivera-Perez, H. M., Dang, J., Chang, M T., Halder, R., Rao, R. V., Pellegrini, M., Porter, V., Bredesen, D., Fiala, M. Increased intermediate M1-M2 macrophage polarization and improved cognition in mild cognitive impairment patients on ω-3 supplementation.

196 Background: The aim of the project was to use anesthesia providers in a cancer center to lead process improvements using time-driven activity-based costing (TDABC), a system of measuring process and capacity costs. Methods: The process improvement objectives were centered on eliminating unnecessary patient care processes and improving patient flow. Teams were tasked with planning, process mapping, improving processes, and measuring costs. Projects were done in four anesthesia sites: ambulatory surgery, bone marrow aspiration, pediatric CT and XRT, and cardiopulmonary areas. Results: Process mapping identified areas for improvement and costs before and after the improvement. The Table highlights four project areas’ average total cost and time savings per patient using TDABC methodology. Conclusions: TDABC is a costing methodology that measures the costs of care utilizing process maps. Anesthesia providers had front-line insight in improving process flow and found the process mapping useful to improve processes and measure the cost savings of the improvement. In each area there was improvement or no adverse effect on patient outcomes. This project demonstrates that TDABC illustrates inefficiencies and provides a method to evaluate the cost savings of process improvements. As cancer care reimbursement evolves, the ability to control costs while providing value-based care is essential. [Table: see text]