tbuckley/cabot-search huggingface dataset:
Comparison of Cardiac Events Associated With Azithromycin vs Amoxicillin
Authors: Haridarshan Patel, Gregory S. Calip, Robert J. DiDomenico, Glen T. Schumock, Katie J. Suda, Todd A. Lee
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Conflicting evidence exists on the association between azithromycin use and cardiac events. <h3>Objective</h3> To compare the odds of cardiac events among new users of azithromycin relative to new users of amoxicillin using real-world data. <h3>Design, Setting, and Participants</h3> This retrospective cohort study used data from Truven Health Analytics MarketScan database from January 1, 2009, to June 30, 2015. Patients receiving either amoxicillin or azithromycin and enrolled in a health care plan 365 days before (baseline period) the dispensing date (index date) were included in the study. Patients were matched 1:1 on high-dimensional propensity scores. Data were analyzed from October 1, 2018, to December 31, 2019. <h3>Exposures</h3> New use of azithromycin compared with new use of amoxicillin. <h3>Main Outcomes and Measures</h3> The primary outcome consisted of cardiac events, including syncope, palpitations, ventricular arrhythmias, cardiac arrest, or death as a primary diagnosis for hospitalization at 5, 10, and 30 days from the index date. Logistic regression models were used to estimate odds ratios (ORs) with 95% CIs. <h3>Results</h3> After matching, the final cohort included 2 141 285 episodes of each index therapy (N = 4 282 570) (mean [SD] age of patients, 35.7 [22.3] years; 52.6% female). Within 5 days after therapy initiation, 1474 cardiac events (0.03%) occurred (708 in the amoxicillin cohort and 766 in the azithromycin cohort). The 2 most frequent events were syncope (1032 [70.0%]) and palpitations (331 [22.5%]). The odds of cardiac events with azithromycin compared with amoxicillin were not significantly higher at 5 days (OR, 1.08; 95% CI, 0.98-1.20), 10 days (OR, 1.05; 95% CI, 0.97-1.15), and 30 days (OR, 0.98; 95% CI, 0.92-1.04). Among patients receiving any concurrent QT-prolonging drug, the odds of cardiac events with azithromycin were 1.40 (95% CI, 1.04-1.87) greater compared with amoxicillin. Among patients 65 years or older and those with a history of cardiovascular disease and other risk factors, no increased risk of cardiac events with azithromycin was noted. <h3>Conclusions and Relevance</h3> This study found no association of cardiac events with azithromycin compared with amoxicillin except among patients using other QT-prolonging drugs concurrently. Although azithromycin is a safe therapy, clinicians should carefully consider its use among patients concurrently using other QT-prolonging drugs.
Macrophage membrane-coated nanocarriers Co-Modified by RVG29 and TPP improve brain neuronal mitochondria-targeting and therapeutic efficacy in Alzheimer's disease mice
Authors: Yang Han, Chunhong Gao, Hao Wang, Jiejie Sun, Meng Liang, Ye Feng, Qianqian Liu, Shiyao Fu, Lin Cui, Chunsheng Gao, Yi Li, Yang Yang, Baoshan Sun
Journal: Bioactive Materials (2020)

Neuronal mitochondrial dysfunction caused by excessive reactive oxygen species (ROS) is an early event of sporadic Alzheimer's disease (AD), and considered to be a key pathologic factor in the progression of AD. The targeted delivery of the antioxidants to mitochondria of injured neurons in brain is a promising therapeutic strategy for AD. A safe and effective drug delivery system (DDS) which is able to cross the blood-brain barrier (BBB) and target neuronal mitochondria is necessary. Recently, bioactive materials-based DDS has been widely investigated for the treatment of AD. Herein, we developed macrophage (MA) membrane-coated solid lipid nanoparticles (SLNs) by attaching rabies virus glycoprotein (RVG29) and triphenylphosphine cation (TPP) molecules to the surface of MA membrane (RVG/TPP-MASLNs) for functional antioxidant delivery to neuronal mitochondria. According to the results, MA membranes camouflaged the SLNs from being eliminated by RES-rich organs by inheriting the immunological characteristics of macrophages. The unique properties of the DDS after decoration with RVG29 on the surface was demonstrated by the ability to cross the BBB and the selective targeting to neurons. After entering the neurons in CNS, TPP further lead the DDS to mitochondria driven by electric charge. The Genistein (GS)- encapsulated DDS (RVG/TPP-MASLNs-GS) exhibited the most favorable effects on reliveing AD symptoms in vitro and in vivo by the synergies gained from the combination of MA membranes, RVG29 and TPP. These results demonstrated a promising therapeutic candidate for delaying the progression of AD via neuronal mitochondria-targeted delivery by the designed biomimetic nanosystems.
Low glycosylated ferritin is a sensitive biomarker of severe COVID-19
Authors: Maxime Fauter, Sébastien Viel, Sabine Zaepfel, Pierre Pradat, Julie Fiscus, Marine Villard, Lorna Garnier, Thierry Walzer, Pascal Sève, Thomas Henry, Yvan Jamilloux
Journal: Cellular and Molecular Immunology (2020)

Severe forms of coronavirus disease 2019 (COVID-19) have been associated with a cytokine storm mainly involving interleukin (IL)-6, IL-1β, and TNF. 1,2Several authors have reported features of macrophage activation, thus comparing the cytokine storm of COVID-19 to reactive hemophagocytic lymphohistiocytosis (reHLH). 3,4However, these data have been balanced by other studies primarily involving IL-6 and, therefore, a mechanism closer to the complex immune dysregulation observed in sepsis. 5,6 Considering these discrepancies, serum cytokine profiling may not be the best option for assessing COVID-19 severity and prognosis.Serum ferritin, an inflammatory biomarker, is elevated in most COVID-19 patients and has been correlated with severity and mortality. 7The measurement of the glycosylated fraction of ferritin (GF), which could be readily implemented in routine diagnosis, is of great interest in the diagnosis of reHLH (and in Still's disease, which is frequently associated with macrophage activation syndrome). 8,9Indeed, a GF rate < 25% has a positive predictive value of 88% and a negative predictive value of 100% for reHLH. 8 Here, we assessed whether the GF rate could serve as a biomarker for COVID-19 severity and prognosis.We prospectively analyzed the immunobiochemical parameters of 58 patients with COVID-19 who were hospitalized in the Internal Medicine Department from March 21 to May 9, 2020.All patients had confirmed SARS-CoV-2 infection.Patient characteristics are shown in Table S1.The male/female sex ratio was 1.9, and the mean age was 73.3 (range, 39-99) years.The median time from symptom onset to hospital admission (i.e., first biomarker evaluation) was 8.6 (range, 3-19) days.Upon admission, acute phase reactants were elevated [either C-reactive protein ≥ 5 mg/L, procalcitonin (PCT) ≥ 0.5 μg/L, and/or fibrinogen ≥ 4.2 mg/L] in all but one patient.Lymphopenia was reported in 46% of the patients (mean, 1056 ± 502/mm 3 ).During follow-up, 17 patients had severe worsening of their condition (see "Supplemental Methods"), and seven patients died.Thus, the fatality rate was 12.1%.
Cutaneous manifestations in paediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome-coronavirus 2 infection
Authors: A. D'Cruz, F. Mason, R. D'Souza, J. Freitas, J. Thomas, M. Saha
Journal: British Journal of Dermatology (2020)

Paediatric inflammatory multisystem syndrome temporally associated with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection (PIMS-TS) has been defined by the Royal College of Paediatrics and Child Health as 'a child presenting with persistent fever, inflammation and evidence of single or multi-organ dysfunction' (https://www rcpch ac uk/resources/guidance-paediatric-multisystem-inflammatory-synd rome-temporally-associated-covid-19-pims)  We describe the skin manifestations in 17 paediatric patients presenting from 14 March to 18 May 2020 to a single institution with features of PIMS-TS  Common presenting symptoms in these 17 children included fever, rash and gastrointestinal symptoms  Less common presentations included cough, epistaxis, arthralgia, headache and respiratory symptoms and were only present in one patient  Median age at presentation was 11 years (range 1-16), and the male-to-female ratio was 1 8 : 1 The majority of patients were black, Asian and minority ethnic (BAME);nine were of Afro-Caribbean descent, three were white, two were Turkish, one was Albanian, one was Indian and one was Hispanic  Within this group, nine (53%) presented with a skin rash, eight (47%) with conjunctival involvement and three (18%) with cheilitis  The time of onset of cutaneous disease was variable, but most patients presented with a rash at admission or within a few days of admission  The rash was polymorphous, but the most common skin presentations were a maculopapular eruption and fixed urticaria, particularly on the trunk and limbs  In addition, acral presentations were seen with erythematous oedematous ears and fingers  The but it may represent an antibody or immune complexmediated postinfectious inflammatory syndrome (Verdoni L, Mazza A, Gervasoni A et al  An outbreak of a severe Kawasaki -like disease at the Italian epicentre of the SARS CoV-2 epidemic: an observational cohort study  Lancet 2020;Epub ahead of print)  As dermatologists collate databases of images and histopathology of skin disease with this new virus, SARS-CoV-2, a clearer picture of the pathophysiology of this disease should emerge  We propose that in any child presenting with persistent fever, rash and evidence of systemic inflammation, PIMS-TS should be considered, and urgent specialist referral sought, in light of the serious cardiac complications that may arise  Further investigation is needed into the apparent higher rate of PIMS-TS in BAME children and the association with SARS-CoV-2 infection
Cancer in the Fourth Dimension: What Is the Impact of Circadian Disruption?
Authors: Marie Pariollaud, Katja A. Lamia
Journal: Cancer Discovery (2020)

Abstract Circadian rhythms integrate many physiological pathways, helping organisms to align the timing of various internal processes to daily cycles in the external environment. Disrupted circadian rhythmicity is a prominent feature of modern society, and has been designated as a probable carcinogen. Here, we review multiple studies, in humans and animal models, that suggest a causal effect between circadian disruption and increased risk of cancer. We also discuss the complexity of this connection, which may depend on the cellular context. Significance: Accumulating evidence points to an adverse effect of circadian disruption on cancer incidence and progression, indicating that time of day could influence the effectiveness of interventions targeting cancer prevention and management.
Rammya Mathew: “Back to school” must be backed by a functioning covid-19 testing programme
Authors: Rammya Mathew
Journal: BMJ (2020)

Children in England and Wales have been back at school for just over a week now, and in Scotland for a few weeks longer.GPs are already seeing a surge in cases of viral illness among school age children.From around the country I'm hearing reports of GP surgeries being inundated with calls from parents: they're not generally seeking medical advice because they're worried that their child needs to see a GP, but they're confused about whether their child meets the criteria for self-isolation and covid testing.
Myeloma today: Disease definitions and treatment advances
Authors: Vincent Rajkumar
Journal: American Journal of Hematology (2016)

By S. Vincent Rajkumar Am. J. Hematol. 91:90-100, 2016. DOI: 10.1002/ajh.24236 On page 97 of the above-referenced article, the Dimopoulos et al. 2 year survival data for Kd and Vd in table VII has mistakenly been reversed; Kd should be 72% and Vd should be 65%. We apologize for any confusion this error might have caused.
Kidney-targeted therapies: A quantitative perspective
Authors: Alexander H. van Asbeck, Jürgen Dieker, Milou Boswinkel, Johan van der Vlag, Roland Brock
Journal: Journal of Controlled Release (2020)

Chronic and acute kidney disease constitute a worldwide health burden, but are still lacking efficient therapeutics. Current medication such as anti-inflammatory steroids causes systemic side effects, and is unable to stop the progression of the disease. Efforts have been devoted towards the development of renal-targeted therapies, however, no such approach has reached the clinic, yet. Here, we critically review the current status of renal-targeted drugs and delivery strategies. Specifically, we focus on the quantitative aspect of delivery by compiling information on kidney-to-liver ratios and also investigating to which degree the implementation of a targeting functionality increases the distribution of the drug to the kidney. As we show, two types of functional outcomes can be distinguished: (i) Targeting to the kidney goes along with an increase in kidney-to-liver ratio. This, we denote as direct targeting; (ii) the accumulation of the drug in the kidney increases, but the kidney-to-liver ratio remains unchanged, thereby the carrier leads to a general uptake enhancement. Overall, the most effective targeting was reached with receptor and transporter directed strategies. Reaching glomerular cells and the avoidance of liver accumulation for nanoparticulate formulations pose the greatest challenges.
Mucus barrier, mucins and gut microbiota: the expected slimy partners?
Authors: Paola Paone, Patrice D Cani
Journal: Gut (2020)

The gastrointestinal tract is often considered as a key organ involved in the digestion of food and providing nutrients to the body for proper maintenance. However, this system is composed of organs that are extremely complex. Among the different parts, the intestine is viewed as an incredible surface of contact with the environment and is colonised by hundreds of trillions of gut microbes. The role of the gut barrier has been studied for decades, but the exact mechanisms involved in the protection of the gut barrier are various and complementary. Among them, the integrity of the mucus barrier is one of the first lines of protection of the gastrointestinal tract. In the past, this 'slimy' partner was mostly considered a simple lubricant for facilitating the progression of the food bolus and the stools in the gut. Since then, different researchers have made important progress, and currently, the regulation of this mucus barrier is gaining increasing attention from the scientific community. Among the factors influencing the mucus barrier, the microbiome plays a major role in driving mucus changes. Additionally, our dietary habits (ie, high-fat diet, low-fibre/high-fibre diet, food additives, pre- probiotics) influence the mucus at different levels. Given that the mucus layer has been linked with the appearance of diseases, proper knowledge is highly warranted. Here, we debate different aspects of the mucus layer by focusing on its chemical composition, regulation of synthesis and degradation by the microbiota as well as some characteristics of the mucus layer in both physiological and pathological situations.
Author Correction: PGBD5 promotes site-specific oncogenic mutations in human tumors
Authors: Anton G. Henssen, Richard Koche, Jiali Zhuang, Eileen Jiang, Casie Reed, Amy Eisenberg, Eric Still, Ian C. MacArthur, Elias Rodríguez-Fos, Santiago Gonzalez, Montserrat Puiggròs, Andrew N. Blackford, Christopher E. Mason, Elisa de Stanchina, Mithat Gönen, Anne-Katrin Emde, Minita Shah, Kanika Arora, Catherine Reeves, Nicholas D. Socci, Elizabeth Perlman, Cristina R. Antonescu, Charles W. M. Roberts, Hanno Steen, Elizabeth Mullen, Stephen P. Jackson, David Torrents, Zhiping Weng, Scott A. Armstrong, Alex Kentsis
Journal: Nature Genetics (2020)
Machine learning predicts stem cell transplant response in severe scleroderma
Authors: Jennifer M Franks, Viktor Martyanov, Yue Wang, Tammara A Wood, Ashley Pinckney, Leslie J Crofford, Lynette Keyes-Elstein, Daniel E Furst, Ellen Goldmuntz, Maureen D Mayes, Peter McSweeney, Richard A Nash, Keith M Sullivan, Michael L Whitfield
Journal: Annals of the Rheumatic Diseases (2020)

The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial demonstrated clinical benefit of haematopoietic stem cell transplant (HSCT) compared with cyclophosphamide (CYC). We mapped PBC (peripheral blood cell) samples from the SCOT clinical trial to scleroderma intrinsic subsets and tested the hypothesis that they predict long-term response to HSCT.We analysed gene expression from PBCs of SCOT participants to identify differential treatment response. PBC gene expression data were generated from 63 SCOT participants at baseline and follow-up timepoints. Participants who completed treatment protocol were stratified by intrinsic gene expression subsets at baseline, evaluated for event-free survival (EFS) and analysed for differentially expressed genes (DEGs).Participants from the fibroproliferative subset on HSCT experienced significant improvement in EFS compared with fibroproliferative participants on CYC (p=0.0091). In contrast, EFS did not significantly differ between CYC and HSCT arms for the participants from the normal-like subset (p=0.77) or the inflammatory subset (p=0.1). At each timepoint, we observed considerably more DEGs in HSCT arm compared with CYC arm with HSCT arm showing significant changes in immune response pathways.Participants from the fibroproliferative subset showed the most significant long-term benefit from HSCT compared with CYC. This study suggests that intrinsic subset stratification of patients may be used to identify patients with SSc who receive significant benefit from HSCT.
ARGX-117, a therapeutic complement inhibiting antibody targeting C2
Authors: Inge Van de Walle, Karen Silence, Kevin Budding, Liesbeth Van de Ven, Kim Dijkxhoorn, Elisabeth de Zeeuw, Cafer Yildiz, Sofie Gabriels, Jean-Michel Percier, Johanna Wildemann, Jan Meeldijk, Peter J. Simons, Louis Boon, Linda Cox, Rob Holgate, Rolf Urbanus, Henny G. Otten, Jeanette H.W. Leusen, Christophe Blanchetot, Hans de Haard, C. Erik Hack, Peter Boross
Journal: Journal of Allergy and Clinical Immunology (2020)

BackgroundActivation of the classical and lectin pathway of complement may contribute to tissue damage and organ dysfunction of antibody-mediated diseases and ischemia-reperfusion conditions. Complement factors are being considered as targets for therapeutic intervention.ObjectiveWe sought to characterize ARGX-117, a humanized inhibitory monoclonal antibody against complement C2.MethodsThe mode-of-action and binding characteristics of ARGX-117 were investigated in detail. Furthermore, its efficacy was analyzed in in vitro complement cytotoxicity assays. Finally, a pharmacokinetic/pharmacodynamic study was conducted in cynomolgus monkeys.ResultsThrough binding to the Sushi-2 domain of C2, ARGX-117 prevents the formation of the C3 proconvertase and inhibits classical and lectin pathway activation upstream of C3 activation. As ARGX-117 does not inhibit the alternative pathway, it is expected not to affect the antimicrobial activity of this complement pathway. ARGX-117 prevents complement-mediated cytotoxicity in in vitro models for autoimmune hemolytic anemia and antibody-mediated rejection of organ transplants. ARGX-117 exhibits pH- and calcium-dependent target binding and is Fc-engineered to increase affinity at acidic pH to the neonatal Fc receptor, and to reduce effector functions. In cynomolgus monkeys, ARGX-117 dose-dependently reduces free C2 levels and classical pathway activity. A 2-dose regimen of 80 and 20 mg/kg separated by a week, resulted in profound reduction of classical pathway activity lasting for at least 7 weeks.ConclusionsARGX-117 is a promising new complement inhibitor that is uniquely positioned to target both the classical and lectin pathways while leaving the alternative pathway intact.
Growth rate alterations of human colorectal cancer cells by 157 gut bacteria
Authors: Rahwa Taddese, Daniel R. Garza, Lilian N. Ruiter, Marien I. de Jonge, Clara Belzer, Steven Aalvink, Iris D. Nagtegaal, Bas E. Dutilh, Annemarie Boleij
Journal: Gut Microbes (2020)

Several bacteria in the human gut microbiome have been associated with colorectal cancer (CRC) by high-throughput screens. In some cases, molecular mechanisms have been elucidated that drive tumorigenesis, including bacterial membrane proteins or secreted molecules that interact with the human cancer cells. For most gut bacteria, however, it remains unknown if they enhance or inhibit cancer cell growth. Here, we screened bacteria-free supernatants (secretomes) and inactivated cells of over 150 cultured bacterial strains for their effects on cell growth. We observed family-level and strain-level effects that often differed between bacterial cells and secretomes, suggesting that different molecular mechanisms are at play. Secretomes of Bacteroidaceae, Enterobacteriaceae, and Erysipelotrichaceae bacteria enhanced cell growth, while most Fusobacteriaceae cells and secretomes inhibited growth, contrasting prior findings. In some bacteria, the presence of specific functional genes was associated with cell growth rates, including the virulence genes TcdA, TcdB in Clostridiales and FadA in Fusobacteriaceae, which both inhibited growth. Bacteroidaceae cells that enhanced growth were enriched for genes of the cobalamin synthesis pathway, while Fusobacteriaceae cells that inhibit growth were enriched for genes of the ethanolamine utilization pathway. Together, our results reveal how different gut bacteria have wide-ranging effects on cell growth, contribute a better understanding of the effects of the gut microbiome on host cells, and provide a valuable resource for identifying candidate target genes for potential microbiome-based diagnostics and treatment strategies.
Preemptive Therapy vs Antiviral Prophylaxis in Cytomegalovirus-Seronegative Liver Transplant Recipients With Seropositive Donors
Authors: Matthew B. Roberts, Ronak G. Gandhi, Camille N. Kotton
Journal: JAMA (2020)

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