Recent publications from TDC/Clinical Epidemiology authors

Comprehensive Meta-Analysis of COVID-19 Global Metabolomics Datasets

Wed, 01/13/2021 - 06:00

Metabolites. 2021 Jan 9;11(1):E44. doi: 10.3390/metabo11010044.

ABSTRACT

The novel coronavirus SARS-CoV-2 has spread across the world since 2019, causing a global pandemic. The pathogenesis of the viral infection and the associated clinical presentations depend primarily on host factors such as age and immunity, rather than the viral load or its genetic variations. A growing number of omics studies have been conducted to characterize the host immune and metabolic responses underlying the disease progression. Meta-analyses of these datasets have great potential to identify robust molecular signatures to inform clinical care and to facilitate therapeutics development. In this study, we performed a comprehensive meta-analysis of publicly available global metabolomics datasets obtained from three countries (United States, China and Brazil). To overcome high heterogeneity inherent in these datasets, we have (a) implemented a computational pipeline to perform consistent raw spectra processing; (b) conducted meta-analyses at pathway levels instead of individual feature levels; and (c) performed visual data mining on consistent patterns of change between disease severities for individual studies. Our analyses have yielded several key metabolic signatures characterizing disease progression and clinical outcomes. Their biological interpretations were discussed within the context of the current literature. To the best of our knowledge, this is the first comprehensive meta-analysis of global metabolomics datasets of COVID-19.

PMID:33435351 | DOI:10.3390/metabo11010044

ATR Kinase Is a Crucial Player Mediating the DNA Damage Response in <em>Trypanosoma brucei</em>

Fri, 01/08/2021 - 06:00

Front Cell Dev Biol. 2020 Dec 22;8:602956. doi: 10.3389/fcell.2020.602956. eCollection 2020.

ABSTRACT

DNA double-strand breaks (DSBs) are among the most deleterious lesions that threaten genome integrity. To address DSBs, eukaryotic cells of model organisms have evolved a complex network of cellular pathways that are able to detect DNA damage, activate a checkpoint response to delay cell cycle progression, recruit the proper repair machinery, and resume the cell cycle once the DNA damage is repaired. Cell cycle checkpoints are primarily regulated by the apical kinases ATR and ATM, which are conserved throughout the eukaryotic kingdom. Trypanosoma brucei is a divergent pathogenic protozoan parasite that causes human African trypanosomiasis (HAT), a neglected disease that can be fatal when left untreated. The proper signaling and accuracy of DNA repair is fundamental to T. brucei not only to ensure parasite survival after genotoxic stress but also because DSBs are involved in the process of generating antigenic variations used by this parasite to evade the host immune system. DSBs trigger a strong DNA damage response and efficient repair process in T. brucei, but it is unclear how these processes are coordinated. Here, by knocking down ATR in T. brucei using two different approaches (conditional RNAi and an ATR inhibitor), we show that ATR is required to mediate intra-S and partial G1/S checkpoint responses. ATR is also involved in replication fork stalling, is critical for H2A histone phosphorylation in a small group of cells and is necessary for the recruitment and upregulation of the HR-mediated DNA repair protein RAD51 after ionizing radiation (IR) induces DSBs. In summary, this work shows that apical ATR kinase plays a central role in signal transduction and is critical for orchestrating the DNA damage response in T. brucei.

PMID:33415107 | PMC:PMC7783291 | DOI:10.3389/fcell.2020.602956

A Functional Comparison of Homopentameric Nicotinic Acetylcholine Receptors (ACR-16) Receptors From <em>Necator americanus</em> and <em>Ancylostoma ceylanicum</em>

Wed, 12/16/2020 - 06:00

Front Mol Neurosci. 2020 Nov 26;13:601102. doi: 10.3389/fnmol.2020.601102. eCollection 2020.

ABSTRACT

Effective control of hookworm infections in humans and animals relies on using a small group of anthelmintics. Many of these drugs target cholinergic ligand-gated ion channels, yet the direct activity of anthelmintics has only been studied in a subset of these receptors, primarily in the non-parasitic nematode, Caenorhabditis elegans. Here we report the characterization of a homopentameric ionotropic acetylcholine receptor (AChR), ACR-16, from Necator americanus and Ancylostoma ceylanicum, the first known characterization of human hookworm ion channels. We used two-electrode voltage clamp electrophysiology in Xenopus laevis oocytes to determine the pharmacodynamics of cholinergics and anthelmintics on ACR-16 from both species of hookworm. The A. ceylanicum receptor (Ace-ACR-16) was more sensitive to acetylcholine (EC50 = 20.64 ± 0.32 μM) and nicotine (EC50 = 24.37 ± 2.89 μM) than the N. americanus receptor (Nam-ACR-16) (acetylcholine EC50 = 170.1 ± 19.23 μM; nicotine EC50 = 597.9 ± 59.12 μM), at which nicotine was a weak partial agonist (% maximal acetylcholine response = 30.4 ± 7.4%). Both receptors were inhibited by 500 μM levamisole (Ace-ACR-16 = 65.1 ± 14.3% inhibition, Nam-ACR-16 = 79.5 ± 7.7% inhibition), and responded to pyrantel, but only Ace-ACR-16 responded to oxantel. We used in silico homology modeling to investigate potential structural differences that account for the differences in agonist binding and identified a loop E isoleucine 130 of Nam-ACR-16 as possibly playing a role in oxantel insensitivity. These data indicate that key functional differences exist among ACR-16 receptors from closely related species and suggest mechanisms for differential drug sensitivity.

PMID:33324163 | PMC:PMC7725692 | DOI:10.3389/fnmol.2020.601102

Challenges and opportunities for the adoption of molecular diagnostics for anthelmintic resistance

Fri, 12/11/2020 - 06:00

Int J Parasitol Drugs Drug Resist. 2020 Dec 2;14:264-273. doi: 10.1016/j.ijpddr.2020.11.005. Online ahead of print.

ABSTRACT

Anthelmintic resistance is a significant threat to livestock production systems worldwide and is emerging as an important issue in companion animal parasite management. It is also an emerging concern for the control of human soil-transmitted helminths and filaria. An important aspect of managing anthelmintic resistance is the ability to utilise diagnostic tests to detect its emergence at an early stage. In host-parasite systems where resistance is already widespread, diagnostics have a potentially important role in determining those drugs that remain the most effective. The development of molecular diagnostics for anthelmintic resistance is one focus of the Consortium for Anthelmintic Resistance and Susceptibility (CARS) group. The present paper reflects discussions of this issue that occurred at the most recent meeting of the group in Wisconsin, USA, in July 2019. We compare molecular resistance diagnostics with in vivo and in vitro phenotypic methods, and highlight the advantages and disadvantages of each. We assess whether our knowledge on the identity of molecular markers for resistance towards the different drug classes is sufficient to provide some expectation that molecular tests for field use may be available in the short-to-medium term. We describe some practical aspects of such tests and how our current capabilities compare to the requirements of an 'ideal' test. Finally, we describe examples of drug class/parasite species interactions that provide the best opportunity for commercial use of molecular tests in the near future. We argue that while such prototype tests may not satisfy the requirements of an 'ideal' test, their potential to provide significant advances over currently-used phenotypic methods warrants their development as field diagnostics.

PMID:33307336 | DOI:10.1016/j.ijpddr.2020.11.005

Adjuvanted <em>Schistosoma mansoni</em>-Cathepsin B With Sulfated Lactosyl Archaeol Archaeosomes or AddaVax™ Provides Protection in a Pre-Clinical Schistosomiasis Model

Fri, 12/11/2020 - 06:00

Front Immunol. 2020 Nov 16;11:605288. doi: 10.3389/fimmu.2020.605288. eCollection 2020.

ABSTRACT

Schistosomiasis threatens 800 million people worldwide. Chronic pathology manifests as hepatosplenomegaly, and intestinal schistosomiasis caused by Schistosoma mansoni can lead to liver fibrosis, cirrhosis, and blood in the stool. To assist the only FDA-approved drug, praziquantel, in parasite elimination, the development of a vaccine would be of high value. S. mansoni Cathepsin B (SmCB) is a well-documented vaccine target for intestinal schistosomiasis. Herein, we test the increased efficacy and immunogenicity of SmCB when combined with sulfated lactosyl archaeol (SLA) archaeosomes or AddaVax™ (a squalene based oil-in-water emulsion). Both vaccine formulations resulted in robust humoral and cell mediated immune responses. Impressively, both formulations were able to reduce parasite burden greater than 40% (WHO standard), with AddaVax™ reaching 86.8%. Additionally, SmCB with both adjuvants were able to reduce granuloma size and the amount of larval parasite hatched from feces, which would reduce transmission. Our data support SmCB as a target for S. mansoni vaccination; especially when used in an adjuvanted formulation.

PMID:33304354 | PMC:PMC7701121 | DOI:10.3389/fimmu.2020.605288

Developmental regulation of Dirofilaria immitis microfilariae and evaluation of ecdysone signaling pathway transcript level using droplet digital PCR

Thu, 12/10/2020 - 06:00

Parasit Vectors. 2020 Dec 9;13(1):614. doi: 10.1186/s13071-020-04480-w.

ABSTRACT

BACKGROUND: Current measures for the prevention of dirofilariasis, caused by the dog heartworm, Dirofilaria immitis, rely on macrocyclic lactones, but evidence of drug-resistant isolates has called for alternative approaches to disease intervention. As microfilariae are known to be in a state of developmental arrest in their mammalian host and then undergo two molts once inside the arthropod, the aim of this study was to look at the developmental regulation of D. immitis microfilariae that occurs in their arthropod host using in vitro approaches and to investigate the role of the ecdysone signaling system in this development regulation.

METHODS: Dirofilaria immitis microfilariae extracted from dog blood were incubated under various culture conditions to identify those most suitable for in vitro culture and development of the microfilariae, and to determine the effects of fetal bovine serum (FBS), mosquito cells, and ecdysteroid on the development of the microfilariae. Transcript levels of the ecdysone signaling pathway components were measured with droplet digital PCR (ddPCR).

RESULTS: In vitro conditions that best promote early development of D. immitis microfilariae to the "late sausage stage" have been identified, although shedding of the cuticle was not observed. FBS had inhibitory effects on the development and motility of the microfilariae, but media conditioned with Anopheles gambiae cells were favorable to microfilarial growth. The transcript level study using ddPCR also showed that ecdysone signaling system components were upregulated in developing microfilariae and that 20-hydroxyecdysone increased the proportion of larvae developing to the sausage and late sausage stages in vitro.

CONCLUSIONS: The arthropod host environment provides cues required for the rapid development of D. immitis microfilariae, and the ecdysone signaling system may play an important role in filarial nematode developmental transitions. This study contributes to a better understanding of the developmental process of D. immitis microfilariae.

PMID:33298156 | DOI:10.1186/s13071-020-04480-w

Persistent Functional Decline Following Hospitalization with Influenza or Acute Respiratory Illness

Wed, 12/09/2020 - 06:00

J Am Geriatr Soc. 2020 Dec 8. doi: 10.1111/jgs.16950. Online ahead of print.

ABSTRACT

BACKGROUND/OBJECTIVES: Influenza is associated with significant morbidity and mortality, particularly for older adults. Persistent functional decline following hospitalization has important impacts on older adults' wellbeing and independence, but has been under-studied in relation to influenza. We aimed to investigate persistent functional change in older adults admitted to hospital with influenza and other acute respiratory illness (ARI).

DESIGN: Protective observational cohort study.

SETTING: Canadian Immunization Research Network Serious Outcomes Surveillance Network 2011 to 2012 influenza season.

PARTICIPANTS: A total of 925 patients aged 65 and older admitted to hospital with influenza and other ARI.

MEASUREMENTS: Influenza was laboratory-confirmed. Frailty was measured using a Frailty index (FI). Functional status was measured using the Barthel index (BI); moderate persistent functional decline was defined as a clinically meaningful loss of ≥10 to <20 points on the 100-point BI. Catastrophic disability (CD) was defined as a loss of ≥20 points, equivalent to full loss of independence in two basic activities of daily living.

RESULTS: Five hundred and nineteen (56.1%) were women; mean age was 79.4 (standard deviation=8.4) years. Three hundred and forty-six (37.4%) had laboratory-confirmed influenza. Influenza cases had lower baseline function (BI = 77.0 vs 86.9, P < .001) and higher frailty (FI = 0.23 vs 0.20, P < .001) than those with other ARI. A total of 8.4% died, 8.2% experienced persistent moderate functional decline, and 9.9% experienced CD. Higher baseline frailty was associated with increased odds of experiencing functional decline, CD, and death. The experience of functional decline and CD, and its association with frailty, was the same for influenza and other ARI.

CONCLUSION: Functional loss in hospital is common among older adults; for some this functional loss is persistent and catastrophic. This highlights the importance of prevention and optimal management of acute declines in health, including influenza, to avoid hospitalization. In the case of influenza, for which vaccines exist, this raises the potential of vaccine preventable disability.

PMID:33294986 | DOI:10.1111/jgs.16950

Design, production and immunomodulatory potency of a novel allergen bioparticle

Tue, 12/01/2020 - 06:00

PLoS One. 2020 Dec 1;15(12):e0242867. doi: 10.1371/journal.pone.0242867. eCollection 2020.

ABSTRACT

Allergen immunotherapy (AIT) is the only disease-modifying treatment with evidence for sustained efficacy. However, it is poorly developed compared to symptomatic drugs. The main reasons come from treatment duration implying monthly injections during 3 to 5 years or daily sublingual use, and the risk of allergic side-effects. To become a more attractive alternative to lifelong symptomatic drug use, improvements to AIT are needed. Among the most promising new immunotherapy strategies is the use of bioparticles for the presentation of target antigen to the immune system as they can elicit strong T cell and B cell immune responses. Virus-like particles (VLPs) are a specific class of bioparticles in which the structural and immunogenic constituents are from viral origin. However, VLPs are ill-suited for use in AIT as their antigenicity is linked to structure. Recently, synthetic biology has been used to produce artificial modular bioparticles, in which supramolecular assemblies are made of elements from heterogeneous biological sources promoting the design and use of in vivo-assembling enveloped bioparticles for viral and non-viral antigens presentation. We have used a coiled-coil hybrid assembly for the design of an enveloped bioparticle (eBP) that present trimers of the Der p 2 allergen at its surface, This bioparticle was produced as recombinant and in vivo assembled eBPs in plant. This allergen biotherapeutic was used to demonstrate i) the capacity of plants to produce synthetic supramolecular allergen bioparticles, and ii) the immunomodulatory potential of naturally-assembled allergen bioparticles. Our results show that allergens exposed on eBPs induced a very strong IgG response consisting predominantly of IgG2a in favor of the TH1 response. Finally, our results demonstrate that rDer p 2 present on the surface of BPs show a very limited potential to stimulate the basophil degranulation of patient allergic to this allergen which is predictive of a high safety potential.

PMID:33259521 | DOI:10.1371/journal.pone.0242867

GeoSentinel: past, present and future†

Sat, 11/28/2020 - 06:00

J Travel Med. 2020 Nov 27:taaa219. doi: 10.1093/jtm/taaa219. Online ahead of print.

ABSTRACT

RATIONALE FOR REVIEW: In response to increased concerns about emerging infectious diseases, GeoSentinel, the Global Surveillance Network of the International Society of Travel Medicine (ISTM) in partnership with the United States Centers for Disease Control and Prevention (CDC), was established in 1995 in order to serve as a global provider-based emerging infections sentinel network, conduct surveillance for travel-related infections and communicate and assist global public health responses. This review summarizes the history, past achievements, and future directions of the GeoSentinel Network.

KEY FINDINGS: Funded by the US CDC in 1996, GeoSentinel has grown from a group of eight US-based travel and tropical medicine centers to a global network, which currently consists of 68 sites in 28 countries. GeoSentinel has provided important contributions that have enhanced the ability to use destination-specific differences to guide diagnosis and treatment of returning travelers, migrants, and refugees. During the last two decades, GeoSentinel has identified a number of sentinel infectious disease events including previously unrecognized outbreaks and occurrence of diseases in locations thought not to harbor certain infectious agents. GeoSentinel has also provided useful insight into illnesses affecting different traveling populations such as migrants, business travelers, and students, while characterizing in greater detail the epidemiology of infectious diseases such as typhoid fever, leishmaniasis, and Zika virus disease.

CONCLUSIONS: Surveillance of travel- and migration-related infectious diseases has been the main focus of GeoSentinel for the last 25 years. However, GeoSentinel is now evolving into a network that will conduct both research and surveillance. The large number of participating sites and excellent geographic coverage for identification of both common and illnesses in individuals who have traversed international borders uniquely position GeoSentinel to make important contributions of travel-related infectious diseases in the years to come.

PMID:33247586 | DOI:10.1093/jtm/taaa219

A Multi-Sectoral Approach Improves Early Child Development in a Disadvantaged Community in Peru: Role of Community Gardens, Nutrition Workshops and Enhanced Caregiver-Child Interaction: Project "Wawa Illari"

Thu, 11/26/2020 - 06:00

Front Public Health. 2020 Nov 6;8:567900. doi: 10.3389/fpubh.2020.567900. eCollection 2020.

ABSTRACT

Background: Multi-dimensional monitoring evaluation and learning strategies are needed to address the complex set of factors that affect early child development in marginalized populations, but few studies have explored their effectiveness. Objective: To compare improvement of health and development of children 0-3 years between intervention communities (IC) and control communities (CC) from peripheral settlements of Lima. Sequential interventions included: (1) home and community gardens, (2) conscious nutrition, and (3) parenting workshops following the International Child Development Program (ICDP). Methods: Interventions were delivered by community health promoters (CHPs) using a "step-by-step" learning system. Both IC and CC were monitored before the interventions began, at 8 and 12 months (n = 113 IC and 127 CC children). Data were collected on household characteristics, diet, food security, health indicators (history of diarrhea and respiratory infections, hemoglobin, intestinal parasites, anthropometry), caregiver-child interactions and stress, and achievement of Pan-American Health Organization age-specific developmental milestones. Stepwise multiple logistic regressions were used to determine if the interventions affected food insecurity, as well as motor, social/cognitive and language delays. Results: At baseline, 2.6% were categorized as "suspected developmental delay" and 14.2% were on "alert for development delay." Food insecurity, diarrhea and respiratory infections were lowered following the interventions. Through the "step-by-step" approach, caregivers in IC gained skills in gardening, conscious nutrition and parenting that reduced the risk of food insecurity [Adjusted Risk Ratio = 0.20 (95% CI: 0.08-0.51)] and language delay [0.39 (0.19-0.82)] but not motor or social/cognitive delay. Use of a multiple micronutrient supplement decreased the risk of motor delay [0.12 (0.03-0.56)], but more pets were associated with higher risk of motor [3.24 (1.47-7.14)] and social/cognitive delay [2.72 (1.33-5.55)], and of food insecurity [1.73 (1.13-2.66)]. Conclusion: The combined interventions delivered by CHPs helped to mitigate the impact of adversity on food insecurity and language delay. Additional improvements may have been detected if the interventions had continued for a longer time. Our results indicate that control of infections and pets may be needed to achieve measurable results for motor and social/cognitive development. Continuous monitoring facilitated adjusting implementation strategies and achieving positive developmental outcomes.

PMID:33240834 | PMC:PMC7681241 | DOI:10.3389/fpubh.2020.567900

Fecal host biomarkers predicting severity of Clostridioides difficile infection

Tue, 11/24/2020 - 06:00

JCI Insight. 2020 Nov 24:142976. doi: 10.1172/jci.insight.142976. Online ahead of print.

ABSTRACT

BACKGROUND: Clostridioides difficile is a major cause of healthcare-associated diarrhea. Severity ranges from mild to life-threatening, but this variability remains poorly understood. Microbiological diagnosis of C. difficile infection (CDI) is straightforward, but offers little insight into the patient's prognosis, nor into pathophysiological determinants of clinical trajectory. The aim of this study was to discover host-derived, CDI-specific, fecal biomarkers involved in disease severity.

METHODS: Subjects without and with diarrhea were recruited. CDI was established by commercial, diagnostic real-time PCR assay of tcdB. CDI severity was based on IDSA/SHEA criteria. We developed a liquid chromatography tandem mass spectrometry (LC-MS/MS) approach to identify host-derived protein biomarkers from stool and applied it to diagnostic samples for cohort-wise comparison (CDI-negative vs. non-severe CDI vs. severe CDI). Selected biomarkers were orthogonally confirmed and subsequently verified in a CDI mouse model.

RESULTS: We identified a protein signature from stool, consisting of alpha-2-macroglobulin (A2M), matrix metalloproteinase-7 (MMP7) and alpha-1-antitrypsin (A1AT), that not only discriminates CDI-positive samples from non-CDI ones, but is potentially associated with disease severity. In the mouse model, this signature with the murine homologs of the corresponding proteins was also identified.

CONCLUSIONS: A2M, MMP7 and A1AT serve as biomarkers in patients with CDI and define novel components of the host response that may determine disease severity.

PMID:33232301 | DOI:10.1172/jci.insight.142976

Risk of latent and active tuberculosis infection in travellers: a systematic review and meta-analysis

Mon, 11/23/2020 - 06:00

J Travel Med. 2020 Nov 19:taaa214. doi: 10.1093/jtm/taaa214. Online ahead of print.

ABSTRACT

INTRODUCTION: Achieving tuberculosis (TB) elimination in low TB incidence countries requires identification and treatment of individuals at risk for latent TB infection (LTBI). Persons travelling to high TB incidence countries are potentially at risk for TB exposure. This systematic review and meta-analysis estimates incident LTBI and active TB among individuals travelling from low to higher TB incidence countries.

METHODS: Five electronic databases were searched from inception to 18th February, 2020. We identified incident LTBI and active TB among individuals travelling from low (<10 cases/100000 population) to intermediate (10-100/100000) or high (>100/100000) TB incidence countries. We conducted a meta-analysis and meta-regression using a random effects model of log-transformed proportions (cumulative incidence). Subgroup analyses investigated the impact of travel duration, travel purpose, and TB incidence in the destination country.

RESULTS: Our search identified 799 studies, 120 underwent full-text review, and 10 studies were included. These studies included 1 154 673 travellers observed between 1994 and 2013, comprising 443 health care workers (HCW), 1 068 636 military personnel, and 85 594 general travellers/volunteers. We did not identify any studies that estimated incidence of LTBI or active TB among people travelling to visit friends and relatives (VFRs). The overall cumulative incidence of LTBI was 2.3%, with considerable heterogeneity. Among individuals travelling for a mean/median of up to 6 months, HCWs had the highest cumulative incidence of LTBI (4.3%), while the risk was lower for military (2.5%) and general travellers/volunteers (1.6%). Meta-regression did not identify a difference in incident LTBI based on travel duration and TB incidence in the destination country. Five studies reported cases of active TB, with an overall pooled estimate of 120.7 cases per 100 000 travellers.

CONCLUSIONS: We found that travelling HCWs were at highest risk of developing LTBI. Individual risk activities and travel purpose were most associated with risk of TB infection acquired during travel.

PMID:33225357 | DOI:10.1093/jtm/taaa214

Attempt to assess Canada's expertise in global health research falls short

Tue, 11/03/2020 - 06:00

Health Res Policy Syst. 2020 Nov 3;18(1):130. doi: 10.1186/s12961-020-00634-5.

ABSTRACT

The recent article by Nagi et al. (Health Res Policy Syst 18:37, 2020) considerably underestimates the size of the global health research community in Canada as well as its geographical distribution, its breadth and depth of experience and expertise, and its overall contribution to addressing the world's greatest global health priorities. Global health researchers, practitioners, policy-makers, strategists and funders/donors would benefit from a more accurate in-depth and comprehensive analysis.

PMID:33138844 | DOI:10.1186/s12961-020-00634-5

The phosphoinositide regulatory network in Trypanosoma brucei: Implications for cell-wide regulation in eukaryotes

Thu, 10/29/2020 - 06:00

PLoS Negl Trop Dis. 2020 Oct 29;14(10):e0008689. doi: 10.1371/journal.pntd.0008689. eCollection 2020 Oct.

ABSTRACT

The unicellular eukaryote Trypanosoma brucei undergoes extensive cellular and developmental changes during its life cycle. These include regulation of mammalian stage surface antigen variation and surface composition changes between life stages; switching between glycolysis and oxidative phosphorylation; differential mRNA editing; and changes in posttranscriptional gene expression, protein trafficking, organellar function, and cell morphology. These diverse events are coordinated and controlled throughout parasite development, maintained in homeostasis at each life stage, and are essential for parasite survival in both the host and insect vector. Described herein are the enzymes and metabolites of the phosphatidylinositol (PI) cellular regulatory network, its integration with other cellular regulatory systems that collectively control and coordinate these numerous cellular processes, including cell development and differentiation and the many associated complex processes in multiple subcellular compartments. We conclude that this regulation is the product of the organization of these enzymes within the cellular architecture, their activities, metabolite fluxes, and responses to environmental changes via signal transduction and other processes. We describe a paradigm for how these enzymes and metabolites could function to control and coordinate multiple cellular functions. The significance of the PI system's regulatory functions in single-celled eukaryotes to metazoans and their potential as chemotherapeutic targets are indicated.

PMID:33119588 | DOI:10.1371/journal.pntd.0008689

Efficacy, immunogenicity, and safety of a plant-derived, quadrivalent, virus-like particle influenza vaccine in adults (18-64 years) and older adults (≥65 years): two multicentre, randomised phase 3 trials.

Tue, 10/20/2020 - 02:17

Efficacy, immunogenicity, and safety of a plant-derived, quadrivalent, virus-like particle influenza vaccine in adults (18-64 years) and older adults (≥65 years): two multicentre, randomised phase 3 trials.

Lancet. 2020 Oct 13;:

Authors: Ward BJ, Makarkov A, Séguin A, Pillet S, Trépanier S, Dhaliwall J, Libman MD, Vesikari T, Landry N

Abstract
BACKGROUND: Seasonal influenza remains a substantial public health threat despite the availability of egg-derived and other vaccines. Plant-based manufacturing might address some of the limitations of current vaccines. We describe two phase 3 efficacy studies of a recombinant quadrivalent virus-like particle (QVLP) influenza vaccine manufactured in plants, one in adults aged 18-64 years (the 18-64 study) and one in older people aged 65 years and older (the 65-plus study).
METHODS: We did two randomised, observer-blind, multinational studies in the northern hemisphere in the 2017-18 (the 18-64 study) and 2018-19 (the 65-plus study) influenza seasons. The 18-64 study was done at 73 sites and the 65-plus study was done at 104 sites, both across Asia, Europe, and North America. In the 18-64 study, inclusion criteria were body-mass index less than 40 kg/m2; age 18-64 years at screening visit; and good health. In the 65-plus study, inclusion criteria were body-mass index of maximum 35 kg/m2; aged 65 years or older at screening visit; not living in a rehabilitation centre or care home; and no acute or evolving medical problems. Participants in the 18-64 study were randomly assigned (1:1) to receive either QVLP vaccine (30 μg haemagglutinin per strain) or placebo. Participants in the 65-plus study were randomly assigned (1:1) to receive QVLP vaccine (30 μg haemagglutinin per strain) or quadrivalent inactivated vaccine (QIV; 15 μg haemagglutinin per strain). The primary outcome in the 18-64 study was absolute vaccine efficacy to prevent laboratory-confirmed, respiratory illness caused by antigenically matched influenza strains. The primary outcome in the 65-plus study was relative vaccine efficacy to prevent laboratory-confirmed influenza-like illness caused by any influenza strain. The primary analyses were done in the per-protocol population and safety was assessed in all participants who received the assigned treatment. These studies are registered with ClinicalTrials.gov (18-64 study NCT03301051; 65-plus study NCT03739112).
FINDINGS: In the 18-64 study, between Aug 30, 2017, and Jan 15, 2018, 10 160 participants were randomly assigned to receive either QVLP vaccine (5077 participants) or placebo (5083 participants). The per-protocol population consisted of 4814 participants in the QVLP group and 4812 in the placebo group. The study did not meet its primary endpoint of 70% absolute vaccine efficacy for the QVLP vaccine (35·1% [95% CI 17·9 to 48·7]) against respiratory illness caused by matched strains. 55 (1·1%) of 5064 participants in the QVLP group versus 51 (1·0%) of 5072 in the placebo group had a serious adverse event. Four (0·1%) and six [0·1%] participants had severe treatment-related treatment-emergent adverse events. In the 65-plus study, between Sept 18, 2018, and Feb 22, 2019, 12 794 participants were randomly assigned to receive either QVLP vaccine (6396 participants) or QIV (6398 participants). The per-protocol population consisted of 5996 participants in the QVLP group and 6026 in the QIV group. The study met its primary non-inferiority endpoint with a relative vaccine efficacy of the QVLP vaccine for the prevention of influenza-like illness caused by any strain of 8·8% (-16·7 to 28·7). 263 (4·1%) of 6352 participants in the QVLP group versus 266 (4·2%) of 6366 in the QIV group had serious adverse events (one [<0·1%] vs two [<0·1%] were considered treatment-related); one (<0·1%) versus three (<0·1%) participants had severe treatment-related treatment-emergent adverse events.
INTERPRETATION: These efficacy studies are the first large-scale studies of any plant-derived human vaccine. Together, they show that the plant-derived QVLP vaccine can provide substantial protection against respiratory illness and influenza-like illness caused by influenza viruses in adults. QVLP vaccine was well tolerated and no major safety signal arose in participants who received QVLP vaccine across the two studies.
FUNDING: Medicago.

PMID: 33065035 [PubMed - as supplied by publisher]

A multimodal intervention increases influenza vaccine uptake in rheumatoid arthritis.

Sat, 10/10/2020 - 04:28

A multimodal intervention increases influenza vaccine uptake in rheumatoid arthritis.

Clin Rheumatol. 2020 Oct 08;:

Authors: Valerio V, Bazan MC, Wang M, Mazer BD, Pineau CA, Hazel EM, Bernatsky S, Ward BJ, Colmegna I

Abstract
Annual influenza vaccination is recommended for patients with rheumatoid arthritis (RA), but coverage is suboptimal. We assessed the impact of an implementation strategy in enhancing vaccination uptake in RA. We evaluated a multimodal implementation strategy at rheumatology clinics that included 3 approaches: patient recalls, a nurse providing vaccines, and physician reminders. We compared patient-reported vaccination rates after implementation with those reported before the implementation strategy in a nonequivalent control group. In multivariate analyses, we assessed factors potentially associated with influenza vaccine uptake. One hundred and sixteen RA patients were vaccinated during the intervention. The influenza vaccination rate in RA increased from 48.5% (65/136) before implementation to 62.6% (67/107) after implementation (difference of 14.1, 95% CI 1.5, 26.1). In multivariate analyses, older age, biologics use, and physician recommendation for vaccination were associated with influenza vaccine uptake. A multimodal intervention was associated with increased influenza vaccine coverage among RA patients. Older patients and those on biologics were more likely to be immunized against influenza. Physician's recommendations are important to promote vaccine coverage. Key Points • Despite current recommendations, influenza vaccine uptake among rheumatoid arthritis (RA) patients is suboptimal. • A multimodal implementation strategy facilitating access to influenza vaccine and raising awareness through vaccination reminders improved immunization uptake in RA. • Physicians play a key role in promoting annual seasonal influenza vaccination. • The reasons for vaccine hesitancy in RA should be addressed to reach a vaccination target of 80% required to reduce the burden of this preventable infection.

PMID: 33030631 [PubMed - as supplied by publisher]

Real-world Time to Positivity of 2 Widely Used Commercial Blood Culture Systems in Patients With Severe Manifestations of Sepsis: An Analysis of the FABLED Study.

Sat, 10/03/2020 - 06:17

Real-world Time to Positivity of 2 Widely Used Commercial Blood Culture Systems in Patients With Severe Manifestations of Sepsis: An Analysis of the FABLED Study.

Open Forum Infect Dis. 2020 Sep;7(9):ofaa371

Authors: Butler-Laporte G, Yansouni CP, Paquette K, Lawandi A, Stabler SN, Akhter M, Davidson AC, Gavric M, Jinah R, Saeed Z, Demir K, Sangsari S, Huang K, Mahpour A, Shamatutu C, Caya C, Troquet JM, Clark G, Wong T, Lee TC, Stenstrom R, Sweet D, Cheng MP

Abstract
Background: Of all microbiological tests performed, blood cultures have the most impact on patient care. Timely results are essential, especially in the management of sepsis. While there are multiple available blood culture systems on the market, they have never been compared in a prospective study in a critically ill population.
Methods: We performed an analysis of the FABLED study cohort to compare culture results and time to positivity (TTP) of 2 widely used blood culture systems: BacT/Alert and BACTEC. In this multisite prospective study, patients with severe manifestations of sepsis had cultures drawn before antibiotics using systematic enrollment criteria and blood drawing methodology allowing for minimization of pre-analytical biases.
Results: We enrolled 315 patients; 144 had blood cultures (47 positive) with BacT/Alert and 171 with BACTEC (53 positive). Patients whose blood cultures were processed using the BacT/Alert system were younger (median, 64 vs 70 years; P = .003), had a higher proportion of HIV (9.03% vs 1.75%; P = .008) and a lower qSOFA (P = .003). There were no statistically significant differences in the most commonly identified bacterial species. TTP was shorter for BACTEC (median [interquartile range {IQR}], 12.5 [10-14] hours) compared with BacT/Alert (median [IQR], 17 [14-21] hours; P < .0001).
Conclusions: In this large prospective multi-centre study comparing the two blood culture systems among patients with severe manifestations of sepsis, and using a rigorous pre-analytical methodology, the BACTEC system yielded positive culture results 4.5 hours earlier than BacT/Alert. These results apply to commonly isolated bacteria. However, our study design did not allow direct comparison of TTP for unusual pathogens nor of clinical sensitivity between systems. More research is needed to determine the clinical implications of this finding.

PMID: 33005699 [PubMed]

Expert Forecasts of COVID-19 Vaccine Development Timelines.

Thu, 10/01/2020 - 03:16

Expert Forecasts of COVID-19 Vaccine Development Timelines.

J Gen Intern Med. 2020 Sep 28;:

Authors: Kane PB, Moyer H, MacPherson A, Papenburg J, Ward BJ, Broomell SB, Kimmelman J

PMID: 32989715 [PubMed - as supplied by publisher]

Crohn's Disease Pathobiont Adherent-Invasive E coli Disrupts Epithelial Mitochondrial Networks With Implications for Gut Permeability

Tue, 09/29/2020 - 06:00

Cell Mol Gastroenterol Hepatol. 2020 Sep 28:S2352-345X(20)30156-9. doi: 10.1016/j.jcmgh.2020.09.013. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Adherent-invasive Escherichia coli are implicated in inflammatory bowel disease, and mitochondrial dysfunction has been observed in biopsy specimens from patients with inflammatory bowel disease. As a novel aspect of adherent-invasive E coli-epithelial interaction, we hypothesized that E coli (strain LF82) would elicit substantial disruption of epithelial mitochondrial form and function.

METHODS: Monolayers of human colon-derived epithelial cell lines were exposed to E coli-LF82 or commensal E coli and RNA sequence analysis, mitochondrial function (adenosine triphosphate synthesis) and dynamics (mitochondrial network imaging, immunoblotting for fission and fusion proteins), and epithelial permeability (transepithelial resistance, flux of fluorescein isothiocyanate-dextran and bacteria) were assessed.

RESULTS: E coli-LF82 significantly affected epithelial expression of ∼8600 genes, many relating to mitochondrial function. E coli-LF82-infected epithelia showed swollen mitochondria, reduced mitochondrial membrane potential and adenosine triphosphate, and fragmentation of the mitochondrial network: events not observed with dead E coli-LF82, medium from bacterial cultures, or control E coli. Treatment with Mdivi1 (inhibits dynamin-related peptide 1, guanosine triphosphatase principally responsible for mitochondrial fission) or P110 (prevents dynamin-related peptide 1 binding to mitochondrial fission 1 protein) partially reduced E coli-LF82-induced mitochondrial fragmentation in the short term. E coli-LF82-infected epithelia showed loss of the long isoform of optic atrophy factor 1, which mediates mitochondrial fusion. Mdivi1 reduced the magnitude of E coli-LF82-induced increased transepithelial flux of fluorescein isothiocyanate dextran. By 8 hours after infection, increased cytosolic cytochrome C and DNA fragmentation were apparent without evidence of caspase-3 or apoptosis inducing factor activation.

CONCLUSIONS: Epithelial mitochondrial fragmentation caused by E coli-LF82 could be targeted to maintain cellular homeostasis and mitigate infection-induced loss of epithelial barrier function. Data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO series accession numbers GSE154121 and GSE154122 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154121).

PMID:32992049 | DOI:10.1016/j.jcmgh.2020.09.013

Serodiagnostics for Severe Acute Respiratory Syndrome-Related Coronavirus 2 : A Narrative Review.

Sun, 09/27/2020 - 02:47
Related Articles

Serodiagnostics for Severe Acute Respiratory Syndrome-Related Coronavirus 2 : A Narrative Review.

Ann Intern Med. 2020 09 15;173(6):450-460

Authors: Cheng MP, Yansouni CP, Basta NE, Desjardins M, Kanjilal S, Paquette K, Caya C, Semret M, Quach C, Libman M, Mazzola L, Sacks JA, Dittrich S, Papenburg J

Abstract
Accurate serologic tests to detect host antibodies to severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) will be critical for the public health response to the coronavirus disease 2019 pandemic. Many use cases are envisaged, including complementing molecular methods for diagnosis of active disease and estimating immunity for individuals. At the population level, carefully designed seroepidemiologic studies will aid in the characterization of transmission dynamics and refinement of disease burden estimates and will provide insight into the kinetics of humoral immunity. Yet, despite an explosion in the number and availability of serologic assays to test for antibodies against SARS-CoV-2, most have undergone minimal external validation to date. This hinders assay selection and implementation, as well as interpretation of study results. In addition, critical knowledge gaps remain regarding serologic correlates of protection from infection or disease, and the degree to which these assays cross-react with antibodies against related coronaviruses. This article discusses key use cases for SARS-CoV-2 antibody detection tests and their application to serologic studies, reviews currently available assays, highlights key areas of ongoing research, and proposes potential strategies for test implementation.

PMID: 32496919 [PubMed - indexed for MEDLINE]

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