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Economic burden of adverse drug reactions and potential for pharmacogenomic testing in Singaporean adults.
Adverse drug reactions (ADRs) contribute to hospitalization but data on its economic burden is scant. Pre-emptive pharmacogenetic (PGx) testing can potentially reduce ADRs and its associated costs. The objectives of this study were to quantify the economic burden of ADRs and to estimate the breakeven cost of pre-emptive PGx testing in Singapore. We collected itemized costs for 1000 random non-elective hospitalizations of adults admitted to a tertiary-care general hospital in Singapore. The presence of ADRs at admission and their clinical characteristics were reported previously. The economic burden of ADRs was assessed from two perspectives: (1) Total cost and (2) incremental costs. The breakeven cost of PGx testing was estimated by dividing avoidable hospitalization costs for ADRs due to selected drugs by the number of patients taking those drugs. The total cost of 81 admissions caused by ADRs was US9906 vs. US9884 vs. US114 per patient. These results suggest that future studies designed to directly measure the clinical and cost impact of a pre-emptive genotyping program will help inform clinical practice and health policy decisions
Information Rate in Humans during Visuomotor Tracking
Previous investigations concluded that the human brainâs information processing rate remains fundamentally constant, irrespective of task demands. However, their conclusion rested in analyses of simple discrete-choice tasks. The present contribution recasts the question of human information rate within the context of visuomotor tasks, which provides a more ecologically relevant arena, albeit a more complex one. We argue that, while predictable aspects of inputs can be encoded virtually free of charge, real-time information transfer should be identified with the processing of surprises. We formalise this intuition by deriving from first principles a decomposition of the total information shared by inputs and outputs into a feedforward, predictive component and a feedback, error-correcting component. We find that the information measured by the feedback component, a proxy for the brainâs information processing rate, scales with the difficulty of the task at hand, in agreement with cost-benefit models of cognitive effort
Host Restriction Factor SAMHD1 Limits Human T Cell Leukemia Virus Type 1 Infection of Monocytes via STING-Mediated Apoptosis
SummaryHuman T cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T cell leukemia and HTLV-1-associated myelopathies. In addition to T cells, HTLV-1 infects cells of the myeloid lineage, which play critical roles in the host innate response to viral infection. Investigating the monocyte depletion observed during HTLV-1 infection, we discovered that primary human monocytes infected with HTLV-1 undergo abortive infection accompanied by apoptosis dependent on SAMHD1, a host restriction factor that hydrolyzes endogenous dNTPs to below the levels required for productive reverse transcription. Reverse transcription intermediates (RTI) produced in the presence of SAMHD1 induced IRF3-mediated antiviral and apoptotic responses. Viral RTIs complexed with the DNA sensor STING to trigger formation of an IRF3-Bax complex leading to apoptosis. This study provides a mechanistic explanation for abortive HTLV-1 infection of monocytes and reports a link between SAMHD1 restriction, HTLV-1 RTI sensing by STING, and initiation of IRF3-Bax driven apoptosis
Activation of Nrf2 signaling augments Vesicular Stomatitis Virus Oncolysis via Autophagy-Driven Suppression of Antiviral Immunity
Activation of Nrf2 signaling augments Vesicular Stomatitis Virus Oncolysis via Autophagy-Driven Suppression of Antiviral Immunity
The Biobanque quĂ©bĂ©coise de la COVID-19 (BQC19)âA cohort to prospectively study the clinical and biological determinants of COVID-19 clinical trajectories
SARS-CoV-2 infection causing the novel coronavirus disease 2019 (COVIDâ19) has been responsible for more than 2.8 million deaths and nearly 125 million infections worldwide as of March 2021. In March 2020, the World Health Organization determined that the COVIDâ19 outbreak is a global pandemic. The urgency and magnitude of this pandemic demanded immediate action and coordination between local, regional, national, and international actors. In that mission, researchers require access to high-quality biological materials and data from SARS-CoV-2 infected and uninfected patients, covering the spectrum of disease manifestations. The âBiobanque quĂ©bĂ©coise de la COVID-19â (BQC19) is a panâprovincial initiative undertaken in QuĂ©bec, Canada to enable the collection, storage and sharing of samples and data related to the COVID-19 crisis. As a disease-oriented biobank based on high-quality biosamples and clinical data of hospitalized and non-hospitalized SARS-CoV-2 PCR positive and negative individuals. The BQC19 follows a legal and ethical management framework approved by local health authorities. The biosamples include plasma, serum, peripheral blood mononuclear cells and DNA and RNA isolated from whole blood. In addition to the clinical variables, BQC19 will provide in-depth analytical data derived from the biosamples including whole genome and transcriptome sequencing, proteome and metabolome analyses, multiplex measurements of key circulating markers as well as anti-SARS-CoV-2 antibody responses. BQC19 will provide the scientific and medical communities access to data and samples to better understand, manage and ultimately limit, the impact of COVID-19. In this paper we present BQC19, describe the process according to which it is governed and organized, and address opportunities for future research collaborations. BQC19 aims to be a part of a global communal effort addressing the challenges of COVIDâ19
Robust estimation of bacterial cell count from optical density
Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data
Molecular mechanisms of monocyte depletion and CD4+ T-cell persistence during human T-cell leukemia virus infection
Human T-cell Leukemia Virus type 1 (HTLV-1) was the first human retrovirus discovered in 1980. It is the causal agent of two well characterized human diseases, Adult T-cell Leukemia (ATL) and HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). Few treatment options have been developed for ATL and HAM/TSP; the median survival times for ATL remains under a year, and treatment options of HAM/TSP remain palliative in nature. Thankfully the incidence of disease in HTLV-1 infected patients is relatively low, with only approximately 5% of individuals developing ATL and 2% HAM/TSP. One major obstacle in the development of effective therapies is a lack of understanding regarding the factors that determine HTLV-1 associated pathology. The route of transmission, contaminated breast milk and blood, almost exclusively lead to ATL or HAM/TSP development respectively, but it is unclear as to why. This suggests that the early events of HTLV-1 infection may be key in discerning pathological outcomes. Unfortunately this time point is understudied, in part due to the fact that de novo infection is asymptomatic. The activity of cytotoxic T-cell lymphocytes seems to be vital in controlling viral replication, and is likely a key determinant in disease progression. We thus set out to study the early events of HTLV-1 infection in two important immunologically relevant peripheral blood mononuclear cell populations, monocytes and CD4+ T-cells. HTLV-1 infection of primary human monocytes resulted in the depletion of this cell type. This was not mediated by viral accessory proteins, as host restriction factor SAMHD1 prevented the completion of reverse transcription. The DNA by-products of this inhibition induced a potent STING-mediated immunological response, that triggered Bax and IRF3 activation and complex formation that led to apoptosis. Infection of activated CD4+ T-cells on the other hand, resulted in persistent cellular survival. This was mediated by the viral accessory protein Tax, known to have oncogenic properties. Tax expression activated the AKT pathway, which resulted in the inactivation of the pro-apoptotic FOXO3a transcription factor. This led to the long-term survival of an activated CD4+ T-cell population that was capable of viral transmission. Overall this work has demonstrated the molecular consequences of HTLV-1 infection in two important cell types, monocytes and CD4+ T-cells. These events likely shape the subsequent immunological events that control viral replication and likely influence HTLV-1 disease pathology.Le virus T-lymphotropique humain de type 1 (HTLV-1) a Ă©tĂ© le premier rĂ©trovirus humain Ă avoir Ă©tĂ© dĂ©couvert en 1980. Il est l'agent causal de deux maladies humaines bien caractĂ©risĂ©es, la leucĂ©mie lymphocytaire de l'adulte (ATL) et la myĂ©lopathie associĂ©e au HTLV-1/ParaparĂ©sie spastique tropicale (HAM / TSP). Peu d'options de traitement ont Ă©tĂ© dĂ©veloppĂ©es pour l'ATL et la HAM/TSP; les temps de survie mĂ©dians pour l'ATL restent infĂ©rieurs Ă un an, et les options thĂ©rapeutiques de la HAM/TSP sont de nature palliative. Cependant, l'incidence de la maladie chez les patients infectĂ©s par le HTLV-1 est relativement faible, avec seulement environ 5% des individus dĂ©veloppant l'ATL et 2% la HAM/TSP. L'obstacle majeur au dĂ©veloppement de thĂ©rapies efficaces est le manque de comprĂ©hension des facteurs qui dĂ©terminent la pathologie associĂ©e au HTLV-1. Les voies de transmission, le lait maternel contaminĂ© et le sang, entraĂźnent presque exclusivement le dĂ©veloppement de l'ATL ou de la HAM/TSP, mais la cause de ceci n'est pas connue. Cela suggĂšre que les premiers Ă©vĂ©nements de l'infection par le HTLV-1 peuvent ĂȘtre la clĂ© pour rĂ©vĂ©ler les consĂ©quences pathologiques de la maladie. Malheureusement, les Ă©tapes prĂ©coces de l'infection sont peu Ă©tudiĂ©es, dĂ» au fait que l'infection de novo est asymptomatique. L'activitĂ© des lymphocytes T cytotoxiques semble ĂȘtre essentielle pour contrĂŽler la rĂ©plication virale et est probablement un facteur clĂ© dans la progression de la maladie. Nous avons donc entrepris d'Ă©tudier les premiers Ă©vĂ©nements de l'infection par le HTLV-1 dans deux populations cellulaires mononuclĂ©es importantes et immunologiquement pertinentes du sang pĂ©riphĂ©rique, les monocytes et les lymphocytes T CD4+. L'infection des monocytes primaires humains par le HTLV-1 a entraĂźnĂ© la dĂ©plĂ©tion de ce type cellulaire. Cela n'est pas mĂ©diĂ©e par les protĂ©ines accessoires virales, car le facteur de restriction SAMHD1 a empĂȘchĂ© l'achĂšvement de la transcription inverse. Les sous-produits de l'ADN produits lors de cette inhibition ont induit une rĂ©ponse immunologique puissante mĂ©diĂ©e par STING. Ceci a dĂ©clenchĂ© l'activation des protĂ©ines Bax et IRF3 et la formation de complexes qui ont conduit Ă l'apoptose des cellules.D'autre part, l'infection par le virus des cellules T CD4+ activĂ©es, les a fait entrer dans un Ă©tat de survie cellulaire persistante. Le transactivateur viral Tax en est responsable car il est connu pour ses propriĂ©tĂ©s oncogĂ©niques. La seule expression de Tax a activĂ© la voie AKT, entraĂźnant l'inactivation du facteur de transcription pro-apoptotique FOXO3a. Cela a conduit Ă la survie Ă long terme d'une population de lymphocytes T CD4+ activĂ©s capables de transmettre le virus. Ce travail de doctorat a permis de dĂ©montrer les consĂ©quences molĂ©culaires de l'infection par HTLV-1 dans deux types cellulaires importants, les monocytes et les cellules T CD4+. Ces Ă©vĂ©nements ont une consĂ©quence sur les Ă©vĂšnements immunologiques qui en dĂ©coulent et qui contrĂŽlent la rĂ©plication virale et influencent probablement la pathologie de la maladie dĂ» au HTLV-1
Information Rate in Humans during Visuomotor Tracking
Previous investigations concluded that the human brainâs information processing rate remains fundamentally constant, irrespective of task demands. However, their conclusion rested in analyses of simple discrete-choice tasks. The present contribution recasts the question of human information rate within the context of visuomotor tasks, which provides a more ecologically relevant arena, albeit a more complex one. We argue that, while predictable aspects of inputs can be encoded virtually free of charge, real-time information transfer should be identified with the processing of surprises. We formalise this intuition by deriving from first principles a decomposition of the total information shared by inputs and outputs into a feedforward, predictive component and a feedback, error-correcting component. We find that the information measured by the feedback component, a proxy for the brainâs information processing rate, scales with the difficulty of the task at hand, in agreement with cost-benefit models of cognitive effort
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