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 US$570,404. Costs were significantly higher for bleeding/elevated international normalized ratio (US$9906 vs. US$2251, p = 6.58 × 10-3) compared to other ADRs, and for drugs acting on the blood coagulation system (US$9884 vs. US$2229, p = 4.41 × 10-3) compared to other drug classes. There were higher incremental laboratory costs due to ADRs causing or being present at admission. The estimated breakeven cost of a pre-emptive PGx test for patients taking warfarin, clopidogrel, chemotherapeutic and neuropsychiatric drugs was US$114 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 brain’s 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 brain’s 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

The Biobanque québécoise de la COVID-19 (BQC19)—A cohort to prospectively study the clinical and biological determinants of COVID-19 clinical trajectories

SARS-CoV-2 infection causing the novel coronavirus disease 2019 (COVID–19) 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 COVID–19 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 “Biobanque québécoise de la COVID-19” (BQC19) is a pan–provincial initiative undertaken in Québec, 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 COVID–19

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 été le premier rétrovirus humain à avoir été découvert en 1980. Il est l'agent causal de deux maladies humaines bien caractérisées, la leucémie lymphocytaire de l'adulte (ATL) et la myélopathie associée au HTLV-1/Paraparésie spastique tropicale (HAM / TSP). Peu d'options de traitement ont été développées pour l'ATL et la HAM/TSP; les temps de survie médians pour l'ATL restent inférieurs à un an, et les options thérapeutiques de la HAM/TSP sont de nature palliative. Cependant, l'incidence de la maladie chez les patients infectés par le HTLV-1 est relativement faible, avec seulement environ 5% des individus développant l'ATL et 2% la HAM/TSP. L'obstacle majeur au développement de thérapies efficaces est le manque de compréhension des facteurs qui déterminent la pathologie associée au HTLV-1. Les voies de transmission, le lait maternel contaminé et le sang, entraînent presque exclusivement le développement de l'ATL ou de la HAM/TSP, mais la cause de ceci n'est pas connue. Cela suggère que les premiers événements de l'infection par le HTLV-1 peuvent être la clé pour révéler les conséquences pathologiques de la maladie. Malheureusement, les étapes précoces de l'infection sont peu étudiées, dû au fait que l'infection de novo est asymptomatique. L'activité des lymphocytes T cytotoxiques semble être essentielle pour contrôler la réplication virale et est probablement un facteur clé dans la progression de la maladie. Nous avons donc entrepris d'étudier les premiers événements de l'infection par le HTLV-1 dans deux populations cellulaires mononuclées importantes et immunologiquement pertinentes du sang périphérique, les monocytes et les lymphocytes T CD4+. L'infection des monocytes primaires humains par le HTLV-1 a entraîné la déplétion de ce type cellulaire. Cela n'est pas médiée par les protéines accessoires virales, car le facteur de restriction SAMHD1 a empêché l'achèvement de la transcription inverse. Les sous-produits de l'ADN produits lors de cette inhibition ont induit une réponse immunologique puissante médiée par STING. Ceci a déclenché l'activation des protéines Bax et IRF3 et la formation de complexes qui ont conduit à l'apoptose des cellules.D'autre part, l'infection par le virus des cellules T CD4+ activées, les a fait entrer dans un état de survie cellulaire persistante. Le transactivateur viral Tax en est responsable car il est connu pour ses propriétés oncogéniques. La seule expression de Tax a activé la voie AKT, entraînant l'inactivation du facteur de transcription pro-apoptotique FOXO3a. Cela a conduit à la survie à long terme d'une population de lymphocytes T CD4+ activés capables de transmettre le virus. Ce travail de doctorat a permis de démontrer les conséquences moléculaires de l'infection par HTLV-1 dans deux types cellulaires importants, les monocytes et les cellules T CD4+. Ces événements ont une conséquence sur les évènements immunologiques qui en découlent et qui contrôlent la réplication virale et influencent probablement la pathologie de la maladie dû au HTLV-1

Information Rate in Humans during Visuomotor Tracking

Previous investigations concluded that the human brain’s 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 brain’s information processing rate, scales with the difficulty of the task at hand, in agreement with cost-benefit models of cognitive effort