An automated approach to identify scientific publications reporting pharmacokinetic parameters [version 1; peer review: awaiting peer review]

Pharmacokinetic (PK) predictions of new chemical entities are aided by prior knowledge from other compounds. The development of robust algorithms that improve preclinical and clinical phases of drug development remains constrained by the need to search, curate and standardise PK information across the constantly-growing scientific literature. The lack of centralised, up-to-date and comprehensive repositories of PK data represents a significant limitation in the drug development pipeline.In this work, we propose a machine learning approach to automatically identify and characterise scientific publications reporting PK parameters from in vivo data, providing a centralised repository of PK literature. A dataset of 4,792 PubMed publications was labelled by field experts depending on whether in vivo PK parameters were estimated in the study. Different classification pipelines were compared using a bootstrap approach and the best-performing architecture was used to develop a comprehensive and automatically-updated repository of PK publications. The best-performing architecture encoded documents using unigram features and mean pooling of BioBERT embeddings obtaining an F1 score of 83.8% on the test set. The pipeline retrieved over 121K PubMed publications in which in vivo PK parameters were estimated and it was scheduled to perform weekly updates on newly published articles. All the relevant documents were released through a publicly available web interface (https://app.pkpdai.com) and characterised by the drugs, species and conditions mentioned in the abstract, to facilitate the subsequent search of relevant PK data. This automated, open-access repository can be used to accelerate the search and comparison of PK results, curate ADME datasets, and facilitate subsequent text mining tasks in the PK domain.</ns4:p

Systematic Review and Patient-Level Meta-Analysis of SARS-CoV-2 Viral Dynamics to Model Response to Antiviral Therapies

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral loads change rapidly following symptom onset, so to assess antivirals it is important to understand the natural history and patient factors influencing this. We undertook an individual patient-level meta-analysis of SARS-CoV-2 viral dynamics in humans to describe viral dynamics and estimate the effects of antivirals used to date. This systematic review identified case reports, case series, and clinical trial data from publications between January 1, 2020, and May 31, 2020, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A multivariable Cox proportional hazards (Cox-PH) regression model of time to viral clearance was fitted to respiratory and stool samples. A simplified four parameter nonlinear mixed-effects (NLME) model was fitted to viral load trajectories in all sampling sites and covariate modeling of respiratory viral dynamics was performed to quantify time-dependent drug effects. Patient-level data from 645 individuals (age 1 month to 100 years) with 6,316 viral loads were extracted. Model-based simulations of viral load trajectories in samples from the upper and lower respiratory tract, stool, blood, urine, ocular secretions, and breast milk were generated. Cox-PH modeling showed longer time to viral clearance in older patients, men, and those with more severe disease. Remdesivir was associated with faster viral clearance (adjusted hazard ratio (AHR) = 9.19, P < 0.001), as well as interferon, particularly when combined with ribavirin (AHR = 2.2, P = 0.015; AHR = 6.04, P = 0.006). Combination therapy should be further investigated. A viral dynamic dataset and NLME model for designing and analyzing antiviral trials has been established

Clinical impact of a targeted next-generation sequencing gene panel for autoinflammation and vasculitis.

BACKGROUND: Monogenic autoinflammatory diseases (AID) are a rapidly expanding group of genetically diverse but phenotypically overlapping systemic inflammatory disorders associated with dysregulated innate immunity. They cause significant morbidity, mortality and economic burden. Here, we aimed to develop and evaluate the clinical impact of a NGS targeted gene panel, the "Vasculitis and Inflammation Panel" (VIP) for AID and vasculitis. METHODS: The Agilent SureDesign tool was used to design 2 versions of VIP; VIP1 targeting 113 genes, and a later version, VIP2, targeting 166 genes. Captured and indexed libraries (QXT Target Enrichment System) prepared for 72 patients were sequenced as a multiplex of 16 samples on an Illumina MiSeq sequencer in 150bp paired-end mode. The cohort comprised 22 positive control DNA samples from patients with previously validated mutations in a variety of the genes; and 50 prospective samples from patients with suspected AID in whom previous Sanger based genetic screening had been non-diagnostic. RESULTS: VIP was sensitive and specific at detecting all the different types of known mutations in 22 positive controls, including gene deletion, small INDELS, and somatic mosaicism with allele fraction as low as 3%. Six/50 patients (12%) with unclassified AID had at least one class 5 (clearly pathogenic) variant; and 11/50 (22%) had at least one likely pathogenic variant (class 4). Overall, testing with VIP resulted in a firm or strongly suspected molecular diagnosis in 16/50 patients (32%). CONCLUSIONS: The high diagnostic yield and accuracy of this comprehensive targeted gene panel validate the use of broad NGS-based testing for patients with suspected AID

'We Have the Internet in Our Hands’: Bangladeshi College Students’ Use of ICTs For Health Information

Information and Communications Technologies (ICTs) which enable people to access, use and promote health information through digital technology, promise important health systems innovations which can challenge gatekeepers’ control of information, through processes of disintermediation. College students, in pursuit of sexual and reproductive health (SRH) information, are particularly affected by gatekeeping as strong social and cultural norms restrict their access to information and services. This paper examines mobile phone usage for obtaining health information in Mirzapur, Bangladesh. It contrasts college students’ usage with that of the general population, asks whether students are using digital technologies for health information in innovative ways, and examines how gender affects this

Evolution of the knowledge economy: a historical perspective with an application to the case of Europe

The goal of the article is to explore the evolution of original concept of knowledge economy based on science intensive production sectors toward service type economies which significantly changed the role of scientific research and technological innovation for economic growth. The paper argues that this transition is due not only to the structural changes in global production, but the theoretical evolution and aradigmatic shift of the concept of “knowledge economy” in general and “knowledge” in particular has played a significant role. The paper examines the different interpretation of knowledge within new types of intangible economies (e.g., new/Internet, weightless, service, creative, cultural economies) where knowledge is perceived to be generated not as a product of scientific research but as a service or creative activity and critically examined the role of scientific research in a service led knowledge economy. Additionally the paper argue how these phenomena, which marked the global economy in the last decades, enable the transition of the standard concept of knowledge economy originated from industrial production and manufacturing to a knowledge economy equalized with various types of expanding intangible economies, primarily those based on service and creative industries

Low wintertime vitamin D levels in a sample of healthy young adults of diverse ancestry living in the Toronto area: associations with vitamin D intake and skin pigmentation

<p>Abstract</p> <p>Background</p> <p>Vitamin D plays a critical role in bone metabolism and many cellular and immunological processes. Recent research indicates that concentrations of serum 25-hydroxyvitamin D [25(OH)D], the main indicator of vitamin D status, should be in excess of 75 nmol/L. Low levels of 25(OH)D have been associated with several chronic and infectious diseases. Previous studies have reported that many otherwise healthy adults of European ancestry living in Canada have low vitamin D concentrations during the wintertime. However, those of non-European ancestry are at a higher risk of having low vitamin D levels. The main goal of this study was to examine the vitamin D status and vitamin D intake of young Canadian adults of diverse ancestry during the winter months.</p> <p>Methods</p> <p>One hundred and seven (107) healthy young adults self-reporting their ancestry were recruited for this study. Each participant was tested for serum 25(OH)D concentrations and related biochemistry, skin pigmentation indices and basic anthropometric measures. A seven-day food diary was used to assess their vitamin D intake. An ANOVA was used to test for significant differences in the variables among groups of different ancestry. Linear regression was employed to assess the impact of relevant variables on serum 25(OH)D concentrations.</p> <p>Results</p> <p>More than 93% of the total sample had concentrations below 75 nmol/L. Almost three-quarters of the subjects had concentrations below 50 nmol/L. There were significant differences in serum 25(OH)D levels (p < 0.001) and vitamin D intake (p = 0.034) between population groups. Only the European group had a mean vitamin D intake exceeding the current Recommended Adequate Intake (RAI = 200 IU/day). Total vitamin D intake (from diet and supplements) was significantly associated with 25(OH)D levels (p < 0.001). Skin pigmentation, assessed by measuring skin melanin content, showed an inverse relationship with serum 25(OH)D (p = 0.033).</p> <p>Conclusion</p> <p>We observe that low vitamin D levels are more prevalent in our sample of young healthy adults than previously reported, particularly amongst those of non-European ancestry. Major factors influencing 25(OH)D levels were vitamin D intake and skin pigmentation. These data suggest a need to increase vitamin D intake either through improved fortification and/or supplementation.</p

Effects of therapy with [177Lu-DOTA0,Tyr3]octreotate on endocrine function

Purpose: Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues is a novel therapy for patients with somatostatin receptor-positive tumours. We determined the effects of PRRT with [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) on glucose homeostasis and the pituitary-gonadal, pituitary-thyroid and pituitary-adrenal axes. Methods: Hormone levels were measured and adrenal function assessed at baseline and up to 24 months of follow-up. Results: In 35 men, mean serum inhibin B levels were decreased at 3 months post-therapy (205 ± 16 to 25 ± 4 ng/l, p 550 nmol/l, n = 18). Five patients developed elevated HbA1clevels (> 6.5%). Conclusion: In men177Lu-octreotate therapy induced transient inhibitory effects on spermatogenesis, but non-SHBG-bound T levels remained unaffected. In the long term, gonadotropin levels decreased significantly in postmenopausal women. Only a few patients developed hypothyroidism or elevated levels of HbA1c. Therefore, PRRT with177Lu-octreotate can be regarded as a safe treatment modality with respect to short-and long-term endocrine function

Useful pharmacodynamic endpoints in children: selection, measurement, and next steps.

Pharmacodynamic (PD) endpoints are essential for establishing the benefit-to-risk ratio for therapeutic interventions in children and neonates. This article discusses the selection of an appropriate measure of response, the PD endpoint, which is a critical methodological step in designing pediatric efficacy and safety studies. We provide an overview of existing guidance on the choice of PD endpoints in pediatric clinical research. We identified several considerations relevant to the selection and measurement of PD endpoints in pediatric clinical trials, including the use of biomarkers, modeling, compliance, scoring systems, and validated measurement tools. To be useful, PD endpoints in children need to be clinically relevant, responsive to both treatment and/or disease progression, reproducible, and reliable. In most pediatric disease areas, this requires significant validation efforts. We propose a minimal set of criteria for useful PD endpoint selection and measurement. We conclude that, given the current heterogeneity of pediatric PD endpoint definitions and measurements, both across and within defined disease areas, there is an acute need for internationally agreed, validated, and condition-specific pediatric PD endpoints that consider the needs of all stakeholders, including healthcare providers, policy makers, patients, and families.Pediatric Research advance online publication, 11 April 2018; doi:10.1038/pr.2018.38

Hyper-precarious lives : Migrants, work and forced labour in the Global North

This paper unpacks the contested inter-connections between neoliberal work and welfare regimes, asylum and immigration controls, and the exploitation of migrant workers. The concept of precarity is explored as a way of understanding intensifying and insecure post-Fordist work in late capitalism. Migrants are centrally implicated in highly precarious work experiences at the bottom end of labour markets in Global North countries, including becoming trapped in forced labour. Building on existing research on the working experiences of migrants in the Global North, the main part of the article considers three questions. First, what is precarity and how does the concept relate to working lives? Second, how might we understand the causes of extreme forms of migrant labour exploitation in precarious lifeworlds? Third, how can we adequately theorize these particular experiences using the conceptual tools of forced labour, slavery, unfreedom and precarity? We use the concept of ‘hyper-precarity’ alongside notions of a ‘continuum of unfreedom’ as a way of furthering human geographical inquiry into the intersections between various terrains of social action and conceptual debate concerning migrants’ precarious working experiences