The Shifting Legitimation of an Information System: Local, Global and Large Scale

ICT infrastructure and information systems have come to play a vital role in globalization. Walsham (2008) highlights three major aspects of this phenomenon: software outsourcing, virtual teams, and information system (IS) roll-out. In this paper we examine shifts over several years of globally distributed development and roll-out of an open source information system targeted at the public health care sector in developing countries, which touches on all three aspects. In following the development of an system as it co-evolved with the various institutional settings in which it was embedded, we highlight shifting sources of legitimation in institutional processes involved in health information systems implementation. The attention to changing sources of acceptance and legitimation frames our view on knowledge between local cultures and related stakeholders, in the interplay with global FOSS development

A constitutive active MAPK/ERK pathway due to BRAFV600E positively regulates AHR pathway in PTC

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor mediating the toxicity and tumor-promoting properties of dioxin. AHR has been reported to be overexpressed and constitutively active in a variety of solid tumors, but few data are currently available concerning its role in thyroid cancer. In this study we quantitatively explored a series of 51 paired-normal and papillary thyroid carcinoma (PTC) tissues for AHR-related genes. We identified an increased AHR expression/activity in PTC, independently from its nuclear dimerization partner and repressor but strictly related to a constitutive active MAPK/ERK pathway. The AHR up-regulation followed by an increased expression of AHR target genes was confirmed by a meta-analysis of published microarray data, suggesting a ligand-independent active AHR pathway in PTC. In-vitro studies using a PTC-derived cell line (BCPAP) and HEK293 cells showed that BRAF(V600E) may directly modulate AHR localization, induce AHR expression and activity in an exogenous ligand-independent manner. The AHR pathway might represent a potential novel therapeutic target for PTC in the clinical practice

Mutations in the aryl hydrocarbon receptor interacting protein gene are not highly prevalent among subjects with sporadic pituitary adenomas.

CONTEXT: Limited screening suggests that three germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene are not involved in sporadic pituitary tumorigenesis. Multiple novel mutations of this gene have since been identified in familial isolated pituitary adenoma cohorts. OBJECTIVE: The objective of the study was to undertake full AIP coding sequence screening to assess for the presence of germline and somatic mutations in European Union subjects with sporadic pituitary tumors. DESIGN: The study design was the analysis of DNA from peripheral blood lymphocytes and analysis of exons 1-6 and paraexonic intron sequences of AIP. Multiplex ligation-dependent probe amplification was used to screen separate sporadic pituitary tumor tissue samples for discrete and extensive deletions or mutations of the AIP gene. Setting: The study was conducted in university tertiary referral Clinical Genetics, Molecular Biology, and Endocrinology Departments. RESULTS: In 107 patients [prolactinomas (n =49), nonfunctioning tumors (n = 29), somatotropinomas (n = 26), ACTH-secreting tumors (n = 2), TSH-secreting tumors (n = 1)], no germline mutations of AIP were demonstrated. Among a group of 41 tumor samples from other subjects, a novel AIP mutation (R22X) was found in one sample in which the corresponding allele was deleted; follow-up screening of the patient demonstrated a germline R22X AIP mutation. CONCLUSIONS: AIP mutations do not appear to play a prominent role in sporadic pituitary tumorigenesis in this population of European subjects

Online consultations in mental healthcare: Modelling determinants of use and experience based on an international survey study at the onset of the pandemic

Introduction: While online consultations have shown promise to be a means for the effective delivery of high -quality mental healthcare and the first implementations of these digital therapeutic contacts go back nearly two decades, uptake has remained limited over the years. The onset of the COVID-19 pandemic dramatically altered this relative standstill and created a unique turning point, with a massive amount of both professionals and clients having first hands-on experiences with technology in mental healthcare.Objective: The current study aimed to document the uptake of online consultations and explore if specific characteristics of mental health professionals across and beyond Europe could predict this.Methods: An international survey was designed to assess mental health professionals' (initial) experiences with online consultations at the onset of the pandemic: their willingness to make use of them and their prior and current experiences, alongside several personal characteristics. Logistic mixed-effects models were used to identify predictors of the use of online consultations, personal experience with this modality, and the sense of telepresence.Results: A total of 9115 healthcare professionals from 73 countries participated of which about two-thirds used online consultations during the initial COVID-19 outbreak. The current study identifies multiple determinants relating to the use and experience of online consultations, including the professionals' age, experience with the technology before the outbreak, the professional context, and training.Conclusions: Despite strong evidence supporting the relevance of training in digital mental health, this is clearly still lacking. Nevertheless, the COVID-19 pandemic presented a first, and potentially transformative, experience with online consultations for many healthcare professionals. The insights from this study can help supportprofessionals and, importantly, (mental) healthcare organisations to create optimal circumstances for selective and high-quality continued use of online consultations

The evidence-based role of catecholaminergic PET tracers in Neuroblastoma. A systematic review and a head-to-head comparison with mIBG scintigraphy

Background: Molecular imaging is pivotal in staging and response assessment of children with neuroblastoma (NB). [123I]-metaiodobenzylguanidine (mIBG) is the standard imaging method; however, it is characterised by low spatial resolution, time-consuming acquisition procedures and difficult interpretation. Many PET catecholaminergic radiotracers have been proposed as a replacement for [123I]-mIBG, however they have not yet made it into clinical practice. We aimed to review the available literature comparing head-to-head [123I]-mIBG with the most common PET catecholaminergic radiopharmaceuticals. Methods: We searched the PubMed database for studies performing a head-to-head comparison between [123I]-mIBG and PET radiopharmaceuticals including meta-hydroxyephedrine ([11C]C-HED), 18F-18F-3,4-dihydroxyphenylalanine ([18F]DOPA) [124I]mIBG and Meta-[18F]fluorobenzylguanidine ([18F]mFBG). Review articles, preclinical studies, small case series (< 5 subjects), case reports, and articles not in English were excluded. From each study, the following characteristics were extracted: bibliographic information, technical parameters, and the sensitivity of the procedure according to a patient-based analysis (PBA) and a lesion-based analysis (LBA). Results: Ten studies were selected: two regarding [11C]C-HED, four [18F]DOPA, one [124I]mIBG, and three [18F]mFBG. These studies included 181 patients (range 5-46). For the PBA, the superiority of the PET method was reported in two out of ten studies (both using [18F]DOPA). For LBA, PET detected significantly more lesions than scintigraphy in seven out of ten studies. Conclusions: PET/CT using catecholaminergic tracers shows superior diagnostic performance than mIBG scintigraphy. However, it is still unknown if such superiority can influence clinical decision-making. Nonetheless, the PET examination appears promising for clinical practice as it offers faster image acquisition, less need for sedation, and a single-day examination

Cytokine dysregulation despite immunoglobulin replacement therapy in common variable immunodeficiency (CVID)

IntroductionCommon variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency. CVID is a heterogeneous disorder with a presumed multifactorial etiology. Intravenous or subcutaneous immunoglobulin replacement therapy (IgRT) can prevent severe infections but not underlying immune dysregulation.MethodsIn this study, we evaluated the serum concentrations of proinflammatory (TNF-α, IL-1β, IL-6) and immunoregulatory cytokines (IL-10), as well as lipopolysaccharide (LPS) and soluble CD14 (sCD14) in CVID individuals with infectious only (INF-CVID), and those with additional systemic autoimmune and inflammatory disorders (NIC-CVID), and healthy donors (HD).ResultsOur results showed increased serum concentrations of TNF-α, IL-1β, IL-6, and IL-10 in both INF-CVID and NIC-CVID subjects compared to HD. However, elevations of TNF-α, IL-1β, IL-6, and IL-10 were significantly more marked in NIC-CVID than INF-CVID. Additionally, LPS concentrations were increased only in NIC-CVID but not in INF-CVID compared to HD. Circulating levels of sCD14 were significantly increased in NIC-CVID compared to both INF-CVID and HD.DiscussionThese findings indicate persistent cytokine dysregulation despite IgRT in individuals with CVID. Moreover, the circulating cytokine profile reveals the heterogeneity of immune dysregulation in different subgroups of CVID subjects

CSpritz: accurate prediction of protein disorder segments with annotation for homology, secondary structure and linear motifs

CSpritz is a web server for the prediction of intrinsic protein disorder. It is a combination of previous Spritz with two novel orthogonal systems developed by our group (Punch and ESpritz). Punch is based on sequence and structural templates trained with support vector machines. ESpritz is an efficient single sequence method based on bidirectional recursive neural networks. Spritz was extended to filter predictions based on structural homologues. After extensive testing, predictions are combined by averaging their probabilities. The CSpritz website can elaborate single or multiple predictions for either short or long disorder. The server provides a global output page, for download and simultaneous statistics of all predictions. Links are provided to each individual protein where the amino acid sequence and disorder prediction are displayed along with statistics for the individual protein. As a novel feature, CSpritz provides information about structural homologues as well as secondary structure and short functional linear motifs in each disordered segment. Benchmarking was performed on the very recent CASP9 data, where CSpritz would have ranked consistently well with a Sw measure of 49.27 and AUC of 0.828. The server, together with help and methods pages including examples, are freely available at URL: http://protein.bio.unipd.it/cspritz/

2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy.

Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment Study (COGS) initiative. We carry out replication using Asian COGS samples (n=522, 53 events) and the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study (n=315, 108 events). Rs4458204_A near CCL20 (2q36.3) is found to be associated with breast cancer-specific death at a genome-wide significant level (n=2,641, 440 events, combined allelic hazard ratio (HR)=1.81 (1.49-2.19); P for trend=1.90 × 10(-9)). Such survival-associated variants can represent ideal targets for tailored therapeutics, and may also enhance our current prognostic prediction capabilities

2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy

Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment Study (COGS) initiative. We carry out replication using Asian COGS samples (n=522, 53 events) and the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study (n=315, 108 events). Rs4458204-A near CCL20 (2q36.3) is found to be associated with breast cancer-specific death at a genome-wide significant level (n=2,641, 440 events, combined allelic hazard ratio (HR)=1.81 (1.49-2.19); P for trend=1.90 × 10 â ̂'9). Such survival-associated variants can represent ideal targets for tailored therapeutics, and may also enhance our current prognostic prediction capabilities