Johnston Press and the Crisis in Ireland's Local Newspaper Industry, 2005-2014

Reflecting international trends, Ireland’s local newspaper industry has suffered steep circulation and advertising revenue falls since the late-2000s, and has struggled to reshape traditional business models for the digital era. In harsh trading conditions, local titles are operating on reduced editorial resources and are weakened in their capacity to fulfil their traditional watchdog and informed-citizenry functions. Perhaps no company better encapsulates the industry’s recent difficulties than UK media group Johnston Press. In 2005, it paid more than €200m to acquire fourteen local titles in Ireland, but nine years later sold them for just €8.5m. The article draws on this case-study to consider wider issues related to the corporatisation of local news provision, the sustainability of local news industries in small media markets such as Ireland’s, and the increasing disconnect between local journalism’s commodity value and its public good value

Trends and predictors of transmitted drug resistance (TDR) and clusters with TDR in a local Belgian HIV-1 epidemic

We aimed to study epidemic trends and predictors for transmitted drug resistance (TDR) in our region, its clinical impact and its association with transmission clusters. We included 778 patients from the AIDS Reference Center in Leuven (Belgium) diagnosed from 1998 to 2012. Resistance testing was performed using population-based sequencing and TDR was estimated using the WHO-2009 surveillance list. Phylogenetic analysis was performed using maximum likelihood and Bayesian techniques. The cohort was predominantly Belgian (58.4%), men who have sex with men (MSM) (42.8%), and chronically infected (86.5%). The overall TDR prevalence was 9.6% (95% confidence interval (CI): 7.7-11.9), 6.5% (CI: 5.0-8.5) for nucleoside reverse transcriptase inhibitors (NRTI), 2.2% (CI: 1.4-3.5) for non-NRTI (NNRTI), and 2.2% (CI: 1.4-3.5) for protease inhibitors. A significant parabolic trend of NNRTI-TDR was found (p = 0.019). Factors significantly associated with TDR in univariate analysis were male gender, Belgian origin, MSM, recent infection, transmission clusters and subtype B, while multivariate and Bayesian network analysis singled out subtype B as the most predictive factor of TDR. Subtype B was related with transmission clusters with TDR that included 42.6% of the TDR patients. Thanks to resistance testing, 83% of the patients with TDR who started therapy had undetectable viral load whereas half of the patients would likely have received a suboptimal therapy without this test. In conclusion, TDR remained stable and a NNRTI up-and-down trend was observed. While the presence of clusters with TDR is worrying, we could not identify an independent, non-sequence based predictor for TDR or transmission clusters with TDR that could help with guidelines or public health measures

Radiotherapeutic alternatives for previously irradiated recurrent gliomas

Re-irradiation for recurrent gliomas has been discussed controversially in the past. This was mainly due to only marginal palliation while being associated with a high risk for side effects using conventional radiotherapy

Like Frying Multiple Eggs in One Pan: a Qualitative Study Exploring the Understanding of Inter-speciality Training in Cancer Care

High-quality cancer care is a key priority worldwide. Caring for people affected by cancer requires a range of specific knowledge, skills and experience to deliver the complex care regimens both within the hospital and within the community environment. In June 2022, the European Cancer Organisation along with 33 European cancer societies began working together to develop a curriculum for inter-speciality training for healthcare professionals across Europe. As part of the project, this research consisted of a qualitative survey distributed to the European Union societies via email. The aim of this paper is to disseminate the qualitative findings from healthcare professionals across Europe. Questionnaires were sent out to a convenience sample of 219 healthcare professionals and patient advocates with a response rate of 55% (n = 115). The findings identified that there were four key themes: 'What is inter-speciality training?', 'Barriers and challenges', 'Support throughout the cancer journey' and 'New ways of working'. These results are part of a larger needs analysis and scoping review to inform the development of a core competency framework which will be part of an inter-speciality curriculum for specialist cancer doctors, nurses and other healthcare professionals across Europe. Healthcare professionals will be able to access education and training through the virtual learning environment and workshops and by clinical rotations to other specialties

Alzheimer's Disease-Linked Mutations in Presenilin-1 Result in a Drastic Loss of Activity in Purified γ-Secretase Complexes

BACKGROUND: Mutations linked to early onset, familial forms of Alzheimer's disease (FAD) are found most frequently in PSEN1, the gene encoding presenilin-1 (PS1). Together with nicastrin (NCT), anterior pharynx-defective protein 1 (APH1), and presenilin enhancer 2 (PEN2), the catalytic subunit PS1 constitutes the core of the γ-secretase complex and contributes to the proteolysis of the amyloid precursor protein (APP) into amyloid-beta (Aβ) peptides. Although there is a growing consensus that FAD-linked PS1 mutations affect Aβ production by enhancing the Aβ1-42/Aβ1-40 ratio, it remains unclear whether and how they affect the generation of APP intracellular domain (AICD). Moreover, controversy exists as to how PS1 mutations exert their effects in different experimental systems, by either increasing Aβ1-42 production, decreasing Aβ1-40 production, or both. Because it could be explained by the heterogeneity in the composition of γ-secretase, we purified to homogeneity complexes made of human NCT, APH1aL, PEN2, and the pathogenic PS1 mutants L166P, ΔE9, or P436Q. METHODOLOGY/PRINCIPAL FINDINGS: We took advantage of a mouse embryonic fibroblast cell line lacking PS1 and PS2 to generate different stable cell lines overexpressing human γ-secretase complexes with different FAD-linked PS1 mutations. A multi-step affinity purification procedure was used to isolate semi-purified or highly purified γ-secretase complexes. The functional characterization of these complexes revealed that all PS1 FAD-linked mutations caused a loss of γ-secretase activity phenotype, in terms of Aβ1-40, Aβ1-42 and APP intracellular domain productions in vitro. CONCLUSION/SIGNIFICANCE: Our data support the view that PS1 mutations lead to a strong γ-secretase loss-of-function phenotype and an increased Aβ1-42/Aβ1-40 ratio, two mechanisms that are potentially involved in the pathogenesis of Alzheimer's disease

Doctors under the microscope: the birth of medical audit

In 1989 a UK government White Paper introduced medical audit as a comprehensive and statutory system of assessment and improvement in quality of care in hospitals. A considerable body of research has described the evolution of medical audit in terms of a struggle between doctors and National Health Service managers over control of quality assurance. In this paper we examine the emergence of medical audit from 1910 to the early 1950s, with a particular focus on the pioneering work of the American surgeons Codman, MacEachern and Ponton. It is contended that medical professionals initially created medical audit in order to articulate a suitable methodology for assessing individual and organisational performance. Rather than a means of protecting the medical profession from public scrutiny, medical auditing was conceived and operationalised as a managerial tool for fostering the active engagement of senior hospital managers and discharging public accountability. These early debates reveal how accounting was implicated in the development of a system for monitoring and improving the work of medical professionals, advancing the quality of hospital care, and was advocated in ways, which included rather than excluded managers

Cardiac and vascular structure and function parameters do not improve with alternate nightly home hemodialysis: An interventional cohort study

Background: Nightly extended hours hemodialysis may improve left ventricular hypertrophy and function and endothelial function but presents problems of sustainability and increased cost. The effect of alternate nightly home hemodialysis (NHD) on cardiovascular structure and function is not known

RegaDB: Community-driven data management and analysis for infectious diseases

Summary: RegaDB is a free and open source data management and analysis environment for infectious diseases. RegaDB allows clinicians to store, manage and analyse patient data, including viral genetic sequences. Moreover, RegaDB pr

Mutations in or near the Transmembrane Domain Alter PMEL Amyloid Formation from Functional to Pathogenic

PMEL is a pigment cell-specific protein that forms physiological amyloid fibrils upon which melanins ultimately deposit in the lumen of the pigment organelle, the melanosome. Whereas hypomorphic PMEL mutations in several species result in a mild pigment dilution that is inherited in a recessive manner, PMEL alleles found in the Dominant white (DW) chicken and Silver horse (HoSi)—which bear mutations that alter the PMEL transmembrane domain (TMD) and that are thus outside the amyloid core—are associated with a striking loss of pigmentation that is inherited in a dominant fashion. Here we show that the DW and HoSi mutations alter PMEL TMD oligomerization and/or association with membranes, with consequent formation of aberrantly packed fibrils. The aberrant fibrils are associated with a loss of pigmentation in cultured melanocytes, suggesting that they inhibit melanin production and/or melanosome integrity. A secondary mutation in the Smoky chicken, which reverts the dominant DW phenotype, prevents the accumulation of PMEL in fibrillogenic compartments and thus averts DW–associated pigment loss; a secondary mutation found in the Dun chicken likely dampens a HoSi–like dominant mutation in a similar manner. We propose that the DW and HoSi mutations alter the normally benign amyloid to a pathogenic form that antagonizes melanosome function, and that the secondary mutations found in the Smoky and Dun chickens revert or dampen pathogenicity by functioning as null alleles, thus preventing the formation of aberrant fibrils. We speculate that PMEL mutations can model the conversion between physiological and pathological amyloid

Intrafraction motion of the prostate during an IMRT session: a fiducial-based 3D measurement with Cone-beam CT

Background: Image-guidance systems allow accurate interfractional repositioning of IMRT treatments, however, these may require up to 15 minutes. Therefore intrafraction motion might have an impact on treatment precision. 3D geometric data regarding intrafraction prostate motion are rare; we therefore assessed its magnitude with pre- and post-treatment fiducial-based imaging with cone-beam-CT (CBCT). Methods: 39 IMRT fractions in 5 prostate cancer patients after (125)I-seed implantation were evaluated. Patient position was corrected based on the (125)I-seeds after pre-treatment CBCT. Immediately after treatment delivery, a second CBCT was performed. Differences in bone- and fiducial position were measured by seed-based grey-value matching. Results: Fraction time was 13.6 +/- 1.6 minutes. Median overall displacement vector length of (125)Iseeds was 3 mm (M = 3 mm, Sigma = 0.9 mm, sigma = 1.7 mm; M: group systematic error, Sigma: SD of systematic error, sigma: SD of random error). Median displacement vector of bony structures was 1.84 mm (M = 2.9 mm, Sigma = 1 mm, sigma = 3.2 mm). Median displacement vector length of the prostate relative to bony structures was 1.9 mm (M = 3 mm, Sigma = 1.3 mm, sigma = 2.6 mm). Conclusion: a) Overall displacement vector length during an IMRT session is < 3 mm. b) Positioning devices reducing intrafraction bony displacements can further reduce overall intrafraction motion. c) Intrafraction prostate motion relative to bony structures is < 2 mm and may be further reduced by institutional protocols and reduction of IMRT duration