Combination therapy with oral treprostinil for pulmonary arterial hypertension. A double-blind placebo-controlled clinical trial

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy. Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response. Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56–0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro–brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil–assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12–60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting. Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening. Clinical trial registered with www.clinicaltrials.gov (NCT01560624)

'I'm not going to tell you cos you need to think about this': A conversation analysis study of managing advice resistance and supporting autonomy in undergraduate supervision

This is an accepted manuscript of an article published by Springer in Postdigital Science and Education, available online at: https://doi.org/10.1007/s42438-020-00194-5 The accepted version of the publication may differ from the final published version.This article firstly, critically analyses a face-to-face supervision meeting between an undergraduate and a supervisor, exploring how the supervisor handles the twin strategies of fostering autonomy while managing resistance to advice. Conversation Analysis is used as both a theory and a method, with a focus on the use of accounts to support or resist advice. The main contribution is the demonstration of how both the supervisor and student are jointly responsible for the negotiation of advice, which is recycled and calibrated in response to the student’s resistance. The supervisor defuses complaints by normalising them, and moving his student on to practical solutions, often with humour. He lists his student’s achievements as the foundation on which she can assert agency and build the actions he recommends. Supervisor-student relationships are investigated through the lens of the affective dimensions of learning, to explore how caring or empathy may serve to reduce resistance and make advice more palatable. By juxtaposing physically present supervision with digitally-mediated encounters, while acknowledging their mutual entanglement, the postdigital debate is furthered. In the context of Covid-19, and rapid decisions by universities to bring in digital platforms to capture student-teacher interactions, the analysis presented is in itself an act of resistance against the technical control systems of the academy and algorithmic capitalism

Irish post-primary students' attitudes towards ethnic minorities

The changing ethnic make-up of Irish society has impacted upon schools. Existing, largely qualitative studies have highlighted mixed attitudes towards ethnic minorities. Literature has also focused on the role of the state in articulating a discourse that shapes school-level responses to minorities. This paper critiques the idea of a unitary state discourse and the role of other educational bodies, such as schools, in drawing upon a range of alternate public discourses to shape how they act, is identified. Drawing upon a large quantitative study involving 4970 post-primary pupil respondents, this paper finds that many Irish post-primary students report low levels of social distance from Black African Immigrants, Muslims and Eastern Europeans. Negative attitudes are most prevalent with respect to members of the Travelling community. The potential positive impact of school-level programmes – such as those related to global justice and inequalities – is identified through the lower levels of negative attitudes towards ethnic minorities reported by Transition Year students who have experienced such programmes

Histone H2AX and Fanconi anemia FANCD2 function in the same pathway to maintain chromosome stability

Fanconi anemia (FA) is a chromosome fragility syndrome characterized by bone marrow failure and cancer susceptibility. The central FA protein FANCD2 is known to relocate to chromatin upon DNA damage in a poorly understood process. Here, we have induced subnuclear accumulation of DNA damage to prove that histone H2AX is a novel component of the FA/BRCA pathway in response to stalled replication forks. Analyses of cells from H2AX knockout mice or expressing a nonphosphorylable H2AX (H2AX(S136A/S139A)) indicate that phosphorylated H2AX (γH2AX) is required for recruiting FANCD2 to chromatin at stalled replication forks. FANCD2 binding to γH2AX is BRCA1-dependent and cells deficient or depleted of H2AX show an FA-like phenotype, including an excess of chromatid-type chromosomal aberrations and hypersensitivity to MMC. This MMC hypersensitivity of H2AX-deficient cells is not further increased by depleting FANCD2, indicating that H2AX and FANCD2 function in the same pathway in response to DNA damage-induced replication blockage. Consequently, histone H2AX is functionally connected to the FA/BRCA pathway to resolve stalled replication forks and prevent chromosome instability

Death to the bad buys: Targeting cancer via Apo2L/TRAIL

The original publication can be found at www.springerlink.comAll higher organisms consist of an ordered society of individual cells that must communicate to maintain and regulate their functions. This is achieved through a complex but highly regulated network of hormones, chemical mediators, chemokines and other cytokines, acting as ligands for intra or extra-cellular receptors. Ligands and receptors of the tumor necrosis factor (TNF) superfamilies are examples of signal transducers, whose integrated actions influence the development, homeostasis and adaptive responses of many cells and tissue types. Apo2L/TRAIL is one of several members of the tumour necrosis factor superfamily that induce apoptosis through the engagement of death receptors. Apo2L/TRAIL interacts with an unusually complex receptor system, which in humans comprises two death receptors and three decoy receptors. This molecule has received considerable attention recently because of the finding that many cancer cell types are sensitive to Apo2L/TRAIL-induced apoptosis, while most normal cells appear to be resistant to this action of Apo2L/TRAIL. In this review, we specifically emphasise on the actions of Apo2L/TRAIL with respect to its apoptotic signaling pathways and summarise what is known about its physiological role. The potential therapeutic usefulness of Apo2L/TRAIL, especially in combination with chemotherapeutic agents, is also discussed in some detail.S. Bouralexis, D. M. Findlay and A. Evdokio