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Prospective evaluation of the cardiovascular effects of BRAF and MEK inhibitors in patients with melanoma
No full textBACKGROUND Rapidly accelerated fibrosarcoma B-type (BRAF) and MEK inhibitors have revolutionized outcomes for
patients with BRAF-mutated melanoma. However, they are associated with cardiovascular adverse effects. The realworld incidence and risk factors for these effects are poorly described.
OBJECTIVES The aim of this study was to characterize the incidence and risk factors for BRAF inhibitor– and MEK
inhibitor–associated hypertension and cancer therapy–related cardiac dysfunction (CTRCD) in a real-world setting.
METHODS A prospective, longitudinal, cohort study was undertaken among patients with melanoma treated with
BRAF and MEK inhibitors in a regional cancer network (March 2021 to March 2023). Baseline cardiotoxicity risk stratification was assessed using the European Society of Cardiology cardio-oncology guideline–recommended tool.
Comprehensive cardiovascular assessment was performed at baseline and at 4, 12, and 24 weeks, including home and
clinic blood pressure, echocardiography, stress perfusion cardiovascular magnetic resonance imaging and blood biomarkers. CTRCD was defined using International Cardio-Oncology Society definitions.
RESULTS A total of 61 participants were enrolled. Twenty-eight participants (45.9%) developed hypertension and
45.9% developed CTRCD: 24 (85.7%) mild, 3 (10.7%) moderate, and 1 (3.6%) severe. All moderate or severe CTRCD was
evident by 4 weeks and at least partially reversible. No patient at low baseline risk developed moderate or severe
CTRCD. Patients with CTRCD had higher median baseline N-terminal pro–B-type natriuretic peptide compared with those
without (109 pg/mL [Q1-Q3: 51-380 pg/mL] vs 54 pg/mL [Q1-Q3: 29-149 pg/mL]; P = 0.047). There were no robust
associations between hypertension nor cardiovascular magnetic resonance imaging–derived myocardial or perfusion
characteristics and incident CTRCD.
CONCLUSIONS BRAF inhibitor– and MEK inhibitor–associated hypertension and CTRCDare common. The presentresults
reinforce the utility of baseline cardiotoxicity risk stratification, including assessment of N-terminal pro–B-type natriuretic
peptide. Future guidelines should consider recommending early surveillance echocardiography for higher risk patients
Revolutionising geothermal heat extraction from abandoned mines for a sustainable energy future
No full textNo abstract available
The Impact of Different Mining Techniques on the Geothermal Potential of Abandoned Coal Mines
No full textAbandoned and flooded coal mines have a huge geothermal potential. By circulating mine water and extracting its heat, it can provide a renewable, low-carbon low-enthalpy heat source for domestic and industrial purposes. But capital costs from drilling into those mine workings are significant, and investigating the geothermal potential of a mine system prior to drilling are essential for the success of any mine water geothermal energy (MWGE) system. Numerical modelling provides a quick and low-cost methodology to assess the feasibility of a planned MWGE system, for example to determine optimal mine water abstraction and re-injection sites.
Past coal mining was typically done using two different mining techniques. 1) The room-and-pillar (also referred to as pillar-and-stall) method was used to mine coal through digging tunnels (galleries and roadways), leaving pillars of coal untouched to prevent collapse of the coal seam. 2) The long-wall mining technique used machines to extract the entire coal seam, and allowed collapse in a controlled manner, thereby creating a porous layer of rubble referred to as ‘goaf’. Often both techniques were used within a single mine system. These two techniques result in very different remnant mine geometries, and it is important to address these differences in any MWGE modelling attempt.
We have developed a computationally fast and flexible modelling tool GEMSToolbox to assess the feasibility of mine workings as MWGE system by combining numerical and (semi-)analytical methods. The tool accounts for both room-and-pillar and long-wall mining techniques. In this study, we investigate the geothermal effects of both techniques for mines that are entirely constructed through one technique only, and for mines that combine the two techniques. Both techniques suffer from significant uncertainties in the effective model parameters: e.g. mine galleries may have collapsed since the mine closure, while for goaf, the effective porosity and hydraulic transmissivity are poorly constrained. Furthermore, in mine systems where both techniques were applied, water preferentially flows through the galleries, which potentially makes heat extraction from the goaf areas less efficient. The results of this study are applied to a real-world mine block in the North East of England
Emergence of SARS-CoV-2 subgenomic RNAs that enhance viral fitness and immune evasion
Get PDFCoronaviruses express their structural and accessory genes via a set of subgenomic RNAs, whose synthesis is directed by transcription regulatory sequences (TRSs) in the 5′ genomic leader and upstream of each body open reading frame. In SARS-CoV-2, the TRS has the consensus AAACGAAC; upon searching for emergence of this motif in the global SARS-CoV-2 sequences, we find that it evolves frequently, especially in the 3′ end of the genome. We show well-supported examples upstream of the Spike gene—within the nsp16 coding region of ORF1b—which is expressed during human infection, and upstream of the canonical Envelope gene TRS, both of which have evolved convergently in multiple lineages. The most frequent neo-TRS is within the coding region of the Nucleocapsid gene, and is present in virtually all viruses from the B.1.1 lineage, including the variants of concern Alpha, Gamma, Omicron and descendants thereof. Here, we demonstrate that this TRS leads to the expression of a novel subgenomic mRNA encoding a truncated C-terminal portion of Nucleocapsid, which is an antagonist of type I interferon production and contributes to viral fitness during infection. We observe distinct phenotypes when the Nucleocapsid coding sequence is mutated compared to when the TRS alone is ablated. Our findings demonstrate that SARS-CoV-2 is undergoing evolutionary changes at the functional RNA level in addition to the amino acid level
Species-specific behaviour and environmental drivers of trap interactions in wild ornamental fishes
No full textThe harvest of animals from the wild is a pervasive selective force, especially in fisheries, where harvesting often targets individuals with specific traits. While most research has focused on large-scale commercial or recreational fisheries, little attention has been paid to artisanal fisheries, particularly those targeting ornamental species. Furthermore, environmental factors such as temperature and oxygen levels influence the behaviour of fishes, such as boldness and sociability, but their role in the harvesting process remains poorly understood. Here, we used underwater video to examine how two ornamental Amazonian fishes, Hemigrammus sp. and Copella nattereri, interact with artisanal trap gear. We quantified the number of passes, inspections, entries and exits using latency to inspect and enter traps as proxies for boldness, and coefficients of dispersion (CDs) to assess sociability and group coordination. We found that the majority of fish that inspected traps did not enter them, and a given trap typically caught one species over the other. Overall, Copella were captured more frequently, but within individual trials there was no statistical difference in catch numbers between species. While both species inspected traps, Hemigrammus exhibited significantly more passes and a higher rate of inspection. Latency to inspect and enter traps did not differ between species but decreased with increasing temperature for both. Hemigrammus also displayed greater group coordination, with higher CD values across behaviours. Notably, temperature had opposing effects on coordination: for Hemigrammus, CD of inspections increased with temperature and CD of exits decreased, whereas for Copella, inspection CD decreased and exit CD increased. These findings reveal that different species interact with fishing gear in behaviourally distinct ways, influenced by environmental conditions. This highlights the potential for selective pressures to vary not only by species, but also with ecological context. Understanding such dynamics is critical for predicting how artisanal fisheries may shape behavioural traits in wild populations
Exploring young people’s experiences of a text-based support service: a qualitative analysis of the support that young people think is important in a suicidal crisis
No full textSuicide is a global health priority. In the UK, suicidal ideation is highest in young people. Therefore, it is vital that suicide prevention resources, such as support services, are suited to young people to support their wellbeing. Therefore, this study aimed to explore young people’s experiences of using Shout, a UK text-based support service, when experiencing suicidal thoughts. Ten participants (18–25 years old) were recruited to the study. During each interview, participant demographic and health information were collected, followed by an audio recorded, semi-structured interview. Interviews explored participants’ most recent experience of contacting Shout in response to thoughts of suicide. Qualitative data were analysed using Interpretative Phenomenological Analysis and three overarching themes were identified: service availability, receiving a person-centred approach and solution-focused support. Together, these themes indicate that young people value timely, personable support from text-based support services where proactive solutions for the future are identified collaboratively. This study adds to the research landscape on digital suicide prevention highlighting the importance of text-based support services conveying hope and a solutions-focused approach when supporting young people experiencing distress
Old orogen–young topography: lithological contrasts controlling erosion and relief formation in the Bohemian Massif
Get PDFIn several low mountain ranges throughout Europe, high-grade metamorphic and granitic rocks of the Variscan orogen are exposed – even though the topography of this Paleozoic mountain range was largely leveled during the Permian and later covered by sediments. The Bohemian Massif is one of these low mountain ranges and consists of high-grade metamorphic and magmatic rocks that dip southward below the weakly consolidated Neogene sediments of the Alpine Molasse Basin. Morphologically, the Bohemian Massif is characterized by rolling hills and extensive low-relief surfaces above 500 m, which contrast with deeply incised canyons characterized by steep and morphologically active valley flanks. These morphological features and the occurrence of marine sediments several hundred meters above sea level are a clear indication of relief rejuvenation due to significant surface uplift during the last few million years.
To constrain landscape change and its rate, we used the concentration of cosmogenic 10Be in river sands to determine 20 catchment-wide erosion rates and correlated these with topographic metrics characterizing both the hillslopes and the drainage systems. Erosion rates range from 22 to 51 m Myr−1, which is generally low compared to tectonically active mountain ranges such as the Alps. Low erosion rates in the Bohemian Massif seem to contradict the steep topography observed close to the receiving streams (i.e., the Danube River and the Vltava River), which have morphological characteristics of alpine landscapes. We found that erosion rate is correlated with catchment-wide topographic metrics, representing both hillslope and channel morphology. Highest erosion rates occur in catchments featuring high channel steepness and a large area fraction with significant geophysical relief. Catchments with abundant deeply incised canyons erode about twice as fast as those characterized primarily by elevated low-relief surfaces.
We interpret the measured erosion rates and related topographic patterns as the landscape response to slow and large-scale uplift in concert with strong variations in bedrock erodibility between rocks of the Bohemian Massif and the Neogene Molasse Basin. We propose that lithology is ultimately responsible for the topographic difference between the mountainous Bohemian Massif and the low-relief Molasse zone despite a common uplift history during the last few million years. As erosion progresses, the basement rocks with their high resistance to erosion are exposed. The repeated emergence of such bedrock barriers reduces the erosion rate during topographic adjustment and governs the evolution of elevated low-relief surfaces at different elevation levels. The resulting stepped landscape requires neither spatial nor temporal changes in uplift rate but can form by erodibility contrasts under uniform uplift conditions
Drawing boundaries, building legitimacy: a revamped view of market definition
No full textThis piece pitches an idea on market definition: that establishing the scope of a “market” could be used to evidence the legitimacy of competition law enforcement. This piece refutes the suggestion that market definition should be abandoned. Instead, by connecting competition law’s enforcement to the “market,” competition authorities could show that competition law is enforced in line with its purpose, reinforcing the internal coherence of the law and distinguishing competition law from other areas of law which may apply to the same actors and conduct. At a time when the competences of competition authorities are contested, the reference to the “relevant market” as representation of the collective interest may be a way to justify the applicability of competition law
Ambiguity and dilution in Kazakhstan's Gulag heritage
Get PDFKazakhstan is the location of some of the most important Gulag heritage from the Soviet period of domination. However, commemoration, conservation and interpretation of Gulag sites is at best partial, visitation low and the attitude to this element of Kazakh history is ambiguous. This paper considers key heritage sites and museums in Kazakhstan and a qualitative case study approach is adopted based on a combination of interviews with twenty-four key stakeholders involved in the development and operation of Gulag tourism. Direct observations and qualitative document analysis of the major national Gulag museums and other important Gulag heritage sites was also undertaken. This research questions the orthodoxy inherent in the supposed attraction of dark tourism sites and seeks to ascertain why domestic and international visitation remains low given the scale and importance of the Gulag narrative
How do informal international organizations promote the Sustainable Development Goals through orchestration?
No full textInformal intergovernmental organizations (IIGOs), such as G20, G7, and BRICS, have become increasingly pivotal actors in global governance. By implication, they are afforded a key role in advancing the Sustainable Development Goals (SDGs). Without a permanent secretariat, however, IIGOs govern through orchestration, relying heavily on intermediary organizations. For instance, the G20 frequently enlists the OECD to provide analytical support and to implement its Action Plan on the 2030 Agenda for Sustainable Development. This article examines the dynamics between informal and formal international organizations, exploring how IIGOs choose specific intermediaries. Using the case of the G20 and a mixed-method approach, I examine how IIGOs select intermediaries to promote the SDGs. To do so, I extend Downie's (2022b) G20 orchestration dataset, providing a more comprehensive resource for global governance studies. I find that the G20 considers both goal alignment and the focality of the intermediaries, favoring intermediaries with common members and greater public attention. By shedding light on IIGO–intermediary dynamics, this research enhances understanding of institutional interactions within hybrid institutional complexes (HICs) and provides insights for strengthening international cooperation, which are particularly important to facilitating sustainable development
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