Chemical characteristics of macroscopic pyrogenic carbon following millennial-scale environmental exposure

Pyrogenic Carbon (PyC) is ubiquitous in global environments, and is now known to form a significant, and dynamic component of the global carbon cycle, with at least some forms of PyC persisting in their depositional environment for many millennia. Despite this, the factors that determine the turnover of PyC remain poorly understood, as do the physical and chemical changes that this material undergoes when exposed to the environment over tens of thousands of years. Here, we present the results of an investigation to address these knowledge gaps through chemical and physical analysis of a suite of wood PyC samples exposed to the environment for varying time periods, to a maximum of >90,000 years. This includes an assessment of the quantity of resistant carbon, known as Stable Polyaromatic Carbon (SPAC) versus more chemically labile carbon in the samples. We find that, although production temperature is likely to determine the initial ‘degradation potential’ of PyC, an extended exposure to environmental conditions does not necessarily mean that remaining PyC always progresses to a ‘SPAC-dominant’ state. Instead, some ancient PyC can be composed largely of chemical components typically thought of as environmentally labile, and it is likely that the depositional environment drives the trajectory of preservation versus loss of PyC over time. This has important implications for the size of global PyC stocks, which may have been underestimated, and also for the potential loss of previously stored PyC, when its depositional environment alters through environmental or climatic changes

Experiences of Establishing an Academic Early Phase Clinical Trials Unit

Background: Early phase trials are essential in drug development, determining appropriate dose levels and assessing preliminary activity. These trials are undertaken by industry and academia, with increasing collaborations between the two. There is pressure to perform these trials quickly, safely and robustly. However, there are inherent differences between developing and managing early phase, compared to late phase, drug trials. This paper describes an approach to establishing an academically-led early phase trial portfolio, highlighting lessons learned and sharing experiences. Methods: In 2009 the University of Leeds Clinical Trials Research Unit became the Clinical Trials Coordinating Office for Myeloma UK’s phase I and II trials. We embarked on a transition from working extensively in phase III to early phase trials development and conduct. This involved evaluating and revising our well-established standard operating procedures, visiting other academic early phase units, and developing essential new documentation and processes. Results: A core team of trial and data managers and statisticians was established to facilitate expertise and knowledge retention. A detailed training plan was implemented focusing on essential standard practices for early phase. These included pharmacovigilance, recruitment, trial design and set-up, data and site monitoring, and oversight committees. Training in statistical methods for early phase trials was incorporated. Conclusion: Initial scoping of early phase trial management and conduct was essential in establishing this early phase portfolio. Many of the processes developed were successful. However, regular review and evaluation were implemented to enable changes and ensure efficiencies. It is recommended that others embarking on this venture build on the experiences described in this article

A randomised phase II trial of temozolomide with or without cannabinoids in patients with recurrent glioblastoma (ARISTOCRAT):Protocol for a multi-centre, double-blind, placebo-controlled trial

BackgroundGlioblastoma (GBM) is the most common adult malignant brain tumour, with an incidence of 5 per 100,000 per year in England. Patients with tumours showing O -methylguanine-DNA methyltransferase (MGMT) promoter methylation represent around 40% of newly diagnosed GBM. Relapse/tumour recurrence is inevitable. There is no agreed standard treatment for patients with GBM, therefore, it is aimed at delaying further tumour progression and maintaining health-related quality of life (HRQoL). Limited clinical trial data exist using cannabinoids in combination with temozolomide (TMZ) in this setting, but early phase data demonstrate prolonged overall survival compared to TMZ alone, with few additional side effects. Jazz Pharmaceuticals (previously GW Pharma Ltd.) have developed nabiximols (trade name Sativex®), an oromucosal spray containing a blend of cannabis plant extracts, that we aim to assess for preliminary efficacy in patients with recurrent GBM.MethodsARISTOCRAT is a phase II, multi-centre, double-blind, placebo-controlled, randomised trial to assess cannabinoids in patients with recurrent MGMT methylated GBM who are suitable for treatment with TMZ. Patients who have relapsed ≥ 3 months after completion of initial first-line treatment will be randomised 2:1 to receive either nabiximols or placebo in combination with TMZ. The primary outcome is overall survival time defined as the time in whole days from the date of randomisation to the date of death from any cause. Secondary outcomes include overall survival at 12 months, progression-free survival time, HRQoL (using patient reported outcomes from QLQ-C30, QLQ-BN20 and EQ-5D-5L questionnaires), and adverse events.DiscussionPatients with recurrent MGMT promoter methylated GBM represent a relatively good prognosis sub-group of patients with GBM. However, their median survival remains poor and, therefore, more effective treatments are needed. The phase II design of this trial was chosen, rather than phase III, due to the lack of data currently available on cannabinoid efficacy in this setting. A randomised, double-blind, placebo-controlled trial will ensure an unbiased robust evaluation of the treatment and will allow potential expansion of recruitment into a phase III trial should the emerging phase II results warrant this development.Trial registration ISRCTN: 11460478. ClinicalTrials.Gov: NCT0562970

Dark materials: Pre-Columbian black lithic carvings from St Vincent and the wider Caribbean

A small number of pre-Columbian black lithic carvings have been found at archaeological sites across the Caribbean, as well as in parts of neighbouring mainland South America. The identity of the material used to create these artefacts is often unknown, but suggestions include lignite, wood, petrified wood, manja(c)k, jet (or ‘jet-like’ materials) and hardened asphalt. These identifications are often historical and lacking any scientific basis, and as such can be unreliable. However, identification of the material has the potential to inform on the source of the carving and thereby pre-Columbian trade routes within the circum-Caribbean region. Four analytical techniques (reflectance microscopy, FTIR, Py-GC/MS, x-ray fluorescence) were applied to samples taken from two carvings found on St Vincent and five comparative materials. Both artefacts were found to be most likely carved from cannel coal, indicating that they originated in South America (where cannel coal is found extensively in locations in Colombia and Venezuela), as the material is not found within the Caribbean region

The malaria parasite sheddase SUB2 governs host red blood cell membrane sealing at invasion.

Red blood cell (RBC) invasion by malaria merozoites involves formation of a parasitophorous vacuole into which the parasite moves. The vacuole membrane seals and pinches off behind the parasite through an unknown mechanism, enclosing the parasite within the RBC. During invasion, several parasite surface proteins are shed by a membrane-bound protease called SUB2. Here we show that genetic depletion of SUB2 abolishes shedding of a range of parasite proteins, identifying previously unrecognized SUB2 substrates. Interaction of SUB2-null merozoites with RBCs leads to either abortive invasion with rapid RBC lysis, or successful entry but developmental arrest. Selective failure to shed the most abundant SUB2 substrate, MSP1, reduces intracellular replication, whilst conditional ablation of the substrate AMA1 produces host RBC lysis. We conclude that SUB2 activity is critical for host RBC membrane sealing following parasite internalisation and for correct functioning of merozoite surface proteins

A choline-releasing glycerophosphodiesterase essential for phosphatidylcholine biosynthesis and blood stage development in the malaria parasite.

The malaria parasite Plasmodium falciparum synthesizes significant amounts of phospholipids to meet the demands of replication within red blood cells. De novo phosphatidylcholine (PC) biosynthesis via the Kennedy pathway is essential, requiring choline that is primarily sourced from host serum lysophosphatidylcholine (lysoPC). LysoPC also acts as an environmental sensor to regulate parasite sexual differentiation. Despite these critical roles for host lysoPC, the enzyme(s) involved in its breakdown to free choline for PC synthesis are unknown. Here we show that a parasite glycerophosphodiesterase (PfGDPD) is indispensable for blood stage parasite proliferation. Exogenous choline rescues growth of PfGDPD-null parasites, directly linking PfGDPD function to choline incorporation. Genetic ablation of PfGDPD reduces choline uptake from lysoPC, resulting in depletion of several PC species in the parasite, whilst purified PfGDPD releases choline from glycerophosphocholine in vitro. Our results identify PfGDPD as a choline-releasing glycerophosphodiesterase that mediates a critical step in PC biosynthesis and parasite survival

Decision-making in cancer care for people living with dementia

Objective: Increasing numbers of people are expected to live with comorbid cancer and dementia. Cancer treatment decision-making for these individuals is complex, particularly for those lacking capacity, requiring support across the cancer care pathway. There is little research to inform practice in this area. This ethnographic study reports on the cancer decision-making experiences of people with cancer and dementia, their families, and healthcare staff. Methods: Participant observations, informal conversations, semi-structured interviews, and medical note review, in two NHS trusts. Seventeen people with dementia and cancer, 22 relatives and 19 staff members participated. Results: Decision-making raised complex ethical dilemmas and challenges and raised concerns for families and staff around whether correct decisions had been made. Whose decision it was and to what extent a person with dementia and cancer was able to make decisions was complex, requiring careful and ongoing consultation and close involvement of relatives. The potential impact dementia might have on treatment understanding and toleration required additional consideration by clinicians when evaluating treatment options. Conclusions: Cancer treatment decision-making for people with dementia is challenging, should be an ongoing process and has emotional impacts for the individual, relatives, and staff. Longer, flexible, and additional appointments may be required to support decision-making by people with cancer and dementia. Evidence-based decision-making guidance on how dementia impacts cancer prognosis, treatment adherence and efficacy is required

A Global Strategy for Ecologically Sustainable Transport and other Linear Infrastructure

The current Global Strategy for Ecologically Sustainable Transport and other Linear Infrastructure primarily sets up the objectives and principles for governments and organizations for mainstreaming biodiversity and ecological connectivity on transport infrastructure development. Additionally, it addresses the overall framework of stakeholders who must be engaged as key players in: • launching proactive policies, • establishing appropriate legal frameworks, • supporting better planning, • promoting multi-sector cooperation, and • encouraging innovative science-based solutions. We consider this as a living document as future versions may integrate additional elements with regards to governance, policy, and financing, in the attempt to develop a common comprehensive language and grounds for cooperation. This “Global Strategy” has been developed by an international working group coordinated by IENE and supported by an international coalition formed from the international conferences on transport and ecology and conservation organisations as IENE, ICOET, ANET, ACLIE, WWF and IUCN. The working group is drawn from global experts in transport and ecology and aims to work towards finding a ‘win-win’ solution for securing mainstreaming biodiversity and ecological connectivity and avoiding, mitigating, or compensating ecosystems’ fragmentation during transport infrastructure development or adaptation. This Strategy builds upon five years of development of the guidelines “International Guidance for Ecologically - Friendly Linear Infrastructure (IGELI)” initiated at the ICOET 2015 conference in North Carolina, USA. IGELI was an international debate with experts from all over the world continued during workshops held at the international conferences of IENE (Lyon, France, 2016 and Eindhoven, Holland, 2018), ICOET (Salt Lake City, USA, 2017 and Sacramento, USA, 2019), IUCN (Hawaii, USA, 2016) and ACLIE (Kruger National Park, South Africa, 2019). Summarising the Decision 14/3 on mainstreaming of biodiversity in the energy and mining, infrastructure, manufacturing, and processing sectors (CBD/ COP/DEC/14/3/30 November 2018) of 14th COP CBD (Sharm El Sheikh, Egypt, Nov 2018) (Convention on Biological Diversity 2018), the international coalition of the working group, initiated to promote the Strategy at the CBD COP 15 in China. We hope, this Strategy provides a useful tool and roadmap for promoting the urgent need of supporting biodiversity conservation and securing ecological connectivity at all scales of governance, policies, planning and implementation of transport projects internationally. The creation of an International Observatory for monitoring the fragmentation status globally as an important threat for biodiversity loss is proposed as a common ambition of the working group members and their organizations.IENE, ICOET, ANET, ACLIE, WWF, IUCN, WWF, WCPA, Connectivity Conservation Specialist Grou