PEARLS - A multicentre phase II/III trial of extended field radiotherapy for androgen sensitive prostate cancer patients with PSMA-avid pelvic and/or para-aortic lymph nodes at presentation.

PEARLS is a multi-stage randomised controlled trial for prostate cancer patients with pelvic and/or para-aortic PSMA-avid lymph node disease at presentation. The aim of the trial is to determine whether extending the radiotherapy field to cover the para-aortic lymph nodes (up to L1/L2 vertebral interspace) can improve outcomes for this patient group.

An Electro-Microbial Process to Uncouple Food Production from Photosynthesis for Application in Space Exploration.

Here we propose the concept of an electro-microbial route to uncouple food production from photosynthesis, thereby enabling production of nutritious food in space without the need to grow plant-based crops. In the proposed process, carbon dioxide is fixed into ethanol using either chemical catalysis or microbial carbon fixation, and the ethanol created is used as a carbon source for yeast to synthesize food for human or animal consumption. The process depends upon technologies that can utilize electrical energy to fix carbon into ethanol and uses an optimized strain of the yeast Saccharomyces cerevisiae to produce high-quality, food-grade, single-cell protein using ethanol as the sole carbon source in a minimal medium. Crops performing photosynthesis require months to mature and are challenging to grow under the conditions found in space, whereas the electro-microbial process could generate significant quantities of food on demand with potentially high yields and productivities. In this paper we explore the potential to provide yeast-based protein and other nutrients relevant to human dietary needs using only ethanol, urea, phosphate, and inorganic salts as inputs. It should be noted that as well as having potential to provide nutrition in space, this novel approach to food production has many valuable terrestrial applications too. For example, by enabling food production in climatically challenged environments, the electro-microbial process could potentially turn deserts into food bowls. Similarly, surplus electricity generated from large-scale renewable power sources could be used to supplement the human food chain.

Eukaryogenesis: The Rise of an Emergent Superorganism.

Although it is widely taught that all modern life descended via modification from a last universal common ancestor (LUCA), this dominant paradigm is yet to provide a generally accepted explanation for the chasm in design between prokaryotic and eukaryotic cells. Counter to this dominant paradigm, the viral eukaryogenesis (VE) hypothesis proposes that the eukaryotes originated as an emergent superorganism and thus did not evolve from LUCA via descent with incremental modification. According to the VE hypothesis, the eukaryotic nucleus descends from a viral factory, the mitochondrion descends from an enslaved alpha-proteobacteria and the cytoplasm and plasma membrane descend from an archaeal host. A virus initiated the eukaryogenesis process by colonising an archaeal host to create a virocell that had its metabolism reprogrammed to support the viral factory. Subsequently, viral processes facilitated the entry of a bacterium into the archaeal cytoplasm which was also eventually reprogrammed to support the viral factory. As the viral factory increased control of the consortium, the archaeal genome was lost, the bacterial genome was greatly reduced and the viral factory eventually evolved into the nucleus. It is proposed that the interaction between these three simple components generated a superorganism whose emergent properties allowed the evolution of eukaryotic complexity. If the radical tenets of the VE hypothesis are ultimately accepted, current biological paradigms regarding viruses, cell theory, LUCA and the universal Tree of Life (ToL) should be fundamentally altered or completely abandoned.

Formalising the induction of patient and public involvement contributors on trial oversight committees.

BACKGROUND: Clinical Trials Units are encouraged to integrate Patient and Public Involvement (PPI) into all aspects of trial design, running and oversight. This research explored the induction and training of PPI Contributors joining trial oversight committees and was used to update the Medical Research Council Clinical Trials Unit at University College London's (MRC CTU at UCL) induction pack for new PPI Contributors. METHODS: Published and unpublished materials provided by other CTUs and research organisations on training for PPI Contributors on oversight committees were reviewed, with themes then triangulated to identify the most common topics covered in induction training. A face-to-face workshop with PPI Contributors from the MRC CTU at UCL reviewed a draft updated Induction Pack. Findings from these discussions were incorporated into a revised induction pack which was then re-reviewed by the workshop attendees. RESULTS: No published literature on this subject was found. However, several common themes were identified from unpublished materials. Workshop attendees agreed with most of the themes suggested in the initial draft pack based on the literature search and also provided a number of additional topics for discussion. CONCLUSIONS: There is very little consistency in the induction of PPI Contributors on oversight committees. Whilst most local guidance explains the general role of a PPI Contributor, more context and background of the particular trial needs to be provided to allow for adequate induction of new committee members. The Induction Pack created provides a framework upon which trial managers can build a full picture of their study.

Clinical Trials Units are encouraged to integrate Patient and Public Involvement (PPI) into all aspects of their trials. This research explored the induction and training of PPI Contributors (e.g. patients, carers and members of the public) joining trial oversight committees. These committees regularly review trial progress and ensure participant safety. PPI Contributors sit on the committees to provide important guidance and advice on what the trial is like for a participant taking part.We looked at existing materials and research to find out what is already in use and how useful PPI Contributors felt it may be. We also held a workshop with existing PPI Contributors who had experience of participating in trials and sitting on oversight committees to find out what information they felt would be useful during the induction of a new member.Our research was used to create an induction pack for new PPI Contributors at the Medical Research Council Clinical Trials Unit at University College London (MRC CTU at UCL). We have made this resource available to all researchers and in this report we describe how it was created.

Evidence supporting a viral origin of the eukaryotic nucleus.

The defining feature of the eukaryotic cell is the possession of a nucleus that uncouples transcription from translation. According to the updated Viral Eukaryogenesis (VE) hypothesis presented here, the eukaryotic nucleus descends from the viral factory of a DNA virus that infected the archaeal ancestor of the eukaryotes. The VE hypothesis implies that many unique features of the nucleus, including the mechanisms by which the eukaryotic nucleus uncouples transcription from translation, should be viral rather than cellular in origin. The modern eukaryotic nucleus uncouples transcription from translation using a complex process employing hundreds of eukaryotic specific genes acting in concert. This intricate process is primed by the eukaryote specific 7-methylguanylate (m7G) cap on eukaryotic mRNA that targets mRNA for splicing, nuclear export, and cytoplasmic translation. It is shown here that homologues of the eukaryotic m7G capping apparatus are present in viruses of the Mimiviridae yet are apparently absent from archaea generally, and specifically from Lokiarchaeota, a proposed archaeal relative of the eukaryotes. Phylogenetic analysis of the m7G capping apparatus shows that eukaryotic nuclei and Mimiviridae obtained this shared pathway from a common ancestral source that predated the origin of the Last Eukaryotic Common Ancestor (LECA). These results are consistent with the hypothesis that the eukaryotic nucleus and the Mimiviridae obtained these abilities from an ancient virus that could be considered the 'First Eukaryotic Nuclear Ancestor' (FENA).

Engineering Education as the Development of Critical Sociotechnical Literacy.

Recent policy documents position engineering as a way to broaden participation for students in STEM fields. However, a recent review of the literature on engineering education found that fewer than 1% of reviewed articles focused on issues of equity and broadening participation. For this reason, there are few frameworks to build on when designing for equitable engineering instruction in K-12 settings. Diversifying participation in engineering means that we need to not just bring learners into existing engineering practices, structures, and ways of knowing, but that we take a critical look at the field of engineering education and challenge researchers and educators to create learning opportunities that build on diverse ways of knowing about engineering and being engineers in the world, with a focus on relating course materials to learners' everyday lives. In this paper, we leverage the diverse histories, epistemologies, and ways of knowing in engineering to outline the possibilities for learners to critically engage with engineering in K-12 settings and we ask the question, "How can we design learning environments to help students critically understand the intrinsic and systemic sociotechnical relationships between people, communities, and the built environment?" To answer this question, we propose an instructional framework for developing learners' critical sociotechnical literacy, which is a place-based approach for critically engaging learners in understanding the impacts of engineering and technology on their own communities and everyday lives in order to restory these spaces for a more equitable and just future.

Research priorities for the management of broken bones of the upper limb in people over 50: a UK priority setting partnership with the James Lind Alliance.

OBJECTIVE: To determine research priorities for the management of broken bones of the upper limb in people over 50, which represent the shared priorities of patients, their families, carers and healthcare professionals. DESIGN/SETTING: A national (UK) research priority setting partnership. PARTICIPANTS: People aged 50 and over who have experienced a fracture of the upper limb, carers involved in their care, family and friends of patients, healthcare professionals involved in the treatment of these patients. METHODS: Using a multiphase methodology in partnership with the James Lind Alliance over 15 months (September 2017 to December 2018), a national scoping survey asked respondents to submit their research uncertainties. These were amalgamated into a smaller number of research questions. The existing evidence was searched to ensure that the questions had not already been answered. A second national survey asked respondents to prioritise the research questions. A final shortlist of 25 questions was taken to a multi-stakeholder workshop where a consensus was reached on the top 10 priorities. RESULTS: There were 1898 original uncertainties submitted by 328 respondents to the first survey. These original uncertainties were refined into 51 research questions of which 50 were judged to be true uncertainties following a review of the research evidence. There were 209 respondents to the second (interim prioritisation) survey. The top 10 priorities encompass a broad range of uncertainties in management and rehabilitation of upper limb fractures. CONCLUSIONS: The top 10 UK research priorities highlight uncertainties in how we assess outcomes, provide information, achieve pain control, rationalise surgical intervention, optimise rehabilitation and provide psychological support. The breadth of these research areas highlights the value of this methodology. This work should help to steer research in this area for the next 5-10 years and the challenge for researchers now is to refine and deliver answers to these research priorities.

Quantification of bowling workload and changes in cognitive function in elite fast bowlers in training compared with Twenty20 Cricket.

BACKGROUND: Bowling overs are the primary recorded measure for workloads in cricket for youth through to professionals. However, the validity of this measure has never been tested. Additionally, despite the cognitive component of cricket being suggested to be very high, changes in psychomotor processing speed has again not been explored. METHODS: Eight professional English county cricket bowlers participated in the study. Participants wore global positioning systems with a tri-axial accelerometer during a Twenty20 match and training. Bowling overs were expressed relative to external forces. Additionally, cognitive function (as measured by psychomotor speed) was assessed pre and post Twenty20 game and training. RESULTS: When expressed relative to high intensity running distance or external forces from the tri-axial accelerometer, the cost of each over (6 deliveries) was over 100% higher in a Twenty20 game compared to training. Psychomotor speed was unchanged although error within the cognitive task increased post Twenty20 (391±82±547±104 ms) and training (414±110±561±238 ms). This data suggests that reaction time is unchanged from cricket but the chance of making the incorrect decision is increased. CONCLUSIONS: Movements in fielding should be quantified or bowling workloads adjusted to account for the high intensity fielding associated with Twenty20 cricket. Cognitive function was impaired following bowling, suggesting practitioners may also monitor psychomotor changes when assessing fatigue and allow appropriate time to mentally recover.

Research priorities in fragility fractures of the lower limb and pelvis: a UK priority setting partnership with the James Lind Alliance.

OBJECTIVE: To determine research priorities in fragility fractures of the lower limb and pelvis which represent the shared priorities of patients, their friends and families, carers and healthcare professionals. DESIGN/SETTING: A national (UK) research priority setting partnership. PARTICIPANTS: Patients over 60 years of age who have experienced a fragility fracture of the lower limb or pelvis; carers involved in their care (both in and out of hospital); family and friends of patients; healthcare professionals involved in the treatment of these patients including but not limited to surgeons, anaesthetists, paramedics, nurses, general practitioners, physicians, physiotherapists and occupational therapists. METHODS: Using a multiphase methodology in partnership with the James Lind Alliance over 18 months (August 2016-January 2018), a national scoping survey asked respondents to submit their research uncertainties. These were amalgamated into a smaller number of research questions. The existing evidence was searched to ensure that the questions had not been answered. A second national survey asked respondents to prioritise the research questions. A final shortlist of 25 questions was taken to a multistakeholder workshop where a consensus was reached on the top 10 priorities. RESULTS: There were 963 original uncertainties submitted by 365 respondents to the first survey. These original uncertainties were refined into 88 research questions of which 76 were judged to be true uncertainties following a review of the research evidence. Healthcare professionals and other stakeholders (patients, carers, friends and families) were represented equally in the responses. The top 10 represent uncertainties in rehabilitation, pain management, anaesthesia and surgery. CONCLUSIONS: We report the top 10 UK research priorities in patients with fragility fractures of the lower limb and pelvis. The priorities highlight uncertainties in rehabilitation, postoperative physiotherapy, pain, weight-bearing, infection and thromboprophylaxis. The challenge now is to refine and deliver answers to these research priorities.

Rivaroxaban and retropharyngeal haemorrhage.

Haemorrhage is a well-known and accepted complication of anticoagulation. A retropharyngeal haemorrhage (RH) is a rare condition that without prompt recognition and management may result in fatal complications. We report a case of RH in a 67-year-old man anticoagulated with rivaroxaban for atrial fibrillation. The patient presented to the emergency department, with a two-day history of atraumatic right-sided neck swelling and associated progressive odynophagia, dysphagia and dysphonia. Rivaroxaban is a potent new oral anticoagulant that has been approved for use by National Institute for Health and Care Excellence (NICE) but still has no approved reversal agent. Despite its rarity, an RH is a potentially life threatening complication of anticoagulation that must be carefully considered. This is especially true for a drug that cannot be easily reversed. We present a discussion of this case presentation with possible differential diagnoses and a review of the literature, and recommend the use of Capp's triad as a diagnostic criterion.

A little more conversation please? Qualitative study of researchers' and patients' interview accounts of training for patient and public involvement in clinical trials.

BACKGROUND: Training in patient and public involvement (PPI) is recommended, yet little is known about what training is needed. We explored researchers' and PPI contributors' accounts of PPI activity and training to inform the design of PPI training for both parties. METHODS: We used semi-structured qualitative interviews with researchers (chief investigators and trial managers) and PPI contributors, accessed through a cohort of clinical trials, which had been funded between 2006 and 2010. An analysis of transcripts of audio-recorded interviews drew on the constant comparative method. RESULTS: We interviewed 31 researchers and 17 PPI contributors from 28 trials. Most researchers could see some value in PPI training for researchers, although just under half had received such training themselves, and some had concerns about the purpose and evidence base for PPI training. PPI contributors were evenly split in their perceptions of whether researchers needed training in PPI. Few PPI contributors had themselves received training for their roles. Many informants across all groups felt that training PPI contributors was unnecessary because they already possessed the skills needed. Informants were also concerned that training would professionalise PPI contributors, limiting their ability to provide an authentic patient perspective. However, informants welcomed informal induction 'conversations' to help contributors understand their roles and support them in voicing their opinions. Informants believed that PPI contributors should be confident, motivated, intelligent, focussed on helping others and have relevant experience. Researchers looked for these qualities when selecting contributors, and spoke of how finding 'the right' contributor was more important than accessing 'the right' training. CONCLUSIONS: While informants were broadly receptive to PPI training for researchers, they expressed considerable reluctance to training PPI contributors. Providers of training will need to address these reservations. Our findings point to the importance of reconsidering how training is conceptualised, designed and promoted and of providing flexible, learning opportunities in ways that flow from researchers' and contributors' needs and preferences. We also identify some areas of training content and the need for further consideration to be given to the selection of PPI contributors and models for implementing PPI to ensure clinical trials benefit from a diversity of patient perspectives.

Traumatic rupture of sternocleidomastoid muscle following an epileptic seizure.

A 29-year-old man, a known epileptic, presented to an accident and emergency department following a tonic-clonic seizure, suffering a second seizure in the department. Subsequently, he reported neck pain, swelling and stiffness. An otorhinolaryngology neck examination revealed a tender left side with two palpable masses and a reduced range of movement. Ultrasound confirmed a ruptured middle third of the left sternocleidomastoid muscle, which was successfully treated non-surgically with analgaesia and intensive physiotherapy. Uncommonly, sternocleidomastoid muscle rupture has been reported following high-velocity trauma, but to the best of our knowledge this is the first case described in the literature following an epileptic seizure.

Patient and public involvement in the early stages of clinical trial development: a systematic cohort investigation.

BACKGROUND: Randomised controlled trials (RCTs) are considered particularly likely to benefit from patient and public involvement (PPI). Decisions made by professional researchers at the outset may go on to have a significant impact on the potential for PPI contributions. OBJECTIVE: To increase knowledge of PPI within the early development of RCTs by systematically describing the reported level, nature and acceptability of proposed PPI to the funders. METHODS: Documentation from the outline application process for all RCTs that received funding from the Health Technology Assessment (HTA) Programme 2006-2010 was requested. For each application, data were extracted on trial characteristics, references to PPI in the development of the outline application and funding Board feedback, and plans for PPI in the full application and after the trial was funded. RESULTS: 110 applications were eligible with outline applications available for 90 (82%). The cohort covered a wide range of interventions and conditions. 54% (49/90) provided some information about PPI. 26 (28.9%) indicated PPI within the development of the outline application itself; 32 (35.6%) planned involvement in the full application and 43 (48%) once the trial was funded. Recruitment at diagnosis and surgical interventions were less likely to describe PPI. Blinded trials and trials in which participants may receive placebo only, more frequently described PPI activity. The HTA commissioning Board feedback rarely referred to PPI. CONCLUSIONS: Incorporation of PPI within the development of the outline application or specification of plans for future involvement was low. Funder requests for applicants to provide information on PPI and justification for its absence should be welcomed but further research is needed to identify the impact of this on its contributions to research. Comments on PPI by reviewers should be directional rather than state that an increase is required. Challenges facing applicants in initiating PPI prior to funding need to be addressed.