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Background Chronic pain is common and costly. Antidepressants are prescribed to reduce pain. However, there has not been a network meta-analysis examining all antidepressants across all chronic pain conditions, so effectiveness and safety for most antidepressants for pain conditions remain unknown. Objective To assess the efficacy and safety of antidepressants for chronic pain (except headache) in adults. Our primary outcomes were as follows: substantial pain relief (50%), pain intensity, mood and adverse events. Our secondary outcomes were as follows: moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change, serious adverse events and withdrawal. Design This was a systematic review with a network meta-analysis. We searched CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, AMED and PsycINFO databases for randomised controlled trials of antidepressants for chronic pain conditions up until 4 January 2022. The review was registered in PROSPERO (CRD42020171855), and the protocol was published in the Cochrane Library (https://doi.org/10.1002/14651858.CD014682). Setting We analysed trials from all settings. Participants We included trials in which participants had chronic pain, defined as longer than 3 months, from any condition excluding headache. Interventions We included all antidepressants. Main outcome measures Our primary outcome was substantial pain relief, defined as a reduction ˃ 50%. We also measured pain intensity, mood and adverse events. Secondary measures included moderate pain relief (above 30% reduction), physical function, sleep, quality of life, Global Impression of Change, serious adverse events, and withdrawal from trial. Results We identified 176 studies with a total of 28,664 participants. Most studies were placebo-controlled (n = 83) and parallel armed (n = 141). The most common pain conditions examined were fibromyalgia (59 studies), neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of randomised controlled trials was 10 weeks. Most studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. Standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that for duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Limitations The evidence for antidepressants other than duloxetine is poor. For duloxetine, it is not clear whether the effect applies to groups with both pain and low mood, since these groups were excluded from trials. There is also insufficient evidence on long-term outcomes and on adverse effects. Conclusions There is only reliable evidence for duloxetine in the treatment of chronic pain. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Data for all other antidepressants were of low certainty. However, the findings should not be read as an encouragement to prescribe antidepressants where other non-pharmacological intervention could be equally effective, especially in the absence of good evidence on side effects and safety. Future work There is a need for large, methodologically sound trials testing the effectiveness of antidepressants for chronic pain. These trials should examine long-term outcomes (> 6 months) and include people with low mood. There should also be better reporting of adverse events, tolerance of drugs, and long-term compliance. Study registration This study is registered as PROSPERO CRD42020171855. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128782) and is published in full in Health Technology Assessment; Vol. 28, No. 62. See the NIHR Funding and Awards website for further award information. Plain language summary What was the question? Chronic pain is pain that lasts for more than 3 months. Over one-third of people across the world experience chronic pain. This often has a detrimental impact on people’s mood, disability and well-being. Antidepressants are often prescribed to reduce pain, but we are not sure which antidepressants work best for different types of pain, or whether they are safe. We wanted to find out whether antidepressants were effective and safe for management of chronic pain. What did we do? We searched for studies that had compared any antidepressant with any other treatment for any type of chronic pain (except headache). We compared all the treatments against each other using a statistical method called network meta-analysis. This method allows us to rank the treatments in order of best to worst for each outcome. What did we find? We found 176 studies that included a total of 28,664 people with chronic pain. Most of the studies (83/176) compared an antidepressant with a placebo (which looks like the real medicine but does not have any medicine in it). The evidence from our analysis suggests that: Duloxetine is the antidepressant that we have the most confidence in. It was the best antidepressant for reducing pain and improving physical function. A standard dose of duloxetine was equally as effective for reducing pain as a high dose of duloxetine. Milnacipran was also effective at reducing pain, but we are not as confident in this result as in the one for duloxetine because there were fewer studies with fewer people involved. Aside from duloxetine and milnacipran, we do not have confidence in the results from any other antidepressant included in this review, and even for duloxetine and milnacipran, we do not know the long-term effects. It is important to recognise that the lack of evidence for the majority of antidepressants in this review does not necessarily equal a lack of benefit. Rather, this means that the large, high-quality trials required for us to be certain of an antidepressant’s effectiveness have not been undertaken. Altogether, although duloxetine and milnacipran are effective, the results of this review should not be read as an encouragement to prescribe antidepressants where other non-pharmacological intervention could be equally effective, especially in the absence of good evidence on side effects and safety. These conclusions were informed by our patient and public involvement group. Scientific summary Background Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients’ global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis examining all antidepressants across all chronic pain conditions. Objectives Our objective was to assess the efficacy and safety of antidepressants for chronic pain (except headache) in adults. Our primary outcomes were as follows: substantial pain relief (50%), pain intensity, mood and adverse events. Our secondary outcomes were as follows: moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events and withdrawal. Search methods We searched CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, AMED and PsycINFO databases for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions up until 4 January 2022. Selection criteria We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant or the same antidepressant at different doses, then the study was required to be double-blind. RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) were included but rated as at high risk of bias. We excluded RCTs where the follow-up was < 2 weeks and those with < 10 participants in each trial arm. We included any antidepressant at any dose, for any indication but used primarily for treatment of people with chronic pain and compared to placebo or active intervention. Participants We included adults (aged 18 years or older) reporting primary or secondary pain in any part of their body (except headache) as their primary complaint, that matched the International Association for the Study of Pain definition of chronic pain (i.e. at least 3 months’ duration). We included all trials regardless of the severity of participants’ chronic pain, although we extracted whether severity was part of the inclusion criteria of the individual studies. We excluded studies where the participants’ primary pain condition was headache or migraine. Data collection and analysis Two authors separately screened, extracted data and judged risk of bias. We synthesised the data using Bayesian network meta-analysis (NMA) and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve. We primarily used the Confidence in Network Meta-Analysis (CINeMA) framework and ‘Risk Of Bias due to Missing Evidence in Network meta-analysis’ (ROB-MEN) tool to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used Grading of Recommendations, Assessment, Development and Evaluations (GRADE) to assess the certainty of the evidence. Main results This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (n = 83) and parallel-armed (n = 141). The most common pain conditions examined were fibromyalgia (59 studies), neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks; seven studies provided no useable data and were omitted from the NMAs. The majority of studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. In duloxetine trials, standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Primary efficacy outcomes For pain relief, duloxetine standard dose showed a small to moderate effect for substantial pain relief [odds ratio 0.91, 95% confidence interval (CI) 0.56 to 0.84] and continuous pain intensity [standardised mean difference (SMD) −0.31, 95% CI −0.39 to −0.24]. For pain intensity, milnacipran standard dose also showed a small effect (SMD −0.22, 95% CI −0.39 to 0.06) with moderate-certainty evidence. For mood, mirtazapine had a moderate effect (SMD −0.5, 95% CI −0.78 to −0.22), while duloxetine showed a small effect (−0.16, 95% CI −0.22 to −0.1); however, it is important to note that most trials excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the ‘normal’ or ‘subclinical’ ranges at baseline already. Secondary efficacy outcomes Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were equally as efficacious as high doses. Safety There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes. Authors’ conclusions Our review and NMAs show that despite studies investigating 25 different antidepressants, there is reliable evidence for only duloxetine in the treatment of chronic pain. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Data for all other antidepressants were of low certainty. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy and safety of any antidepressant. Study registration This study is registered as PROSPERO CRD42020171855. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128782) and is published in full in Health Technology Assessment; Vol. 28, No. 62. See the NIHR Funding and Awards website for further award information.

Background: Incidental and screen-detected pulmonary nodules are common. The increasing capabilities of advanced diagnostic bronchoscopy will increase bronchoscopists’ procedural volume necessitating optimization of procedural scheduling and workflow. Objectives: The objectives of this study were to determine total time in the procedure room, total bronchoscopy procedure time, and robotic-assisted bronchoscopy procedure time longitudinally and per specific procedure performed. Design: A single-center observational study of all consecutive patients undergoing shape-sensing robotic-assisted bronchoscopy (RAB) biopsy procedures for the evaluation of pulmonary lesions with variable probability for malignancy. Methods: Chart review to collect patient demographics, lesion characteristics, and procedural specifics. Descriptive and comparative statistics are reported. Results: Actual bronchoscopy procedure time may decrease with increased institutional experience over time, however, there is limited ability to reduce non-bronchoscopy related time within the procedure room. The use of cone beam computed tomography (CBCT), rapid on-site evaluation (ROSE), and performance of staging endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) in a single procedure are each associated with additional time requirements. Conclusion: Institutional procedural block times should adapt to the nature of advanced diagnostic bronchoscopy procedures to allow for the accommodation of new modalities such as RAB combined with other technologies including radial endobronchial ultrasound, CBCT, ROSE, and staging linear EBUS. Identifying institutional median procedural times may assist in scheduling and ideal block time utilization.

Abstract Mating systems, influenced by the social and ecological environment and individual attributes, are fundamental components of animal social organisation, impacting behaviour, animal distribution, ecosystem processes, individual reproductive success, and population dynamics. Bats are of particular interest for studies of mating systems as they are thought to exhibit a greater diversity in mating systems than any other mammalian order, and thus make great models for improving our fundamental understanding of causes and consequences of social organisation. Here, we review the current knowledge of bat mating systems. Our analyses show that research on bat mating systems has not kept pace with research on bats in general and that traditional typologies do not accommodate the mating system of several species. Therefore, we propose an alternative, functional framework to categorise mating systems of bats and by extension of other taxa. We argue that mating systems can be classified according to a male reproductive skew continuum, with an increasing skew from monogamy to true lekking. We include an additional category of lek‐like mating system along the continuum to account for previous trans‐categorical cases that have the appearance of resource defence but are functionally akin to a lek. The new framework has a total of seven categories: promiscuity, monogamy, female defence polygyny, resource defence polygyny, a lek‐like mating system, exploded classical lek, and clustered classical lek. Applying this framework to bats reveals that lek mating systems are more prevalent in bats than previously recognised. It is our aim that this review and the proposed framework provide a greater understanding of bat mating systems particularly and provoke research into the factors that shape mating systems across animal taxa more generally.

Outbreaks of sarcoptic mange are sporadically reported in koala populations across Australia, but disease characteristics (e.g., distribution across the body) remain poorly understood. In an area of Northern Victoria regular cases coming into care suggest mange may have become enzootic, and here we characterise those koala mange admission records. In 18% (n = 10) of mange affected koala reports that had a recorded outcome (n = 55), the animals died before the carers could locate them, and of the remaining 45 koalas that were alive upon carer arrival, 80% (n = 36) had to be euthanised due to severe mange. The number of admissions varied among years (highest observed in 2019), and over 60% of affected koala admissions were male. Male admissions peaked in austral spring and again in late austral summer-autumn (mating and birthing seasons), with female admissions only exhibiting the latter peak (birthing season). Fissures of the epidermis of the front paws occurred in 100% of admitted koalas, with 70% also showing these signs elsewhere on ventral surfaces or limbs. Only male koalas had signs of mange on the chest and face, and only female koalas had signs of mange on their back. Collectively, this study suggests sarcoptic mange can be a severe disease in koalas, and that male koalas may play an important role in seasonal transmission dynamics. We discuss how these findings may help inform intervention strategies.

Abstract A model of the evolution of the onshore wind turbine blade mass installed in Denmark is proposed described by a Weibull distribution, and the age of the blades is estimated from decommissioning data to t50%,onshore = 29 years when half of the blade mass of an installation year has been decommissioned. This is considerably longer than the 20 year design lifetime of onshore turbines, which is often assumed to be an estimate of the End‐of‐Life of turbine blades. Thus, blade waste predictions using the simple assumption may predict that installed blade masses are entering recycling processes about 9 years sooner that what is observed in Denmark. The blade mass for decommissioning in Denmark is estimated to peak at 2000 and 5000 ton/year in 2028 and 2045 using the Weibull model.

Abstract Public transport accessibility to urban and regional services has been found to relate to various social and economic processes, such as unemployment, transport mode choice, property prices, and public health. A frequent type of measures representing accessibility are location-based. While these offer advantages, like flexibility and ease of interpretation, their estimation usually requires specialized skills and substantial computational resources. To lower these barriers, we have prepared a suite of accessibility indicators for key services across Great Britain at a spatially disaggregated level. The dataset includes ready-to-use public transport accessibility indicators for employment, general practitioners (GP, or family physician), hospitals, grocery stores, supermarkets, primary and secondary schools, and urban centres. It also includes the raw travel time matrix from each origin to every potential destination, a primary input for such indicator estimation. Altogether, this resource offers various levels of application, from direct input into a range of research topics to the foundation for creating comprehensive custom indicators.

Q fever is a zoonosis caused by Coxiella burnetii, primarily affecting those in close contact with domestic ruminants, the main source of human infection. Coxiella burnetii has also been detected in various wildlife species globally. In Australia, serological and molecular studies have shown exposure to and infection by C. burnetii in macropods, bandicoots, and koalas. However, the extent to which these species contribute to human infection remains unclear. An unpublished public health investigation into a Q fever case in a person involved in koala care could not conclusively link the infection to koalas due to the patient’s broad animal exposure. This study aimed to explore the potential role of koalas in transmitting C. burnetii to humans by investigating the presence of C. burnetii DNA in urogenital tract (UGT) swabs from koalas. DNA was extracted from UGT swabs from koalas in three regions in New South Wales, Australia. An optimised multiplex qPCR assay detected C. burnetii DNA in 2 out of 225 samples (0.89%) at approximately 10 genome equivalents per reaction. Both positive samples amplified all three gene targets. MLVA genotyping identified two distinct C. burnetii genotypes previously isolated from Australian Q fever cases. These findings highlight the need for vaccination against Q fever for those in close contact with koalas.

Background Quality of life and care varies between and within the care homes in which almost half a million older people live and over half a million direct care staff (registered nurses and care assistants) work. The reasons are complex, understudied and sometimes oversimplified, but staff and their work are a significant influence. Objective(s) To explore variations in the care home nursing and support workforce; how resident and relatives’ needs in care homes are linked to care home staffing; how different staffing models impact on care quality, outcomes and costs; how workforce numbers, skill mix and stability meet residents’ needs; the contributions of the care home workforce to enhancing quality of care; staff relationships as a platform for implementation by providers. Design Mixed-method (QUAL-QUANT) parallel design with five work packages. WP1 – two evidence syntheses (one realist); WP2 – cross-sectional survey of routine staffing and rated quality from care home regulator; WP3 – analysis of longitudinal data from a corporate provider of staffing characteristics and quality indicators, including safety; WP4 – secondary analysis of care home regulator reports; WP5 – social network analysis of networks likely to influence quality innovation. We expressed our synthesised findings as a logic model. Setting English care homes, with and without nursing, with various ownership structures, size and location, with varying quality ratings. Participants Managers, residents, families and care home staff. Findings Staffing’s contribution to quality and personalised care requires: managerial and staff stability and consistency; sufficient staff to develop ‘familial’ relationships between staff and residents, and staff–staff reciprocity, ‘knowing’ residents, and skills and competence training beyond induction; supported, well-led staff seeing modelled behaviours from supervisors; autonomy to act. Outcome measures that capture the relationship between staffing and quality include: the extent to which resident needs and preferences are met and culturally appropriate; resident and family satisfaction; extent of residents living with purpose; safe care (including clinical outcomes); staff well-being and job satisfaction were important, but underacknowledged. Limitations Many of our findings stem from self-reported and routine data with known biases – such as under reporting of adverse incidents; our analysis may reflect these biases. COVID-19 required adapting our original protocol to make it feasible. Consequently, the effects of the pandemic are reflected in our research methods and findings. Our findings are based on data from a single care home operator and so may not be generalised to the wider population of care homes. Conclusions Innovative and multiple methods and theory can successfully highlight the nuanced relationship between staffing and quality in care homes. Modifiable characteristics such as visible philosophies of care and high-quality training, reinforced by behavioural and relational role modelling by leaders can make the difference when sufficient amounts of consistent staff are employed. Greater staffing capacity alone is unlikely to enhance quality in a cost-effective manner. Social network analysis can help identify the right people to aid adoption and spread of quality and innovation. Future research should focus on richer, iterative, evaluative testing and development of our logic model using theoretically and empirically defensible – rather than available – inputs and outcomes. Study registration This study is registered as PROSPERO CRD42021241066 and Research Registry registration: 1062. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 15/144/29) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 8. See the NIHR Funding and Awards website for further award information. Plain language summary This study was about the relationship between staffing and quality in care homes. Almost half a million older people live in care homes in England. Why quality of care and quality of life for residents vary so much between and within homes is unknown, but staff and the ways they work are likely to be important. Researching staffing and quality is difficult: quality means different things to different people and a lot of things shape how quality feels to residents, families and staff. In the past, researchers have oversimplified the problem to study it and may have missed important influences. We took a more complex view. In five interlinked work packages, we collected and analysed: (1) research journal articles; (2) national data from different care homes; (3) data from a large care organisation to look at what it is about staffing that influences quality; (4) reports and ratings of homes from the Care Quality Commission; and (5) we looked at the networks between staff in homes that shape how quality improvement techniques might spread. We used theories about how our findings might be linked to plan for this data collection and analysis. The results were combined into something called a ‘logic model’ – a diagram and explanation that make it easier for managers, researchers and people interested in care homes to see how staffing influences quality. Staffing considerations that might improve quality include: not swapping managers too much; having sufficient and consistent staff for family-like relationships in homes and putting residents’ needs first; supporting staff and giving them freedom to act; and key staff leading by example. Research examining care home quality should capture those aspects that mean the most to residents, their families and staff. Scientific summary Background An estimated 425,000 older people in England live in 18,000 care homes: with nursing, without nursing, or dual registered homes. They are some of the oldest and the most vulnerable people in society. Resident dependency levels and care needs are often similar in homes with and without nursing – but their workforces differ significantly. In homes with nursing care, registered nurses (RNs) are employed to provide clinical care and supervise care delivery, mainly from a large workforce of non-registered care assistants. Care homes without nursing comprise only social care staff or care assistants. The NHS provides health care – including nursing care – as required; for example, supporting specialist care for residents at the end of life. Staffing profiles and establishments vary between providers and so studying care homes and their workforce is complex. Conceptually, quality is similarly complex; it is contested, contingent, contextualised, dynamic and often deeply personal. Two dimensions of quality require consideration in care homes: quality of care and quality of life. While care home staff and their work are likely determinants of quality, research into the staffing–quality relationship is comparatively scant. Measuring quality often focuses on clinical outcomes, such as pressure ulcer prevalence, falls or medication errors. Many studies are in North American long-term care and the few English studies’ primary focus has been on staff turnover and quality and working conditions and quality. Our mixed-methods study addresses some of the theoretical gaps and methodological challenges associated with understanding staffing’s relationship to quality. Using established theory we focused on the structures, processes and outcomes of quality. Our aim of investigating workforce models of nursing and care support in care homes that effectively benefit residents, relatives and staff was addressed through six objectives, which were the focus of five linked work packages (WP). Objectives Describe variations in the characteristics of the care home nursing and support workforce (WP1). Identify the dependency and needs of residents and relatives in care homes and their association with care home staffing (WP2, WP3). Examine how different care home staffing models (including new roles) impact on quality of care, resident outcomes and NHS resources (WP1, WP2, WP3). Explain how care home workforce (numbers, skill mix and stability) might meet the dependency and needs of residents (WP1, WP2, WP3, WP4). Explore and understand the contributions of the nursing and support workforce (including innovations in nursing and support roles) in care homes to enhance quality of care (WP1, WP4). Translate methods used for modelling the relationships between staffing and quality to provide a platform for sector-wide implementation (WP5). Methods A mixed-method (QUAL-QUANT) parallel design built around Donabedian’s theoretical framework of structures, processes and outcomes was the basis for our exploration of the relationship between care home staffing and quality. The coronavirus disease 2019 (COVID-19) pandemic meant some deviation from our original protocol was necessary. Work package 1 (WP1) was two evidence reviews: a systematic review synthesising 36 studies of care home staff perceptions of their roles and responsibilities in promoting quality; a realist review (n = 66 studies) then developed evidence and theory-based explanations of how care home staff behaviours promote quality of care and quality of life, why and in what circumstances. Work packages 2 and 3 used routinely collected measures of staffing and examined their relationship to quality. WP2 was a cross-sectional observational study, modelling the relationship between care quality – as measured in Care Quality Commission (CQC) inspection reports – and care home workforce characteristics from the National Minimum Data Set for Social Care (NMDS-SC). WP3 analysed routinely collected longitudinal data measures of workforce, nurse-sensitive indicators of care quality, resident characteristics and home characteristics from a large corporate care home provider over 42 months. A cost analysis from a provider perspective was also undertaken. Work package 4 used documentary analysis of 30 purposively sampled, publicly available, inspection reports from the English national quality regulator (CQC) from homes rated as outstanding or inadequate to examine (1) how staffing structures influenced quality and (2) the care processes that explain the relationship between staffing and quality. In WP5, care homes (n = 11) were purposively sampled and social network analysis (SNA) using questionnaires and roster name generation was used to map the self-reported advice and influence relationships present in care homes. To assess homes’ readiness for innovation and work-related barriers to adoption of our (translated) findings, eight managers completed an adapted version of the Normalisation MeAsure Development questionnaire (NoMAD) questionnaire – an operationalised instrument of Normalisation Process Theory. Public and stakeholder involvement and engagement We worked closely with the public and stakeholders throughout, from question formulation through to synthesis. Two advisory groups were formed: (1) a resident and relative group and (2) a care home manager group. The study steering committee (SSC) contained key stakeholders – including relatives – to provide oversight and guidance. These mechanisms ensured perspectives other than the research team informed and improved research design and implementation and prompted wider conversations and learnRNing that benefited the research. Ethics approval Work package 2 and WP3 were approved (2 August 2017) by the Social Care Research Ethics Committee (17/WM/0232). WP5 was approved (21 June 2019) by the University of Leeds, Faculty of Medicine and Health, Ethics and Governance Committee (HREC 18-028). Findings The five linked WP findings were synthesised using a logic model to explain what is likely to work, why and how, and the interactions between structures, processes and outcomes important for the staffing–quality relationship. Managerial stability was important: care homes with a manager in-post in the 12 months prior to a CQC inspection were more likely to be rated as good or outstanding (WP2). Managers made those workforce decisions necessary for meeting residents’ care and safety needs (WP4). Managers of care homes rated good or outstanding had authority and flexibility to secure the workforce they judged necessary (WP4). Cohesive working relationships between managers and their corporate senior management team or owner helped managers enact their decisions (WP4). Higher staff-to-bed ratios were associated with a greater chance of a good or outstanding CQC inspection score (WP2). More care from RNs was associated with fewer falls with fractures, urinary tract infections (UTIs) and medication errors (WP3). Use of agency nurses to cover for staff sickness or unfilled vacancies was not associated with more falls, infections or pressure ulcers, but was associated with more medication errors (WP3). Simply increasing nursing input is unlikely to be a cost-effective way of reducing adverse incidents in care homes (WP3). WP4 (and WP1ii) identified the importance of having ‘sufficient’ staff to meet residents’ needs and preferences and improve outcomes. But detail of how staffing levels were determined by managers and consistent use of tools to support professional judgement about staffing (WP4) was lacking. Staff stability and minimising agency staff use were perceived as necessary conditions for quality (WP4). Having experienced care staff, that is, staff in post for 5 years, was likely to improve quality, as measured by ratings (WP2). A stable workforce was also associated with skills and competence (WP1i, WP1ii, WP4). Opportunities for staff induction, training and continuing professional development, alongside staff supervision, were extensive in care homes rated as outstanding (WP4). High staff turnover reduced opportunities for developing broader staff skills and competence, narrowing it to staff induction and mandatory training (WP4). Staffing consistency was important for organising care and work (WP1i, WP1ii, WP4). Larger homes were less likely to be rated positively (WP2). Other WPs highlighted the importance of team size (not home size) as a lever for promoting quality (WP1i, WP1ii, WP4). Small groups of linked residents and staff (5–15 residents per staff member based on level of resident dependency) promoted familiarity, communication and a family-like environment for cultivating relationships (WP1ii). Establishing these family-like relationships and ‘knowing’ residents promoted personalisation of resident care (WP1i), encouraging staff to go beyond purely assisting residents with physical tasks, towards addressing wider social and emotional needs (WP1ii). The reviews (WP1i, WP1ii) highlight where the requisite roles and responsibilities of the workforce might help achieve this. Developing relationships based on consultation – with families, professionals outside the home and residents – to support residents was a feature of homes rated as outstanding (WP1i, WP1ii, WP4). These relationships informed care planning and personalisation of care (WP1i). Relationships between staff and families also legitimised family involvement in care to support quality (WP1ii). Unit-level supervisors that role modelled relationship building were important levers for realising team ambitions of relationship-based quality (WP1ii, WP4). Staffing consistency was important for teamworking. In care homes rated outstanding, staff reported working together and supporting each other towards a collective vision of care and support (WP4). Staff that felt supported, valued and – with (managerial) ‘permission’ – able to prioritise residents’ needs, adapted and adopted behaviours promoting residents’ expressing preferences for care (WP1ii, WP4). More autonomy in day-to-day work, with associated accountability, led to greater staff engagement and satisfaction (WP1ii, WP4). Team reciprocity was linked to open communication, information exchange, advice and influence (WP1ii, WP5). Reciprocity encouraged teams to draw on each other’s knowledge and skills to promote individualised care and enhance quality (WP1i, WP1ii, WP4). Combining written and verbal staff communication was a feature in homes rated as outstanding and linked to better resident care (WP4). Visible unit-level supervisors – not always managers – fostered teamworking. They also minimised conflicts, enabling team reciprocity and relationships (WP1ii). Social networks can promote or hinder the behavioural mechanisms influencing quality (WP5). Networks that were interconnected, dense or cohesive, built around strong advice and influence relationships, had higher chances of implementing change associated with innovation around quality (WP5). The care home manager – as opinion leader (i.e. providing most advice and influence and receiving most advice and influence) – was pivotal in implementing innovation-related change (WP5). Leadership and management behaviours promoted resident-centred approaches; ensured effective communication; promoted staff confidence; offered practical and emotional support and recognition to staff; and encouraged diversity (WP1ii). Staff feeling valued was linked to greater staff commitment and contribution to quality (WP4). A managerially endorsed philosophy of care (valuing residents and staff) encouraged the staff behaviours needed for individualised resident care (WP1ii, WP4). Based on our analysis, measuring the following resident outcomes would provide a more meaningful picture of the relationship between staffing and quality: the extent to which resident needs and preferences are met (and culturally appropriate) (WP1i, WP1ii, WP4); resident and family satisfaction (WP1i, WP1ii, WP4); residents living with purpose to promote their quality of life and well-being (WP1i, WP1ii, WP4); and safe care for residents (including clinical outcomes) (WP1i, WP1ii, WP2, WP3, WP4). Staff well-being and job satisfaction were important outcomes which influenced quality as experienced by residents. Conclusions Our study makes a novel and important contribution to understanding the importance of the relationship between staff, their work and behaviours and quality in care homes. We have attempted to shift the debate away from a reductionist picture of numbers of staff and their relationship to clinical indicators, towards a more nuanced recognition of the ways in which staff in the right amounts and with the right behaviours can meet resident’s needs and preferences. Staffing needs to be stable, skilled and competent to realise the benefits of person-focused organisation of care, and enhanced teamworking. Leadership, reward and recognition of staff and a shared philosophy of care provide needed context for the relationships required to improve quality as experienced by residents. Our findings will be useful for people and organisations making policy and delivering services that want to work towards the best ways to deploy and support quality in care homes using their most valuable resource: their staff. Implications for social care Understanding that numbers of staff alone are a necessary but not sufficient condition for care home quality. Quality improves in homes when more care is provided by RNs. Simply introducing ‘more’ staff (particularly RNs) is unlikely to be a cost-effective way of reducing adverse incidents in care homes. Quality relies on the who, what and how of staffing arrangements and organisation of work. Leadership is key, influencing how organisational resources are used to promote the environments and cultures needed for quality-promoting relationships to flourish. Realising and supporting the potential of the staffing resource (clinical, care, social and cultural skills and competence) are essential for quality. Opportunities for learning and development demonstrate an organisation values staff and may support staff retention. A focus on the structures that support staffing consistency (stability, skill and competence) is important for influencing processes (the organisation of care and teamworking) and outcomes for residents and staff. Developing transparent approaches that enable care home managers to effectively judge and make decisions about staffing levels is crucial for safe and appropriate care for residents. Reciprocal relationships, beyond the immediate care team and including residents, their families and health and social care professionals promote quality. Leadership and management behaviours influence staff commitment and thus their contribution to quality. A ‘visible’ unit supervisor and staff who ‘connect’ and influence the team are essential for quality and innovation in care homes. Implications for research Future research should: Unpack the contribution of direct care support workforce (including care assistants, senior care assistants and nursing associates) working at different levels of skills and competence to care home quality. Explore how training for care assistants, senior care assistants and nursing associates contributes to improving quality. Consider differences for temporary (i.e. step-up or step-down care) versus permanent (i.e. long-term placement) care home residents. Explore how resident population levels of dependency are related to quality. Use innovative methods to capture quality in ways that recognise individual stakeholder views, values, expectations and preferences and address both quality of care and quality of life. Develop robust social network interventions to change network structures to enhance reciprocity and advice and influence relationships to embed innovations for enhancing quality. Consider machine learning methods for analysis of routine data because these methods are better able to identify non-linear relationships between staffing and care quality indicators than traditional regression analysis in order to better identify minimum adequate staffing levels. Use methods to promote more accurate modelling of the staffing–quality relationship through data linkage. Further test and develop our logic model. Study registration This study is registered as PROSPERO CRD42021241066 and Research Registry registration: 1062. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 15/144/29) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 8. See the NIHR Funding and Awards website for further award information.

Abstract The diamond potential of kimberlites is difficult to assess due to several mantle and magmatic processes affecting diamond content. Traditionally, initial evaluations are based on the compositions of mantle-derived minerals (garnet, chromite, clinopyroxene), which allow an assessment of pressure-temperature conditions and lithologies suitable for diamond formation. Here we explore a complementary approach that considers the conditions of diamonds destruction by interaction with melts/fluids (metasomatism). We test the hypothesis that carbonate-rich metasomatism related to kimberlite melt infiltration into the deep lithosphere is detrimental to diamond preservation. Our results show that high diamond grades in kimberlites worldwide are exclusively associated with high-Mg/Fe olivine, which corresponds to mantle lithosphere minimally affected by kimberlite-related metasomatism. Diamond dissolution in strongly metasomatised lithosphere containing low-Mg/Fe olivine provides a causal link to the empirical associations between low diamond grades, abundant Ti-Zr-rich garnets and kimberlites with high Ti and low Mg contents. This finding show-cases olivine geochemistry as a viable tool in diamond exploration.

Invasive fungal diseases (IFDs) comprise a growing healthcare burden, especially given the expanding population of immunocompromised hosts. Early diagnosis of IFDs is required to optimise therapy with antifungals, especially in the setting of rising rates of antifungal resistance. Molecular techniques including nucleic acid amplification tests and whole genome sequencing have potential to offer utility in overcoming limitations with traditional phenotypic testing. However, standardisation of methodology and interpretations of these assays is an ongoing undertaking. The utility of targeted Aspergillus detection has been well-defined, with progress in investigations into the role of targeted assays for Candida, Pneumocystis, Cryptococcus, the Mucorales and endemic mycoses. Likewise, whilst broad-range polymerase chain reaction assays have been in use for some time, pathology stewardship and optimising diagnostic yield is a continuing exercise. As costs decrease, there is also now increased access and experience with whole genome sequencing, including metagenomic sequencing, which offers unparalleled resolution especially in the investigations of potential outbreaks. However, their role in routine diagnostic use remains uncommon and standardisation of techniques and workflow are required for wider implementation.

The innovative (and sometimes painful) story of Athens’ self-transformation from a self-defined and self-confident independent city-state to a culture-market and service economy that discovered it could thrive best by selling its heritage to others is one I have written on in the past from a number of angles. To the elite of Athens, both community leaders and leaders in the city’s culture, the most poignant stories may have been those of the city’s schools, in particular the school that defined (for traditionalists who were not themselves philosophers) what “Athenian philosophy” meant: the Academy, the school of Plato. I should like in this short study to follow the leaders, the ‘scholarchs’ of that school – all of them ‘working philosophers’ as well as what we would call administrators – who successfully adapted it to survive through, and draw on the clientele of, the last three generations or so of the Roman Republic. I should like to see if these behaviors and characters – and they, while they do not always fit what we expect from a classical philosopher, make more sense if understood by the school’s ‘driving clientele,’ and finally what sort of story this adds up to.

Abstract Omega‐6 fatty acids are the primary polyunsaturated fatty acids in most Western diets, while their role in diabetes remains controversial. Exposure of omega‐6 fatty acids to an oxidative environment results in the generation of a highly reactive carbonyl species known as trans, trans‐2,4‐decadienal (tt‐DDE). The timely and efficient detoxification of this metabolite, which has actions comparable to other reactive carbonyl species, such as 4‐hydroxynonenal, acrolein, acetaldehyde, and methylglyoxal, is essential for disease prevention. However, the detoxification mechanism for tt‐DDE remains elusive. In this study, the enzyme Aldh9a1b is identified as having a key role in the detoxification of tt‐DDE. Loss of Aldh9a1b increased tt‐DDE levels and resulted in an abnormal retinal vasculature and glucose intolerance in aldh9a1b−/− zebrafish. Transcriptomic and metabolomic analyses revealed that tt‐DDE and aldh9a1b deficiency in larval and adult zebrafish induced insulin resistance and impaired glucose homeostasis. Moreover, alterations in hyaloid vasculature is induced by aldh9a1b knockout or by tt‐DDE treatment can be rescued by the insulin receptor sensitizers metformin and rosiglitazone. Collectively, these results demonstrated that tt‐DDE is the substrate of Aldh9a1b which causes microvascular damage and impaired glucose metabolism through insulin resistance.

Background Medicine prescribing, monitoring and administration in care homes can be significantly enhanced. Effective interventions to improve pharmaceutical care and resident outcomes are required. The enablement of pharmacists to prescribe provides an opportunity for pharmacist independent prescribers to assume responsibility for improving pharmaceutical care, medication-related outcomes and resident safety whilst reducing general practitioner workload. Objective(s) To determine the effectiveness and cost-effectiveness of pharmacist independent prescribing in care homes. Design Development work was undertaken through five work packages before the delivery of the definitive trial. Triads of pharmacist independent prescribers, care home and general practice with responsibility over 20 care home residents were recruited and cluster randomised to intervention or usual care for 6 months. Researchers were blinded at recruitment stage only. Recruitment of 880 residents was required to provide 80% statistical power, to show a 21% reduction in falls over 6 months, assuming 20% attrition. Randomisation was undertaken electronically at triad level, stratified by geographical area. Intention-to-treat analysis undertaken using a negative binomial model. Parameters were estimated using a generalised estimating equation approach. Costs were captured from an NHS perspective. Quality of life (EuroQol; five domain; five level) was collected by proxy to enable cost/quality-adjusted life-year estimation. A concurrent process evaluation was performed. Safety was monitored through a review of pharmacist independent prescriber activities, independent concerns reporting and review of adverse events. Participants Forty-nine triads of general practitioners, pharmacist independent prescribers and care homes were recruited with 454 residents allocated to the intervention arm and 428 to the control arm. Intervention Medication review and care planning, medication reconciliation, staff training, support with care home medication-related procedures, deprescribing and authorisation of monthly prescriptions. Main outcome measure Fall rate per person over 6 months. Results Data for 449 intervention and 427 control residents available for final analysis. The 6-month fall rate ratio in favour of intervention was 0.91 (95% confidence interval 0.66 to 1.26; p=0.58). No significant difference in secondary outcomes was identified except Drug Burden Index (rate ratio 0.83, 95% confidence interval 0.75 to 0.92; p

Abstract The RON receptor tyrosine kinase is an exceptionally interesting target in oncology and immunology. It is not only overexpressed in a wide variety of tumors but also has been shown to be expressed on myeloid cells associated with tumor infiltration, where it serves to dampen tumour immune responses and reduce the efficacy of anti-CTLA4 therapy. Potent and selective inhibitory antibodies to RON might therefore both inhibit tumor cell growth and stimulate immune rejection of tumors. We derived cloned and sequenced a new panel of exceptionally avid anti-RON antibodies with picomolar binding affinities that inhibit MSP-induced RON signaling and show remarkable potency in antibody dependent cellular cytotoxicity. Antibody specificity was validated by cloning the antibody genes and creating recombinant antibodies and by the use of RON knock out cell lines. When radiolabeled with 89-Zirconium, the new antibodies 3F8 and 10G1 allow effective immuno-positron emission tomography (immunoPET) imaging of RON-expressing tumors and recognize universally exposed RON epitopes at the cell surface. The 10G1 was further developed into a novel bispecific T cell engager with a 15 pM EC50 in cytotoxic T cell killing assays.

Introduction Over 50% of older adults are prescribed a medicine where the risk of harm outweighs the chances of benefit. During a hospital admission, older adults and carers expect medicines to be reviewed for appropriateness and any inappropriate medicines proactively deprescribed. While the principle of proactive deprescribing is an expectation of good prescribing practice, it is yet to become routine. The CompreHensive geriAtRician-led MEdication Review (CHARMER) study aims to develop and test a five-component behaviour change intervention to equip geriatricians and pharmacists to proactively deprescribe inappropriate medicines with older adults in hospital. This study aims to test the feasibility and acceptability of study processes and CHARMER implementation.Methods and analysis A two-arm purposive allocation feasibility study is being undertaken at four acute hospitals in England, UK (three intervention and one control). The target sample is 400 patients across all hospitals. Primary outcome measures are: (1) participant recruitment rate and (2) participant attrition rate. Secondary outcome measures are: (1) hospital readmission rate; (2) mortality rate and (3) quality of life. Quantitative data will be checked for completeness and quality, and practitioner and patient demographics descriptively analysed. We will undertake a rapid qualitative analysis on observations, interviews and study meeting minutes data. A subsequent thematic analysis will be undertaken with codes mapped to the Theoretical Domains Framework and Normalisation Process Theory. Triangulation of qualitative and quantitative data will be undertaken.Ethics and dissemination Ethics approval was obtained from Wales Research Ethics Committee 1 (IRAS ID 312494) and study approval from the Health Research Authority (22/WA/0087). Informed consent will be sought from all hospital staff involved in data collection activities and for patients involved in enhanced data collection activities. The findings of this study will be disseminated in peer-reviewed journals and conference presentations.Trial registration ISRCTN11899506.

Immune checkpoint inhibitors are known to have a wide range of autoimmune toxicities, such as acute interstitial nephritis. Immunotherapy induced glomerulonephritis has been described, but anti-glomerular basement membrane disease (anti-GBM) is rarely reported. We present a case report of a 60-year-old woman with squamous cell carcinoma of the cervix who was treated with pembrolizumab, an anti-programmed cell death protein 1, and who developed severe acute kidney injury 4 months after therapy initiation. The immune workup showed a positive serum anti-GBM antibody (24 U/mL). The kidney biopsy showed crescentic glomerulonephritis with linear immunoglobulin G2 glomerular basement membrane staining, compatible with anti-GBM glomerulonephritis. The patient was treated with plasmapheresis, IV steroids, and cyclophosphamide, but she developed kidney failure, necessitating dialysis. Few case reports, such as the present case, provide a possible link between anti-GBM glomerulonephritis and immune checkpoint inhibitors, warranting early clinical suspicion and investigation in patients who are treated with these agents and subsequently develop acute kidney injury.

Parenchyma of pulmonary cancers acquires contractile properties that resemble those of muscles but presents some particularities. These non-muscle contractile tissues could be stimulated either electrically or chemically (KCl). They present the Frank–Starling mechanism, the Hill hyperbolic tension–velocity relationship, and the tridimensional time-independent tension–velocity–length relationship. Relaxation could be obtained by the inhibition of crossbridge molecular motors or by a decrease in the intracellular calcium concentration. They differ from muscles in that their kinetics are ultraslow as evidenced by their low shortening velocity and myosin ATPase activity. Contractility is generated by non-muscle myosin type II A and II B. The activation of the β-catenin/WNT pathway is accompanied by the high level of the non-muscle myosin observed in lung cancers.

In this paper we present findings of research into Trust, specifically within the context of Autonomous Systems. The research is based upon an exploratory workshop attended by domain experts from academia and industry. The aim of the work is to synthesise interdisciplinary and high-level understandings of pertinent issues into a singular and cohesive Master Narrative relating to Trust an Autonomous Systems. The inquiry constructs a Master Narrative that casts Trust as a notion that is necessarily constructed by complex relationships, disciplinary lenses, and multiple concurrent stakeholders. We term this ‘Trust as a Distributed Concern’. The paper describes the research and analysis which underpins the concept of Trust as a Distributed Concern and discusses how the concept may be operationalised in research and innovation contexts.

Membrane proteins (MPs) are functionally important but structurally complex. In particular, MPs often carry three structural features, i.e., transmembrane domains (TMs), disulfide bonds (SSs), and N-glycosylation (N-GLYCO). All three features have been intensively studied; however, how the three features potentially correlate has been less addressed in the literature. With the growing accuracy from computational prediction, we used publicly available information on SSs and N-GLYCO and analyzed the potential relationships among post-translational modifications (PTMs) and the predicted membrane topology in the human proteome. Our results suggested a very close relationship between SSs and N-GLYCO that behaved similarly, whereas a complementary relation between the TMs and the two PTMs was also revealed, in which the high SS and/or N-GLYCO presence is often accompanied by a low TM occurrence in a protein. Furthermore, the occurrence of SSs and N-GLYCO in a protein heavily relies on the protein length; however, TMs seem not to possess such length dependence. Finally, SSs exhibits larger potential dynamics than N-GLYCO, which is confined by the presence of sequons. The special classes of proteins possessing extreme or unique patterns of the three structural features are comprehensively identified, and their structural features and potential dynamics help to identify their susceptibility to different physiological and pathophysiological insults, which could help drug development and protein engineering.

The interpretation of somatic variants in cancer is challenging due to the scale and complexity of sequencing data. Here, the authors present PORI, an open-source framework for interpreting somatic variants in cancer using graph knowledge base tools, automated reporting, and manual curation.

Background: Total knee arthroplasty (TKA) serves as a reliable treatment option for patients with end-stage arthritis, but patient dissatisfaction rate remains high. With the projected increase in the volume of arthroplasty operations, surgeons have aimed for methods in which to improve the patient outcomes. Robotic-assisted TKA has become increasingly popular. The learning curve for such technology has been investigated, but these prior studies have only been performed by fellowship-trained arthroplasty surgeons. The goal of this study was to investigate the learning curve for non-fellowship-trained orthopedic surgeons to ameliorate any concerns about increased operative time. Methods: Retrospective analysis of robotic-assisted TKAs and manual TKAs, performed by two non-fellowship-trained orthopedic surgeons, was conducted on a total of 160 patients. For each individual surgeon, the robotic-assisted TKAs were divided into 3 cohorts of 20 consecutive patients. Data from 20 consecutive manual TKAs were also gathered for each surgeon. The mean operative times were compared. Cohorts were then grouped together for both surgeons and compared in a similar fashion. Results: For surgeon 1, mean operative times were significantly increased for robotic-assisted cohorts compared with those for the manual cohort. For surgeon 2, the first robotic-assisted cohort was significantly longer. However, there were no significant differences for the second and third robotic-assisted cohorts. In the combined surgeon group, there was no significant difference between operative times for the third robotic cohort and the manual cohort. Conclusion: This study demonstrates that the general orthopedic surgeon in a community hospital may be able to adequately perform robotic-assisted surgery in a similar timeframe to their manual TKA within their first 40 robotic-arm-assisted TKA.

Abstract Background and Aims In recent years, Beijing, similar to many other large cities in China, has experienced rapid urbanization in many new areas. These have often been locations of population aging but have not had concomitant development of required community care services for older persons. This study aims to understand the perception and utilization of newly developed community care services by the older persons living in this region for providing knowledge to improve the services. Methods Applying Andersen's behavior model, this study used binary logistic regression of the factors influencing the perception and utilization of community care services and analyzed data collected by questionnaires to 301 older persons in the new urban areas of Beijing. Results Education, income, activities of daily living, instrumental activities of daily living, mental health, and economic needs are statistically significant factors affecting older persons' perception of community care services. Age, perception of community care services, income, neighborhood relationships, mental health, and emotional needs are significant factors affecting older persons' utilization of community care services. Conclusion Demographic characteristics, health status, social support, and care needs were significant factors in the perception and utilization of community care services, after controlling for many variables. Improving older persons' perceptions of community care services is likely to promote their access to the services, which should help meet the challenges of rapid population aging in providing community care services to support aging in place in the new urban areas of Beijing, China.

ObjectiveThis study aims to investigate maternal, fetal, and perinatal outcomes during the 2018-2020 Ebola outbreak in Democratic Republic of Congo (DRC).MethodsMortality between pregnant and non-pregnant women of reproductive age admitted to DRC's Mangina Ebola treatment center (ETC) were compared using propensity score matching. Propensity scores were calculated using age, initial Ebola viral load, Ebola vaccination status, and investigational therapeutic. Additionally, fetal and perinatal outcomes of pregnancies were also described.ResultsTwenty-seven pregnant women were admitted to the Mangina ETC during December 2018-January 2020 among 162 women of childbearing age. We found no evidence of increase mortality among pregnant women compared to non-pregnant women (relative risk:1.0, 95%CI: 0.58-1.72). Among surviving mothers, pregnancy outcomes were poor with at least 58% (11/19) experiencing loss of pregnancy while 16% (3/19) were discharged with viable pregnancy. Two mothers with viable pregnancies were vaccinated, and all received investigational therapeutics. Two live births occurred, with one infant surviving after the infant and mother received an investigational post-exposure prophylaxis and Ebola therapeutic respectively.ConclusionsPregnancy was not associated with increased mortality among women with EVD in the Mangina ETC. Fetal and perinatal outcomes remained poor in pregnancies complicated by EVD, though novel therapeutics may have potential for improving these outcomes.

Background. Fungal infections are a recognized complication of immunosuppression in solid organ transplant recipients. Phaeohyphomycoses are fungal infections caused by a diverse group of dematiaceous fungi. Methods. We share the learning points from 2 Australian cases of phaeohyphomycosis secondary to Phaeacreomonium species (spp). A literature review was performed using Medline, Embase, and Google Scholar to identify this condition among kidney transplant recipients. Results. With the 2 cases reported in this article, a total of 17 cases were identified in the literature. Phaeacremonium spp is ubiquitous in humid and temperate flora, including Australia. Minor trauma is likely the source of inoculation in most cases and diagnosis is often delayed. Presently, no guidelines for management exist given the rarity of this condition. Most known cases have been treated with surgical debulking combined with long-course antifungal therapy. Conclusion. This paper describes 2 Australian cases of phaeohyphomycosis in kidney transplant recipients. A high index of suspicion, especially in the immunosuppressed, is essential for timely diagnosis in kidney transplant recipients. There are several diagnostic and therapeutic challenges that remain with this condition.

In this paper, we discuss how the increasing prevalence of Speculative Design in educational, research and commercial contexts may reflect and nurture a challenge to the dominance of ‘scientism’. The successes associated with 20th-century modernism are now, in the 21st-century, key factors in the intractability and complexity of 21st-century challenges. Speculative and Design-led approaches offer practical means to break down such intractability but do so over relatively short timeframes. We argue that, if we adopt a longer-term perspective, then disrupting the dominance of scientism so that the benefits of Speculative Design are ‘built in’ rather than ‘added on’ is realistic and desirable. In exploring this proposition, we come to reason that the ultimate measure of Speculative Design’s success is to disappear completely.

Introduction Participants in randomised controlled trials (trials) are generally younger and healthier than many individuals encountered in clinical practice. Consequently, the applicability of trial findings is often uncertain. To address this, results from trials can be calibrated to more representative data sources. In a network meta-analysis, using a novel approach which allows the inclusion of trials whether or not individual-level participant data (IPD) is available, we will calibrate trials for three drug classes (sodium glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP1) receptor analogues and dipeptidyl peptidase-4 (DPP4) inhibitors) to the Scottish diabetes register.Methods and analysis Medline and EMBASE databases, the US clinical trials registry (clinicaltrials.gov) and the Chinese Clinical Trial Registry (chictr.org.cn) will be searched from 1 January 2002. Two independent reviewers will apply eligibility criteria to identify trials for inclusion. Included trials will be phase 3 or 4 trials of SGLT2 inhibitors, GLP1 receptor analogues or DPP4 inhibitors, with placebo or active comparators, in participants with type 2 diabetes, with at least one of glycaemic control, change in body weight or major adverse cardiovascular event as outcomes. Unregistered trials will be excluded.We have identified a target population from the population-based Scottish diabetes register. The chosen cohort comprises people in Scotland with type 2 diabetes who either (1) require further treatment due to poor glycaemic control where any of the three drug classes may be suitable, or (2) who have adequate glycaemic control but are already on one of the three drug classes of interest or insulin.Ethics and dissemination Ethical approval for IPD use was obtained from the University of Glasgow MVLS College Ethics Committee (Project: 200160070). The Scottish diabetes register has approval from the Scottish A Research Ethics Committee (11/AL/0225) and operates with Public Benefit and Privacy Panel for Health and Social Care approval (1617-0147).PROSPERO registration number CRD42020184174.

Abstract The modern western Pacific basins and arcs formed during the Cenozoic are considered to be underlain by Indian‐type asthenospheric mantle. Nevertheless, Mesozoic volcanic arcs are rare in the western Pacific, and as a result, the nature of the mantle source and subduction history in the western Pacific remains unclear. The Gagua Ridge constitutes the western boundary of the Philippine Sea Plate; however, its geologic nature and genesis are unclear. Here, we determine whole‐rock major and trace elements and Sr‐Nd‐Pb‐Hf‐Mg isotopic compositions and emplacement ages of the volcanic rocks from the Gagua Ridge. These rocks are classified as trachy‐andesites and basaltic andesites. They are characterized by depletion in Nb‐Ta and enrichment in large ion lithosphile elements, confirming their arc affinity. 40Ar‐39Ar analyses of plagioclase yields ages of 124‐123 Ma for the basaltic andesite group and ∼115 Ma for the trachy‐andesite group. The elevated Zr‐Hf‐K of these rocks coupled with high Th/La ratios indicate melting of subducted sediments. The anomalously high Nb/Ta (mean ∼33) can be explained by slab melting with residual rutile. These rocks also show the highest δ26Mg (−0.14 to 0.4‰) for arc lavas ever reported and the δ26Mg values are coupled with rare earth element compositions, which can be explained by interaction of sediment melts with altered peridotite/altered oceanic crust in the subduction zone. These volcanic rocks have Nd‐Hf isotopes similar to the Pacific mantle, indicating the presence of Pacific‐type mantle in the Early Cretaceous western Pacific.

Mucormycosis is an uncommon, yet deadly invasive fungal infection caused by the Mucorales moulds. These pathogens are a WHO-assigned high-priority pathogen group, as mucormycosis incidence is increasing, and there is unacceptably high mortality with current antifungal therapies. Current diagnostic methods have inadequate sensitivity and specificity and may have issues with accessibility or turnaround time. Patients with diabetes mellitus and immune compromise are predisposed to infection with these environmental fungi, but COVID-19 has established itself as a new risk factor. Mucorales also cause healthcare-associated outbreaks, and clusters associated with natural disasters have also been identified. Robust epidemiological surveillance into burden of disease, at-risk populations, and emerging pathogens is required. Emerging serological and molecular techniques may offer a faster route to diagnosis, while newly developed antifungal agents show promise in preliminary studies. Equitable access to these emerging diagnostic techniques and antifungal therapies will be key in identifying and treating mucormycosis, as delayed initiation of therapy is associated with higher mortality.