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Abstract Introduction ASCEND PLUS is a randomised controlled trial assessing the effects of oral semaglutide on the primary prevention of cardiovascular events in around 20,000 individuals with type 2 diabetes in the UK. The trial’s innovative design includes a decentralised direct-to-participant invitation, recruitment, and follow-up model, relying on self-completion of online forms or telephone or video calls with research nurses, with no physical sites. Extensive patient and public involvement and engagement (PPIE) was essential to the design and conduct of ASCEND PLUS. Aim To report the process and conduct of PPIE activity in ASCEND PLUS, evaluate effects on trial design, reflect critically on successes and aspects that could have been improved, and identify themes and learning relevant to implementation of PPIE in future trials. Methods PPIE activity was coordinated centrally and included six PPIE focus groups and creation of an ASCEND PLUS public advisory group (PAG) during the design phase. Recruitment to these groups was carefully considered to ensure diversity and inclusion, largely consisting of adults living with type 2 diabetes from across the UK. Two members of the PAG also joined the trial Steering Committee. Steering Committee meetings, focus groups, and PAG meetings were conducted online, with two hybrid workshops to discuss PPIE activity and aspects of the trial. Results PPIE activity was critical to shaping the design and conduct of ASCEND PLUS. Key examples included supporting choice for participants to either complete the screening/consent process independently online, or during a telephone or video call interview with a research nurse. A concise ‘initial information leaflet’ was developed to be sent with the initial invitations, with the ‘full’ information leaflet sent later to those interested in joining the trial. The PAG reviewed the content and format of participant- and public-facing materials, including written documents, online screening forms, animated videos, and the trial website, to aid clarity and accessibility, and provided input into the choice of instruments to assess quality of life. Conclusions PPIE is integral in ASCEND PLUS and will continue throughout the trial. This involvement has been critical to optimising the trial design, successfully obtaining regulatory and ethical approval, and conducting the trial.

Purpose: To review the literature reporting on complications and failure rates after primary anterior cruciate ligament reconstruction (ACLR) in patients ≥40 years. Methods: This was a secondary analysis from a prior systematic review of the MEDLINE, CINAHL, SportDiscus, Embase, Web of Science, and Cochrane databases on studies evaluating clinical outcomes in ACLR patients ≥40 years. Studies were included based on the following criteria: English-language studies reporting on postoperative complications and/or ACLR failure rates in patients ≥40 years. Case reports, technical notes, studies with duplicate reporting of patient cohorts, or studies using publicly available registry data were excluded. ACLR failure definitions, failure rates, graft rupture rates, revision ACLR and non-ACLR revision rates, and complication rates were recorded. Results: Twenty-one studies were included following full-text review. Autografts were used in 89.0% of cases. Definitions for ACLR failure varied, ranging from (1) revision ACLR, (2) graft rupture, (3) clinical examination of increased knee laxity, and (4) postoperative arthrofibrosis requiring an additional surgery. The median ACLR failure rate was 5.0% (range, 0%-12.1%) among the 9 studies reporting this outcome, with only 4 of the studies providing explicit definitions of failure. The median ACLR revision surgery, graft rupture, and non-ACLR revision surgery rates were 0% (range, 0%-7.7%), 2.7% (range, 0%-9.1%), and 7.2% (range 0%-34.4%), respectively. Commonly reported complications included pain (range, 0%-14.0%), stiffness (range, 0%-12.7%), hematoma (range, 2.5%-8.8%), neurovascular (range, 0%-41.7%), and undefined (range, 0%-13.8%). Conclusions: ACLR in patients over 40 years old shows low failure rates. Level of Evidence: Level IV, systematic review of Level II-IV studies.

Background Systematic annual screening for sight-threatening diabetic retinopathy is established in several countries but is resource intensive. Personalised (individualised) medicine offers the opportunity to extend screening intervals for people at low risk of progression and to target high-risk groups. However, significant concern exists among all stakeholders around the safety of changing programmes. Evidence to guide decisions is limited, with, to the best of our knowledge, no randomised controlled trials to date. Objectives To develop an individualised approach to screening for sight-threatening diabetic retinopathy and test its acceptability, safety, efficacy and cost-effectiveness. To estimate the changing incidence of patient-centred outcomes. Design A risk calculation engine; a randomised controlled trial, including a within-trial cost-effectiveness study; a qualitative acceptability study; and an observational epidemiological cohort study were developed. A patient and public group was involved in design and interpretation. Setting A screening programme in an English health district of around 450,000 people. Participants People with diabetes aged ≥ 12 years registered with primary care practices in Liverpool. Interventions The risk calculation engine estimated each participant’s risk at each visit of progression to screen-positive diabetic retinopathy (individualised intervention group) and allocated their next appointment at 6, 12 or 24 months (high, medium or low risk, respectively). Main outcome measures The randomised controlled trial primary outcome was attendance at first follow-up assessing the safety of individualised compared with usual screening. Secondary outcomes were overall attendance, rates of screen-positive and sight-threatening diabetic retinopathy, and measures of visual impairment. Cost-effectiveness outcomes were cost/quality-adjusted life year and incremental cost savings. Cohort study outcomes were rates of screen-positive diabetic retinopathy and sight-threatening diabetic retinopathy. Data sources Local screening programme (retinopathy), primary care (demographic, clinical) and hospital outcomes. Methods A seven-person patient and public involvement group was recruited. Data were linked into a purpose-built dynamic data warehouse. In the risk assessment, the risk calculation engine used patient-embedded covariate data, a continuous Markov model, 5-year historical local population data, and most recent individual demographic, retina and clinical data to predict risk of future progression to screen-positive. The randomised controlled trial was a masked, two-arm, parallel assignment, equivalence randomised controlled trial, with an independent trials unit and 1 : 1 allocation to individualised screening (6, 12 or 24 months, determined by risk calculation engine at each visit) or annual screening (control). Cost-effectiveness was assessed using a within-trial analysis over a 2-year time horizon, including NHS and societal perspectives and costs directly observed within the randomised controlled trial. Acceptability was assessed by purposive sampling of 60 people with diabetes and 21 healthcare professionals with semistructured interviews analysed thematically; this was a constant comparative method until saturation. The cohort was an 11-year retrospective/prospective screening population data set. Results In the randomised controlled trial, 4534 participants were randomised: 2097 out of 2265 in the individualised arm (92.6%) and 2224 out of 2269 in the control arm (98.0%) remained after withdrawals. Attendance rates at first follow-up were equivalent (individualised 83.6%, control 84.7%) (difference –1.0%, 95% confidence interval –3.2% to 1.2%). Sight-threatening diabetic retinopathy detection rates were non-inferior: individualised 1.4%, control 1.7% (difference –0.3%, 95% confidence interval –1.1% to 0.5%). In the cost-effectiveness analysis, the mean differences in complete-case quality-adjusted life years (EuroQol-5 Dimensions, five-level version, and Health Utilities Index Mark 3) did not significantly differ from zero. Incremental cost savings per person not including treatment costs were from the NHS perspective £17.34 (confidence interval £17.02 to £17.67) and the societal perspective £23.11 (confidence interval £22.73 to £23.53). In the individualised arm, 43.2% fewer screening appointments were required. In terms of acceptability, changing to variable intervals was acceptable for the majority of people with diabetes and health-care professionals. Annual screening was perceived as unsustainable and an inefficient use of resources. Many people with diabetes and healthcare professionals expressed concerns that 2-year screening intervals may detect referable eye disease too late and might have a negative effect on perceptions about the importance of attendance and diabetes care. The 6-month interval was perceived positively. Among people with dementia, there was considerable misunderstanding about eye-related appointments and care. In the cohort study, the numbers of participants (total 28,384) rose over the 11 years (2006/7, n = 6637; 2016/17, n = 14,864). Annual incidences ranged as follows: screen-positive 4.4–10.6%, due to diabetic retinopathy 2.3–4.6% and sight-threatening diabetic retinopathy 1.3–2.2%. The proportions of screen-positive fell steadily but sight-threatening diabetic retinopathy rates remained stable. Limitations Our findings apply to a single city-wide established English screening programme of mostly white people with diabetes. The cost-effectiveness analysis was over a short timeline for a long-standing disease; the study, however, was designed to test the safety and effectiveness of the screening regimen, not the cost-effectiveness of screening compared with no screening. Cohort data collection was partly retrospective: data were unavailable on people who had developed sight-threatening diabetic retinopathy or died prior to 2013. Conclusions Our randomised controlled trial can reassure stakeholders involved in diabetes care that extended intervals and personalised screening is feasible, where data linkage is possible, and can be safely introduced in established screening programmes with potential cost savings compared with annual screening. Rates of screen-positive diabetic retinopathy and sight-threatening diabetic retinopathy are low and show consistent falls over time. Involvement of patients in research is crucial to success. Future work Future work could include external validation with other programmes followed by scale-up of individualised screening outside a research setting and economic modelling beyond the 2-year time horizon. Trial registration This trial is registered as ISRCTN87561257. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 11, No. 6. See the NIHR Journals Library website for further project information. Plain language summary Diabetic retinopathy remains a leading cause of vision loss for people with diabetes. Annual photographic screening allows early detection and prompt treatment in many countries. A new approach is to vary how often this is undertaken at each visit, after calculating each person’s risk of progression; we have called this ‘individualised’ screening. We tested this variable-interval risk-based approach against annual screening in a randomised controlled trial of 4534 people in Liverpool. Six-, 12- or 24-month intervals represented high, medium and low risks, respectively, of becoming screen-positive by the next appointment. With our patient and public involvement group, we designed a computer-based risk-calculation system using personal information from screening, general practitioners and hospitals. Attendance rates at the next screening appointment were similar in the individualised (84%) and annual (control) (85%) groups. Similar amounts of sight-threatening diabetic retinopathy were detected in the two arms (1.4% individualised, 1.7% control), with 43% fewer visits. In this study in a single geographical region, savings estimated to accrue to the NHS per person over 2 years were £17.34 and £23.11 for wider society, but estimates did not include treatment costs. During interviews, 60 people with diabetes and 21 healthcare professionals said that individualised screening would be acceptable because of increasing rates of diabetes and the chance to target high-risk people. Patients had anxieties about the reliability of the risk-calculation and restricting access, requesting opportunities for earlier screening if risks changed. Varying screening intervals based on a person’s own risk of progression appears feasible and safe. Low-risk people would be spared unnecessary appointments. Introducing an individualised approach could now move to wider testing and validation in other UK and international settings. The trial only ran for 2 years and was in a long-established programme with low rates of disease, so monitoring of attendance and retinopathy rates should be included as part of wider testing. Scientific summary Background Diabetic retinopathy remains the most common cause of visual impairment in working populations worldwide. Systematic annual screening to detect and treat sight-threatening diabetic retinopathy (STDR) is established in several countries including the United Kingdom (UK) and has greatly improved the detection of treatable disease. With the rapid increase in the prevalence of diabetes, new approaches to screening are required. Risk stratification, personalised (individualised) medicine, and clinical bioinformatics offer opportunities to extend the screening interval for people at low risk of progression and to target those at high risk. However there is significant concern among people with diabetes, healthcare professionals and health commissioners in the UK around the safety and acceptability of changing an established and successful programme. To ensure that health care is available for all it is imperative that it is not only efficacious but cost-efficient, that is, it delivers care at an affordable cost for commissioners. Evidence to guide these decisions is very limited and there are no randomised controlled trials (RCTs). Much of the data on prevalence and incidence of diabetic retinopathy and progression to more severe stages of disease come from the 1980s to 1990s and before the introduction of systematic screening and improvements in diabetes and blood pressure control. Data on the current progression rates in screening populations are limited and are reported variably. We conducted a programme of quantitative and qualitative research to develop and test the acceptability, safety, efficacy and cost-effectiveness of an individualised approach to screening for STDR. To provide data for future planning of early detection programmes and the design of future research studies we designed a longitudinal observational cohort study of the population of people with diabetes in Liverpool. We aimed to investigate the prevalence and incidence of the stages in the natural history of diabetic retinopathy, namely screen-positive, sight-threatening and treatable disease, and visual impairment, all key patient-centred outcomes in the disease. Changes to the programme and their implications A number of changes to the programme occurred in the early years. A systematic review was published at around the time of the programme start. We used these data to design aspects of the study and conducted a literature review instead. Data for the cohort study proved not to be available on people who had died prior to programme start. We adopted a mixed retrospective and prospective analysis but this added some difficulty in interpreting the findings. In 2016 resources were repurposed from the cohort study to support recruitment of the RCT, which was behind schedule. The scope of the cohort study was narrowed to focus only on the data available from the screening programme, meaning that we were unable to complete data collection on the patient-centred outcomes after sight-threatening retinopathy had been confirmed, namely treatment and visual impairment. Recruitment of non-attenders proved beyond the resources available and was abandoned. Further research is needed to address these unanswered questions. Methods The programme included the development of a bespoke data warehouse, the development of a risk-calculation engine, a RCT, a within-trial cost-effectiveness study, a qualitative study of acceptability, and an observational cohort study. We recruited and fully embedded a seven-person patient and public involvement group which was maintained throughout the programme. The setting was the screening programme of a single English health district (clinical commissioning group). All people with diabetes aged 12 years and over registered with general practices in the Liverpool city area were invited by letter to participate in the research programme. Consent was through an opt-out process. A purpose-built dynamic data warehouse was developed to support all aspects of the programme including bespoke processes addressing inconsistency in routinely collected data, multiple data platforms and lack of technical manuals. Data on eligible participants were sourced from primary care (demographic, clinical), Liverpool Diabetes Eye Screening Programme (retinopathy) and hospital outcomes (true screen-positive, STDR). Data were cross referenced against opt-out records before further use within the programme. A risk-calculation engine was developed for the assessment of individual risk of progressing to screen-positive using patient-focused covariate selection, a continuous-time Markov model, 5-year historical local population data, and the most recent individual demographic, retina and clinical data. The risk-calculation engine was linked to the data warehouse. The Patient and Public Involvement group determined the risk criterion of

Driving safety analysis has recently experienced unprecedented improvements thanks to technological advances in precise positioning sensors, artificial intelligence (AI)-based safety features, autonomous driving systems, connected vehicles, high-throughput computing, and edge computing servers. Particularly, deep learning (DL) methods empowered volume video processing to extract safety-related features from massive videos captured by roadside units (RSU). Safety metrics are commonly used measures to investigate crashes and near-conflict events. However, these metrics provide limited insight into the overall network-level traffic management. On the other hand, some safety assessment efforts are devoted to processing crash reports and identifying spatial and temporal patterns of crashes that correlate with road geometry, traffic volume, and weather conditions. This approach relies merely on crash reports and ignores the rich information of traffic videos that can help identify the role of safety violations in crashes. To bridge these two perspectives, we define a new set of network-level safety metrics (NSM) to assess the overall safety profile of traffic flow by processing imagery taken by RSU cameras. Our analysis suggests that NSMs show significant statistical associations with crash rates. This approach is different than simply generalizing the results of individual crash analyses, since all vehicles contribute to calculating NSMs, not only the ones involved in crash incidents. This perspective considers the traffic flow as a complex dynamic system where actions of some nodes can propagate through the network and influence the crash risk for other nodes. The analysis is carried out using six video cameras in the state of Arizona along with a 5-year crash report obtained from the Arizona Department of Transportation (ADOT). The results confirm that NSMs modulate the baseline crash probability. Therefore, online monitoring of NSMs can be used by traffic management teams and AI-based traffic monitoring systems for risk analysis and traffic control.

Medical laboratory workers handle clinical specimens, which are a threat of exposure to infectious agents. Notably, medical laboratory science students report for internships with only theoretical knowledge of biosafety and biorisk management practices, predisposing them to a higher risk of laboratory hazards. In this study, we assessed the influence of entry-level students' adherence to practices and attitudes towards biosafety and biorisk management during the Internship. An online survey tool was used to explore the practices and attitudes towards laboratory biosafety and risk management. Of the 96 students, 60 (62.5%) anonymous responses were received, and of these, 60.3% were direct entrants, and 32.8% were diploma entrants. Most (91.7%) of the students attended hospital internships, with 60.2% in Biosafety Level (BSL)-2 laboratories and 70.2% rotating in all the core areas of laboratory medicine. The 8.3% who did not attend any internship were under the direct entry category. Exposure to biohazards was not significantly associated with laboratory safety level and student entry category (P> 0.05). Recommended laboratory biosafety practices were not significantly associated with the safety level of the laboratory and student entry category (P> 0.05). Poor attitudes towards certain laboratory biosafety practices were not significantly associated with the biosafety level of the training laboratory (P> 0.05), whereas training (P = 0.021) and clean-up procedures (P = 0.048) were associated with laboratory safety levels, respectively. The direct entrants had no access to BSL-3 laboratories, and this category of students had a negative attitude towards internship attendance. Therefore, there is a need to create a multi-channel full range laboratory biosafety and biorisk management teaching reforms based on practical application, real case studies, and laboratory simulation to be incorporated into the curriculum to benefit the direct entrant.

Abstract CSL112 (apolipoprotein A‐I [apoA‐I, human]) is a novel drug in development to reduce the risk of recurrent cardiovascular events following acute myocardial infarction by increasing cholesterol efflux capacity (CEC). This phase I study aimed to compare the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of CSL112 in Japanese and White subjects. A total of 34 Japanese subjects were randomized to receive a single infusion of CSL112 (2, 4, or 6 g) or placebo and 18 White subjects were randomized to receive a single dose of 6 g CSL112 or placebo, followed by PK/PD assessment and adverse events monitoring. In addition, PK/PD parameters were compared across the CSL112 clinical development program. Plasma exposure of apoA‐I increased in a dose‐dependent but nonlinear manner in Japanese subjects receiving a single dose of CSL112. Mean baseline‐corrected area under the curve from 0 to 72 h (AUC0–72) increased from 840 to 6490 mg h/dl, in the 2 and 6 g cohorts, respectively, followed by dose‐dependent increase of CEC. The plasma PK profile of apoA‐I and increases in total and ATP binding cassette transporter A1 dependent CEC were comparable in Japanese and White subjects. The geometric mean ratio (Japanese:White) for plasma apoA‐I AUC0–72 and maximum plasma concentration (Cmax) was 1.08 and 0.945, respectively. Cross‐study comparison analysis demonstrated similar CSL112 exposure and CEC enhancement in Japanese and non‐Japanese subjects (including patients with cardiovascular disease) and further confirmed consistent PKs/PDs of CSL112. This study suggests CSL112 acutely enhances CEC and is well‐tolerated with no differences between Japanese and White subjects.

Crop-raiding by elephants is one of the most prevalent forms of human–elephant conflict and is increasing with the spread of agriculture into wildlife range areas. As the magnitude of conflicts between people and elephants increases across Africa and Asia, mitigating and reducing the impacts of elephant crop-raiding has become a major focus of conservation intervention. In this study, we tested the responses of semi-captive elephants to the “smelly” elephant repellent, a novel olfactory crop-raiding mitigation method. At two trial sites, in Zambia and Thailand, African elephants (Loxodonta africana) and Asian elephants (Elephas maximus) were exposed to the repellent, in order to test whether or not they entered an area protected by the repellent and whether they ate the food provided. The repellent elicited clear reactions from both study groups of elephants compared to control conditions. Generalised linear models revealed that the elephants were more alert, sniffed more, and vocalised more when they encountered the repellent. Although the repellent triggered a response, it did not prevent elephants from entering plots protected by the repellent or from eating crops, unlike in trials conducted with wild elephants. Personality played a role in responses towards the repellent, as the elephants that entered the experimental plots were bolder and more curious individuals. We conclude that, although captive environments provide controlled settings for experimental testing, the ecological validity of testing human–elephant conflict mitigation methods with captive wildlife should be strongly considered. This study also shows that understanding animal behaviour is essential for improving human–elephant coexistence and for designing deterrence mechanisms. Appreciating personality traits in elephants, especially amongst “problem” elephants who have a greater propensity to crop raid, could lead to the design of new mitigation methods designed to target these individuals.

Abstract We developed a mathematical model for autologous stem cell therapy to cure sickle cell disease (SCD). Experimental therapies using this approach seek to engraft stem cells containing a curative gene. These stem cells are expected to produce a lifelong supply of red blood cells (RBCs) containing an anti‐sickling hemoglobin. This complex, multistep treatment is expensive, and there is limited patient data available from early clinical trials. Our objective was to quantify the impact of treatment parameters, such as initial stem cell dose, efficiency of lentiviral transduction, and degree of bone marrow preconditioning on engraftment efficiency, peripheral RBC numbers, and anti‐sickling hemoglobin levels over time. We used ordinary differential equations to model RBC production from progenitor cells in the bone marrow, and hemoglobin assembly from its constituent globin monomers. The model recapitulates observed RBC and hemoglobin levels in healthy and SCD phenotypes. Treatment simulations predict dynamics of stem cell engraftment and RBC containing the therapeutic gene product. Post‐treatment dynamics show an early phase of reconstitution due to short lived stem cells, followed by a sustained RBC production from stable engraftment of long‐term stem cells. This biphasic behavior was previously reported in the literature. Sensitivity analysis of the model quantified relationships between treatment parameters and efficacy. The initial dose of transduced stem cells, and the intensity of myeloablative bone marrow preconditioning are predicted to most positively impact long‐term outcomes. The quantitative systems pharmacology approach used here demonstrates the value of model‐assisted therapeutic design for gene therapies in SCD.

A teoria arquivística muitas vezes é trivial, exagerada, desnecessária ou irrelevante. Embora a teoria em outras disciplinas possa produzir novos pensamentos e estimular o progresso intelectual, a teoria arquivística não pode desempenhar um papel análogo e não pode promover a profissão arquivística. Ela tende a simplificar em excesso o que é complicado e complicar além da medida o que é simples. Muitas teorias arquivísticas são relações públicas de Babbitry que ameaçam estratificar excessivamente a profissão.

The tropical savanna in Brazil known as the Cerrado covers circa 23% of the Brazilian territory, but only 3% of this area is protected. High rates of deforestation and degradation in the woodland and forest areas have made the Cerrado the second-largest source of carbon emissions in Brazil. However, data on these emissions are highly uncertain because of the spatial and temporal variability of the aboveground biomass (AGB) in this biome. Remote-sensing data combined with local vegetation inventories provide the means to quantify the AGB at large scales. Here, we quantify the spatial distribution of woody AGB in the Rio Vermelho watershed, located in the centre of the Cerrado, at a high spatial resolution of 30 metres, with a random forest (RF) machine-learning approach. We produced the first high-resolution map of the AGB for a region in the Brazilian Cerrado using a combination of vegetation inventory plots, airborne light detection and ranging (LiDAR) data, and multispectral and radar satellite images (Landsat 8 and ALOS-2/PALSAR-2). A combination of random forest (RF) models and jackknife analyses enabled us to select the best remote-sensing variables to quantify the AGB on a large scale. Overall, the relationship between the ground data from vegetation inventories and remote-sensing variables was strong (R2 = 0.89), with a root-mean-square error (RMSE) of 7.58 Mg ha−1 and a bias of 0.43 Mg ha−1.