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Total knee arthroplasty (TKA) is a common surgery for osteoarthritis, with increasing prevalence expected in the near future. This systematic review and meta‐analysis compared the effectiveness of computerized TKA versus traditional TKA, focusing on postoperative outcomes measured by the Western Ontario and McMaster Universities osteoarthritis index (WOMAC) and the Knee Society score (KSS). A search on PubMed and Cochrane databases on November 14, 2023 for retrospective randomized controlled trials (RCTs) yielded data on WOMAC and KSS. The search strategy was predefined, and methodological quality of studies was critically appraised. Two researchers extracted data. Unpaired t‐testing assessed the mean monthly changes in KSS and WOMAC for computer‐aided versus traditional TKA. Review Manager 5.3 was used for data synthesis and analysis. Out of 729 records, five RCTs enrolling 339 patients were eligible and analyzed using a random effects meta‐analysis. The mean monthly ΔKSS score differed significantly between the traditional and computerized groups (11.47 ± 8.76 vs. 9.26 ± 6.05, respectively; p

Abstract Background Tumor recurrence remains the main barrier to survival after surgery for pleural mesothelioma (PM). Soluble mesothelin‐related protein (SMRP) and cancer antigen 125 (CA‐125) are established blood‐based biomarkers for monitoring PM. We prospectively studied the utility of these biomarkers after pleurectomy decortication (PD). Methods Patients who underwent PD and achieved complete macroscopic resection with available preoperative SMRP levels were included. Tumor marker levels were determined within 60 days of three timepoints: (1) preoperation, (2) post‐operation, and (3) recurrence. Results Of 356 evaluable patients, 276 (78%) had recurrence by the end of follow‐up interval. Elevated preoperative SMRP levels were associated with epithelioid histology (p

Abstract Atrial fibrillation (AF) recurrence has become common in patients who have undergone catheter ablation. High neutrophil lymphocyte ratios (NLR) have been linked to an increased risk of recurrent AF. The research is, however, not conclusive. This meta‐analysis addressed the value of easily accessible and affordable pre‐ and postablation NLR levels as indicators of AF recurrence in patients who had undergone ablation. We searched PubMed, SCOPUS, and Google Scholar for pertinent studies through May 2023. Using random effects models, the aggregated odds ratio (OR) of pre‐ and post‐NLR and AF recurrence was estimated. Inter‐study heterogeneity was described using I2 statistics and leave‐one‐out sensitivity analysis. A p‐value

Abstract The concept of ‘peopled landscapes’ is based on the notion that it is not possible, nor socially or politically desirable, to remove people from the environment in the era of the Anthropocene. As such, it is necessary to document and develop ways to coexist and flourish. This review examines emergent scholarship about peopled landscapes and biodiversity conservation by considering invasive plant management and rewilding as social processes. While invasive plant management and rewilding are often understood as separate, thinking through social scientific research and examples from Australia and the UK, we demonstrate how both forms of human action in landscapes can be more usefully understood as social relations with nature involving social change and social action. Drawing attention to agency, practices and capacity, we show how diverse forms of human and nonhuman actions are recognised, attributed or acknowledged in biodiversity conservation in peopled landscapes. In practice, centring the idea of peopled landscapes (rather than conceiving of the environment as where the impact of people is minimised) shows how invasive plant management and rewilding can be understood as related responses to environmental problems. Flourishing and coexistence in peopled landscapes require recognition of the diverse human and nonhuman agencies that shape the politics of acceptable action, and illustrate the inseparability of environmental and social justice. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Following the recent rejection of a formal Anthropocene series/epoch by the Subcommission on Quaternary Stratigraphy (SQS) of the International Commission on Stratigraphy (ICS), and its subsequent confirmation by the International Union of Geological Sciences (IUGS), the opportunity arises to reset the definition of the Anthropocene. The case for informally recognizing the Anthropocene to be a major planetary event of Earth system transformation offers a promising way forward, but this has been criticized by proponents of an Anthropocene series/epoch. In order to move on from the assumption that it must be a time interval, and to foster a more transdisciplinary and inclusive approach, the main points of the critique must be directly addressed.

Abstract Introduction Cabotegravir plus rilpivirine (CAB + RPV) is the first complete long‐acting (LA) regimen recommended for maintaining HIV‐1 virological suppression. Cabotegravir And Rilpivirine Implementation Study in European Locations (CARISEL) is an implementation–effectiveness study examining the implementation of CAB+RPV LA administered every 2 months (Q2M) in European HIV centres. We present staff study participant (SSP) perspectives on the administration of CAB+RPV LA over 12 months. Methods Eighteen clinics were randomized to one of two implementation support packages: standard arm (Arm‐S) or enhanced arm (Arm‐E). Arm‐S included video injection training and provider/patient toolkits. Additionally, Arm‐E included skilled wrap‐around team meetings, face‐to‐face injection training and continuous quality improvement (CQI) calls. SSPs completed surveys on the acceptability, appropriateness and feasibility of CAB+RPV LA as an intervention and its implementation into their clinics, as well as barriers and facilitators to implementation. All surveys were completed at Month (M)1 (baseline), M5 and M12; data collection was completed by February 2022. Qualitative data were obtained from semi‐structured interviews at M1, M5 and M12. The primary objective was assessed via formal statistical comparisons between study arms of the Acceptability of Implementation Measure, Implementation Appropriateness Measure and Feasibility of Implementation Measure surveys (1–5 Likert scale ranging from 1 = “completely disagree” to 5 = “completely agree”). Equivalent measures anchored to CAB+RPV LA as a therapy were also assessed. Results Seventy SSPs completed surveys and interviews at M1, 68 at M5 and 62 at M12. Mean acceptability/appropriateness/feasibility scores were ≥3.8 (out of 5) at M12 for implementation‐ and intervention‐based measures. An analysis of covariance showed no significant differences between study arms for these outcomes. Although barriers were noted, most SSPs were not overly concerned that these would impact implementation; concern about these anticipated barriers also decreased over time. At M12, 90.3% (n = 56/62) of SSPs held a positive opinion about CAB+RPV LA implementation. Qualitative interviews and CQI calls highlighted three top practices that supported implementation: implementation planning; education about CAB+RPV LA clinical efficacy; and education around administering injections and managing pain/discomfort after injections. Conclusions CARISEL demonstrated that CAB+RPV LA dosed Q2M was successfully implemented across a range of European locations, with SSPs finding implementation highly acceptable, appropriate and feasible. ClinicalTrials.gov number NCT04399551

Background Early age at menarche (AAM) has been associated with a higher risk of carotid artery intima‐media thickness (cIMT), an indicator of subclinical vascular disease, albeit the mechanisms underlying this association remain elusive. A better understanding of the relationship between AAM, modifiable cardiometabolic risk factors, and subclinical atherosclerosis may contribute to improved primary prevention and cardiovascular disease treatment. We aimed to investigate the putative causal role of AAM on cIMT, and to identify and quantify the potentially mediatory effects of cardiometabolic risk factors underlying this relationship. Methods and Results We conducted linkage disequilibrium score regression analyses between our exposure of interest, AAM, our outcome of interest, cIMT and potential mediators of the AAM‐cIMT association to gauge cross‐trait genetic overlap. We considered as mediators the modifiable anthropometric risk factors body mass index (BMI), systolic blood pressure (SBP), lipid traits (total cholesterol, triglycerides, high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol), and glycemic traits (fasting glucose). We then leveraged the paradigm of Mendelian randomization to infer causality between AAM and cIMT, and to identify whether cardiometabolic risk factors served as potential mediators of this effect. Our analyses showed that genetically predicted AAM was inversely associated with cIMT, BMI, SBP, and triglycerides, and positively associated with high‐density lipoprotein, low‐density lipoprotein, and total cholesterol. We showed that the effect of genetically predicted AAM on cIMT may be partially mediated through BMI (20.1% [95% CI, 1.4% to 38.9%]) and SBP (13.5% [95% CI, 0.5%–26.6%]). Our cluster‐specific Mendelian randomization revealed heterogeneous causal effect estimates of age at menarche on BMI and SBP. Conclusions We highlight supporting evidence for a potential causal association between earlier AAM and cIMT, and almost one third of the effect of AAM on cIMT may be mediated by BMI and SBP. Early intervention aimed at lowering BMI and hypertension may be beneficial in reducing the risk of developing subclinical atherosclerosis due to earlier age at menarche.

Abstract The modification of landscapes is increasing the interface between humans and wildlife, while conflicts concerning predator impacts on human activities persist. Some previously persecuted but now protected predator species are experiencing recovery and range expansion. Tolerance is considered essential for achieving coexistence between humans and wildlife; however, its conceptualisation remains unresolved. Little is known about tolerance in the context of recovering predators, particularly which drivers are relevant to all or specific species and human interests. Using an online questionnaire survey shared with members of organisations with interests in rural land‐based activities, we collected data on interests and beliefs, and attitudes, perceptions, experience and management preferences for six recovering vertebrate predators in the United Kingdom (n = 819). We created a species tolerance score representing the management choices of the respondents in different conflict scenarios, which differed in the degree of impact on the predator population. Our species tolerance score was characterised by a complex combination of the interests and beliefs of the respondents about wildlife management, perceptions and experience of that species (perceived benefits, population trend, positive and negative experience, indirect negative experience) and negative experience of other recovering predators. We found a tolerance gradient between interest groups with notable overlap between groups with primary interests in wildlife conservation, shooting, farming and fishing. Although higher perceived benefits consistently corresponded to higher tolerance, having a negative experience of the species dampened the effect of perceived benefits on tolerance. When both negative personal and indirect experiences were reported, tolerance was dramatically reduced. The classification of species from least to most tolerated was consistent between interest groups. The application of our species tolerance score as the normative dimension (i.e. acceptability) in Brenner and Metcalf's (2020) Social Tolerance of Wildlife Framework highlights that tolerance (negative attitude—high acceptability) is potentially rare and more positive attitudes must be achieved before acceptance of the impacts of species can increase. Our findings highlight that considering only primary interests may hinder debates concerning recovering predators. Strategies to reduce negative experiences or change how they are perceived could significantly increase tolerance in combination with increasing positive experiences. Read the free Plain Language Summary for this article on the Journal blog.

Key Clinical Message The case highlights an unusual presentation where sleep issues preceded psychotic symptoms, implying link between disrupted sleep and psychosis onset. Earlier symptoms were viewed as depression but may have signaled psychosis exacerbated by insomnia. Abstract Sleep disorders, prevalent yet frequently overlooked in individuals with psychotic disorders, have significant associations with the onset and severity of psychosis. Here we describe the case of a patient who first presented with insomnia, but whose condition improved with the use of risperidone and was diagnosed with first‐episode psychosis. Multiple studies emphasize the critical relationship between sleep disturbances and psychosis, particularly in the lead‐up to first‐episode psychosis. Structural abnormalities in the brain, notably the thalamus, combined with neurotransmitter imbalances involving dopamine and acetylcholine, seem pivotal in this interrelation. The connection between dopamine, sleep disturbances, and psychosis, specifically the role of D2 dopamine receptors, highlights a potential pathway bridging sleep irregularities with psychosis. The study underscores the need for further research to delineate the relationship between sleep disturbances and psychosis and to assess the efficacy of various therapeutic interventions targeting both conditions.

Abstract Background and Aims To determine the level of diagnostic agreement between remote and face‐to‐face consultation in assessing shoulder complaints. Methods A retrospective service evaluation with three groups of patient data; those assessed only face‐to‐face (group 1), remotely then face‐to‐face (group 2), remotely only (group 3). Patient data were extracted from 6 secondary care shoulder Advanced Physiotherapy Practitioner's (APPs) records, covering six sites. Three‐hundred‐and‐fifty‐nine sets of patient data were included in the final evaluation. The main outcome measure was the percentage of agreement between diagnosis at initial and follow‐up consultation, when assessed by APPs across the three groups. A Pearson χ2 test was used to assess the relationship between the method of consultation and the level of diagnostic agreement. Diagnoses were categorized as either the same, similar, or different by an independent APP. Secondary outcome measures investigated whether age or the length of time between appointments had any effect in determining the level of diagnostic concordance. Results There was exact agreement of 77.05% and 85.52% for groups 1 and 3, respectively, compared with 34.93% for patient data in group 2. Similar clinical impressions across both initial and follow‐up were seen 16.39% of the time in group 1, 7.24% of the time in group 3, and 36.99% in group 2. Lastly, the percentage of times a diagnosis was changed between initial and review appointments occurred in only 6.56% of group 1 contacts, 7.24% of group 3 contacts, but 28.08% of the time in group 2. Conclusion There was a large mismatch in the diagnosis of musculoskeletal shoulder complaints, when patients are initially assessed remotely and then followed‐up in‐person. This has implications for the future provision of shoulder assessment in physiotherapy.

Abstract Aims To evaluate a whole‐food diet strategy (the Monash Pouch diet [MPD]) designed based on the interacting roles dietary factors play with pouch health. Specifically, its tolerability and acceptability, whether it achieved its dietary and metabolic goals, and the effects on symptoms and inflammation were examined. Methods In a 6‐week open‐label trial, patients with ileoanal pouches educated on the MPD were assessed regarding diet tolerability and acceptance, food intake (7‐day food diaries), pouch‐related symptoms (clinical pouchitis disease activity index), and, in 24‐h fecal samples, calprotectin, fermentative biomarkers, and volatile organic compounds (VOC). Results Of 12 patients, 6 male, mean (SD) age 55 (5) and pouch age 13 (2) years, one withdrew with partial small bowel obstruction. Tolerability was excellent in 9 (75%) and acceptance was high (81%). Targeted changes in dietary intake were achieved. Fecal branched‐ to short‐chain fatty acid ratio increased by median 60 [IQR: 11–80]% (P = 0.02). Fecal VOCs for 3 compounds were also increased, 2‐methyl‐5‐propan‐2‐ylcyclohexa‐1,3‐diene (Fold‐change [FC] 2.08), 1,3,3‐trimethyl‐2‐oxabicyclo[2.2.2]octane (FC 3.86), propan‐2‐ol (FC 2.10). All six symptomatic patients achieved symptomatic remission (P = 0.03). Fecal calprotectin at baseline was 292 [176–527] μg/g and at week 5 was 205 [148–310] μg/g (P = 0.72). Conclusion Well tolerated and accepted, the MPD achieved targeted changes in intakes and fermentation of carbohydrates relative to that of protein. There were signals of improvement in symptoms. These results indicate the need for a randomized‐controlled trial. (Trial registration: ACTRN12621000374864; https://www.anzctr.org.au/ACTRN12621000374864.aspx).

Abstract Aims This study compared those living with and without an intestinal stoma in relation to physical and psychological health, stress and coping, quality of life and resilience. Also, identifying factors that could be used to promote better self‐care in stoma patients in the future. Design A cross‐sectional and comparative study design was employed. Methods Participants were recruited via email and social media (Facebook and Twitter) between August 2018 and March 2019, to complete an online survey. The data were analysed using analysis of variance to examine group difference and a series of hierarchical linear regression analyses determining predictors of psychological well‐being. Results Of 278 participants aged 18–68 years who completed the survey, 129 (46%) had a stoma and reported significantly poorer physical health. Approximately one‐fifth experienced problems with stoma management. Psychological well‐being was mediated by the duration of living with a stoma (under 3 years) and frequency of leaks (weekly and monthly).

Abstract The usual procedure for extracting ocean surface information from data acquired from a high‐frequency surface wave radar transmitting from a floating platform is to first compensate for the motion of the antenna in the acquired motion‐contaminated Doppler spectrum and then extract the ocean wave parameters from the motion‐compensated result. The authors propose a new real‐time method to estimate the significant wave height directly from the antenna's received electric field in the time‐domain without requiring prior knowledge of the motion parameters or performing motion compensation. Based on the relation between the ocean surface displacement and the received electric field, this method calculates the significant wave height from the windowed variance of the upper envelope of the received electric field. A preliminary calibration is required, which can be carried out either by the deployment of a wave buoy or by analysing the data over a time period during which the sea state varies. The results from this simple proposed technique show that it may be used to estimate the significant wave height with a root‐mean‐square error (RMSE) between 10 and 14 cm over a wide range of significant wave height values.

Abstract Background and Aims Fontan‐associated liver disease (FALD) is a long‐term complication of the Fontan procedure. Guidelines recommend elastography, but the utility of transient elastography (TE) and two‐dimensional shear wave elastography (2D SWE) is unknown. We aimed to evaluate the relationship between TE and 2D SWE in FALD. Methods This prospective cohort study included 25 patients managed in a specialist clinic between January 2018 and August 2021. Trained clinicians performed 2D SWE (GE Logiq‐E9) and TE (FibroScan 503 Touch) on the same day under the same conditions. Laboratory, echocardiography, and imaging data were collected. The atrioventricular systolic‐to‐diastolic duration (AVV S/D ratio) was calculated as a measure of cardiac diastolic function. Results We analyzed 40 paired measurements. Median age was 22 years. Median liver stiffness measurement (LSM) was 15.4 kPa (12.1–19.6) by TE and 8.0 kPa (7.0–10.3) (P = 0.001) by 2D SWE. There was weak correlation between the modalities (r = 0.41, P = 0.004). There was no correlation between time since Fontan and LSM by TE (r = 0.15, P = 0.19) or 2D SWE (r = 0.19, P = 0.13). There was no difference in LSM irrespective of whether sonographic cirrhosis was present or absent by TE (17.4 kPa [15.9–23.6] vs. 14.9 kPa [12.0–19.4], respectively, P = 0.6) or 2D SWE (9.0 kPa [2.8–10.5] vs. 8.0 kPa [6.7–10.1], P = 0.46). There was no correlation between AVV S/D ratio and LSM by TE (r = 0.16, P = 0.18) or 2D SWE (r = 0.02, P = 0.45). Conclusions In FALD, TE and 2D SWE are poorly correlated. LSM by either modality was not associated with known risk factors for liver fibrosis or Fontan function. Based on these data, the role of elastography in FALD is uncertain.

Abstract Cannabis sativa L. is a versatile crop attracting increasing attention for food, fiber, and medical uses. As a dioecious species, males and females are visually indistinguishable during early growth. For seed or cannabinoid production, a higher number of female plants is economically advantageous. Currently, sex determination is labor‐intensive and costly. Instead, we used rapid and non‐destructive hyperspectral measurement, an emerging means of assessing plant physiological status, to reliably differentiate males and females. One industrial hemp (low tetrahydrocannabinol [THC]) cultivar was pre‐grown in trays before transfer to the field in control soil. Reflectance spectra were acquired from leaves during flowering and machine learning algorithms applied allowed sex classification, which was best using a radial basis function (RBF) network. Eight industrial hemp (low THC) cultivars were field grown on fertilized and control soil. Reflectance spectra were acquired from leaves at early development when the plants of all cultivars had developed between four and six leaf pairs and in three cases only flower buds were visible (start of flowering). Machine learning algorithms were applied, allowing sex classification, differentiation of cultivars and fertilizer regime, again with best results for RBF networks. Differentiating nutrient status and varietal identity is feasible with high prediction accuracy. Sex classification was error‐free at flowering but less accurate (between 60% and 87%) when using spectra from leaves at early growth stages. This was influenced by both cultivar and soil conditions, reflecting developmental differences between cultivars related to nutritional status. Hyperspectral measurement combined with machine learning algorithms is valuable for non‐invasive assessment of C. sativa cultivar and sex. This approach can potentially improve regulatory security and productivity of cannabis farming.

Abstract Calls for using marine protected areas (MPAs) to achieve goals for nature and people are increasing globally. While the conservation and fisheries impacts of MPAs have been comparatively well‐studied, impacts on other dimensions of human use have received less attention. Understanding how humans engage with MPAs and identifying traits of MPAs that promote engagement is critical to designing MPA networks that achieve multiple goals effectively, equitably and with minimal environmental impact. In this paper, we characterize human engagement in California's MPA network, the world's largest MPA network scientifically designed to function as a coherent network (124 MPAs spanning 16% of state waters and 1300 km of coastline) and identify traits associated with higher human engagement. We assemble and compare diverse indicators of human engagement that capture recreational, educational and scientific activities across California's MPAs. We find that human engagement is correlated with nearby population density and that site “charisma” can expand human engagement beyond what would be predicted based on population density alone. Charismatic MPAs tend to be located near tourist destinations, have long sandy beaches and be adjacent to state parks and associated amenities. In contrast, underutilized MPAs were often more remote and lacked both sandy beaches and parking lot access. Synthesis and applications: These results suggest that achieving MPA goals associated with human engagement can be promoted by developing land‐based amenities that increase access to coastal MPAs or by locating new MPAs near existing amenities during the design phase. Alternatively, human engagement can be limited by locating MPAs in areas far from population centres, coastal amenities or sandy beaches. Furthermore, managers may want to prioritize monitoring, enforcement, education and outreach programmes in MPAs with traits that predict high human engagement. Understanding the extent to which human engagement impacts the conservation performance of MPAs is a critical next step to designing MPAs that minimize tradeoffs among potentially competing objectives. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Introduction Patients living in rural areas have worse cancer‐specific outcomes. This study examines the effect of family‐based social capital on genitourinary cancer survival. We hypothesized that rural patients with urban relatives have improved survival relative to rural patients without urban family. Methods We examined rural and urban based Utah individuals diagnosed with genitourinary cancers between 1968 and 2018. Familial networks were determined using the Utah Population Database. Patients and relatives were classified as rural or urban based on 2010 rural–urban commuting area codes. Overall survival was analyzed using Cox proportional hazards models. Results We identified 24,746 patients with genitourinary cancer with a median follow‐up of 8.72 years. Rural cancer patients without an urban relative had the worst outcomes with cancer‐specific survival hazard ratios (HRs) at 5 and 10 years of 1.33 (95% CI 1.10–1.62) and 1.46 (95% CI 1.24–1.73), respectively relative to urban patients. Rural patients with urban first‐degree relatives had improved survival with 5‐ and 10‐year survival HRs of 1.21 (95% CI 1.06–1.40) and 1.16 (95% CI 1.03–1.31), respectively. Conclusions Our findings suggest rural patients who have been diagnosed with a genitourinary cancer have improved survival when having relatives in urban centers relative to rural patients without urban relatives. Further research is needed to better understand the mechanisms through which having an urban family member contributes to improved cancer outcomes for rural patients. Better characterization of this affect may help inform policies to reduce urban–rural cancer disparities.

Background Identifying novel molecular drivers of disease progression in heart failure (HF) is a high‐priority goal that may provide new therapeutic targets to improve patient outcomes. The authors investigated the relationship between plasma proteins and adverse outcomes in HF and their putative causal role using Mendelian randomization. Methods and Results The authors measured 4776 plasma proteins among 1964 participants with HF with a reduced left ventricular ejection fraction enrolled in PHFS (Penn Heart Failure Study). Assessed were the observational relationship between plasma proteins and (1) all‐cause death or (2) death or HF‐related hospital admission (DHFA). The authors replicated nominally significant associations in the Washington University HF registry (N=1080). Proteins significantly associated with outcomes were the subject of 2‐sample Mendelian randomization and colocalization analyses. After correction for multiple testing, 243 and 126 proteins were found to be significantly associated with death and DHFA, respectively. These included small ubiquitin–like modifier 2 (standardized hazard ratio [sHR], 1.56; P

Abstract Migratory species inhabit many communities along their migratory routes. Across taxa, these species repeatedly move into and out of communities, interacting with each other and locally breeding species and competing for resources and niche space. However, their influence is rarely considered in analyses of ecological processes within the communities they temporarily occupy. Here, we explore the impact of migratory species on a breeding community using the framework of acoustic signal space, a limited resource in which sounds of species within communities co‐exist. Migrating New World warblers (Parulidae, hereafter referred to as migrant species) often sing during refueling stops in areas and at times during which locally breeding warbler species (hereafter breeding species) are singing to establish territories and attract mates. We used eBird data to determine the co‐occurrence of 19 migrant and 11 breeding warbler species across spring migration in SW Michigan, generated a signal space from song recordings of these species, and examined patterns of signaling overlap experienced by breeding species as migrants moved through the community. Migrant species were present for two‐thirds of the breeding season of local species, including periods when breeding species established territories and attracted mates. Signaling niche overlap experienced by individual breeding species was idiosyncratic and varied over time, yet niche overlap between migrant and breeding species occurred more commonly than between breeding species or between migrant species. Nevertheless, the proportion of niche overlap between migrant and breeding warblers was similar to overlap among breeding species. Our findings showed that singing by migrant species overlapped the signals of many breeding species, suggesting that migrants could have unexplored impacts on communication in breeding species, potentially affecting song detection and song evolution. Our study contributes to a growing body of research documenting the impacts of migratory species on communities and ecosystems.

Abstract Conservation translocations often inherently involve a risk of genetic diversity loss, and thus loss of adaptive potential, but this risk is rarely quantified or monitored through time. The reintroduction of beavers to Scotland, via the Scottish Beaver Trial in Knapdale, is an example of a translocation that took place in the absence of genetic data for the founder individuals and resulted in a small and suspected to be genetically depauperate population. In this study we use a high‐density SNP panel to assess the genetic impact of that initial translocation and the effect of subsequent reinforcement translocations using animals from a different genetic source to the original founders. We demonstrate that the initial translocation did, indeed, lead to low genetic diversity (Ho = 0.052) and high mean kinship (KING‐robust = 0.159) in the Knapdale population compared to other beaver populations. We also show that the reinforcement translocations have succeeded in increasing genetic diversity (Ho = 0.196) and reducing kinship (KING robust = 0.028) in Knapdale. As yet, there is no evidence of admixture between the two genetic lineages that are now present in Knapdale and such admixture is necessary to realise the full genetic benefits of the reinforcement and for genetic reinforcement and then rescue to occur; future genetic monitoring will be required to assess whether this has happened. We note that, should admixture occur, the Knapdale population will harbour combinations of genetic diversity not currently seen elsewhere in Eurasian beavers, posing important considerations for the future management of this population. We consider our results in the wider context of beaver conservation throughout Scotland and the rest of Britain, and advocate for more proactive genetic sampling of all founders to allow the full integration of genetic data into translocation planning in general.

Abstract Aim The aim of the study was to assess the suitability of an online education package to prepare health professionals to use a new paediatric early warning system. Design Quasi‐experimental mixed methods using co‐production. Methods Participants completed the Package and participated in up to four clinical scenarios. Data were collected using self‐report surveys, and during clinical scenarios; escalation of care, documentation, family involvement, communication handovers were assessed, and recorded debriefings were thematically analysed. Data were integrated using tabulated joint displays. Results Eleven nurses and three doctors were recruited from three mixed adult and paediatric hospitals. Following completion of the Package and clinical scenarios 13/14 (93%) participants agreed preparedness and confidence to use the ESCALATION System had increased. For 53% handovers, the communication framework was followed, for 79% charts, documentation was complete. Participants engaged with the parent (actor) for 97% scenario interactions. The Package was effective and participation in clinical scenarios appeared to enhance learning. Patient or public contribution Consumers participated in the steering group overseeing the study and in the expert panel who reviewed the education package and clinical scenarios.

Background. Hypertension (HTN) is a growing public health concern affecting both economically developed and developing nations. In Ghana, HTN significantly impacts morbidity and mortality. Understanding the perspectives of HTN patients regarding its causes and treatment can enhance HTN management. This study explored patient perspectives on HTN in Ghana. Materials and Methods. An exploratory descriptive approach was used, in conducting in-depth interviews and focus group discussions. Purposeful sampling was used to select HTN patients, and thematic content analysis was employed for data analysis. Overall, 14 face-to-face interviews were carried out, and two FGDs were done. The FGD consisted of a total of 15 participants, 8 females and 7 males. Results. Four key perspectives emerged. These include (1) the description of HTN (patients defined HTN as excessive blood); (2) beliefs about the causes of HTN, some attributed HTN to witchcraft, considering it a curse from the gods and traditional medicine was seen as a potential cure; (3) health-seeking behavior, a notable discrepancy exists between patient and medical understandings of HTN, potentially causing healthcare delays; and (4) family support. Recommendation. The misunderstanding of HTN may hinder timely healthcare-seeking and medication adherence, exacerbating HTN-related complications. Addressing these beliefs through community health promotion programs is urgently needed.

The rapid advancement and widespread adoption of voice assistance technology have shown promise in benefiting individuals with disabilities, offering increased social participation, independence, and leisure activities. However, barriers to their full utilization have been identified, leading to potential abandonment by users with disabilities. This rapid review is aimed at filling the gap in the literature by investigating the utilization of voice assistants among people with disabilities for independent living and community participation. A comprehensive search was conducted in academic literature databases, including PubMed, Embase, and Web of Science, and gray data was sourced from public social media domains through Infegy. The analysis included 48 articles and 281 social media posts that met the inclusion criteria. Neurodiversity, disabilities affecting vision, and general disabilities were the most frequently discussed categories in both sources. The most common tasks performed using voice assistants were interface control, reminders, and environmental control, with a focus on enabling independence. Barriers to use mentioned in the literature included cognitive load during use, speech interpretation, lack of nonverbal control, and privacy concerns, while gray data reported limited functionality and speech interpretation as primary barriers. Amazon Alexa was the most discussed brand in both sources. The findings highlight the need for further research and innovation to fully harness the potential benefits of voice assistants for individuals with disabilities. By addressing the identified barriers and tailoring voice assistance technology to cater to the specific needs of different disability types, this technology can become a powerful tool for enhancing the lives of individuals with disabilities and promoting greater independence and community participation.

Background The American Heart Association's Life's Simple 7, a public health construct capturing key determinants of cardiovascular health, became the Life's Essential 8 after the addition of sleep duration. The authors tested the hypothesis that suboptimal sleep duration is associated with poorer neuroimaging brain health profiles in asymptomatic middle‐aged adults. Methods and Results The authors conducted a prospective magnetic resonance neuroimaging study in middle‐aged individuals without stroke or dementia enrolled in the UK Biobank. Self‐reported sleep duration was categorized as short (

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies in the world, for which the mortality is almost as high as the disease incidence and is predicted to be the second‐highest cause of cancer‐related deaths by 2030. These cancerous tumors consist of diversified gene expressions within the different cellular subpopulations that include neoplastic ductal cells, cancer‐associated fibroblasts, and immune cells, all of which collectively facilitate cellular heterogeneity in the PDAC tumor microenvironment (TME). Active intratumoral interaction within the cell populations in TME induces the proliferation of cancerous cells, accounting for tumorigenesis and rapid metastasis. Methods This review will focus on novel findings uncovering PDAC heterogeneity in different cellular subpopulations using single‐cell RNA‐sequencing (scRNA‐seq) and other single‐cell analysis technologies. It will further explore the emerging role of single‐cell technologies in assessing the role of different subpopulations of neoplastic ductal cells, cancer‐associated fibroblasts, and immune cells in PDAC progression. Results and Conclusion The application of scRNA‐seq in PDAC has started to unveil associations between disease progression and heterogeneity in pancreatic TME and could influence future PDAC treatment. Recent advances in scRNA‐seq have uncovered comprehensive analyses of heterogeneous ecosystems present within the TME. These emerging findings underpins further need for a more in‐depth understanding of intratumoral heterogeneity in the PDAC microenvironment.

Abstract Aim Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all major cancers. Chemotherapy is the mainstay systemic therapy for PDAC, and chemoresistance is a major clinical problem leading to therapeutic failure. This study aimed to identify key differences in gene expression profile in tumors from chemoresponsive and chemoresistant patients. Methods Archived formalin‐fixed paraffin‐embedded tumor tissue samples from patients treated with neoadjuvant chemotherapy were obtained during surgical resection. Specimens were macrodissected and gene expression analysis was performed. Multi‐ and univariate statistical analysis was performed to identify differential gene expression profile of tumors from good (0%–30% residual viable tumor [RVT]) and poor (>30% RVT) chemotherapy‐responders. Results Initially, unsupervised multivariate modeling was performed by principal component analysis, which demonstrated a distinct gene expression profile between good‐ and poor‐chemotherapy responders. There were 396 genes that were significantly (p

Abstract Mouse models are helpful in unveiling the mechanisms underlying sex disparities in asthma. In comparison to their female counterparts, male mice are hyperresponsive to inhaled methacholine, a cardinal feature of asthma that contributes to its symptoms. The physiological details and the structural underpinnings of this hyperresponsiveness in males are currently unknown. Herein, BALB/c mice were exposed intranasally to either saline or house dust mite once daily for 10 consecutive days to induce experimental asthma. Twenty‐four hours after the last exposure, respiratory mechanics were measured at baseline and after a single dose of inhaled methacholine that was adjusted to trigger the same degree of bronchoconstriction in both sexes (it was twice as high in females). Bronchoalveolar lavages were then collected, and the lungs were processed for histology. House dust mite increased the number of inflammatory cells in bronchoalveolar lavages to the same extent in both sexes (asthma, P = 0.0005; sex, P = 0.96). The methacholine response was also markedly increased by asthma in both sexes (e.g., P = 0.0002 for asthma on the methacholine‐induced bronchoconstriction). However, for a well‐matched bronchoconstriction between sexes, the increase in hysteresivity, an indicator of airway narrowing heterogeneity, was attenuated in males for both control and asthmatic mice (sex, P = 0.002). The content of airway smooth muscle was not affected by asthma but was greater in males (asthma, P = 0.31; sex, P < 0.0001). These results provide further insights regarding an important sex disparity in mouse models of asthma. The increased amount of airway smooth muscle in males might contribute functionally to their greater methacholine response and, possibly, to their decreased propensity for airway narrowing heterogeneity.

Abstract Objective Infection‐triggered encephalopathy syndromes (ITES) are potentially devastating neuroinflammatory conditions. Although some ITES syndromes have recognisable MRI neuroimaging phenotypes, there are otherwise few biomarkers of disease. Early detection to enable immune modulatory treatments could improve outcomes. Methods We measured CSF neopterin, quinolinic acid, kynurenine and kynurenine/tryptophan ratio using a liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) system. The CSF of 18 children with ITES were compared with acute encephalitis (n = 20), and three control groups, namely epilepsy (n = 20), status epilepticus (n = 18) and neurogenetic controls (n = 20). Results The main ITES phenotypes in 18 patients were acute encephalopathy with biphasic seizures and late restricted diffusion (AESD, n = 4), febrile infection‐related epilepsy syndrome (FIRES n = 4) and other ITES phenotypes. Influenza A was the most common infectious trigger (n = 5), and 50% of patients had a preceding notable neurodevelopmental or family history. CSF neopterin, quinolinic acid and kynurenine were elevated in ITES group compared to the three control groups (all p

Axial spondyloarthritis (axSpA) is a chronic, immune‐mediated disease characterized by inflammatory axial skeleton involvement and extra‐musculoskeletal manifestations. The continuum of axSpA ranges from nonradiographic axSpA (nr‐axSpA) to ankylosing spondylitis, also known as radiographic axSpA; the latter is defined by definitive radiographic sacroiliitis. Human leukocyte antigen B27 (HLA‐B27) is a genetic marker strongly associated with axSpA; it aids in the diagnosis of axSpA, and its absence leads to delay in diagnosis. For HLA‐B27‐negative patients, disease pathogenesis is poorly understood, signs and symptoms are frequently underrecognized, and diagnosis and treatment are commonly delayed. The proportion of HLA‐B27‐negative patients may be higher among non‐White patients and those with nr‐axSpA, who can face additional diagnostic challenges related to lack of definitive radiographic sacroiliitis. In this narrative review, we discuss the role of HLA‐B27 in the diagnosis and pathogenesis of axSpA and highlight various pathways and genes that may be related to axSpA pathogenesis in HLA‐B27‐negative patients. We also emphasize the need to characterize gut microbial communities in these patients. Adequate understanding of clinical and pathological features underlying HLA‐B27‐negative patients with axSpA will improve diagnosis, treatment, and outcomes for this complex inflammatory disease.

Abstract Kratom is a widely used Asian botanical that has gained popularity in the United States due to a perception that it can treat pain, anxiety, and opioid withdrawal symptoms. The American Kratom Association estimates 10–16 million people use kratom. Kratom‐associated adverse drug reactions (ADRs) continue to be reported and raise concerns about the safety profile of kratom. However, studies are lacking that describe the overall pattern of kratom‐associated adverse events and quantify the association between kratom and adverse events. ADRs reported to the US Food and Drug Administration Adverse Event Reporting System from January 2004 through September 2021 were used to address these knowledge gaps. Descriptive analysis was conducted to analyze kratom‐related adverse reactions. Conservative pharmacovigilance signals based on observed‐to‐expected ratios with shrinkage were estimated by comparing kratom to all other natural products and drugs. Based on 489 deduplicated kratom‐related ADR reports, users were young (mean age 35.5 years), and more often male (67.5%) than female patients (23.5%). Cases were predominantly reported since 2018 (94.2%). Fifty‐two disproportionate reporting signals in 17 system‐organ‐class categories were generated. The observed/reported number of kratom‐related accidental death reports was 63‐fold greater than expected. There were eight strong signals related to addiction or drug withdrawal. An excess proportion of ADR reports were about kratom‐related drug complaints, toxicity to various agents, and seizures. Although further research is needed to assess the safety of kratom, clinicians and consumers should be aware that real‐world evidence points to potential safety threats.

Abstract The “dimensional stability” approach measures different components of ecological stability to investigate how they are related. Yet, most empirical work has used small‐scale and short‐term experimental manipulations. Here, we apply this framework to a long‐term observational dataset of stream macroinvertebrates sampled between the winter flooding and summer monsoon seasons. We test hypotheses that relate variation among stability metrics across different taxa, the magnitude of antecedent (monsoon) and immediate (winter) floods to stability metrics, and the relative importance of disturbance magnitude and taxonomic richness on community dimensional stability. Cluster analysis revealed four distinct stability types, and we found that the magnitude of floods during the prior monsoon was more important in influencing stability than the winter flood itself. For dimensional stability at the community level, taxonomic richness was more important than disturbance magnitude. This work demonstrates that abiotic and biotic factors determine dimensional stability in a natural ecosystem.

Abstract The importance of the immune microenvironment in triple negative and HER2‐amplified breast cancer (BC) is well‐established; less is known about the immune environment in luminal breast cancers. We aimed to assess for the impact of immune biomarkers on BC outcome in a group of luminal B patients with archived tissue and annotated clinical information. Patients with early breast cancer (EBC) treated in a single institution over a 14‐year period, with prospectively collected data were included. Luminal B EBC patients were identified and defined into three cohorts: A: grade 2 or 3, ER & PR positive, HER2‐negative; B: Any grade, ER positive, PR and HER2‐negative (Ki67 ≥ 14% in cohorts A & B); and C: Any grade, ER or PR positive, HER2‐positive. Within each cohort, patients with a relapsed BC event (R) were compared on a 1:1 basis with a control patient (C) who remained disease‐free, balanced for key characteristics in an effort to balance the contribution of each clinical group to outcome. Archival breast, involved and uninvolved axillary nodes were assessed by immunohistochemistry for biomarkers identifying effector and suppressor immune cells, and compared between R and C. In total, 120 patients were included (80, 22, and 18 patients in cohorts A, B, and C, respectively). R were 1.5 years older (p = 0.016), with all other characteristics being balanced. Overall, there were no statistically significant differences in immune biomarkers in breast or nodal tissue of R and C. However, there was a trend toward higher levels of TILs in breast tumors of C, while GAL‐9 was consistently expressed on lymphocytes and tumor cells in all breast and nodes of C and was absent from all tissues of R. These trends in checkpoint molecule expression deserve further research.

Abstract Recovering additional historical weather observations from known archival sources will improve the understanding of how the climate is changing and enable detailed examination of unusual events within the historical record. The UK National Meteorological Archive recently scanned more than 66,000 paper sheets containing 5.28 million hand‐written monthly rainfall observations taken across the UK and Ireland between 1677 and 1960. Only a small fraction of these observations were previously digitally available for climate scientists to analyse. More than 16,000 volunteer citizen scientists completed the transcription of these sheets of observations during early 2020 using the RainfallRescue.org website, built using the Zooniverse platform. A total of 3.34 million observations from more than 6000 locations have so far been quality controlled and made openly available. This has increased the total number of monthly rainfall observations that are available for this time period and region by a factor of six. The newly rescued observations will enable longer and much improved reconstructions of past variations in rainfall across the British and Irish Isles, including for periods of significant flooding and drought. Specifically, this data should allow the official gridded monthly rainfall reconstructions for the UK to be extended back to 1836, and even earlier for some regions.

Abstract A method for time‐domain motion compensation of high frequency (HF) radar signals for the case of a floating transmitter and fixed receiver is proposed when the motion parameters (including the amplitude and angular frequency of the motion) are not known a priori. In this study, the floating platform is assumed to follow a single‐frequency motion model. Additionally, instead of trying to estimate platform motion parameters from the received motion‐contaminated Doppler spectrum, which is proportional to the observed radar cross‐section of the ocean surface from the floating platform, the motion parameters from the autocorrelation function of the received electric field are estimated, which is related to the received radar cross‐section by application of an inverse temporal Fourier transform. By comparing the locations of the zeros of the autocorrelation function for the fixed antenna case with that for an antenna on a floating platform and finding the zeros associated with the platform motion, the motion parameters are estimated. These parameters are matched with actual motion parameter values, from which the motion‐compensated Doppler spectrum is recovered from the Doppler spectrum of the antenna on a floating platform.

Abstract Improvement of end‐use quality remains one of the most important goals in hard winter wheat (HWW) breeding. Nevertheless, the evaluation of end‐use quality traits is confined to later development generations owing to resource‐intensive phenotyping. Genomic selection (GS) has shown promise in facilitating selection for end‐use quality; however, lower prediction accuracy (PA) for complex traits remains a challenge in GS implementation. Multi‐trait genomic prediction (MTGP) models can improve PA for complex traits by incorporating information on correlated secondary traits, but these models remain to be optimized in HWW. A set of advanced breeding lines from 2015 to 2021 were genotyped with 8725 single‐nucleotide polymorphisms and was used to evaluate MTGP to predict various end‐use quality traits that are otherwise difficult to phenotype in earlier generations. The MTGP model outperformed the ST model with up to a twofold increase in PA. For instance, PA was improved from 0.38 to 0.75 for bake absorption and from 0.32 to 0.52 for loaf volume. Further, we compared MTGP models by including different combinations of easy‐to‐score traits as covariates to predict end‐use quality traits. Incorporation of simple traits, such as flour protein (FLRPRO) and sedimentation weight value (FLRSDS), substantially improved the PA of MT models. Thus, the rapid low‐cost measurement of traits like FLRPRO and FLRSDS can facilitate the use of GP to predict mixograph and baking traits in earlier generations and provide breeders an opportunity for selection on end‐use quality traits by culling inferior lines to increase selection accuracy and genetic gains.

Abstract Biodiversity conservation is a complex and transdisciplinary problem that requires engagement and cooperation among scientific, societal, economic, and political institutions. However, historical approaches have often failed to bring together and address the needs of all relevant stakeholders in decision‐making processes. The Tropical Andes, a biodiversity hotspot where conservation efforts often conflict with socioeconomic issues and policies that prioritize economic development, provides an ideal model to develop and implement more effective approaches. In this study, we present a co‐design approach that mainstreams and improves the flow of biodiversity information in the Tropical Andes, while creating tailored outputs that meet the needs of economic and societal stakeholders. We employed a consultative process that brought together biodiversity information users and producers at the local, national, and regional levels through a combination of surveys and workshops. This approach identified priority needs and limitations of the flow of biodiversity information in the region, which led to the co‐design of user‐relevant biodiversity indicators. By leveraging the existing capacities of biodiversity information users and producers, we were able to co‐design multiple biodiversity indicators and prioritize two for full implementation ensuring that the data was findable, accessible, interoperable, and reusable based on the FAIR (Findable, Accessible, Interoperable, and Reusable) principles. This approach helped address limitations that were identified in the stakeholder engagement process, including gaps in data availability and the need for more accessible biodiversity information. Additionally, capacity‐building workshops were incorporated for all producers of biodiversity information involved, which aimed to not only improve the current flow of biodiversity information in the region but also facilitate its future sustainability. Our approach can serve as a valuable blueprint for mainstreaming biodiversity information and making it more inclusive in the future, especially considering the diverse worldviews, values, and knowledge systems between science, policy, and practice.

BACKGROUND Mendelian randomization (MR) offers a powerful approach to study potential causal associations between exposures and health outcomes by using genetic variants associated with an exposure as instrumental variables. In this systematic review, we aimed to summarize previous MR studies and to evaluate the evidence for causality for a broad range of exposures in relation to coronary artery disease and stroke. METHODS AND RESULTS MR studies investigating the association of any genetically predicted exposure with coronary artery disease or stroke were identified. Studies were classified into 4 categories built on the significance of the main MR analysis results and its concordance with sensitivity analyses, namely, robust, probable, suggestive, and insufficient. Studies reporting associations that did not perform any sensitivity analysis were classified as nonevaluable. We identified 2725 associations eligible for evaluation, examining 535 distinct exposures. Of them, 141 were classified as robust, 353 as probable, 110 as suggestive, and 926 had insufficient evidence. The most robust associations were observed for anthropometric traits, lipids, and lipoproteins and type 2 diabetes with coronary artery; disease and clinical measurements with coronary artery disease and stroke; and thrombotic factors with stroke. CONCLUSIONS Despite the large number of studies that have been conducted, only a limited number of associations were supported by robust evidence. Approximately half of the studies reporting associations presented an MR sensitivity analysis along with the main analysis that further supported the causality of associations. Future research should focus on more thorough assessments of sensitivity MR analyses and further assessments of mediation effects or nonlinearity of associations.

Abstract Myeloma patients presenting with renal failure continue to have a poor prognosis despite significant advances in anti‐myeloma therapy. MERIT was a randomised clinical trial (RCT), set up to evaluate if mechanical reduction of elevated free light chain levels (FLC) would result in clinical benefit. Completion of the planned seven plasma exchanges (PEs) in the first 14 days failed to show, for the exchange group, a greater reduction in FLC or any improvement in dialysis independence at 100 days or subsequently. To improve prognosis for these patients requires earlier diagnosis and prompt anti‐myeloma therapy with effectiveness guided by frequent FLC monitoring.

Abstract Insect declines are a global issue with significant ecological and economic ramifications. Yet, we have a poor understanding of the genomic impact these losses can have. Genome‐wide data from historical specimens have the potential to provide baselines of population genetic measures to study population change, with natural history collections representing large repositories of such specimens. However, an initial challenge in conducting historical DNA data analyses is to understand how molecular preservation varies between specimens. Here, we highlight how Next‐Generation Sequencing methods developed for studying archaeological samples can be applied to determine DNA preservation from only a single leg taken from entomological museum specimens, some of which are more than a century old. An analysis of genome‐wide data from a set of 113 red‐tailed bumblebee Bombus lapidarius specimens, from five British museum collections, was used to quantify DNA preservation over time. Additionally, to improve our analysis and further enable future research, we generated a novel assembly of the red‐tailed bumblebee genome. Our approach shows that museum entomological specimens are comprised of short DNA fragments with mean lengths below 100 base pairs (BP), suggesting a rapid and large‐scale post‐mortem reduction in DNA fragment size. After this initial decline, however, we find a relatively consistent rate of DNA decay in our dataset, and estimate a mean reduction in fragment length of 1.9 bp per decade. The proportion of quality filtered reads mapping to our assembled reference genome was around 50%, and decreased by 1.1% per decade. We demonstrate that historical insects have significant potential to act as sources of DNA to create valuable genetic baselines. The relatively consistent rate of DNA degradation, both across collections and through time, mean that population‐level analyses—for example for conservation or evolutionary studies—are entirely feasible, as long as the degraded nature of DNA is accounted for.

Abstract Background Patients with relapsed and refractory solid and central nervous system (CNS) tumors have poor outcomes and need novel therapeutic options. Vincristine, irinotecan, and temozolomide (VIT) is a common chemotherapy regimen in relapsed pediatric tumors with an established toxicity profile. Metformin shows preclinical anti‐cancer activity through multiple pathways. Methods The objective of this Phase I trial was to establish the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of metformin in combination with VIT in children with relapsed and refractory solid and CNS tumors. A 3 + 3 design was used to test the addition of metformin at five dose levels (666, 999, 1333, 1666, and 2000 mg/m2/day). Therapy toxicity, pharmacokinetics, and radiologic response to treatment were evaluated. Results Twenty‐six patients (median age 13 years, range 2–18 years) were enrolled with 22 evaluable for toxicity. The most common diagnoses were Ewing sarcoma (n = 8), rhabdomyosarcoma (n = 3) and atypical teratoid/rhabdoid tumor (n = 3). The MTD was exceeded at Dose Level 5 due to two dose‐limiting toxicities; both were Grade 3 diarrhea requiring prolonged hospitalization and intravenous fluids. The MTD was not determined due to study closure with less than six patients enrolled at Dose Level 4. Frequently observed toxicities were gastrointestinal (most notably diarrhea) and hematologic. Amongst 16 patients evaluable for best overall response, there was one complete response (Ewing sarcoma), three partial responses (Ewing sarcoma, glioblastoma multiforme, and alveolar rhabdomyosarcoma), and five patients with stable disease. Conclusions The MTD of VIT with metformin was not determined due to premature study closure. We recommend an RP2D of Dose Level 4, 1666 mg/m2/day. Radiographic responses were seen in multiple tumor types. Further evaluation for efficacy could be investigated in a Phase II trial.

Abstract Aim The aims of the study were to investigate family and hospital staff views about the use of spring‐infusor devices for administration of intravenous antibiotic medications, to examine if the device is acceptable and feasible and to map a process for implementation. Design A qualitative study with a pragmatist approach, within a larger, mixed methods knowledge translation study. Methods Data were collected by semi‐structured interviews with patients who have cystic fibrosis and their parents and focus groups and interviews with hospital staff. Interviews were concluded when no new themes were identified. Thematic analysis and process mapping was undertaken. Results Six parents, nine children and 30 staff were interviewed. Families preferred spring‐infusors. Staff knowledge, experience and attitudes toward spring‐infusor use was varied. All staff acknowledged that their role is to support patient‐centred care. Spring‐infusors are preferred by families and clinicians above other IV administration devices but misconceptions about spring‐infusor use and numerous procedural challenges reduced their use.

Abstract Combination therapy or concomitant drug administration can be associated with pharmacokinetic drug–drug interactions, increasing the risk of adverse drug events and reduced drug efficacy. Thus far, machine‐learning models have been developed that can classify drug–drug interactions. However, to enable quantification of the pharmacokinetic effects of a drug–drug interaction, regression‐based machine learning should be explored. Therefore, this study investigated the use of regression‐based machine learning to predict changes in drug exposure caused by pharmacokinetic drug–drug interactions. Fold changes in exposure relative to substrate drug monotherapy were collected from 120 clinical drug–drug interaction studies extracted from the Washington Drug Interaction Database and SimCYP compound library files. Drug characteristics (features) were collected such as structure, physicochemical properties, in vitro pharmacokinetic properties, cytochrome P450 metabolic activity, and population characteristics. Three different regression‐based supervised machine‐learning models were then applied to the prediction task: random forest, elastic net, and support vector regressor. Model performance was evaluated using fivefold cross‐validation. Strongest performance was observed with support vector regression, with 78% of predictions within twofold of the observed exposure changes. The results show that changes in drug exposure can be predicted with reasonable accuracy using regression‐based machine‐learning models trained on data available early in drug discovery. This has potential applications in enabling earlier drug–drug interaction risk assessment for new drug candidates.

Abstract Objective To evaluate the relationship between pre‐operative PSA value, 68Ga‐prostate‐specific‐membrane‐antigen (PSMA) PET performance and oncologic outcomes after salvage lymph node dissection (sLND) for biochemical recurrent prostate cancer (PCa). Patients and methods The study included 164 patients diagnosed with ≤2 pelvic lymph‐node recurrence(s) of PCa documented on 68Ga‐PSMA PET scan and treated with pelvic ± retroperitoneal sLND at 11 high‐volume centres between 2012 and 2019. Pathologic findings were correlated to PSA values at time of sLND, categorized in early (1.5 ng/ml). Clinical recurrence (CR)‐free survival after sLND was calculated using multivariable analyses and plotted over pre‐operative PSA value. Results Median [interquartile range (IQR)] PSA at sLND was 1.1 (0.6, 2.0) ng/ml, and 131 (80%) patients had one positive spot at PET scan. All patients received pelvic sLND, whereas 91 (55%) men received also retroperitoneal dissection. Median (IQR) number of node removed was 15 (6, 28). The rate of positive pathology increased as a function of pre‐operative PSA value, with highest rates for patients with pre‐operative PSA > 1.5 ng/ml (pelvic‐only sLNDs: 84%; pelvic + retroperitoneal sLNDs: 90%). After sLND, PSA ≤ 0.3 ng/ml was detected in 67 (41%) men. On multivariable analyses, pre‐operative PSA was associated with PSA response (p

Abstract Premise Many plant communities across the world are undergoing changes due to climate change, human disturbance, and other threats. These community‐level changes are often tracked with the use of permanent vegetative plots, but this approach is not always feasible. As an alternative, we propose using photogrammetry, specifically photograph‐based digital surface models (DSMs) developed using structure‐from‐motion, to establish virtual permanent plots in plant communities where the use of permanent structures may not be possible. Methods In 2021 and 2022, we took iPhone photographs to record species presence in 1‐m2 plots distributed across alpine communities in the northeastern United States. We then compared field estimates of percent coverage with coverage estimated using DSMs. Results Digital surface models can provide effective, minimally invasive, and permanent records of plant species presence and percent coverage, while also allowing managers to mark survey locations virtually for long‐term monitoring. We found that percent coverage estimated from DSMs did not differ from field estimates for most species and substrates. Discussion In order to continue surveying efforts in areas where permanent structures or other surveying methods are not feasible, photogrammetry and structure‐from‐motion methods can provide a low‐cost approach that allows agencies to accurately survey and record sensitive plant communities through time.

Key Clinical Message In non‐healing ulcers with a previous history of burns, clinicians should have a high index of suspicion for Marjolin's ulcer and a low threshold for biopsy, irrespective of age. Abstract Marjolin's ulcer is a rare malignancy arising from chronic inflammation and commonly manifests in burn scars. Thus, in cases of chronic wounds or non‐healing ulcers, health professionals should have a high index of suspicion and a low threshold for biopsy, irrespective of age. Early diagnosis and timely management of tumors can improve the prognosis and overall survival rate. Moreover, further studies are needed to develop an evidence‐based management approach for Marjolin's ulcer.