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Abstract Objective To explore Chat Generative Pretrained Transformer's (ChatGPT's) capability to create multiple‐choice questions about otorhinolaryngology (ORL). Study Design Experimental question generation and exam simulation. Setting Tertiary academic center. Methods ChatGPT 3.5 was prompted: “Can you please create a challenging 20‐question multiple‐choice questionnaire about clinical cases in otolaryngology, offering five answer options?.” The generated questionnaire was sent to medical students, residents, and consultants. Questions were investigated regarding quality criteria. Answers were anonymized and the resulting data was analyzed in terms of difficulty and internal consistency. Results ChatGPT 3.5 generated 20 exam questions of which 1 question was considered off‐topic, 3 questions had a false answer, and 3 questions had multiple correct answers. Subspecialty theme repartition was as follows: 5 questions were on otology, 5 about rhinology, and 10 questions addressed head and neck. The qualities of focus and relevance were good while the vignette and distractor qualities were low. The level of difficulty was suitable for undergraduate medical students (n = 24), but too easy for residents (n = 30) or consultants (n = 10) in ORL. Cronbach's α was highest (.69) with 15 selected questions using students' results. Conclusion ChatGPT 3.5 is able to generate grammatically correct simple ORL multiple choice questions for a medical student level. However, the overall quality of the questions was average, needing thorough review and revision by a medical expert to ensure suitability in future exams.

Abstract The immune response–gut microbiota interaction is implicated in various human diseases, including cancer. Identifying the link between the gut microbiota and systemic inflammatory markers and their association with cancer will be important for our understanding of cancer etiology. The current study was performed on 8090 participants from the population‐based Rotterdam study. We found a significant association (false discovery rate [FDR] ≤0.05) between lymphocytes and three gut microbial taxa, namely the family Streptococcaceae, genus Streptococcus, and order Lactobacillales. In addition, we identified 95 gut microbial taxa that were associated with inflammatory markers (p

Abstract Geographic distribution models of environmentally stable isotopes (the so‐called “isoscapes”) are widely employed in animal ecology, and wildlife forensics and conservation. However, the application of isoscapes is limited to elements and regions for which the spatial patterns have been estimated. Here, we focused on the ubiquitous yet less commonly used stable sulfur isotopes (δ34S). To predict the European δ34S isoscape, we used 242 feather samples from Eurasian Reed Warbler (Acrocephalus scirpaceus) formed at 69 European wetland sites. We quantified the relationships between sample δ34S and environmental covariates using a random forest regression model and applied the model to predict the geographic distribution of δ34S. We also quantified within‐site variation in δ34S and complementarity with other isotopes on both individual and isoscape levels. The predicted feather δ34S isoscape shows only slight differences between the central and southern parts of Europe while the coastal regions were most enriched in 34S. The most important covariates of δ34S were distance to coastline, surface elevation, and atmospheric concentrations of SO2 gases. The absence of a systematic spatial pattern impedes the application of the δ34S isoscape, but high complementarity with other isoscapes advocates the combination of multiple isoscapes to increase the precision of animal tracing. Feather δ34S compositions showed considerable within‐site variation with highest values in inland parts of Europe, likely attributed to wetland anaerobic conditions and redox sensitivity of sulfur. The complex European geography and topography as well as using δ34S samples from wetlands may contribute to the absence of a systematic spatial gradient of δ34S values in Europe. We thus encourage future studies to focus on the geographic distribution of δ34S using tissues from diverse taxa collected in various habitats over large land masses in the world (i.e., Africa, South America, or East Asia).

Abstract Beta‐blocker usage is inconsistently associated with increased fall risk in the literature. However, due to age‐related changes and interindividual heterogeneity in pharmacokinetics and dynamics, it is difficult to predict which older adults are more at risk for falls. Therefore, we wanted to explore whether elevated plasma concentrations of selective and nonselective beta‐blockers are associated with an increased risk of falls in older beta‐blocker users. To answer our research question, we analyzed samples of selective (metoprolol, n = 316) and nonselective beta‐blockers (sotalol, timolol, propranolol, and carvedilol, n = 179) users from the B‐PROOF cohort. The associations between the beta‐blocker concentration and time to first fall were assessed using Cox proportional hazard models. Change of concentration over time in relation to fall risk was assessed with logistic regression models. Models were adjusted for potential confounders. Our results showed that above the median concentration of metoprolol was associated with an increased fall risk (HR 1.55 [1.11–2.16], p = .01). No association was found for nonselective beta‐blocker concentrations. Also, changes in concentration over time were not associated with increased fall risk. To conclude, metoprolol plasma concentrations were associated with an increased risk of falls in metoprolol users while no associations were found for nonselective beta‐blockers users. This might be caused by a decreased β1‐selectivity in high plasma concentrations. In the future, beta‐blocker concentrations could potentially help clinicians estimate fall risk in older beta‐blockers users and personalize treatment.

The introduction of the tethered DROP‐IN gamma probe has enabled targeted robot‐assisted radioguided prostate cancer (PCa) resection of pelvic sentinel lymph nodes (SLNs) and prostate‐specific membrane antigen (PSMA)‐positive lesions. While both procedures use 99mTc‐isotopes, the two vary in signal and background intensity. To understand how the different levels of image guidance impact surgical decision‐making, computer‐vision algorithms are used to extract the DROP‐IN probe kinematic form clinical videos. 44 PCa patients undergo SLN (25) and PSMA‐targeted (19) resections. PSMA‐PET/CT and SPECT/CT create preoperative roadmaps, and intraoperative probe signal intensities are recorded. Using neural network‐based software, probe trajectories are extracted from videos to extract multiparametric kinematics and generate decision‐making and dexterity scores. PSMA‐targeted resections yield significantly lower nodal signal intensities in preoperative SPECT‐CT scans (three‐fold; p = 0.01), intraoperative probe readouts (eight‐fold; p

Abstract Context Robot‐assisted radical prostatectomy (RARP) has become the standard surgical procedure for localized prostate‐cancer (PCa). Nerve‐sparing surgery (NSS) during RARP has been associated with improved erectile function and continence rates after surgery. However, it remains unclear what are the most appropriate indications for NSS. Objective The objective of this study is to systematically review the available parameters for selection of patients for NSS. The weight of different clinical variables, multiparametric magnetic‐resonance‐imaging (mpMRI) findings, and the impact of multiparametric‐nomograms in the decision‐making process on (side‐specific) NSS were assessed. Evidence acquisition This systematic review searched relevant databases and included studies performed from January 2000 until December 2020 and recruited a total of 15 840 PCa patients. Studies were assessed that defined criteria for (side‐specific) NSS and associated them with oncological safety and/or functional outcomes. Risk of bias assessment was performed. Evidence synthesis Nineteen articles were eligible for full‐text review. NSS is primarily recommended in men with adequate erectile function, and with low‐risk of extracapsular extension (ECE) on the side‐of NSS. Separate clinical and radiological variables have low accuracy for predicting ECE, whereas nomograms optimize the risk‐stratification and decision‐making process to perform or to refrain from NSS when oncological safety (organ‐confined disease, PSM rates) and functional outcomes (erectile function and continence rates) were assessed. Conclusions Consensus exists that patients who are at high risk of ECE should refrain from NSS. Several multiparametric preoperative nomograms were developed to predict ECE with increased accuracy compared with single clinical, pathological, or radiological variables, but controversy exists on risk thresholds and decision rules on a conservative versus a less‐conservative surgical approach. An individual clinical judgment on the possibilities of NSS set against the risks of ECE is warranted. Patient summary NSS is aimed at sparing the nerves responsible for erection. NSS may lead to unfavorable tumor control if the risk of capsule penetration is high. Nomograms predicting extraprostatic tumor‐growth are probably most helpful.

Abstract Background Cancer resequencing studies have revealed epigenetic enzymes as common targets for recurrent mutations. The monomethyltransferase MLL3 is among the most recurrently mutated enzymes in ER+ breast cancer. The H3K4me1 marks created by MLL3 can define enhancers. In ER+ breast cancer, ERα genome‐binding sites are primarily distal enhancers. Thus, we hypothesize that mutation of MLL3 will alter the genomic binding and transcriptional regulatory activity of ERα. Methods We investigated the genomic consequences of knocking down MLL3 in an MLL3/PIK3CA WT ER+ breast cancer cell line. Results Loss of MLL3 led to a large loss of H3K4me1 across the genome, and a shift in genomic location of ERα‐binding sites, which was accompanied by a re‐organization of the breast cancer transcriptome. Gene set enrichment analyses of ERα‐binding sites in MLL3 KD identified endocrine therapy resistance terms, and we showed that MLL3 KD cells are resistant to tamoxifen and fulvestrant. Many differentially expressed genes are controlled by the small collection of new locations of H3K4me1 deposition and ERα binding, suggesting that loss of functional MLL3 leads to new transcriptional regulation of essential genes. Motif analysis of RNA‐seq and ChIP‐seq data highlighted SP1 as a critical transcription factor in the MLL3 KD cells. Differentially expressed genes that display a loss of ERα binding upon MLL3 KD also harbor increased SP1 binding. Conclusions Our data show that a decrease in functional MLL3 leads to endocrine therapy resistance. This highlights the importance of genotyping patient tumor samples for MLL3 mutation upon initial resection, prior to deciding upon treatment plans.

Abstract Background Prostate cancer is a clinically heterogeneous disease with a subset of patients rapidly progressing to lethal‐metastatic prostate cancer. Current clinicopathological measures are imperfect predictors of disease progression. Epigenetic changes are amongst the earliest molecular changes in tumourigenesis. To find new prognostic biomarkers to enable earlier intervention and improved outcomes, we performed methylome sequencing of DNA from patients with localised prostate cancer and long‐term clinical follow‐up. Methods We used whole‐genome bisulphite sequencing (WGBS) to comprehensively map and compare DNA methylation of radical prostatectomy tissue between patients with lethal disease (n = 7) and non‐lethal (n = 8) disease (median follow‐up 19.5 years). Validation of differentially methylated regions (DMRs) was performed in an independent cohort (n = 185, median follow‐up 15 years) using targeted multiplex bisulphite sequencing of candidate regions. Survival was assessed via univariable and multivariable analyses including clinicopathological measures (log‐rank and Cox regression models). Results WGBS data analysis identified cancer‐specific methylation patterns including CpG island hypermethylation, and hypomethylation of repetitive elements, with increasing disease risk. We identified 1420 DMRs associated with prostate cancer‐specific mortality (PCSM), which showed enrichment for gene sets downregulated in prostate cancer and de novo methylated in cancer. Through comparison with public prostate cancer datasets, we refined the DMRs to develop an 18‐gene prognostic panel. Applying this panel to an independent cohort, we found significant associations between PCSM and hypermethylation at EPHB3, PARP6, TBX1, MARCH6 and a regulatory element within CACNA2D4. Strikingly in a multivariable model, inclusion of CACNA2D4 methylation was a better predictor of PCSM versus grade alone (Harrell's C‐index: 0.779 vs. 0.684). Conclusions Our study provides detailed methylome maps of non‐lethal and lethal prostate cancer and identifies novel genic regions that distinguish these patient groups. Inclusion of our DNA methylation biomarkers with existing clinicopathological measures improves prognostic models of prostate cancer mortality, and holds promise for clinical application.

Abstract Organisms assess biotic and abiotic cues at multiple sites when deciding where to settle. However, due to temporal constraints on this prospecting, the suitability of available habitat may be difficult for an individual to assess when cues are most reliable, or at the time they are making settlement decisions. For migratory birds, the postbreeding season may be the optimal time to prospect and inform settlement decisions for future breeding seasons. We investigated the fall movements of flammulated owls (Psiloscops flammeolus) within breeding habitat after fledglings had gained independence and before adults left for migration. From 2013 to 2016, we trapped owls within a breeding population wherein all nesting owls and their young have been banded since 1981. We used stable isotopes in combination with mark–recapture data to identify local individuals and differentiate potential prospecting behavior from other seasonal movements such as migration or staging. We commonly captured owls in the fall—predominantly hatch‐year owls—that were not known residents of the study area. Several of these nonresident owls were later found breeding within the study area. Stable isotope data suggested a local origin for virtually all owls captured during the fall. Our results suggest that hatch‐year flammulated owls, but also some after‐hatch‐year owls, use the period between the breeding season and fall migration to prospect for future breeding sites. The timing of this behavior is likely driven by seasonally variable costs associated with prospecting. Determining the timing of prospecting and the specific cues that are being assessed will be important in helping predict the extent to which climate change and/or altered disturbance regimes will modify the ecology, behavior, and demographics associated with prospecting.

Abstract Pulmonary hypertension (PH), especially pulmonary arterial and chronic thromboembolic pulmonary hypertension (PAH/CTEPH), are rare and progressive conditions. Despite recent advances in treatment and prognosis, PH is still associated with impaired quality of life and survival. Long‐term PH‐registry data provide information on the changing PH‐epidemiology and may help to direct resources to patient's needs. This retrospective analysis of the Swiss Pulmonary Hypertension Registry includes patients newly diagnosed with PH (mainly PAH/CTEPH) registered from January 2001 to June 2019 at 13 Swiss hospitals. Patient characteristics (age, body mass index, gender, diagnosis), hemodynamics at baseline, treatment, days of follow‐up, and events (death, transplantation, pulmonary endarterectomy, or loss to follow‐up) at last visit were analyzed. Patients were stratified into four time periods according to their date of diagnosis. Survival was analyzed overall and separately for PAH/CTEPH and time periods. 1427 PH patients were included (thereof 560 PAH, 383 CTEPH). Over the years, age at baseline (mean ± SD) significantly increased from 59 ± 14 years in 2001–2005 to 66 ± 14 years in 2016–2019 (p

Abstract It is a critical time to reflect on the National Ecological Observatory Network (NEON) science to date as well as envision what research can be done right now with NEON (and other) data and what training is needed to enable a diverse user community. NEON became fully operational in May 2019 and has pivoted from planning and construction to operation and maintenance. In this overview, the history of and foundational thinking around NEON are discussed. A framework of open science is described with a discussion of how NEON can be situated as part of a larger data constellation—across existing networks and different suites of ecological measurements and sensors. Next, a synthesis of early NEON science, based on >100 existing publications, funded proposal efforts, and emergent science at the very first NEON Science Summit (hosted by Earth Lab at the University of Colorado Boulder in October 2019) is provided. Key questions that the ecology community will address with NEON data in the next 10 yr are outlined, from understanding drivers of biodiversity across spatial and temporal scales to defining complex feedback mechanisms in human–environmental systems. Last, the essential elements needed to engage and support a diverse and inclusive NEON user community are highlighted: training resources and tools that are openly available, funding for broad community engagement initiatives, and a mechanism to share and advertise those opportunities. NEON users require both the skills to work with NEON data and the ecological or environmental science domain knowledge to understand and interpret them. This paper synthesizes early directions in the community’s use of NEON data, and opportunities for the next 10 yr of NEON operations in emergent science themes, open science best practices, education and training, and community building.

Abstract Increased variation in interannual weather due to climate change can exert a powerful influence on the population dynamics of a species. Understanding the influence of severe weather is important for managing weather‐sensitive species. While best management practices target vital rates that are affected by weather, focusing on a single vital rate may not be sufficient if other vital rates are secondarily limiting. A comprehensive modeling framework to forecast future population dynamics while incorporating weather scenarios and vital rate variation within observed ranges that can be affected by management actions are necessary. A potential approach is to combine an integrated population model (IPM) with a population viability analysis (PVA) to generate novel insights about population dynamics. We used the northern bobwhite (Colinus virginianus), a rapidly declining gamebird sensitive to snowfall along the northern extents of the species' range, to demonstrate the utility of a coupled IPM‐PVA framework for projecting the response of a population to weather, management, and changes in vital rates. We created an IPM using two sources of count data spanning seven years, five years of winter survival data, and two years of breeding season demographics for a declining bobwhite population in southwestern Ohio during 2007–2015. Quasi‐extinction probability at the end of the decadal projection during 2019–2029 was 0.384–0.410 for mild, average, and severe winter weather scenarios. Quasi‐extinction probability declined to 0.326 with 20% improvement in nest success and summer survival rates. A concurrent 20% increase in winter survival further reduced quasi‐extinction probability to 0.263, which is a ˜36% reduction in quasi‐extinction probability compared with the baseline scenario with no changes in vital rates. These results suggest that long‐term viability of this population may depend on extensive management of winter habitat to improve survival but will also require management actions to improve fecundity after severe winters. Our modeling approach demonstrated how IPMs can be used to project population responses to future weather conditions and overcome some of the pitfalls of traditional PVA. The coupled framework presented here can serve as a tool for managers to make climate‐informed management decisions.

Abstract Biological invasions are a leading cause of rapid ecological change and often present a significant financial burden. As a vibrant discipline, invasion biology has made important strides in identifying, mapping, and beginning to manage invasions, but questions remain surrounding the mechanisms by which invasive species spread and the impacts they bring about. Frequent, multiscalar ecological monitoring such as that provided through the National Ecological Observatory Network (NEON) can be an important tool for addressing some of these questions. We articulate a set of major outstanding questions in invasion biology, consider how NEON data science is positioned to contribute to addressing these questions, and provide suggestions to help equip a growing contingent of NEON data users in solving invasion biology problems. We demonstrate these ideas through four case studies examining the mechanisms of plant invasions in the U.S. Intermountain West. In Case Study I, we evaluate the relationships between native species richness, non‐native species richness, and probability of invasion across scales. In Case Studies II and III, we explore the relationship between environmental factors and non‐native species presence to understand invasion mechanisms. Case Study IV outlines a method for improving the ability to distinguish invasive plants from native vegetation in remotely sensed data by leveraging temporal patterns of phenology. There are many novel elements in the NEON sampling design that make it uniquely poised to shed light on the mechanisms that can help us understand invasibility, prediction, and progression, as well as on the variability, longevity, and interactions of multiple invasive species’ impacts. Thus, knowledge gained through analysis of NEON data is expected to inform sound decision‐making in unique ways for managers of systems experiencing biological invasions.

Summary Purpose Half of adult cancer survivors under age 50 years are obese. Excess body weight is associated with cancer recurrence, and effective weight loss interventions for younger cancer survivors are needed. Commercially available, online weight loss programmes are readily accessible, but few have been studied in this population. This study employed a single‐arm, pre‐post intervention (baseline‐6 month/baseline‐12 month comparisons) to preliminarily explore feasibility, efficacy and safety of an online, commercially available weight loss programme in breast (n = 30) and testicular (n = 16) cancer survivors under age 50 years. Methods The intervention included three daily components: exercise, nutritional/behavioural modification strategies and health lessons. Intention‐to‐treat and completers analyses were conducted. Feasibility was measured by participation (number of participants enrolled/number screened), retention (number of participants attending 6/12 month study visit/number of enrolled) and self‐reported adherence rates (average of mean percent adherence to each of the three intervention components). Efficacy was assessed by changes in initial weight (percent weight loss). Safety was assessed by adverse events. Results The mean participation rate was 42%. The retention rate was 59% at 6 and 49% at 12 months. The adherence rate for all participants (completers/dropouts/lost‐to‐follow‐up) was 50.1% at 6 and 44% at 12 months. Completers reported adherence rates of 68% at 12 months. Study participants lost 5.3% body weight at 12 months; completers lost 9%. Only three unexpected adverse events (unrelated to the intervention) were reported. Conclusion Clinically significant weight loss was observed, although retention rates were low. Findings generally support preliminary feasibility, efficacy and safety of this online weight loss programme, and future randomized control trials should be explored.

BackgroundLow 25‐hydroxyvitamin D levels are associated with an increased risk of cardiovascular events, but the effect of vitamin D supplementation on markers of vascular function associated with major adverse cardiovascular events is unclear. Methods and ResultsWe conducted a systematic review and individual participant meta‐analysis to examine the effect of vitamin D supplementation on flow‐mediated dilatation of the brachial artery, pulse wave velocity, augmentation index, central blood pressure, microvascular function, and reactive hyperemia index. MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.gov were searched until the end of 2016 without language restrictions. Placebo‐controlled randomized trials of at least 4 weeks duration were included. Individual participant data were sought from investigators on included trials. Trial‐level meta‐analysis was performed using random‐effects models; individual participant meta‐analyses used a 2‐stage analytic strategy, examining effects in prespecified subgroups. 31 trials (2751 participants) were included; 29 trials (2641 participants) contributed data to trial‐level meta‐analysis, and 24 trials (2051 participants) contributed to individual‐participant analyses. Vitamin D3 daily dose equivalents ranged from 900 to 5000 IU; duration was 4 weeks to 12 months. Trial‐level meta‐analysis showed no significant effect of supplementation on macrovascular measures (flow‐mediated dilatation, 0.37% [95% confidence interval, −0.23 to 0.97]; carotid‐femoral pulse wave velocity, 0.00 m/s [95% confidence interval, −0.36 to 0.37]); similar results were obtained from individual participant data. Microvascular function showed a modest improvement in trial‐level data only. No consistent benefit was observed in subgroup analyses or between different vitamin D analogues. ConclusionsVitamin D supplementation had no significant effect on most markers of vascular function in this analysis.