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Abstract Background Preclinical rheumatoid arthritis (Pre‐RA) is defined as the early stage before the development of clinical RA. While cachexia is a well‐known and potentially modifiable complication of RA, it is not known if such an association exists also in the Pre‐RA stage. To investigate such issue, we aimed to compare the longitudinal alterations in the muscle composition and adiposity of participants with Pre‐RA with the matched controls. Methods In this observational cohort study, the Osteoarthritis Initiative (OAI) participants were categorized into Pre‐RA and propensity score (PS)‐matched control groups. Pre‐RA was retrospectively defined as the absence of RA from baseline to year‐2, with progression to physician‐diagnosed clinical RA between years 3–8 of the follow‐up period. Using a validated deep learning algorithm, we measured MRI biomarkers of thigh muscles and adiposity at baseline and year‐2 follow‐ups of the cohort. The outcomes were the differences between Pre‐RA and control groups in the 2‐year rate of change for thigh muscle composition [cross‐sectional area (CSA) and intramuscular adipose tissue (Intra‐MAT)] and adiposity [intermuscular adipose tissue (Inter‐MAT) and subcutaneous adipose tissue (SAT)]. Linear mixed‐effect regression models were used for comparison. Results After 1:3 PS‐matching of the groups for confounding variables (demographics, risk factors, co‐morbidities, and knee osteoarthritis status), 408 thighs (102 Pre‐RA and 306 control) of 322 participants were included (age mean ± SD: 61.7 ± 8.9 years; female/male: 1.8). Over a 2‐year period, Pre‐RA was associated with a larger decrease in total thigh muscle CSA [estimate, 95% confidence interval (CI): −180.13 mm2/2‐year, −252.80 to −107.47, P‐value

Abstract The UK sixth carbon budget has recommended domestic biomass supply should increase to meet growing demand, planting a minimum of 30,000 hectares of perennial energy crops a year by 2035, with a view to establishing 700,000 hectares by 2050 to meet the requirements of the balanced net zero pathway. Miscanthus is a key biomass crop to scale up domestic biomass production in the United Kingdom. A cohesive land management strategy, based on robust evidence, will be required to ensure upscaling of miscanthus cultivation maximizes the environmental and economic benefits and minimizes undesirable consequences. This review examines research into available land areas, environmental impacts, barriers to uptake, and the challenges, benefits, and trade‐offs required to upscale miscanthus production on arable land and grassland in the United Kingdom. Expansion of perennial biomass crops has been considered best restricted to marginal land, less suited to food production. The review identifies a trade‐off between avoiding competition with food production and a risk of encroaching on areas containing high‐biodiversity or high‐carbon stocks, such as semi‐natural grasslands. If areas of land suitable for food production are needed to produce the biomass required for emission reduction, the review indicates there are multiple strategies for miscanthus to complement long‐term food security rather than compete with it. On arable land, a miscanthus rotation with a cycle length of 10–20 years can be employed as fallow period for fields experiencing yield decline, soil fatigue, or persistent weed problems. On improved grassland areas, miscanthus presents an option for diversification, flood mitigation, and water quality improvement. Strategies need to be developed to integrate miscanthus into farming systems in a way that is profitable, sensitive to local demand, climate, and geography, and complements rather than competes with food production by increasing overall farm profitability and resilience.

Abstract Harvest time is an important variable that determines the yield of miscanthus biomass, its possible end uses, and the nutrient offtake from the field. Green harvests result in a higher yield and greater nutrient removal from the field. Brown miscanthus harvests, carried out in late winter or early spring, result in lower yields and a lower nutrient offtake, whereby the harvested biomass is better suited to use in combustion. To look at the long‐term impact of green harvests on miscanthus, this experiment followed the yield development of two miscanthus hybrids subjected to green and brown harvests over a period of seven years at one site in Southern Germany. The standard commercial hybrid Miscanthus × giganteus (Mxg) was compared with a novel late‐ripening Miscanthus sinensis hybrid: Syn55. Average yields of Mxg were 19.9 t ha−1 for green harvests and 13.2 t ha−1 for brown harvests compared to 13.9 and 12.9 t ha−1 for green and brown harvested Syn55, respectively. Yields of Mxg were very different for green and brown harvests; green harvested Mxg had very high nutrient offtake, while brown harvested Mxg had the lowest nutrient offtakes of all treatments. Syn55 showed a less marked difference between green and brown harvests likely due to its tendency to retain its leaves over winter. Syn55 was however not tolerant of a green harvest, with yields of brown harvested stands surpassing the yield of green harvested stands in several years. Although Mxg demonstrated consistently high yields when harvested in October, some signs of yield decline were detected in both hybrids when harvested green, which was due to insufficient carbohydrate relocation. Alternating green and brown harvests are recommended to allow stands to replenish carbohydrate stores and to form a litter layer.

Abstract Tuberculosis (TB) is a life‐threatening infectious disease. The standard treatment is up to 90% effective; however, it requires the administration of four antibiotics (isoniazid, rifampicin, pyrazinamide, and ethambutol [HRZE]) over long time periods. This harsh treatment process causes adherence issues for patients because of the long treatment times and a myriad of adverse effects. Therefore, the World Health Organization has focused goals of shortening standard treatment regimens for TB in their End TB Strategy efforts, which aim to reduce TB‐related deaths by 95% by 2035. For this purpose, many novel and promising combination antibiotics are being explored that have recently been discovered, such as the bedaquiline, pretomanid, and linezolid (BPaL) regimen. As a result, testing the number of possible combinations with all possible novel regimens is beyond the limit of experimental resources. In this study, we present a unique framework that uses a primate granuloma modeling approach to screen many combination regimens that are currently under clinical and experimental exploration and assesses their efficacies to inform future studies. We tested well‐studied regimens such as HRZE and BPaL to evaluate the validity and accuracy of our framework. We also simulated additional promising combination regimens that have not been sufficiently studied clinically or experimentally, and we provide a pipeline for regimen ranking based on their efficacies in granulomas. Furthermore, we showed a correlation between simulation rankings and new marmoset data rankings, providing evidence for the credibility of our framework. This framework can be adapted to any TB regimen and can rank any number of single or combination regimens.

Background Given that autoantibodies to peptidylarginine deiminase 4 (PAD4) are associated with erosive disease in established rheumatoid arthritis (RA), this study was conducted to compare the clinical and prognostic use of anti‐PAD4 antibodies in patients with early and established RA. Methods Sera from patients with early (duration

Abstract Miscanthus, a C4 perennial rhizomatous grass, is a low‐input energy crop suitable for marginal land, which cultivation can improve soil quality and promote soil organic carbon (SOC) sequestration. In this study, four promising Miscanthus hybrids were chosen to evaluate their short‐term potential, in six European marginal sites, to sequester SOC and improve physical, chemical, and biological soil quality in topsoil. Overall, no differences among Miscanthus hybrids were detected in terms of impacts on soil quality and SOC sequestration. SOC sequestration rate after 4 years was of +0.4 Mg C ha−1 year−1, but land‐use transition from former cropland or grassland showed contrasting SOC sequestration trajectories. In unfertilized marginal lands, cultivation of high‐yielding Miscanthus genotypes caused a depletion of K (−216 kg ha−1 year−1), followed by Ca (−56 kg ha−1 year−1), Mg (−102 kg ha−1 year−1) and to a lesser extent of N. On the contrary, the biological turnover of organic matter increased the available P content (+164 kg P2O5 ha−1 year−1). SOC content was identified as the main driver of changes in biological soil quality. High input of labile plant C stimulated an increment of microbial biomass and enzymatic activity. Here, a novel approach was applied to estimate C input to soil from different Miscanthus organs. Despite the high estimated plant C input to soil (0.98 Mg C ha−1 year−1), with significant differences among sites and Miscanthus hybrids, it was not identified as a driver of SOC sequestration. On the contrary, initial SOC and nutrients (N, P) content, as well as their elemental stoichiometric ratios with C, were the key factors controlling SOC dynamics. Introducing Miscanthus on marginal lands impacts positively soil biological quality over the short term, but targeted fertilization plans are needed to secure crop yield over the long term as well as the C sink capacity of this perennial cropping system.

Abstract Objectives Sex‐specific disparities in morbidity and mortality of COVID‐19 illness are not well understood. Neutralizing antibodies (Ab) may protect against severe COVID‐19 illness. We investigated the association of sex with disease progression and SARS‐CoV‐2 Ab response. Methods In this exploratory analysis of the phase 3, multicenter, randomized, placebo‐controlled Convalescent Plasma in Outpatients (C3PO) trial, we examined whether sex was associated with progression to severe illness, defined as a composite of all‐cause hospitalization, emergency/urgent care visit, or death within 15 days from study enrollment. Patients had a positive severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) test, symptom onset within 7 days, stable condition for emergency department discharge, and were either ≥50 years old or had at least one high‐risk feature for disease progression. Patients received blinded convalescent plasma or placebo in a 1:1 fashion and were evaluated on days 15 and 30 after infusion. Blood samples were collected on day 0 (pre‐/post‐infusion), 15, and 30 to measure Ab levels with the Broad Institute using the Plaque Reduction Neutralization Test assay. Results Of 511 patients enrolled (median age 54 [Iinterquartile range 41–62] years, 46% male, 66% white, 20% black, 3.5% Asian), disease progression occurred in 36.7% of males and 25.9% of females (unadjusted risk difference 10.8%, 95% confidence interval [CI], 2.8–18.8%). Sex‐disparities did not persist when adjusted for treatment group, age, viremic status, symptom onset, and tobacco use (adjusted risk difference 5.6%, 95% confidence interval [CI], −2.2% to 13.4%), but were present in the subgroup presenting 3 or more days after symptom onset (adjusted risk difference 12.6%, 95% CI, 3.4% to 21.9%). Mean baseline Ab levels (log scale) available for 367 patients were similar between sexes (difference 0.19 log units, 95% CI, −0.08 to 0.46). The log‐scale mean increase from baseline to day 15 after adjusting for treatment assignment and baseline levels was larger in males than females (3.26 vs. 2.67). A similar difference was noted when the groups were subdivided by outcome. Conclusions Progression of COVID‐19 was similar in males and females when adjusted for age, tobacco use, and viremia status in this study. However, in the cohort presenting 3 or more days after symptom onset, COVID‐19 outcomes were worse in males than females. Neutralizing Ab levels increased more in males but did not correlate with sex differences in outcomes.

Background Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams–Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams–Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability. Methods and Results We performed genome sequencing on 473 individuals with Williams–Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway‐level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome‐wide association studies. We show that SVAS severity in Williams–Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes (ACAN and LTBP4) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome‐wide association studies for aneurysm, bicuspid aortic valve, or aortic size. Conclusions Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta‐focused genome‐wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.

Abstract Selinexor is an orally bioavailable selective inhibitor of nuclear export compound that inhibits exportin‐1 (XPO1), a novel therapeutic target that is overexpressed in multiple myeloma (MM) and is responsible for the transport of ∼220 nuclear proteins to the cytoplasm, including tumour suppressor proteins. Inhibition of this process has demonstrated substantial antimyeloma activity in preclinical studies, both alone and in combination with established MM therapeutics. Based on a clinical trial programme encompassing multiple combination regimens, selinexor‐based therapy has been approved for the treatment of relapsed/refractory MM (RRMM), with selinexor‐dexamethasone approved in the later‐relapse setting for penta‐refractory patients and selinexor‐bortezomib‐dexamethasone approved for patients who have received ≥1 prior therapy. Here, we provide a comprehensive review of the clinical data on selinexor‐based regimens, including recent updates from the 2022 American Society of Hematology annual meeting, and summarise ongoing studies of this novel targeted agent in newly diagnosed MM and RRMM.

Abstract High‐yielding crops with C4 photosynthesis arising in tropical climates are being bred for, and increasingly grown in, temperate climates. Miscanthus, a C4 from Eastern Asia is a leading perennial biomass crop, but commercial deployment is limited by low temperatures in Northern Europe, low clonal multiplication rates and slow establishment rates requiring up to 4 years to reach mature yields. While new seeded hybrids have multiplication rates >2000, direct field sown seed has proven impractical. Protocols for safe establishment of seeded hybrids require that seedlings are raised in the glasshouse in compost filled modules (also known as ‘plugs’) which are transplanted into the field in springtime. To protect seedlings from damage from late frosts, drought and grazing and to increase temperature stimulating growth rates, plug plants were covered with oxo‐degradable plastic mulch film designed for maize. At two sites in the UK, this mulch film significantly reduced plant losses at transplanting and overwintering, increased stem heights and shoot counts, and reduced the time to mature yield from 4 to 3 years (p

Abstract Demand for sustainably produced biomass is expected to increase with the need to provide renewable commodities, improve resource security and reduce greenhouse gas emissions in line with COP26 commitments. Studies have demonstrated additional environmental benefits of using perennial biomass crops (PBCs), when produced appropriately, as a feedstock for the growing bioeconomy, including utilisation for bioenergy (with or without carbon capture and storage). PBCs can potentially contribute to Common Agricultural Policy (CAP) (2023–27) objectives provided they are carefully integrated into farming systems and landscapes. Despite significant research and development (R&D) investment over decades in herbaceous and coppiced woody PBCs, deployment has largely stagnated due to social, economic and policy uncertainties. This paper identifies the challenges in creating policies that are acceptable to all actors. Development will need to be informed by measurement, reporting and verification (MRV) of greenhouse gas emissions reductions and other environmental, economic and social metrics. It discusses interlinked issues that must be considered in the expansion of PBC production: (i) available land; (ii) yield potential; (iii) integration into farming systems; (iv) R&D requirements; (v) utilisation options; and (vi) market systems and the socio‐economic environment. It makes policy recommendations that would enable greater PBC deployment: (1) incentivise farmers and land managers through specific policy measures, including carbon pricing, to allocate their less productive and less profitable land for uses which deliver demonstrable greenhouse gas reductions; (2) enable greenhouse gas mitigation markets to develop and offer secure contracts for commercial developers of verifiable low‐carbon bioenergy and bioproducts; (3) support innovation in biomass utilisation value chains; and (4) continue long‐term, strategic R&D and education for positive environmental, economic and social sustainability impacts.

Abstract Due to its versatility and storability, biomass is an important resource for renewable materials and energy. Miscanthus hybrids combine high yield potential, low input demand, tolerance of certain marginal land types and several ecosystem benefits. To date, miscanthus breeding has focussed on increasing yield potential by maximising radiation interception through: (1) selection for early emergence, (2) increasing the growth rate to reach canopy closure as fast as possible, and (3) delayed flowering and senescence. The objective of this study is to compare early season re‐growth in miscanthus hybrids cultivated across Europe. Determination of differences in early canopy development on end‐of‐year yield traits is required to provide information for breeding decisions to improve future crop performance. For this purpose, a trial was planted with four miscanthus hybrids (two novel seed‐based hybrids M. sinensis × sinensis [M sin × sin] and M. sacchariflorus × sinensis [M sac × sin], a novel rhizome‐based M sac × sin and a standard Miscanthus × giganteus [M × g] clone) in the UK, Germany, Croatia and Italy, and was monitored in the third and fourth growing season. We determined differences between the hybrids in base temperature, frost sensitivity and emergence strategy. M × g and M sac × sin mainly emerged from belowground plant organs, producing fewer but thicker shoots at the beginning of the growing season but these shoots were susceptible to air frosts (determined by recording 0°C 2 m above ground surface). By contrast, M sin × sin emerged 10 days earlier, avoiding damage by late spring frosts and producing a high number of thinner shoots from aboveground shoots. Therefore, we recommend cultivating M sac × sin at locations with low risk and M sin × sin at locations with higher risk of late spring frosts. Selecting miscanthus hybrids that produce shoots throughout the vegetation period is an effective strategy to limit the risk of late frost damage and avoid reduction in yield from a shortened growing season.

Abstract Objectives Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) virus infection in pregnancy is associated with higher incidence of placental dysfunction, referred to by a few studies as a ‘preeclampsia‐like syndrome’. However, the mechanisms underpinning SARS‐CoV‐2‐induced placental malfunction are still unclear. Here, we investigated whether the transcriptional architecture of the placenta is altered in response to SARS‐CoV‐2 infection. Methods We utilised whole‐transcriptome, digital spatial profiling, to examine gene expression patterns in placental tissues from participants who contracted SARS‐CoV‐2 in the third trimester of their pregnancy (n = 7) and those collected prior to the start of the coronavirus disease 2019 (COVID‐19) pandemic (n = 9). Results Through comprehensive spatial transcriptomic analyses of the trophoblast and villous core stromal cell subpopulations in the placenta, we identified SARS‐CoV‐2 to promote signatures associated with hypoxia and placental dysfunction. Notably, genes associated with vasodilation (NOS3), oxidative stress (GDF15, CRH) and preeclampsia (FLT1, EGFR, KISS1, PAPPA2) were enriched with SARS‐CoV‐2. Pathways related to increased nutrient uptake, vascular tension, hypertension and inflammation were also enriched in SARS‐CoV‐2 samples compared to uninfected controls. Conclusions Our findings demonstrate the utility of spatially resolved transcriptomic analysis in defining the underlying pathogenic mechanisms of SARS‐CoV‐2 in pregnancy, particularly its role in placental dysfunction. Furthermore, this study highlights the significance of digital spatial profiling in mapping the intricate crosstalk between trophoblasts and villous core stromal cells, thus shedding light on pathways associated with placental dysfunction in pregnancies with SARS‐CoV‐2 infection.

Abstract In high‐income nations, multiple micronutrient (MMN) supplementation during pregnancy is a common practice. We aimed to describe maternal characteristics associated with supplement use and daily dose of supplemental nutrients consumed in pregnancy, and whether guideline alignment and nutrient status are related to supplement use. The Queensland Family Cohort is a prospective, Australian observational longitudinal study. Maternal characteristics, nutrient intake from food and supplements, and biochemical nutrient status were assessed in the second trimester (n = 127). Supplement use was reported by 89% of participants, of whom 91% reported taking an MMN supplement. Participants who received private obstetric care, had private health insurance and had greater alignment to meat/vegetarian alternatives recommendations were more likely to report MMN supplement use. Private obstetric care and general practitioner shared care were associated with higher daily dose of supplemental nutrients consumed compared with midwifery group practice. There was high reliance on supplements to meet nutrient reference values for folate, iodine and iron, but only plasma folate concentrations were higher in MMN supplement versus nonsupplement users. Exceeding the upper level of intake for folic acid and iron was more likely among combined MMN and individual supplement/s users, and associated with higher plasma concentrations of the respective nutrients. Given the low alignment with food group recommendations and potential risks associated with high MMN supplement use, whole food diets should be emphasized. This study confirms the need to define effective strategies for optimizing nutrient intake in pregnancy, especially among those most vulnerable where MMN supplement use may be appropriate.

Abstract New biomass crop hybrids for bioeconomic expansion require yield projections to determine their potential for strategic land use planning in the face of global challenges. Our biomass growth simulation incorporates radiation interception and conversion efficiency. Models often use leaf area to predict interception which is demanding to determine accurately, so instead we use low‐cost rapid light interception measurements using a simple laboratory‐made line ceptometer and relate the dynamics of canopy closure to thermal time, and to measurements of biomass. We apply the model to project the European biomass potentials of new market‐ready hybrids for 2020–2030. Field measurements are easier to collect, the calibration is seasonally dynamic and reduces influence of weather variation between field sites. The model obtained is conservative, being calibrated by crops of varying establishment and varying maturity on less productive (marginal) land. This results in conservative projections of miscanthus hybrids for 2020–2030 based on 10% land use conversion of the least (productive) grassland and arable for farm diversification, which show a European potential of 80.7–89.7 Mt year−1 biomass, with potential for 1.2–1.3 EJ year−1 energy and 36.3–40.3 Mt year−1 carbon capture, with seeded Miscanthus sacchariflorus × sinensis displaying highest yield potential. Simulated biomass projections must be viewed in light of the field measurements on less productive land with high soil water deficits. We are attempting to model the results from an ambitious and novel project combining new hybrids across Europe with agronomy which has not been perfected on less productive sites. Nevertheless, at the time of energy sourcing issues, seed‐propagated miscanthus hybrids for the upscaled provision of bioenergy offer an alternative source of renewable energy. If European countries provide incentives for growers to invest, seeded hybrids can improve product availability and biomass yields over the current commercial miscanthus variety.

Abstract Miscanthus, a C4 perennial rhizomatous grass from Asia is a leading candidate for the supply of sustainable biomass needed to grow the bioeconomy. European Miscanthus breeding programmes have recently produced a new range of seeded hybrids with the objective of increasing scalability to large acreages limited by current clonal propagation. For the EU‐GRACE project, new replicated field trials were established in seven locations across Europe in 2018 with eight intraspecific M. sinensis hybrids (sin × sin) and six M. sacchariflorus × M. sinensis (sac × sin) from Dutch and UK breeding programmes, respectively, with clonal Miscanthus × giganteus. The planting density of the sin × sin was double that of sac × sin (30,000 & 15,000 plants ha−1), creating commercially relevant upscaling comparisons between systems. Over the first 3 years, the establishment depended on location and hybrid. The mature sin × sin hybrids formed tight tufts of shoots up to 2.5 m tall which flower and senesce earlier than the taller sac × sin hybrids. Following the third growing season, the highest yields were recorded in Northern Italy at a low altitude (average 13.7 (max 21) Mg DM ha−1) and the lowest yielding was on the industrially damaged marginal land site in Northern France (average 7.0 (max 10) Mg DM ha−1). Moisture contents at spring harvest were lowest in Croatia (21.7%) and highest in Wales, UK (41.6%). Overall, lower moisture contents at harvest, which are highly desirable for transport, storage and for most end‐use applications, were found in sin × sin hybrids than sac × sin (30% and 40%, respectively). Yield depended on climate interactions with the hybrid and their associated planting systems. The sin × sin hybrids appeared better adapted to northern Europe and sac × sin hybrids to southern Europe. Longer‐term yield observations over crop lifespans will be needed to explore the biological (yield persistence) and economic costs and benefits of the different hybrid systems.

Abstract Background A primary goal in transoral robotic surgery (TORS) for oropharyngeal squamous cell cancer (OPSCC) survivors is to optimize swallowing function. However, the uncertainty in the outcomes of TORS including postoperative residual positive margin (PM) and extranodal extension (ENE), may necessitate adjuvant therapy, which may cause significant swallowing toxicity to survivors. Methods A secondary analysis was performed on a prospective registry data with low‐ to intermediate‐risk human papillomavirus–related OPSCC possibly resectable by TORS. Decision trees were developed to model the uncertainties in TORS compared with definitive radiation therapy (RT) and chemoradiation therapy (CRT). Swallowing toxicities were measured by Dynamic Imaging Grade of Swallowing Toxicity (DIGEST), MD Anderson Dysphagia Inventory (MDADI), and the MD Anderson Symptom Inventory–Head and Neck (MDASI‐HN) instruments. The likelihoods of PM/ENE were varied to determine the thresholds within which each therapy remains optimal. Results Compared with RT, TORS resulted in inferior swallowing function for moderate likelihoods of PM/ENE (>60% in short term for all instruments, >75% in long term for DIGEST and MDASI) leaving RT as the optimal treatment. Compared with CRT, TORS remained the optimal therapy based on MDADI and MDASI but showed inferior swallowing outcomes based on DIGEST for moderate‐to‐high likelihoods of PM/ENE (>75% for short‐term and >40% for long‐term outcomes). Conclusion In the absence of reliable estimation of postoperative PM/ENE concurrent with significant postoperative PM, the overall toxicity level in OPSCC patients undergoing TORS with adjuvant therapy may become more severe compared with patients receiving nonsurgical treatments thus advocating definitive (C)RT protocols.

Abstract Background This study investigated the association of hearing loss and tinnitus with overall health‐related quality of life (HRQoL) among long‐term oropharyngeal cancer (OPC) survivors. Methods This study included OPC survivors treated between 2000 and 2013 and surveyed from September 2015 to July 2016. Hearing loss and tinnitus were measured by asking survivors to rate their “difficulty with hearing loss and/or ringing in the ears” from 0 (not present) to 10 (as bad as you can imagine). Hearing loss and tinnitus scores were categorized as follows: 0 for none, 1–4 for mild, and 5–10 for moderate to severe. The primary outcome was the mean score of MD nderson Symptom Inventory Head & Neck module interference component as a HRQoL surrogate dichotomized as follows: 0 to 4 for none to mild and 5 to 10 for moderate to severe interference. Results Among 880 OPC survivors, 35.6% (314), reported none, 39.3% (347) reported mild, and 25.1% (221) reported moderate to severe hearing loss and tinnitus. On multivariable analysis, mild (OR, 5.83; 95% CI; 1.48–22.88; p = 0.012) and moderate (OR, 30.01; 95% CI; 7.96–113.10; p

Objective Patient‐reported outcome (PRO) data have assumed increasing importance in the care of patients with rheumatoid arthritis (RA), yet physician‐derived disease activity measures, such as Clinical Disease Activity Index (CDAI), remain the most accepted metrics to assess disease activity. The possibility that newer longitudinal PRO data might be used as a proxy for the CDAI has not been evaluated. Methods Using data from a large pragmatic trial, we evaluated patients with RA initiating golimumab intravenous or infliximab. The classification target was low disease activity (LDA) (CDAI ≤10) at the first visit between months 3 and 12. Data were randomly partitioned into training (80%) and test (20%) data sets. Multiple machine learning (ML) methods (eg, random forests, gradient boosting, support vector machines) were used to classify CDAI disease activity category, conduct feature selection, and assess feature importance. Model performance evaluated cross‐validated error, comparing different ML approaches using both training and test data. Results A total of 494 patients were analyzed, and 36.4% achieved LDA. The most important classification features included several Patient‐Reported Outcomes Measurement Information System measures (social participation, pain interference, pain intensity, and physical function), patient global, and baseline CDAI. Among all ML methods, random forests performed best. Overall model accuracy and positive predictive values for all ML methods were approximately 80%. Conclusion ML methods coupled with longitudinal PRO data appear useful and can achieve reasonable accuracy in classifying LDA among patients starting a new biologic. This approach has promise for real‐world evidence generation in the common circumstance when physician‐derived disease activity data are not available yet PRO measures are.

Abstract Miscanthus, a C4 perennial rhizomatous grass, is capable of growing in varied climates and soil types in Europe, including on marginal lands. It can produce high yields with low nutrient inputs when harvested after complete senescence. Senescence induction and rate depend on complex genetic, environmental, and management interactions. To explore these interactions, we analysed four miscanthus hybrids (two novel seed‐based hybrids, GRC 3 [Miscanthus sinensis × sinensis] and GRC 14 [M. sacchariflorus × sinensis]; GRC 15, a novel M. sacchariflorus × sinensis clone; and GRC 9, a standard Miscanthus × giganteus clone) in Italy, Croatia, Germany and the UK. Over all trial locations and hybrids, the average aboveground biomass of the 3‐year‐old stands in August 2020 was 15 t DM ha−1 with nutrient contents of 7.6 mg N g−1 and 14.6 mg K g−1. As expected, delaying the harvest until spring reduced overall yield and nutrient contents (12 t DM ha−1, 3.3 mg N g−1, and 5.5 mg K g−1). At lower latitudes, the late‐ripening M. sacchariflorus × sinensis GRC 14 and GRC 15 combined high yields with low nutrient contents. At the most elevated latitude location (UK), the early‐ripening M. sinensis × sinensis combined high biomass yields with low nutrient offtakes. The clonal Miscanthus × giganteus with intermediate flowering and senescence attained similar low nutrient contents by spring harvest at all four locations. Seasonal changes in yield and nutrient levels analysed in this study provide: (1) a first step towards recommending hybrids for specific locations and end uses in Europe; (2) crucial data for determination of harvest time and practical steps in the valorization of biomass; and (3) key sustainability data for life cycle assessments. Identification of trade‐offs resulting from genetic × environment × management interactions is critical for increasing sustainable biomass supply from miscanthus grown on marginal lands.

Abstract To help meet greenhouse gas mitigation targets perennial biomass crops will need to be planted at large scales and at a much greater pace over the coming decades. Miscanthus is a leading biomass crop but rapid upscaling is technically challenging due to costly and time‐consuming clonal propagation. Seed‐based hybrids are considered a viable route to rapid upscaling, but direct sowing has not been found feasible under temperate climate conditions due to high thermal requirements for germination and slow early plant development compared with larger seeded annuals. Seed‐based plug plants, initially propagated in greenhouses, provide a suitable route to improve field establishment. Here, we describe an input optimization experiment for seeded Miscanthus plugs raised for spring planting in a naturally lit greenhouse with the following treatments: supplemental heat to maintain a minimum of 15°C, supplemental predawn light from modern LEDs at PPFD 300–400 μmol m−2 s−1, two proprietary types of compost (known as 50k and 70k), and two compost volumes (35 and 15 cm3). Our results showed that variations in all four factors had significant effects on above‐ and belowground biomass: (i) supplemental heat increased root‐to‐shoot ratio, (ii) supplemental light increased total biomass and root‐to‐shoot ratio, (iii) compost type affected total biomass and (iv) compost volume was positively correlated with total biomass and stem base diameter. No factor had a significant effect on axillary shoot formation. We recommend nurseries in the United Kingdom use LEDs as predawn supplemental light but no supplemental heat, compost that has both good water‐holding capacity and aeration, and a larger compost volume, which provided optimized cost‐plug resilience for spring‐sown, seed‐based Miscanthus plug production.

Abstract Miscanthus is a leading perennial biomass crop that can produce high yields on marginal lands. Moisture content is a highly relevant biomass quality trait with multiple impacts on efficiencies of harvest, transport, and storage. The dynamics of moisture content during senescence and overwinter ripening are determined by genotype × environment interactions. In this paper, unmanned aerial vehicle (UAV)‐based remote sensing was used for high‐throughput plant phenotyping (HTPP) of the moisture content dynamics during autumn and winter senescence of 14 contrasting hybrid types (progeny of M. sinensis x M. sinensis [M. sin x M. sin, eight types] and M. sinensis x M. sacchariflorus [M. sin x M. sac, six types]). The time series of moisture content was estimated using machine learning (ML) models and a range of vegetation indices (VIs) derived from UAV‐based remote sensing. The most important VIs for moisture content estimation were selected by the recursive feature elimination (RFE) algorithm and were BNDVI, GDVI, and PSRI. The ML model transferability was high only when the moisture content was above 30%. The best ML model accuracy was achieved by combining VIs and categorical variables (5.6% of RMSE). This model was used for phenotyping senescence dynamics and identifying the stay‐green (SG) trait of Miscanthus hybrids using the generalized additive model (GAM). Combining ML and GAM modeling, applied to time series of moisture content values estimated from VIs derived from multiple UAV flights, proved to be a powerful tool for HTPP.

Abstract Oxidation of reactive carbon fuels climate‐ and pollution‐relevant chemistry. Deciduous forests are important sources of reactive carbon (particularly isoprene). Organization in turbulence can physically separate (“segregate”) oxidants from reactive carbon, causing oxidation to increase or decrease relative to the (ubiquitous) assumption of well‐mixed conditions. We use large eddy simulation coupled to a multilayer canopy model and simplified chemistry to quantify the impact of segregation on near‐canopy hydroxyl radical (OH) reactivity. Simulations mimic summer clear‐sky midday and morning conditions at a homogeneous deciduous forest. OH‐isoprene segregation alters OH reactivity inside the canopy by up to 9%, but the impact strongly depends on height, soil NO emissions, and sunlight. Uniquely, we identify the drivers of changes by isolating the roles of isoprene and OH. Our findings also suggest that segregation may create discrepancies between direct measurements and bottom‐up estimates of OH reactivity, separate from the issue of mischaracterized or unknown OH sinks.

Abstract Mothers with gestational diabetes are at increased risk of giving birth by caesarean section. A standardised assessment method may help to guide in recommendations in planning caesarean birth. We analysed 203 women with gestational diabetes managed in a single centre and developed an aggregate heuristic risk score. Among 155 women who had not had a previous caesarean birth, five risk factors (previous birth, weight gain during pregnancy, mother's height, and glycated haemoglobin and fasting blood glucose results at the beginning of pregnancy) were found associated with primary caesarean birth. Risk of primary caesarean birth in low‐risk women (score 0–1) was 13.8%, medium‐risk (score 2–3) 24.5% and high risk (score ≥ 4) 66.7%. The area under the receiver operating characteristic (AUROC) for primary caesarean birth prediction is 0.726 ± 0.003. Machine learning models were then deployed on 97 patients to explore the role of temporal blood glucose in predicting caesarean birth, achieving an AUROC of 0.857 ± 0.008. In conclusion, Oxford caesarean prediction score could help clinicians counselling women with gestational diabetes about their individual risk of primary caesarean birth. Temporal blood glucose measurements may improve the prediction subject to further validation.

Abstract Stent migration due to haemodynamic drag remains the primary cause of type I endoleak, potentially leading to aneurysm rupture. The prevalence of migration and endoleak can be partially attributed to deficiencies in stent‐graft radial spring design and a lack in understanding of the mechanical properties of endovascular stents. A converged finite element model of a custom radial extensometer was developed, fit, and validated using experimental results for bare stent wire (“uncovered”) with outer diameter of 12 mm stent. During stent constriction to 50 % of the original cross‐sectional area, a comparison of experimental and modeled results produced an r2 value of 0.946, a standard error of 0.099 N, and a mean percent error of 1.69 %. This validated finite element model can be used to analyze the mechanisms responsible for radial force generation in 316L stainless steel self‐expanding endovascular stents, as well as to evaluate new stent designs.

Abstract Emergency clinicians often resuscitate cardiac arrest patients, and after acute resuscitation, clinicians face multiple decisions regarding disposition. Recent evidence suggests that out‐of‐hospital cardiac arrest patients with return of spontaneous circulation have higher odds of survival to hospital discharge, long‐term survival, and improved functional outcomes when treated at centers that can provide advanced multidisciplinary care. For community clinicians, a high volume cardiac arrest center may be hours away. While current guidelines recommend against neurological prognostication in the first hours or days after return of spontaneous circulation, there are early findings suggestive of irrecoverable brain injury in which the patient would receive no benefit from transfer. In this Concepts article, we describe a simplified approach to quickly evaluate neurological status in cardiac arrest patients and identify findings concerning for irrecoverable brain injury. Characteristics of the arrest and resuscitation, initial neurological assessment, and brain computed tomography together can identify patients with high likelihood of irrecoverable anoxic injury. Patients who may benefit from centers with access to continuous electroencephalography are discussed. This approach can be used to identify patients who may benefit from rapid transfer to cardiac arrest centers versus those who may benefit from care close to home. Risk stratification also can provide realistic expectations for recovery to families.

Abstract Background The national incidence and characteristics of out‐of‐hospital cardiac arrest in the United States is unclear. We sought to describe the national characteristics of adult out‐of‐hospital cardiac arrest reported in the National Emergency Medical Services Information System (NEMSIS). Methods We used 2016 NEMSIS data, consisting of most emergency medical services (EMS) responses from 46 states and territories. We limited the analysis to adult (age ≥18 years) emergency “9‐1‐1” events. We defined out‐of‐hospital cardiac arrest as: (1) patient condition reported as cardiac arrest, (2) EMS reported attempted resuscitation of cardiac arrest, (3) EMS performance of cardiopulmonary resuscitation (CPR), or (4) EMS performance of defibrillation. We determined the incidence of adult out‐of‐hospital cardiac arrest among EMS responses. We also determined patient demographics (age, sex, race, ethnicity, location, US census region, and urbanicity), response characteristics (dispatch complaint and elapsed time) and clinical interventions (medications and procedures) of adult out‐of‐hospital cardiac arrest. We analyzed the data using descriptive techniques, calculating binomial proportions with exact 95% confidence intervals (CI). Results Among 18,679,873 adult 9‐1‐1 responses, there were 224,992 with patient condition cardiac arrest, 344,274 with EMS‐reported attempted cardiac arrest resuscitation, 149,775 with EMS performance of CPR, and 185,388 cases with EMS performance of defibrillation, resulting in a total of 574,824 out‐of‐hospital cardiac arrest (incidence 30.8 per 1000 EMS 9‐1‐1 responses, 95% CI = 30.69–30.85). Among identified out‐of‐hospital cardiac arrest responses, most involved patients who were older (mean = 62.4 ± 20.1 years). Most out‐of‐hospital cardiac arrest occurred at home (58.8%), in the South census region (65.4%), and in urban settings (79.8%). The most commonly reported medications used in out‐of‐hospital cardiac arrest were: epinephrine (22.5%), amiodarone (2.9%), sodium bicarbonate (6.2%), glucose (3.0%), and naloxone (5.1%). Commonly reported procedures included CPR (26.1%), orotracheal intubation (14.2%), bag‐valve‐mask ventilation (10.1%), manual defibrillation (29.3%) and automated external defibrillation (5.6%). Out‐of‐hospital cardiac arrest EMS treatment times were: elapsed response time (median = 7 minutes [interquartile range (IQR) = 5–10]), scene time (median = 17 minutes [IQR = 12–25]), and elapsed transport time (median = 11 minutes [IQR = 6–17]). Conclusions Using information available in the 2016 NEMSIS data, we estimate that there were over 570,000 reported adult out‐of‐hospital cardiac arrests in the United States. These results highlight the challenges of characterizing the epidemiology of adult out‐of‐hospital cardiac arrest in the United States.

Abstract Introduction Outcomes after frontline treatment of Burkitt lymphoma (BL) have improved with the introduction of dose‐intense chemotherapy regimens, such as CODOX‐M/IVAC. While rituximab has increased survival rates for most forms of high‐grade B‐cell lymphoma, there has previously been hesitancy about incorporating it into BL treatment, partly due to concerns about increased toxicity. Prospective data using the standard dose CODOX‐M/IVAC regimen in combination with rituximab are lacking. We conducted a single‐arm phase 2 trial to assess the efficacy and toxicity of R‐CODOX‐M/R‐IVAC. Methods Eligible patients were aged 18–65 years, with newly diagnosed BL with MYC rearrangement as the sole cytogenetic abnormality, and high‐risk disease, defined by an International Prognostic Index (IPI) score of 3‐5. Patients received two cycles of R‐CODOX‐M chemotherapy alternating with two cycles of R‐IVAC, followed by two further cycles of rituximab alone. The primary endpoint was 2‐year progression‐free survival. Results Thirty‐eight patients were registered but after central pathology review, 27 patients had confirmed BL and commenced study treatment. Median age was 35 years, 14.8% patients had central nervous system involvement and 18.5% were HIV positive. Twenty‐two (81.4%) patients completed four cycles of chemotherapy. There were two treatment‐related deaths (7.4%). Two‐year progression‐free and overall survival rates were 77.2% (90% confidence interval [CI]: 56.0‐89.0) and 80.7% (90% CI: 59.6‐91.5), respectively. Conclusions This prospective trial demonstrates excellent survival rates with R‐CODOX‐M/R‐IVAC in a high‐risk BL cohort. It provides reassuring evidence regarding the feasibility of this regimen and also provides a benchmark for future studies.

Abstract High yielding perennial crops are being developed as a sustainable feedstock for renewable energy and bioproducts. Miscanthus is a leading biomass crop, but most plantations comprise a sterile hybrid Miscanthus × giganteus that is clonally propagated. To develop new varieties across large areas, rhizome cloning is inefficient, time consuming and expensive. Alternative approaches use seed, and in temperate regions, this has been successfully applied by raising seedlings as plug plants in glasshouses before transfer to the field. Direct sowing has yet to be proven commercially viable because poor germination has resulted in inconsistent stand establishment. Oversowing using seed clusters is a common approach to improve the establishment of crops and it was hypothesized that such an approach will improve uniformity of density in early Miscanthus stands and thereby improve yield. Sowing multiple seeds creates potential for new interactions, and we identified at least two inhibitory mechanisms related to seed numbers. Germinating seed produced allelopathic effects on nearby seed thereby inhibiting plant growth. The inhibitory effect of Miscanthus seed on germination percentages was related to seed number within clusters. An extract from germinating Miscanthus seed inhibited the germination of Miscanthus seed. The extract was analysed by HPLC, which identified a complex mixture including several known allelopathic compounds including proanthocyanidins and vanillic acid. There was also evidence of root competition in soil in a controlled environment experiment. When the experiment on competition was replicated at field scale, the establishment rates were much lower and there was evidence of shoot competition. We conclude that the numbers of seed required to ensure an acceptable level of establishment in the field may be economically impractical until other agronomic techniques are included either to reduce the inhibitory effects of higher seed numbers or to reduce oversowing rates.

Abstract Spatially explicit farm‐gate production costs and the economic potential of three types of energy crops grown on available marginal land in China for 2017 and 2040 were investigated using a spatial accounting method and construction of cost–supply curves. The average farm‐gate cost from all available marginal land was calculated as 32.9 CNY/GJ for Miscanthus Mode, 27.5 CNY/GJ for Switchgrass Mode, 32.4 CNY/GJ for Miscanthus & Switchgrass Mode, and 909 CNY/GJ for Jatropha Mode in 2017. The costs of Miscanthus and switchgrass were predicted to decrease by approximately 11%‐15%, whereas the cost of Jatropha was expected to increase by 5% in 2040. The cost of Jatropha varies significantly from 193 to 9,477 CNY/GJ across regions because of the huge differences in yield across regions. The economic potential of the marginal land was calculated as 28.7 EJ/year at a cost of less than 25 CNY/GJ for Miscanthus Mode, 4.0 EJ/year at a cost of less than 30 CNY/GJ for Switchgrass Mode, 29.6 EJ/year at a cost of less than 25 CNY/GJ for Miscanthus & Switchgrass Mode, and 0.1 EJ/year at a cost of less than 500 CNY/GJ for Jatropha Mode in 2017. It is not feasible to develop Jatropha production on marginal land based on existing technologies, given its high production costs. Therefore, the Miscanthus & Switchgrass Mode is the most economical way, because it achieves the highest economic potential compared with other modes. The sensitivity analysis showed that the farm‐gate costs of Miscanthus and switchgrass are most sensitive to uncertainties associated with yield reduction and harvesting costs, while, for Jatropha, the unpredictable yield has the greatest impact on its farm‐gate cost. This study can help policymakers and industrial stakeholders make strategic and tactical bioenergy development plans in China (exchange rate in 2017: 1€ = 7.63￥; all the joules in this paper are higher heat value).