Radar for Europa Assessment and Sounding: Ocean to Near-Surface (REASON).

The Radar for Europa Assessment and Sounding: Ocean to Near-surface (REASON) is a dual-frequency ice-penetrating radar (9 and 60 MHz) onboard the Europa Clipper mission. REASON is designed to probe Europa from exosphere to subsurface ocean, contributing the third dimension to observations of this enigmatic world. The hypotheses REASON will test are that (1) the ice shell of Europa hosts liquid water, (2) the ice shell overlies an ocean and is subject to tidal flexing, and (3) the exosphere, near-surface, ice shell, and ocean participate in material exchange essential to the habitability of this moon. REASON will investigate processes governing this material exchange by characterizing the distribution of putative non-ice material (e.g., brines, salts) in the subsurface, searching for an ice-ocean interface, characterizing the ice shell's global structure, and constraining the amplitude of Europa's radial tidal deformations. REASON will accomplish these science objectives using a combination of radar measurement techniques including altimetry, reflectometry, sounding, interferometry, plasma characterization, and ranging. Building on a rich heritage from Earth, the moon, and Mars, REASON will be the first ice-penetrating radar to explore the outer solar system. Because these radars are untested for the icy worlds in the outer solar system, a novel approach to measurement quality assessment was developed to represent uncertainties in key properties of Europa that affect REASON performance and ensure robustness across a range of plausible parameters suggested for the icy moon. REASON will shed light on a never-before-seen dimension of Europa and - in concert with other instruments on Europa Clipper - help to investigate whether Europa is a habitable world.

Climate change and environmental sustainability in otolaryngology: A state-of-the-art review.

BACKGROUND: Climate change has been identified by the World Health Organization (WHO) as the greatest existing threat to human health. Given the direct exposure of the upper aerodigestive system to pollutants, patients in otolaryngology are at high risk for increased disease burden in the setting of climate change and worsening air quality. Given this and the environmental impact of surgical care, it is essential for surgeons to understand their role in addressing climate health through quality-driven clinical initiatives, education, advocacy, and research. METHODS: A state-of-the-art review was performed of the existing literature on the otolaryngologic health impacts of climate change and environmental sustainability efforts in surgery with specific attention to studies in otolaryngology - head and neck surgery. FINDINGS: Climate variables including heat and air pollution are associated with increased incidence of allergic rhinitis, chronic rhinosinusitis and head and neck cancer. A number of studies have shown that sustainability initiatives in otolaryngology are safe and provide direct cost benefit. CONCLUSION: Surgeons have the opportunity to lead on climate health and sustainability to address the public health burden of climate change.

Interventions for postburn pruritus.

BACKGROUND: Postburn pruritus (itch) is a common and distressing symptom experienced on healing or healed burn or donor site wounds. Topical, systemic, and physical treatments are available to control postburn pruritus; however, it remains unclear how effective these are. OBJECTIVES: To assess the effects of interventions for treating postburn pruritus in any care setting. SEARCH METHODS: In September 2022, we searched the Cochrane Wounds Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase, and EBSCO CINAHL Plus. We also searched clinical trials registries and scanned references of relevant publications to identify eligible trials. There were no restrictions with respect to language, publication date, or study setting. SELECTION CRITERIA: Randomised controlled trials (RCTs) that enrolled people with postburn pruritus to compare an intervention for postburn pruritus with any other intervention, placebo or sham intervention, or no intervention. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of the evidence. MAIN RESULTS: We included 25 RCTs assessing 21 interventions with 1166 randomised participants. These 21 interventions can be grouped into six categories: neuromodulatory agents (such as doxepin, gabapentin, pregabalin, ondansetron), topical therapies (such as CQ-01 hydrogel, silicone gel, enalapril ointment, Provase moisturiser, beeswax and herbal oil cream), physical modalities (such as massage therapy, therapeutic touch, extracorporeal shock wave therapy, enhanced education about silicone gel sheeting), laser scar revision (pulsed dye laser, pulsed high-intensity laser, fractional CO2 laser), electrical stimulation (transcutaneous electrical nerve stimulation, transcranial direct current stimulation), and other therapies (cetirizine/cimetidine combination, lemon balm tea). Most RCTs were conducted at academic hospitals and were at a high risk of performance, attrition, and detection bias. While 24 out of 25 included studies reported change in burn-related pruritus, secondary outcomes such as cost-effectiveness, pain, patient perception, wound healing, and participant health-related quality of life were not reported or were reported incompletely. Neuromodulatory agents versus antihistamines or placebo There is low-certainty evidence that doxepin cream may reduce burn-related pruritus compared with oral antihistamine (mean difference (MD) -2.60 on a 0 to 10 visual analogue scale (VAS), 95% confidence interval (CI) -3.79 to -1.42; 2 studies, 49 participants). A change of 2 points represents a minimal clinically important difference (MCID). Due to very low-certainty evidence, it is uncertain whether doxepin cream impacts the incidence of somnolence as an adverse event compared to oral antihistamine (risk ratio (RR) 0.64, 95% CI 0.32 to 1.25; 1 study, 24 participants). No data were reported on pain in the included study. There is low-certainty evidence that gabapentin may reduce burn-related pruritus compared with cetirizine (MD -2.40 VAS, 95% CI -4.14 to -0.66; 1 study, 40 participants). A change of 2 points represents a MCID. There is low-certainty evidence that gabapentin reduces the incidence of somnolence compared to cetirizine (RR 0.02, 95% CI 0.00 to 0.38; 1 study, 40 participants). No data were reported on pain in the included study. There is low-certainty evidence that pregabalin may result in a reduction in burn-related pruritus intensity compared with cetirizine with pheniramine maleate (MD -0.80 VAS, 95% CI -1.24 to -0.36; 1 study, 40 participants). A change of 2 points represents a MCID. There is low-certainty evidence that pregabalin reduces the incidence of somnolence compared to cetirizine (RR 0.04, 95% CI 0.00 to 0.69; 1 study, 40 participants). No data were reported on pain in the included study. There is moderate-certainty evidence that ondansetron probably results in a reduction in burn-related pruritus intensity compared with diphenhydramine (MD -0.76 on a 0 to 10 numeric analogue scale (NAS), 95% CI -1.50 to -0.02; 1 study, 38 participants). A change of 2 points represents a MCID. No data were reported on pain and adverse events in the included study. Topical therapies versus relevant comparators There is moderate-certainty evidence that enalapril ointment probably decreases mean burn-related pruritus compared with placebo control (MD -0.70 on a 0 to 4 scoring table for itching, 95% CI -1.04 to -0.36; 1 study, 60 participants). No data were reported on pain and adverse events in the included study. Physical modalities versus relevant comparators Compared with standard care, there is low-certainty evidence that massage may reduce burn-related pruritus (standardised mean difference (SMD) -0.86, 95% CI -1.45 to -0.27; 2 studies, 166 participants) and pain (SMD -1.32, 95% CI -1.66 to -0.98). These SMDs equate to a 4.60-point reduction in pruritus and a 3.74-point reduction in pain on a 10-point VAS. A change of 2 VAS points in itch represents a MCID. No data were reported on adverse events in the included studies. There is low-certainty evidence that extracorporeal shock wave therapy (ESWT) may reduce burn-related pruritus compared with sham stimulation (SMD -1.20, 95% CI -1.65 to -0.75; 2 studies, 91 participants). This equates to a 5.93-point reduction in pruritus on a 22-point 12-item Pruritus Severity Scale. There is low-certainty evidence that ESWT may reduce pain compared with sham stimulation (MD 2.96 on a 0 to 25 pressure pain threshold (PPT), 95% CI 1.76 to 4.16; 1 study, 45 participants). No data were reported on adverse events in the included studies. Laser scar revision versus untreated or placebo controls There is moderate-certainty evidence that pulsed high-intensity laser probably results in a reduction in burn-related pruritus intensity compared with placebo laser (MD -0.51 on a 0 to 1 Itch Severity Scale (ISS), 95% CI -0.64 to -0.38; 1 study, 49 participants). There is moderate-certainty evidence that pulsed high-intensity laser probably reduces pain compared with placebo laser (MD -3.23 VAS, 95% CI -5.41 to -1.05; 1 study, 49 participants). No data were reported on adverse events in the included studies. AUTHORS' CONCLUSIONS: There is moderate to low-certainty evidence on the effects of 21 interventions. Most studies were small and at a high risk of bias related to blinding and incomplete outcome data. Where there is moderate-certainty evidence, practitioners should consider the applicability of the evidence for their patients.

Feed balances for ruminant livestock: gridded estimates for data-constrained regions.

Demand for animal-source foods and livestock feed are forecast to increase across sub-Saharan Africa. In this context, there is a need to estimate the availability of livestock feed to support decision-making at local, sub-national and national levels. In this study, we assess feed balances for ruminant livestock in Ethiopia and Burkina Faso. Feed availability was estimated using remotely sensed products and detailed feed composition data. Feed requirements were estimated for maintenance, growth, lactation, gestation and locomotion using a data-intensive model. Biomass available as animal feed was estimated to be 8.6 tonnes of DM per hectare in the Ethiopian highlands and midlands, 3.2 tonnes DM per hectare in the Ethiopian lowlands, 2.9 tonnes DM per hectare in Burkina Faso's Sudanian agro-ecological zone and 1.0 tonne DM per hectare in the Sahel. The energy requirements of lactating cows were estimated to be 62.1 Megajoules (MJs) per animal per day in the Ethiopian highlands and midlands, 62.7 MJ in the Ethiopian lowlands, 88.5 MJ in Burkina Faso's Sudanian agro-ecological zone and 53.1 MJ per animal per day in the Sahel. Feed scarcity hotspots are most prominently located in the Ethiopian highlands and the Sahelian agro-ecological zone of Burkina Faso. Demand-side policy and investment initiatives can address hotspots by influencing herd sizes, nutritional requirements and herd mobility. Supply-side policy and investment initiatives can secure existing feed resources, develop new sources of feed and incentivise trade in feed resources. Improving feed balances will be of value to decision-makers with the aims of optimising livestock productivity, minimising exposure to climatic shocks and minimising greenhouse gas emission intensity.

First-line Avelumab plus Chemotherapy in Patients with Advanced Solid Tumors: Results from the Phase Ib/II JAVELIN Chemotherapy Medley Study.

PURPOSE: Chemotherapy can potentially enhance the activity of immune checkpoint inhibitors by promoting immune priming. The phase Ib/II JAVELIN Chemotherapy Medley trial (NCT03317496) evaluated first-line avelumab + concurrent chemotherapy in patients with advanced urothelial carcinoma or non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Avelumab 800 or 1,200 mg was administered continuously every 3 weeks with standard doses of cisplatin + gemcitabine in patients with urothelial carcinoma, or carboplatin + pemetrexed in patients with nonsquamous NSCLC. Dual primary endpoints were dose-limiting toxicity (DLT; phase Ib) and confirmed objective response (phase Ib/II). RESULTS: In phase Ib, urothelial carcinoma and NSCLC cohorts received avelumab 800 mg (n = 13 and n = 6, respectively) or 1,200 mg (n = 6 each) + chemotherapy. In evaluable patients with urothelial carcinoma treated with avelumab 800 or 1,200 mg + chemotherapy, DLT occurred in 1/12 (8.3%) and 1/6 (16.7%), respectively; no DLT occurred in the NSCLC cohort. In phase II, 35 additional patients with urothelial carcinoma received avelumab 1,200 mg + chemotherapy. Across all treated patients, safety profiles were similar irrespective of avelumab dose. Objective response rates (95% confidence internal) with avelumab 800 or 1,200 mg + chemotherapy, respectively, across phase Ib/II, were 53.8% (25.1-80.8) and 39.0% (24.2-55.5) in urothelial carcinoma, and 50.0% (11.8-88.2) and 33.3% (4.3-77.7) in NSCLC. CONCLUSIONS: Preliminary efficacy and safety findings with avelumab + chemotherapy in urothelial carcinoma and NSCLC were consistent with previous studies of similar combination regimens. Conclusions about clinical activity are limited by small patient numbers. SIGNIFICANCE: This phase Ib/II trial evaluated avelumab (immune checkpoint inhibitor) administered concurrently with standard first-line chemotherapy in patients with advanced urothelial carcinoma or advanced nonsquamous NSCLC without actionable mutations. Efficacy and safety appeared consistent with previous studies of similar combinations, although patient numbers were small.

Experiences and resultant care gaps among women with HIV in Canada: concept mapping the Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CHIWOS) findings.

OBJECTIVES: The community-based, longitudinal, Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CHIWOS) explored the experiences of women with HIV in Canada over the past decade. CHIWOS' high-impact publications document significant gaps in the provision of healthcare to women with HIV. We used concept mapping to analyse and present a summary of CHIWOS findings on women's experiences navigating these gaps. DESIGN: Concept mapping procedures were performed in two steps between June 2019 and March 2021. First, two reviewers (AY and PM) independently reviewed CHIWOS manuscripts and conference abstracts written before 1 August 2019 to identify main themes and generate individual concept maps. Next, the preliminary results were presented to national experts, including women with HIV, to consolidate findings into visuals summarising the experiences and care gaps of women with HIV in CHIWOS. SETTING: British Columbia, Ontario and Quebec, Canada. PARTICIPANTS: A total of 18 individual CHIWOS team members participated in this study including six lead investigators of CHIWOS and 12 community researchers. RESULTS: Overall, a total of 60 peer-reviewed manuscripts and conference abstracts met the inclusion criteria. Using concept mapping, themes were generated and structured through online meetings. In total, six composite concept maps were co-developed: quality of life, HIV care, psychosocial and mental health, sexual health, reproductive health, and trans women's health. Two summary diagrams were created encompassing the concept map themes, one for all women and one specific to trans women with HIV. Through our analysis, resilience, social support, positive healthy actions and women-centred HIV care were highlighted as strengths leading to well-being for women with HIV. CONCLUSIONS: Concept mapping resulted in a composite summary of 60 peer-reviewed CHIWOS publications. This activity allows for priority setting to optimise care and well-being for women with HIV.

Phylogenomics and morphology of Celmisiinae (Asteraceae: Astereae): Taxonomic and evolutionary implications.

The tribe Astereae (Asteraceae) includes 36 subtribes and 252 genera, and is distributed worldwide in temperate and tropical regions. One of the subtribes, Celmisiinae Saldivia, has been recently circumscribed to include six genera and ca. 160 species, and is restricted to eastern Australia, New Zealand, and New Guinea. The species show an impressive range of growth habit, from small herbs and ericoid subshrubs to medium-sized trees. They live in a wide range of habitats and are often dominant in subalpine and alpine vegetation. Despite the well-supported circumscription of Celmisiinae, uncertainties have remained about their internal relationships and classification at genus and species levels. This study exploited recent advances in high-throughput sequencing to build a robust multi-gene phylogeny for the subtribe Celmisiinae. The target enrichment Angiosperms353 bait set and the hybpiper-nf and paragone-nf pipelines were used to retrieve, infer, and assemble orthologous loci from 75 taxa representing all the main putative clades within the subtribe. Because of the diploidised ploidy level in Celmisiinae, as well as missing data in the assemblies, uncertainty remains surrounding the inference of orthology detection. However, based on a variety of gene-family sets, coalescent and concatenation-based phylogenetic reconstructions recovered similar topologies. Paralogy and missing data in the gene-families caused some problems, but the estimated phylogenies were well-supported and well-resolved. The phylogenomic evidence supported Celmisiinae and three main clades: the Pleurophyllum clade (Pleurophyllum, Macrolearia and Damnamenia), mostly in the New Zealand Subantarctic Islands, Celmisia of mainland New Zealand and Australia, and Shawia (including 'Olearia pro parte' and Pachystegia) of New Zealand, Australia and New Guinea. The results presented here add to the accumulating support for the Angiosperms353 bait set as an efficient method for documenting plant diversity.

Twin peaks: Matrix isolation studies of H2S·amine complexes shedding light on fundamental S-H⋯N bonding.

Noncovalent bonding between atmospheric molecules is central to the formation of aerosol particles and cloud condensation nuclei and, consequently, radiative forcing. While our understanding of O-H⋯B interactions is well developed, S-H⋯B hydrogen bonding has received far less attention. Sulfur- and nitrogen-containing molecules, particularly amines, play a significant role in atmospheric chemistry, yet S-H⋯N interactions are not well understood at a fundamental level. To help characterize these systems, H2S and methyl-, ethyl-, n-propyl-, dimethyl-, and trimethylamine (MA, EA, n-PA, DMA, and TMA) have been investigated using matrix isolation Fourier transform infrared spectroscopy and high-level theoretical methods. Experiments showed that H2S forms hydrogen bonded complexes with each of the amines, with bond strengths following the trend MA ≈ EA ≈ n-PA < TMA ≤ DMA, in line with past experimental work on H2SO4·amine complexes. However, the calculated results indicated that the trend should be MA < DMA < TMA, in line with past theoretical work on H2SO4·amine complexes. Evidence of strong Fermi resonances indicated that anharmonicity may play a critical role in the stabilization of each complex. The theoretical results were able to replicate experiment only after binding energies were recalculated to include the anharmonic effects. In the case of H2SO4·amine complexes, our results suggest that the discrepancy between theory and experiment could be reconciled, given an appropriate treatment of anharmonicity.

Manual versus machine: How accurately does the Medical Text Indexer (MTI) classify different document types into disease areas?

The Medical Subject Headings (MeSH) thesaurus is a controlled vocabulary developed by the U.S. National Library of Medicine (NLM) for classifying journal articles. It is increasingly used by researchers studying medical innovation to classify text into disease areas and other categories. Although this process was once manual, human indexers are now assisted by algorithms that automate some of the indexing process. NLM has made one of their algorithms, the Medical Text Indexer (MTI), available to researchers. MTI can be used to easily assign MeSH descriptors to arbitrary text, including from document types other than publications. However, the reliability of extending MTI to other document types has not been studied directly. To assess this, we collected text from grants, patents, and drug indications, and compared MTI's classification to expert manual classification of the same documents. We examined MTI's recall (how often correct terms were identified) and found that MTI identified 78% of expert-classified MeSH descriptors for grants, 78% for patents, and 86% for drug indications. This high recall could be driven merely by excess suggestions (at an extreme, all diseases being assigned to a piece of text); therefore, we also examined precision (how often identified terms were correct) and found that most MTI outputs were also identified by expert manual classification: precision was 53% for grant text, 73% for patent text, and 64% for drug indications. Additionally, we found that recall and precision could be improved by (i) utilizing ranking scores provided by MTI, (ii) excluding long documents, and (iii) aggregating to higher MeSH categories. For simply detecting the presence of any disease, MTI showed > 94% recall and > 87% precision. Our overall assessment is that MTI is a potentially useful tool for researchers wishing to classify texts from a variety of sources into disease areas.

When another one bites the dust: Environmental impact of global copper demand on local communities in the Atacama mining hotspot as registered by tree rings.

Assessing the impact of mining activity on the availability of environmental pollutants is crucial for informing health policies in anticipation of future production scenarios of critical minerals essential for the transition to a net-zero carbon society. However, temporal and spatial monitoring is often sparse, and measurements may not extend far enough back in time. In this study, we utilize variations of chemical elements contained in tree-rings collected in local villages from an area heavily affected by copper mining in the Atacama Desert since the early 20th century to evaluate the temporal distribution of pollutants and their relationship with local drivers. By combining time-varying data on local drivers, such as copper production and the dry tailings deposit area, we show how the surge in copper production during the 1990s, fueled by trade liberalization and increased international demand, led to a significant increment in the availability of metal(loid)s related to mining activities on indigenous lands. Our findings suggest that the environmental legislation in Chile may be underestimating the environmental impact of tailing dams in neighboring populations, affecting the well-being of Indigenous Peoples from the Atacama mining hotspot region. We argue that future changes in production rates driven by international demand could have negative repercussions on the environment and local communities. Therefore, mining emissions and the management of tailing dams should be carefully considered to anticipate their potential negative effects on human and ecosystem health.

Herbivore effects increase with latitude across the extent of a foundational seagrass.

Climate change is altering the functioning of foundational ecosystems. While the direct effects of warming are expected to influence individual species, the indirect effects of warming on species interactions remain poorly understood. In marine systems, as tropical herbivores undergo poleward range expansion, they may change food web structure and alter the functioning of key habitats. While this process ('tropicalization') has been documented within declining kelp forests, we have a limited understanding of how this process might unfold across other systems. Here we use a network of sites spanning 23° of latitude to explore the effects of increased herbivory (simulated via leaf clipping) on the structure of a foundational marine plant (turtlegrass). By working across its geographic range, we also show how gradients in light, temperature and nutrients modified plant responses. We found that turtlegrass near its northern boundary was increasingly affected (reduced productivity) by herbivory and that this response was driven by latitudinal gradients in light (low insolation at high latitudes). By contrast, low-latitude meadows tolerated herbivory due to high insolation which enhanced plant carbohydrates. We show that as herbivores undergo range expansion, turtlegrass meadows at their northern limit display reduced resilience and may be under threat of ecological collapse.

Environmental Impact of Adult Tonsillectomy: Life Cycle Assessment and Cost Comparison of Techniques.

OBJECTIVES: To quantify and compare the cost and environmental impact of different techniques for adult tonsillectomy surgery, and to identify target areas for impact reduction. METHODS: Fifteen consecutive adult tonsillectomy surgeries were prospectively randomized to one of three tonsillectomy techniques: cold, monopolar electrocautery, or low-temperature radiofrequency ablation (Coblation). Life cycle assessment was used to comprehensively evaluate the environmental impact of study surgeries. Outcomes assessed included multiple measures of environmental impact, including greenhouse gas (GHG) emissions, and cost. Environmental impact measures were analyzed to identify highest-yield areas for improvement, and outcomes were compared between surgical techniques using statistical analysis. RESULTS: GHG emissions for cold, monopolar electrocautery, and Coblation techniques were 157.6, 184.5, and 204.7 kilograms of carbon dioxide equivalents (kgCO2 -eq) per surgery, respectively, with costs totaling $472.51, $619.10, and $715.53 per surgery, respectively. Regardless of surgery technique, anesthesia medications and disposable equipment contributed most to environmental harm. Cold technique demonstrated reduced environmental impact related to disposable surgical equipment in the categories of greenhouse gas emissions, acidification of soil and water, eutrophication of air, ozone depletion, release of carcinogenic, and non-carcinogenic toxic substances, and respiratory pollutant production (p < 0.05 for all comparisons with other techniques). CONCLUSION: Within the boundaries of operating room processes, cold technique minimizes cost and environmental impact of adult tonsillectomy surgery, with statistical significance noted in the impact of disposable surgical equipment. Areas of highest potential for improvement identified include reducing use of disposable equipment and collaboration with the Anesthesiology care team to streamline medication use. LEVEL OF EVIDENCE: 2, randomized trial Laryngoscope, 134:622-628, 2024.

Modeling State Firearm Law Adoption Using Temporal Network Models.

Policy Points Promoting healthy public policies is a national priority, but state policy adoption is driven by a complex set of internal and external factors. This study employs new social network methods to identify underlying connections among states and to predict the likelihood of new firearm-related policy adoption given changes to this interstate network. This approach could be used to assess the likelihood that a given state will adopt a specific new firearm-related law and to identify points of influence that could either inhibit or promote wider diffusion of specific laws. CONTEXT: US states are largely responsible for the regulation of firearms within their borders. Each state has developed a different legal environment with regard to firearms based on different values and beliefs of citizens, legislators, governors, and other stakeholders. Predicting the types of firearm laws that states may adopt is therefore challenging. METHODS: We propose a parsimonious model for this complex process and provide credible predictions of state firearm laws by estimating the likelihood they will be passed in the future. We employ a temporal exponential-family random graph model to capture the bipartite state law-state network data over time, allowing for complex interdependencies and their temporal evolution. Using data on all state firearm laws over the period 1979-2020, we estimate these models' parameters while controlling for factors associated with firearm law adoption, including internal and external state characteristics. Predictions of future firearm law passage are then calculated based on a number of scenarios to assess the effects of a given type of firearm law being passed in the future by a given state. FINDINGS: Results show that a set of internal state factors are important predictors of firearm law adoption, but the actions of neighboring states may be just as important. Analysis of scenarios provide insights into the mechanics of how adoption of laws by specific states (or groups of states) may perturb the rest of the network structure and alter the likelihood that new laws would become more (or less) likely to continue to diffuse to other states. CONCLUSIONS: The methods used here outperform standard approaches for policy diffusion studies and afford predictions that are superior to those of an ensemble of machine learning tools. The proposed framework could have applications for the study of policy diffusion in other domains.

Early warning signals have limited applicability to empirical lake data.

Research aimed at identifying indicators of persistent abrupt shifts in ecological communities, a.k.a regime shifts, has led to the development of a suite of early warning signals (EWSs). As these often perform inaccurately when applied to real-world observational data, it remains unclear whether critical transitions are the dominant mechanism of regime shifts and, if so, which EWS methods can predict them. Here, using multi-trophic planktonic data on multiple lakes from around the world, we classify both lake dynamics and the reliability of classic and second generation EWSs methods to predict whole-ecosystem change. We find few instances of critical transitions, with different trophic levels often expressing different forms of abrupt change. The ability to predict this change is highly processing dependant, with most indicators not performing better than chance, multivariate EWSs being weakly superior to univariate, and a recent machine learning model performing poorly. Our results suggest that predictive ecology should start to move away from the concept of critical transitions, developing methods suitable for predicting resilience loss not limited to the strict bounds of bifurcation theory.

One versus three weeks hypofractionated whole breast radiotherapy for early breast cancer treatment: the FAST-Forward phase III RCT.

Background: FAST-Forward aimed to identify a 5-fraction schedule of adjuvant radiotherapy delivered in 1 week that was non-inferior in terms of local cancer control and as safe as the standard 15-fraction regimen after primary surgery for early breast cancer. Published acute toxicity and 5-year results are presented here with other aspects of the trial. Design: Multicentre phase III non-inferiority trial. Patients with invasive carcinoma of the breast (pT1-3pN0-1M0) after breast conservation surgery or mastectomy randomised (1 : 1 : 1) to 40 Gy in 15 fractions (3 weeks), 27 Gy or 26 Gy in 5 fractions (1 week) whole breast/chest wall (Main Trial). Primary endpoint was ipsilateral breast tumour relapse; assuming 2% 5-year incidence for 40 Gy, non-inferiority pre-defined as < 1.6% excess for 5-fraction schedules (critical hazard ratio = 1.81). Normal tissue effects were assessed independently by clinicians, patients and photographs. Sub-studies: Two acute skin toxicity sub-studies were undertaken to confirm safety of the test schedules. Primary endpoint was proportion of patients with grade ≥ 3 acute breast skin toxicity at any time from the start of radiotherapy to 4 weeks after completion. Nodal Sub-Study patients had breast/chest wall plus axillary radiotherapy testing the same three schedules, reduced to the 40 and 26 Gy groups on amendment, with the primary endpoint of 5-year patient-reported arm/hand swelling. Limitations: A sequential hypofractionated or simultaneous integrated boost has not been studied. Participants: Ninety-seven UK centres recruited 4096 patients (1361:40 Gy, 1367:27 Gy, 1368:26 Gy) into the Main Trial from November 2011 to June 2014. The Nodal Sub-Study recruited an additional 469 patients from 50 UK centres. One hundred and ninety and 162 Main Trial patients were included in the acute toxicity sub-studies. Results: Acute toxicity sub-studies evaluable patients: (1) acute grade 3 Radiation Therapy Oncology Group toxicity reported in 40 Gy/15 fractions 6/44 (13.6%); 27 Gy/5 fractions 5/51 (9.8%); 26 Gy/5 fractions 3/52 (5.8%). (2) Grade 3 common toxicity criteria for adverse effects toxicity reported for one patient. At 71-month median follow-up in the Main Trial, 79 ipsilateral breast tumour relapse events (40 Gy: 31, 27 Gy: 27, 26 Gy: 21); hazard ratios (95% confidence interval) versus 40 Gy were 27 Gy: 0.86 (0.51 to 1.44), 26 Gy: 0.67 (0.38 to 1.16). With 2.1% (1.4 to 3.1) 5-year incidence ipsilateral breast tumour relapse after 40 Gy, estimated absolute differences versus 40 Gy (non-inferiority test) were -0.3% (-1.0-0.9) for 27 Gy (p = 0.0022) and -0.7% (-1.3-0.3) for 26 Gy (p = 0.00019). Five-year prevalence of any clinician-assessed moderate/marked breast normal tissue effects was 40 Gy: 98/986 (9.9%), 27 Gy: 155/1005 (15.4%), 26 Gy: 121/1020 (11.9%). Across all clinician assessments from 1 to 5 years, odds ratios versus 40 Gy were 1.55 (1.32 to 1.83; p < 0.0001) for 27 Gy and 1.12 (0.94-1.34; p = 0.20) for 26 Gy. Patient and photographic assessments showed higher normal tissue effects risk for 27 Gy versus 40 Gy but not for 26 Gy. Nodal Sub-Study reported no arm/hand swelling in 80% and 77% in 40 Gy and 26 Gy at baseline, and 73% and 76% at 24 months. The prevalence of moderate/marked arm/hand swelling at 24 months was 10% versus 7% for 40 Gy compared with 26 Gy. Interpretation: Five-year local tumour incidence and normal tissue effects prevalence show 26 Gy in 5 fractions in 1 week is a safe and effective alternative to 40 Gy in 15 fractions for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer. Future work: Ten-year Main Trial follow-up is essential. Inclusion in hypofractionation meta-analysis ongoing. A future hypofractionated boost trial is strongly supported. Trial registration: FAST-Forward was sponsored by The Institute of Cancer Research and was registered as ISRCTN19906132. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 09/01/47) and is published in full in Health Technology Assessment; Vol. 27, No. 25. See the NIHR Funding and Awards website for further award information.

Patients diagnosed with early breast cancer are often recommended to have radiotherapy after surgery because research has shown that it lowers the risk of the cancer returning. However, it may cause some short- and long-term side effects. Previous clinical trials showed that the same, or even better, outcomes with a lower total dose of radiotherapy given in fewer, larger daily doses compared with older historical treatment schedules. The National Institute for Health and Care Research Health Technology Assessment Programme-funded FAST-Forward Trial aimed to see whether the number of doses could be reduced further without reducing the beneficial effects of radiotherapy. Between November 2011 and June 2014, 4096 patients agreed to take part in the FAST-Forward Main Trial testing three schedules of radiotherapy to the breast. Standard treatment given on 15 days over 3 weeks (Control Group) was compared with two different lower dose schedules where treatment was given on 5 days over 1 week (lower dose Test Groups). An additional 469 patients entered a sub-study where the gland area under the arm also received radiotherapy (Nodal Sub-Study). Main Trial 5-year results reported in April 2020 showed that the number of patients whose cancer had returned in the treated breast was low in all groups: around 2 in 100 (2.1%) for the Control Group, and 1.7% in the higher dose and 1.4% in the lower dose Test Groups. The majority of reported side effects assessed by patients and doctors up to 5 years after radiotherapy were mild for all treatment groups. Patients in the Control Group and in the lower dose Test Group experienced similar levels of side effects. More side effects were reported in the higher dose Test Group, although differences were small. Overall, the FAST-Forward findings suggest that the lower dose 1-week schedule gave similar results in terms of the cancer returning and side effects to the standard 3-week treatment and this schedule can now be used to help treat future patients.

An ancient river landscape preserved beneath the East Antarctic Ice Sheet.

The East Antarctic Ice Sheet (EAIS) has its origins ca. 34 million years ago. Since then, the impact of climate change and past fluctuations in the EAIS margin has been reflected in periods of extensive vs. restricted ice cover and the modification of much of the Antarctic landscape. Resolving processes of landscape evolution is therefore critical for establishing ice sheet history, but it is rare to find unmodified landscapes that record past ice conditions. Here, we discover an extensive relic pre-glacial landscape preserved beneath the central EAIS despite millions of years of ice cover. The landscape was formed by rivers prior to ice sheet build-up but later modified by local glaciation before being dissected by outlet glaciers at the margin of a restricted ice sheet. Preservation of the relic surfaces indicates an absence of significant warm-based ice throughout their history, suggesting any transitions between restricted and expanded ice were rapid.

Ecological habitat partitioning and feeding specialisations of coastal minke whales (Balaenoptera acutorostrata) using a recently designated MPA in northeast Scotland.

In the design of protected areas for cetaceans, spatial maps rarely take account of the life-history and behaviour of protected species relevant to their spatial ambit, which may be important for their management. In this study, we examined the distribution and feeding behaviours of adult versus juvenile minke whales (Balaenoptera acutorostrata) from long-term studies in the Moray Firth in northeast Scotland, where a Marine Protected Area (MPA) has recently been designated. Data were collected during dedicated boat surveys between 2001 and 2022 inclusive, from which 784 encounters with 964 whales of confirmed age-class (471 juveniles and 493 adults) were recorded from 56,263 km of survey effort, resulting in 238 focal follows. Adults and juveniles were occasionally seen together, but their distributions were not statistically correlated, and GIS revealed spatial separation / habitat partitioning by age-class-with juveniles preferring shallower, inshore waters with sandy-gravel sediments, and adults preferring deeper, offshore waters with greater bathymetric slope. GAMs suggested that the partitioning between age-classes was predominantly based on the differing proximity of animals to the shore, with juveniles showing a preference for the gentlest seabed slopes, and both adults and juveniles showing a similar preference for sandy gravel sediment types. However, the GAMs only used sightings data with available survey effort (2008 to 2022) and excluded depth due to collinearity issues. Whilst adult minkes employed a range of "active" prey-entrapment specialisations, showing inter-individual variation and seasonal plasticity in their targeted prey, juveniles almost exclusively used "passive" (low energy) feeding methods targeting low-density patches of inshore prey. These findings corroborate the need to incorporate demographic and behavioural data into spatial models when identifying priority areas for protected cetacean species. Not all areas within an MPA have equal value for a population and a better knowledge of the spatial preferences of these whales within the designated Scottish MPAs, appointed for their protection, is considered vital for their conservation.

Progression of stroke risk in patients aged <65 years diagnosed with atrial fibrillation: a cohort study in general practice.

BACKGROUND: As a result of new technologies, atrial fibrillation (AF) is more likely to be diagnosed in people aged <65 years. AIM: To investigate the risk of someone diagnosed with AF aged <65 years developing an indication for anticoagulation before they reach 65 years. DESIGN AND SETTING: Population-based cohort study of patients from English practices using the Clinical Practice Research Datalink, a primary care database of electronic medical records. METHOD: The study included patients aged <65 years newly diagnosed with AF. The CHA2DS2-VASc score was derived at time of diagnosis based on patients' medical records. Patients not eligible for anticoagulation were followed up until they became eligible or turned 65 years old. The primary outcome of interest was development of a risk factor for stroke in AF. RESULTS: Among 18 178 patients aged <65 years diagnosed with AF, 9188 (50.5%) were eligible for anticoagulation at the time of diagnosis. Among the 8990 patients not eligible for anticoagulation, 1688 (18.8%) developed a risk factor during follow-up before reaching 65 years of age or leaving the cohort for other reasons, at a rate of 6.1 per 100 patient-years. Hypertension and heart failure were the most common risk factors to occur, with rates of 2.65 (95% CI = 2.47 to 2.84) and 1.58 (95% CI = 1.45 to 1.72) per 100 patient-years, respectively. The rate of new diabetes was 0.95 (95% CI = 0.85 to 1.06) per 100 patient-years. CONCLUSION: People aged <65 years with AF are at higher risk of developing hypertension, heart failure, and diabetes than the general population, so may warrant regular review to identify new occurrence of such risk factors.

Thromboxane biosynthesis in cancer patients and its inhibition by aspirin: a sub-study of the Add-Aspirin trial.

BACKGROUND: Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy. Ongoing clinical trials are assessing whether aspirin, which inhibits platelet activation, can prevent or delay metastases. METHODS: Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation, was measured after radical cancer therapy and correlated with patient demographics, tumour type, recent treatment, and aspirin use (100 mg, 300 mg or placebo daily) using multivariable linear regression models with log-transformed values. RESULTS: In total, 716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine). Higher levels were associated with raised body mass index, inflammatory markers, and in the colorectal and gastro-oesophageal participants compared to breast participants (P < 0.001) independent of other baseline characteristics. Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%). Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg. CONCLUSIONS: Persistently increased thromboxane biosynthesis was detected after radical cancer therapy, particularly in colorectal and gastro-oesophageal patients. Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin.

Laryngeal Trauma.

Laryngeal trauma is rare but potentially fatal. Initial evaluation includes efficient history and physical examination, imaging, bedside flexible laryngoscopy, and if necessary, operative endoscopic evaluation. Multiple classification systems exist for laryngeal trauma, and each has its merits. We recommend a patient-centered approach, rather than using the classification alone. Secure airways are the primary goal of acute management, with awake tracheostomy more often indicated over oral intubation compared with traumas not involving the larynx. More severe injuries typically require surgical intervention. Early intervention results in optimal voice and airway outcomes.