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Abstract Background Melanoma is the 5th commonest cancer in the UK and survivors require frequent and thorough skin checks. During the Achieving Self-directed Integrated Cancer Aftercare (ASICA) trial, melanoma survivors used an app to submit images of concerning lesions for assessment by a dermatology nurse. In the past, online courses have been used to train non-specialist primary care practitioners (PCPs) in this skill. Objectives This study aimed to determine whether an online course could increase knowledge, confidence, and attitudes towards skin image triage in PCPs in the Grampian area. Methods Preliminary discussions were held with PCPs to determine the need for an online course. The course was designed at the University of Aberdeen and included an introduction to the skin, case studies and quizzes on a variety of skin conditions based on melanoma survivors’ submissions via the ASICA app. Two pre- and post-course questionnaires were administered to all participants to (1) assess knowledge gained and (2) assess any improvements in confidence and attitudes towards triaging skin lesions that could be indicative of skin cancer. All PCPs in the Grampian area were invited to participate with almost 70 medical practices contacted. Results were analysed using a paired sample T-test. Results The course was advertised to all GP practices in the Grampian area and 38 PCPs completed all its stages. Undertaking the course improved all PCPs’ confidence and attitudes towards triaging (p

Abstract Using a combination of short- and long-reads sequencing, we were able to sequence the complete mitochondrial genome of the invasive ‘New Zealand flatworm’ Arthurdendyus triangulatus (Geoplanidae, Rhynchodeminae, Caenoplanini) and its two complete paralogous nuclear rRNA gene clusters. The mitogenome has a total length of 20,309 bp and contains repetitions that includes two types of tandem-repeats that could not be solved by short-reads sequencing. We also sequenced for the first time the mitogenomes of four species of Caenoplana (Caenoplanini). A maximum likelihood phylogeny associated A. triangulatus with the other Caenoplanini but Parakontikia ventrolineata and Australopacifica atrata were rejected from the Caenoplanini and associated instead with the Rhynchodemini, with Platydemus manokwari. It was found that the mitogenomes of all species of the subfamily Rhynchodeminae share several unusual structural features, including a very long cox2 gene. This is the first time that the complete paralogous rRNA clusters, which differ in length, sequence and seemingly number of copies, were obtained for a Geoplanidae.

Background Gallstone disease is a common gastrointestinal disorder in industrialised societies. The prevalence of gallstones in the adult population is estimated to be approximately 10–15%, and around 80% remain asymptomatic. At present, cholecystectomy is the default option for people with symptomatic gallstone disease. Objectives To assess the clinical and cost-effectiveness of observation/conservative management compared with laparoscopic cholecystectomy for preventing recurrent symptoms and complications in adults presenting with uncomplicated symptomatic gallstones in secondary care. Design Parallel group, multicentre patient randomised superiority pragmatic trial with up to 24 months follow-up and embedded qualitative research. Within-trial cost–utility and 10-year Markov model analyses. Development of a core outcome set for uncomplicated symptomatic gallstone disease. Setting Secondary care elective settings. Participants Adults with symptomatic uncomplicated gallstone disease referred to a secondary care setting were considered for inclusion. Interventions Participants were randomised 1: 1 at clinic to receive either laparoscopic cholecystectomy or observation/conservative management. Main outcome measures The primary outcome was quality of life measured by area under the curve over 18 months using the Short Form-36 bodily pain domain. Secondary outcomes included the Otago gallstones’ condition-specific questionnaire, Short Form-36 domains (excluding bodily pain), area under the curve over 24 months for Short Form-36 bodily pain domain, persistent symptoms, complications and need for further treatment. No outcomes were blinded to allocation. Results Between August 2016 and November 2019, 434 participants were randomised (217 in each group) from 20 United Kingdom centres. By 24 months, 64 (29.5%) in the observation/conservative management group and 153 (70.5%) in the laparoscopic cholecystectomy group had received surgery, median time to surgery of 9.0 months (interquartile range, 5.6–15.0) and 4.7 months (interquartile range 2.6–7.9), respectively. At 18 months, the mean Short Form-36 norm-based bodily pain score was 49.4 (standard deviation 11.7) in the observation/conservative management group and 50.4 (standard deviation 11.6) in the laparoscopic cholecystectomy group. The mean area under the curve over 18 months was 46.8 for both groups with no difference: mean difference –0.0, 95% confidence interval (–1.7 to 1.7); p-value 0.996; n = 203 observation/conservative, n = 205 cholecystectomy. There was no evidence of differences in quality of life, complications or need for further treatment at up to 24 months follow-up. Condition-specific quality of life at 24 months favoured cholecystectomy: mean difference 9.0, 95% confidence interval (4.1 to 14.0), p

The objective of this research was to assess the feasibility of remote sensing (RS) technology, specifically an unmanned aerial system (UAS), to estimate Bambara groundnut canopy state variables including leaf area index (LAI), canopy chlorophyll content (CCC), aboveground biomass (AGB), and fractional vegetation cover (FVC). RS and ground data were acquired during Malaysia’s 2018/2019 Bambara groundnut growing season at six phenological stages; vegetative, flowering, podding, podfilling, maturity, and senescence. Five vegetation indices (VIs) were determined from the RS data, resulting in single-stage VIs and cumulative VIs (∑VIs). Pearson’s correlation was used to investigate the relationship between canopy state variables and single stage VIs and ∑VIs over several stages. Linear parametric and non-linear non-parametric machine learning (ML) regressions including CatBoost Regressor (CBR), Random Forest Regressor (RFR), AdaBoost Regressor (ABR), Huber Regressor (HR), Multiple Linear Regressor (MLR), Theil-Sen Regressor (TSR), Partial Least Squares Regressor (PLSR), and Ridge Regressor (RR) were used to estimate canopy state variables using VIs/∑VIs as input. The best single-stage correlations between canopy state variables and VIs were observed at flowering (r > 0.50 in most cases). Moreover, ∑VIs acquired from vegetative to senescence stage had the strongest correlation with all measured canopy state variables (r > 0.70 in most cases). In estimating AGB, MLR achieved the best testing performance (R2 = 0.77, RMSE = 0.30). For CCC, RFR excelled with R2 of 0.85 and RMSE of 2.88. Most models performed well in FVC estimation with testing R2 of 0.98–0.99 and low RMSE. For LAI, MLR stood out in testing with R2 of 0.74, and RMSE of 0.63. Results demonstrate the UAS-based RS technology potential for estimating Bambara groundnut canopy variables.

Abstract Combination of anti-cancer drugs is broadly seen as way to overcome the often-limited efficacy of single agents. The design and testing of combinations are however very challenging. Here we present a uniquely large dataset screening over 5000 targeted agent combinations across 81 non-small cell lung cancer cell lines. Our analysis reveals a profound heterogeneity of response across the tumor models. Notably, combinations very rarely result in a strong gain in efficacy over the range of response observable with single agents. Importantly, gain of activity over single agents is more often seen when co-targeting functionally proximal genes, offering a strategy for designing more efficient combinations. Because combinatorial effect is strongly context specific, tumor specificity should be achievable. The resource provided, together with an additional validation screen sheds light on major challenges and opportunities in building efficacious combinations against cancer and provides an opportunity for training computational models for synergy prediction.

Background: While primary care physicians (PCPs) play a key role in cancer detection, they can find cancer diagnosis challenging, and some patients have considerable delays between presentation and onward referral. Aim: To explore European PCPs’ experiences and views on cases where they considered that they had been slow to think of, or act on, a possible cancer diagnosis. Design & setting: A multicentre European qualitative study, based on an online survey with open-ended questions, asking PCPs for their narratives about cases when they had missed a diagnosis of cancer. Method: Using maximum variation sampling, PCPs in 23 European countries were asked to describe what happened in a case where they were slow to think of a cancer diagnosis, and for their views on why it happened. Thematic analysis was used to analyse the data. Results: A total of 158 PCPs completed the questionnaire. The main themes were as follows: patients’ descriptions did not suggest cancer; distracting factors reduced PCPs’ cancer suspicions; patients’ hesitancy delayed the diagnosis; system factors not facilitating timely diagnosis; PCPs felt that they had acted wrongly; and problems with communicating adequately. Conclusion: The study identified six overarching themes that need to be addressed. Doing so should reduce morbidity and mortality in the small proportion of patients who have a significant, avoidable delay in their cancer diagnosis. The ‘Swiss cheese’ model of accident causation showed how the themes related to each other.

Abstract Background The aminoglycosides are established antibiotics that inhibit bacterial protein synthesis by binding to ribosomal RNA. Additional non-antibiotic aminoglycoside cellular functions have also been identified through aminoglycoside interactions with cellular RNAs. The full extent, however, of genome-wide aminoglycoside RNA interactions in Escherichia coli has not been determined. Here, we report genome-wide identification and verification of the aminoglycoside Kanamycin B binding to Escherichia coli RNAs. Immobilized Kanamycin B beads in pull-down assays were used for transcriptome-profiling analysis (RNA-seq). Results Over two hundred Kanamycin B binding RNAs were identified. Functional classification analysis of the RNA sequence related genes revealed a wide range of cellular functions. Small RNA fragments (ncRNA, tRNA and rRNA) or small mRNA was used to verify the binding with Kanamycin B in vitro. Kanamycin B and ibsC mRNA was analysed by chemical probing. Conclusions The results will provide biochemical evidence and understanding of potential extra-antibiotic cellular functions of aminoglycosides in Escherichia coli.

Abstract Background Various washout policies are widely used in adults living with long-term catheters (LTC). There is currently insufficient evidence on the benefits and potential harms of prophylactic LTC washout policies in the prevention of blockages and other LTC-related adverse events, such as urinary tract infections. CATHETER II tests the hypothesis that weekly prophylactic LTC washouts (normal saline or citric acid) in addition to standard LTC care reduce the incidence of catheter blockage requiring intervention compared to standard LTC care only in adults living with LTC. Methods CATHETER II is a pragmatic three-arm open multi-centre superiority randomised controlled trial with an internal pilot, economic analysis, and embedded qualitative study. Eligible participants are adults aged ≥ 18 years, who have had a LTC in use for ≥ 28 days, have no plans to discontinue the use of the catheter, are able to undertake the catheter washouts, and complete trial documentation or have a carer able to help them. Participants are identified from general practitioner practices, secondary/tertiary care, community healthcare, care homes, and via public advertising strategies. Participants are randomised 1:1:1 to receive a weekly saline (0.9%) washout in addition to standard LTC care, a weekly citric acid (3.23%) washout in addition to standard LTC care or standard LTC care only. Participants and/or carers will receive training to administer the washouts. Patient-reported outcomes are collected at baseline and for 24 months post-randomisation. The primary clinical outcome is catheter blockage requiring intervention up to 24 months post-randomisation expressed per 1000 catheter days. Secondary outcomes include symptomatic catheter-associated urinary tract infection requiring antibiotics, catheter change, adverse events, NHS/ healthcare use, and impact on quality of life. Discussion This study will guide treatment decision-making and clinical practice guidelines regarding the effectiveness of various prophylactic catheter washout policies in men and women living with LTC. This research has received ethical approval from Wales Research Ethics Committee 6 (19/WA/0015). Trial registration ISRCTN ISRCTN17116445 . Registered prospectively on 06 November 2019

Objective To investigate how individuals diagnosed with cancer use out-of-hours (OOH) medical services, describe the behavioural determinants of OOH service use and explore whether there are differences between urban and rural dwellers.Design and setting A cross-sectional questionnaire study conducted in Northeast Scotland.Participants The questionnaire was sent to 2549 individuals diagnosed with cancer in the preceding 12 months identified through the National Health Service Grampian Cancer Care Pathway database. 490 individuals returned the questionnaire (19.2% response rate), 61.8% were urban and 34.9% were rural.Outcomes Outcomes were differences in frequency of medical service use and attitudes towards OOH services between urban and rural participants. Patient experience (qualitative data) was compared.Results Daytime services were used much more frequently than OOH services—83.3% of participants had never contacted an OOH primary care service in the preceding 12 months but 44.2% had used their daytime general practitioner at least four times. There were no significant differences between urban and rural dwellers in the patterns of OOH or daytime service use, the behavioural determinants of service use or the experiences of OOH services. Rural dwellers were significantly less likely to agree that OOH services were close by and more likely to agree that where they lived made it difficult to access these services. Rural dwellers were no more likely to agree or disagree that distance would affect their decision to contact OOH services. Qualitative results highlighted barriers to accessing OOH services exist for all patients but that long travel distances can be offset by service configuration, travel infrastructure and access to a car.Conclusions Urban and rural dwellers have similar beliefs, attitudes towards and patterns of OOH service use. In Northeast Scotland, place of residence is unlikely to be the most important factor in influencing decisions about whether to access OOH medical care.

Abstract To meet the increasing global demand for food, feed, fibre and other plant‐derived products, a steep increase in crop productivity is a scientifically and technically challenging imperative. The CropBooster‐P project, a response to the H2020 call ‘Future proofing our plants’, is developing a roadmap for plant research to improve crops critical for the future of European agriculture by increasing crop yield, nutritional quality, value for non‐food applications and sustainability. However, if we want to efficiently improve crop production in Europe and prioritize methods for crop trait improvement in the coming years, we need to take into account future socio‐economic, technological and global developments, including numerous policy and socio‐economic challenges and constraints. Based on a wide range of possible global trends and key uncertainties, we developed four extreme future learning scenarios that depict complementary future developments. Here, we elaborate on how the scenarios could inform and direct future plant research, and we aim to highlight the crop improvement approaches that could be the most promising or appropriate within each of these four future world scenarios. Moreover, we discuss some key plant technology options that would need to be developed further to meet the needs of multiple future learning scenarios, such as improving methods for breeding and genetic engineering. In addition, other diverse platforms of food production may offer unrealized potential, such as underutilized terrestrial and aquatic species as alternative sources of nutrition and biomass production. We demonstrate that although several methods or traits could facilitate a more efficient crop production system in some of the scenarios, others may offer great potential in all four of the future learning scenarios. Altogether, this indicates that depending on which future we are heading toward, distinct plant research fields should be given priority if we are to meet our food, feed and non‐food biomass production needs in the coming decades.

BackgroundS0931 is assessing recurrence-free survival in renal cell carcinoma (RCC) patients randomized to receive everolimus (EVE) versus placebo for one year following nephrectomy. Due to a higher than expected dropout rate, we assessed EVE trough levels in the adjuvant setting to evaluate the relationship between EVE exposure and probability of toxicity.MethodsPatients received 10 mg daily EVE for nine 6-week cycles. Pre-dose whole blood samples were collected pre-cycle 2 and pre-cycle 3 and analyzed for EVE. Patients with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. Patients were segregated into quartiles (Q) based on EVE levels and logistic regression was used to model the most common adverse event outcomes using EVE trough as a predictor. Hazard and odds ratios were adjusted for age, BMI and performance status.ResultsA total of 467 patients were included in this analysis. Quartiles normalized to an EVE dose of 10 mg/day were  22.8 ng/mL, respectively. EVE trough levels increased with increasing age (p

Abstract We used Compact Reconnaissance Imaging Spectrometer for Mars (CRISM) multispectral mapping data to assess heterogeneity of primary and secondary mineral compositions of Noachian‐aged regions of Martian crust. Multispectral data corroborate interpretations from CRISM targeted observations and Observatoire pour la Mineralogie, l’Eau, les Glaces et l’Activité global mapping of large horizontal differences in vertical crustal structures, and degree and grade of alteration to secondary minerals. CRISM multispectral data analysis conducted at a combination of high spatial resolution and coverage not available in other data sets also reveals previously unrecognized exposures. At one extreme, basaltic crustal material is minimally altered, mostly to smectite clay; at the other, Al‐enriched alteration products are present, alteration is widespread, and superposed surface materials rich in salts and precipitates, suggesting multiple episodes of alteration. The revealed vertical structure of primary mineralogy is consistent with that inferred in previous studies. Controls on the extent and metamorphic grade of secondary mineral assemblages are proximity to heat sources including large impact basins and inferred magmatic bodies.

Acclimation of photosynthesis to light intensity (photoacclimation) takes days to achieve and so naturally fluctuating light presents a potential challenge where leaves may be exposed to light conditions that are beyond their window of acclimation. Experiments generally have focused on unchanging light with a relatively fixed combination of photosynthetic attributes to confer higher efficiency in those conditions. Here a controlled LED experiment and mathematical modelling was used to assess the acclimation potential of contrasting Arabidopsis thaliana genotypes following transfer to a controlled fluctuating light environment, designed to present frequencies and amplitudes more relevant to natural conditions. We hypothesize that acclimation of light harvesting, photosynthetic capacity and dark respiration are controlled independently. Two different ecotypes were selected, Wassilewskija-4 (Ws), Landsberg erecta (Ler) and a GPT2 knock out mutant on the Ws background (gpt2-), based on their differing abilities to undergo dynamic acclimation i.e. at the sub-cellular or chloroplastic scale. Results from gas exchange and chlorophyll content indicate that plants can independently regulate different components that could optimize photosynthesis in both high and low light; targeting light harvesting in low light and photosynthetic capacity in high light. Empirical modelling indicates that the pattern of ‘entrainment’ of photosynthetic capacity by past light history is genotype-specific. These data show flexibility of photoacclimation and variation useful for plant improvement.

Many areas of sugar beet production will face hotter and drier summers as the climate changes. There has been much research on drought tolerance in sugar beet but water use efficiency (WUE) has been less of a focus. An experiment was undertaken to examine how fluctuating soil water deficits effect WUE from the leaf to the crop level and identify if sugar beet acclimates to water deficits to increase WUE in the longer term. Two commercial sugar beet varieties with contrasting upright and prostrate canopies were examined to identify if WUE differs due to contrasting canopy architecture. The sugar beet were grown under four different irrigation regimes (fully irrigated, single drought, double drought and continually water limited) in large 610 L soil boxes in an open ended polytunnel. Measurements of leaf gas exchange, chlorophyll fluorescence and relative water content (RWC) were regularly undertaken and stomatal density, sugar and biomass yields and the associated WUE, SLW and Δ13C were assessed. The results showed that water deficits generally increase intrinsic (WUEi) and dry matter (WUEDM) water use efficiency but reduce yield. Sugar beet recovered fully after severe water deficits, as assessed by leaf gas exchange and chlorophyll fluorescence parameters and, except for reducing canopy size, showed no other acclimation to drought, and therefore no changes in WUE or drought avoidance. Spot measurements of WUEi, showed no differences between the two varieties but the prostrate variety showed lower Δ13C values, and traits associated with more water conservative phenotypes of a lower stomatal density and greater leaf RWC. Leaf chlorophyll content was affected by water deficit but the relationship with WUE was unclear. The difference in Δ13C values between the two varieties suggests traits associated with greater WUEi may be linked to canopy architecture.

IntroductionIdentifying rice (Oryza sativa) germplasm with improved efficiency of primary metabolism is of utmost importance in order to increase yields. One such approach can be attained through screening genetically diverse populations under altered environmental conditions. Growth or treatment under low carbon dioxide (CO2) concentrations can be used as a means of revealing altered leaf photorespiration, respiration and other metabolic variants.MethodsWe developed a pipeline for very high throughput treatment of gamma- and ethyl methanesulfonate- (EMS) induced mutant populations of IR64 rice seedlings at very low CO2 for 7 days. 1050 seedlings per batch at 5th leaf stage were exposed to 60 ppm CO2 for the first day and 30 ppm for the remaining three days. Following this, putative candidates were identified by measuring chlorophyll depletion using SPAD. Screening results showed a distinct difference between the mutants and the WTs.Results and discussionThe mean chlorophyll loss in WTs ranged from 65% to 11% respectively, whereas in the mutant lines chlorophyll loss ranged from 0 to 100%, suggesting considerable phenotypic variation. Rice mutants with a reduced chlorophyll reduction (

BackgroundMelanoma is a relatively common cancer type with a high survival rate, but survivors risk recurrences or second primaries. Consequently, patients receive regular hospital follow-up, but this can be burdensome to attend and not optimally timed to detect arising problems. Total skin self-examination (TSSE) supports improved clinical outcomes from melanoma via earlier detection of recurrences and second primaries, and digital technology has the potential to support TSSE. Recent research with app-based interventions aimed at improving the well-being of older adults has found that they can use the technology and benefit from it, supporting the use of digital health care in diverse demographic groups. Thus, the Achieving Self-directed Integrated Cancer Aftercare (ASICA) digital health care intervention was developed. The intervention provided melanoma survivors with a monthly prompt to perform a TSSE as well as access to a dermatology nurse who provided them with feedback on photographs and descriptions of their skin. ObjectiveWe aimed to explore participants’ attitudes, beliefs, and experiences regarding TSSE practices. Furthermore, we explored how participants experienced technology and how it influenced their practice of TSSE. Finally, we explored the practical and technical experiences of ASICA users. MethodsThis was a nested qualitative evaluation within a dual-center randomized controlled trial of the ASICA intervention. We conducted semistructured telephone interviews with the participants during a randomized controlled trial. The participants were purposively sampled to achieve a representative sample with representative proportions by age, sex, and residential geography. Interviews were transcribed verbatim and analyzed using a framework analysis approach applied within NVivo 12. ResultsA total of 22 interviews were conducted with participants from both groups. In total, 40% (9/22) of the interviewed participants were from rural areas, and 60% (13/22) were from urban areas; 60% (13/22) were from the intervention group, and 40% (9/22) were from the control group. Themes evolved around skin-checking behavior, other people’s input into skin checking, contribution of health care professionals outside ASICA and its value, ideas around technology, practical experiences, and potential improvements. ASICA appeared to change participants’ perceptions of skin checking. Users were more likely to report routinely performing TSSE thoroughly. There was some variation in beliefs about skin checking and using technology for health care. Overall, ASICA was experienced positively by participants. Several practical suggestions were made for the improvement of ASICA. ConclusionsThe ASICA intervention appeared to have positively influenced the attitudes and TSSE practices of melanoma survivors. This study provides important qualitative information about how a digital health care intervention is an effective means of prompting, recording, and responding to structured TSSE by melanoma survivors. Technical improvements are required, but the app offers promise for technologically enhanced melanoma follow-up in future. Trial RegistrationClinicalTrials.gov NCT03328247; https://clinicaltrials.gov/ct2/show/NCT03328247?term=ASICA&rank=1 International Registered Report Identifier (IRRID)RR2-10.1186/s13063-019-3453-x

Agarwood (Aquilaria malaccensis Lamk.) is a forest product commodity with high economic value, but its availability in nature is decreasing due to deforestation and overexploitation. The availability of high-quality seedlings is necessary to meet the demand and conserve the sources of agarwood plants. Therefore, this study investigates the interaction effect between media types and 1-Naphthaleneacetic acid (NAA) concentrations on agarwood shoot development. It also aims to determine the best medium type and NAA concentration to stimulate agarwood shoot development. This research had two stages, namely the shoot induction and development. The shoot induction stage was conducted experimentally, using a completely randomized design (CRD) on a factorial treatment pattern of 2 factors i.e., the types of media and NAA concentrations. The shoots produced from the induction stage were cultured on Murashige-Skoog (MS) media with the same media types but without any NAA addition. Furthermore, the variables observed in both stages were the development of agarwood shoots, and the parameters measured included the number of shoots, number of leaves and shoot lengths. The results showed that the development of agarwood shoots was controlled by the type of medium used. Liquid MS medium supported with filter paper bridge produced the highest average number of shoots with 4.93 and 5.87 shoots explants-1 and length at 3.25 and 3.64 cm explant-1 in the induction and development stage, respectively. These findings will facilitate mass propagation of agarwood shoots, and in turn the availability of agarwood plantlets supports its conservation and production.

Crop canopy architecture is a central component of yield. The arrangement of leaves in three-dimensional space defines the efficiency of absorption of radiation and its conversion into dry matter at the canopy level. The description of architecture is normally associated with light since the optimal distribution of light is associated with that of other essential components such as nitrogen and pigments. However, architecture has been influenced by a number of other unrelated processes through breeding and selection that may have acted independently or even against light use efficiency. This review attempts to provide a broad view and interpretation of canopy architectural properties and the factors affecting crop architecture starting with evolution, domestication, climatic conditions and cultivation patterns, predominantly focusing on field grown agricultural crops. Using examples of modelling with a virtual canopy, we will discuss how architectural traits affect light interception and photosynthesis. Finally, we will discuss the future of architectural research: the concept of the ideal plant type (the ideotype) and which features we can expect to see, as well as the social constraints that may govern future crop architecture.

Aquilaria malaccensis Lamk. is one of the most widespread agarwood-producing plants that face extinction due to overexploitation. Agarwood propagation using in vitro culture techniques is capable of producing large quantities of plants in a shorter time and free from pests and diseases. Therefore, this study was conducted to analyze the effect of auxins type and concentration on agarwood plantlet formation using a split-plot design. The main plot was the type of auxin which included IAA, IBA and NAA, while the subplot was the concentration used which consisted of 0; 5; 10; 15 and 20 µM. The variable observed was agarwood plantlet formation with parameters measured including the number of shoots and leaves, plant height, and number of roots. The results showed that the formation of agarwood plantlets was controlled by the type, concentration, and interaction between the type and concentration of auxin. Furthermore, explants cultured on Murashige Skoog (MS) medium supplemented with 10 µM IBA produced the highest number of shoots (3.39 shoots explant-1) and leaves (7.25 leaves explants-1), while the addition of 10 uM NAA resulted in the highest number of roots (2.52 roots explant-1). This is the first time a study is conducted to evaluate the effect of type and concentration of auxins on agarwood plantlet formation. The production of high-quality shoots and plantlets increased agarwood germplasm availability to prevent extinction and support sustainable production.

Abstract The growing world population and global increases in the standard of living both result in an increasing demand for food, feed and other plant‐derived products. In the coming years, plant‐based research will be among the major drivers ensuring food security and the expansion of the bio‐based economy. Crop productivity is determined by several factors, including the available physical and agricultural resources, crop management, and the resource use efficiency, quality and intrinsic yield potential of the chosen crop. This review focuses on intrinsic yield potential, since understanding its determinants and their biological basis will allow to maximize the plant's potential in food and energy production. Yield potential is determined by a variety of complex traits that integrate strictly regulated processes and their underlying gene regulatory networks. Due to this inherent complexity, numerous potential targets have been identified that could be exploited to increase crop yield. These encompass diverse metabolic and physical processes at the cellular, organ and canopy level. We present an overview of some of the distinct biological processes considered to be crucial for yield determination that could further be exploited to improve future crop productivity.

Abstract Plant scientists and farmers are facing major challenges in providing food and nutritional security for a growing population, while preserving natural resources and biodiversity. Moreover, this should be done while adapting agriculture to climate change and by reducing its carbon footprint. To address these challenges, there is an urgent need to breed crops that are more resilient to suboptimal environments. Huge progress has recently been made in understanding the physiological, genetic and molecular bases of plant nutrition and environmental responses, paving the way towards a more sustainable agriculture. In this review, we present an overview of these progresses and strategies that could be developed to increase plant nutrient use efficiency and tolerance to abiotic stresses. As illustrated by many examples, they already led to promising achievements and crop improvements. Here, we focus on nitrogen and phosphate uptake and use efficiency and on adaptation to drought, salinity and heat stress. These examples first show the necessity of deepening our physiological and molecular understanding of plant environmental responses. In particular, more attention should be paid to investigate stress combinations and stress recovery and acclimation that have been largely neglected to date. It will be necessary to extend these approaches from model plants to crops, to unravel the relevant molecular targets of biotechnological or genetic strategies directly in these species. Similarly, sustained efforts should be done for further exploring the genetic resources available in these species, as well as in wild species adapted to unfavourable environments. Finally, technological developments will be required to breed crops that are more resilient and efficient. This especially relates to the development of multiscale phenotyping under field conditions and a wide range of environments, and use of modelling and big data management to handle the huge amount of information provided by the new molecular, genetic and phenotyping techniques.

KRAS can bind numerous effector proteins, which activate different downstream signaling events. The best known are RAF, phosphatidylinositide (PI)-3' kinase, and RalGDS families, but many additional direct and indirect effectors have been reported. We have assessed how these effectors contribute to several major phenotypes in a quantitative way, using an arrayed combinatorial siRNA screen in which we knocked down 41 KRAS effectors nodes in 92 cell lines. We show that every cell line has a unique combination of effector dependencies, but in spite of this heterogeneity, we were able to identify two major subtypes of KRAS mutant cancers of the lung, pancreas, and large intestine, which reflect different KRAS effector engagement and opportunities for therapeutic intervention.

‘The timing and ecological dynamics of extinction in the late Pleistocene are not well understood. Here, the authors use sediment ancient DNA from permafrost cores to reconstruct the paleoecology of the central Yukon, finding a substantial turnover in ecosystem composition between 13,500-10,000 years BP and persistence of some species past their supposed extinctions.’

Abstract Background Melanoma incidence has quadrupled since 1970 and melanoma is now the second most common cancer in individuals under 50. Targeted immunotherapies for melanoma now potentially enable long-term remission even in advanced melanoma, but these melanoma survivors require ongoing surveillance, with implications for NHS resources and significant social and psychological consequences for patients. Total skin self-examination (TSSE) can detect recurrence earlier and improve clinical outcomes but is underperformed in the UK. To support survivors, the Achieving Self-directed Integrated Cancer Aftercare (ASICA) intervention was developed to prompt and improve TSSE performance, with subsequent reporting of concerns and submission of skin photos to a Dermatology Nurse Practitioner (DNP). ASICA was delivered as a randomized pilot trial. Methods This paper reports on process evaluation. Data on participants’ demographics and the concerns they reported during the trial were tabulated and displayed using Microsoft Excel and SPSS. We explored which participants used ASICA, and how frequently, to report any skin concerns. We also determined how the interactions had worked in terms of quality of skin photographs submitted, clinical assessments made by the DNP, and the assessments and decisions made for each concern. Finally, we explored significant events occurring during the trial. Data on participants’ demographics and the concerns they reported during the trial were tabulated and displayed using SPSS. A semi-structured interview was undertaken with the DNP to gain perspective on the range of concerns presented and how they were resolved. Results Of 121 recruited melanoma patients receiving ASICA for 12 months, 69 participants submitted a total of 123 reports detailing 189 separate skin-related concerns and including 188 skin photographs. Where participants fully complied with follow-up by the DNP, concerns were usually resolved remotely, but 19 (10.1%) were seen at a secondary care clinic and 14 (7.4%) referred to their GP. 49 (25.9%) of concerns were not completely resolved due to partial non-compliance with DNP follow-up. Conclusion Melanoma patients randomized to the ASICA intervention were able to report skin-related concerns that could be resolved remotely through interaction with a DNP. Feasibility issues highlighted by ASICA will support further development and optimization of this digital tool. Trial registration Clinical Trials.gov , NCT03328247 . Registered on 1 November 2017

Aminoglycosides are not only antibiotics but also have wider and diverse non-antibiotic cellular functions. To elucidate the understanding of non-antibiotic cellular functions, here we report transcriptome-profiling analysis of Escherichia coli in the absence or presence of 0.5 and 1 μM of Kanamycin B, concentrations that are neither lethal nor inhibit growth, and identified the differentially expressed genes (DEGs) at two given concentrations of Kanamycin B. Functional classification of the DEGs revealed that they were mainly related to microbial metabolism including two-component systems, biofilm formation, oxidative phosphorylation and nitrogen metabolism in diverse environments. We further showed that Kanamycin B and other aminoglycosides can induce reporter gene expression through the 5′ UTR of napF gene or narK gene (both identified as DEG) and Kanamycin B can directly bind to the RNA. The results provide new insights into a better understanding of the wider aminoglycosides cellular function in E. coli rather than its known antibiotics function.

Phosphite represents a reduced form of phosphate that belongs to a class of crop growth-promoting chemicals termed biostimulants. Previous research has shown that phosphite application can enhance root growth, but its underlying mechanism, especially during environmental stresses, remains elusive. To uncover this, we undertook a series of morphological and physiological analyses under nutrient, water and heat stresses following a foliar application in wheat. Non-invasive 3D imaging of root system architecture directly in soil using X-ray Computed Tomography revealed that phosphite treatment improves root architectural traits and increased root biomass. Biochemical and physiological assays identified that phosphite treatment significantly increases Nitrate Reductase (NR) activity, leaf photosynthesis and stomatal conductance, suggesting improved Nitrogen and Carbon assimilation, respectively. These differences were more pronounced under heat or drought treatment (photosynthesis and photosystem II stability) and nutrient deficiency (root traits and NR). Overall our results suggest that phosphite treatment improves the ability of plants to tolerate abiotic stresses through improved Nitrogen and Carbon assimilation, combined with improved root growth which may improve biomass and yield.

BackgroundMelanoma is common with increasing incidence. Guidelines recommend monthly total skin self-examinations (TSSEs) by survivors to detect recurrent and new primary melanomas. TSSE is underperformed despite evidence of benefit. ObjectiveThis study compares the effect on psychological well-being and TSSE practice of a self-directed digital intervention with treatment as usual in patients treated for a first stage 0 to IIC primary cutaneous melanoma within the preceding 60 months. MethodsThis randomized clinical trial was conducted at 2 UK National Health Service hospitals (Aberdeen Royal Infirmary, Grampian, and Addenbrooke’s, Cambridge). Adults (≥18 years) diagnosed with a first 0 to IIC primary cutaneous melanoma were randomized to receive Achieving Self-directed Integrated Cancer Aftercare (ASICA), a tablet-based intervention prompting and supporting TSSE in survivors of melanoma, or to usual care. The hypothesis was that ASICA would increase TSSE practice in users affected by melanoma and compared with controls without affecting psychological well-being. The main primary outcomes were melanoma worry (Melanoma Worry Scale), anxiety and depression (Hospital Anxiety and Depression Scale), and quality of life (EQ-5D-5L) as well as secondary outcomes collected using postal questionnaires 3, 6, and 12 months following randomization. ResultsA total of 240 recruits were randomized (1:1) into the ASICA (n=121, 50.4%) or control (n=119, 49.6%) groups. There were no significant differences between groups for melanoma worry at 12 months (mean difference: 0.12, 95% CI −0.6 to 0.84; P=.74), 3 months (0.23, 95% CI −0.31 to 0.78; P=.40), or 6 months (−0.1, 95% CI −0.7 to 0.51; P=.76). The ASICA group had lower anxiety scores at 12 months (−0.54, 95% CI −1.31 to 0.230; P=.17), 3 months (−0.13, 95% CI −0.79 to 0.54; P=.71), and significantly at 6 months (−1.00, 95% CI −1.74 to −0.26; P=.009). Depression scores were similar, being lower at 12 months (−0.44, 95% CI −1.11 to 0.23; P=.20) and 3 months (−0.24, 95% CI −0.84 to 0.35; P=.42) but only significantly lower at 6 months (−0.77, 95% CI −1.41 to −0.12; P=.02). The ASICA group had significantly higher quality of life scores at 12 months (0.044, 95% CI 0.003-0.085; P=.04) and 6 months (0.070, 95% CI 0.032-0.107; P5) TSSEs during the study year and significantly higher levels of self-efficacy in conducting TSSE. They also reported significantly higher levels of planning and intention to perform TSSE in the future. ConclusionsUsing ASICA for 12 months does not increase melanoma worry, can reduce anxiety and depression, and may improve quality of life. ASICA has the potential to improve the well-being and vigilance of survivors of melanoma and enable the benefits of regular TSSE. Trial RegistrationClinicalTrials.gov NCT03328247; https://clinicaltrials.gov/ct2/show/NCT03328247 International Registered Report Identifier (IRRID)RR2-10.1186/s13063-019-3453-x

Introduction In an era of personalised healthcare, it has become increasingly important to elicit individual-level preferences. While discrete choice experiments (DCEs) are widely used to measure patient preferences in the delivery of healthcare, the focus has been sample-level analysis. Using the DCE methodology, this project has designed a digital decision aid tool (DAT) with the potential to estimate individual preferences in real time to inform clinical consultation decisions in persistent pain management.Methods Using a feasibility randomised control trial, this study aims to assess the feasibility of using this Understanding Persistent Pain (UPP) DAT in a pharmacy-based clinical setting and to test processes for a future definite randomised trial. Community and practice-based pharmacists (up to 10) will be recruited in The National Health Service (NHS) Grampian and trained in the use of the digital UPP DAT. Pharmacists will recruit up to 60 patients who are living with persistent pain. Patients will be randomised to one of two groups: using the UPP DAT or usual care. Pharmacists will follow-up patients as needed according to clinical need and following standard practice. DCE response data collected by the UPP DAT will be analysed using the penalised logit model, allowing estimation of individual preferences in real time. We will follow-up pharmacists and patients who use the UPP DAT to gather feedback on their experiences.Ethics and dissemination This study received ethical approval from the North of Scotland Research Ethics Committee (21/NS/0059) and received Research & Development Management Permission to proceed from NHS Grampian (2021UA003E). The study has been registered in the ClinicalTrials.gov database. Findings will be disseminated in peer-reviewed publications, presentations and newsletters and made available in the University of Aberdeen and Pharmacy Research UK websites. Participants gave informed consent to participate in the study before taking part.Trial registration number NCT05102578; clinicaltrials.gov.

Objectives To describe trajectories in melanoma survivors’ adherence to monthly total skin self-examination (TSSE) over 12 months, and to investigate whether adherence trajectories can be predicted from demographic, cognitive or emotional factors at baseline.Design A longitudinal observational study nested within the intervention arm of the ASICA (Achieving Self-Directed Integrated Cancer Aftercare) randomised controlled trial.Setting Follow-up secondary care in Aberdeen and Cambridge UK.Participants n=104 adults (48 men/56 women; mean age 58.83 years, SD 13.47, range 28–85 years; mean Scottish Index of Multiple Deprivation score 8.03, SD 1.73, range 2–10) who had been treated for stage 0–IIC primary cutaneous melanoma in the preceding 60 months and were actively participating in the intervention arm of the ASICA trial.Interventions All participants were using the ASICA intervention—a tablet-based intervention designed to support monthly TSSE.Primary and secondary outcome measures The primary outcome was adherence to guideline recommended (monthly) TSSE over 12 months. This was determined from time-stamped TSSE data recorded by the ASICA intervention app.Results Latent growth mixture models identified three TSSE adherence trajectories (adherent −41%; drop-off −35%; non-adherent −24%). People who were non-adherent were less likely to intend to perform TSSE as recommended, intending to do it more frequently (OR=0.21, 95% CI 0.06 to 0.81, p=0.023) and were more depressed (OR=1.31, 95% CI 1.06 to 1.61, p=0.011) than people who were adherent. People whose adherence dropped off over time had less well-developed action plans (OR=0.78, 95% CI 0.63 to 0.96, p=0.016) and lower self-efficacy about TSSE (OR=0.92, 95% CI 0.86 to 0.99, p=0.028) than people who were adherent.Conclusions Adherence to monthly TSSE in people treated for melanoma can be differentiated into adherent, drop-off and non-adherent trajectories. Collecting information about intentions to engage in TSSE, depression, self-efficacy and/or action planning at outset may help to identify those who would benefit from additional intervention.Trial registration number ClinicalTrials.gov Registry (NCT03328247).

Abstract Background Most subsequent new primary or recurrent melanomas might be self-detected if patients are trained to systematically self-examine their skin and have access to timely medical review (patient-led surveillance). Routinely scheduled clinic visits (clinician-led surveillance) is resource-intensive and has not been shown to improve health outcomes; fewer visits may be possible if patient-led surveillance is shown to be safe and effective. The MEL-SELF trial is a randomised controlled trial comparing patient-led surveillance with clinician-led surveillance in people who have been previously treated for localised melanoma. Methods Stage 0/I/II melanoma patients (n = 600) from dermatology, surgical, or general practice clinics in NSW Australia, will be randomised (1:1) to the intervention (patient-led surveillance, n = 300) or control (usual care, n = 300). Patients in the intervention will undergo a second randomisation 1:1 to polarised (n = 150) or non-polarised (n = 150) dermatoscope. Patient-led surveillance comprises an educational booklet, skin self-examination (SSE) instructional videos; 3-monthly email/SMS reminders to perform SSE; patient-performed dermoscopy with teledermatologist feedback; clinical review of positive teledermoscopy through fast-tracked unscheduled clinic visits; and routinely scheduled clinic visits following each clinician’s usual practice. Clinician-led surveillance comprises an educational booklet and routinely scheduled clinic visits following each clinician’s usual practice. The primary outcome, measured at 12 months, is the proportion of participants diagnosed with a subsequent new primary or recurrent melanoma at an unscheduled clinic visit. Secondary outcomes include time from randomisation to diagnosis (of a subsequent new primary or recurrent melanoma and of a new keratinocyte cancer), clinicopathological characteristics of subsequent new primary or recurrent melanomas (including AJCC stage), psychological outcomes, and healthcare use. A nested qualitative study will include interviews with patients and clinicians, and a costing study we will compare costs from a societal perspective. We will compare the technical performance of two different models of dermatoscope (polarised vs non-polarised). Discussion The findings from this study may inform guidance on evidence-based follow-up care, that maximises early detection of subsequent new primary or recurrent melanoma and patient wellbeing, while minimising costs to patients, health systems, and society. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000176864 . Registered on 18 February 2021.