Mutational screening of splicing factor genes in cases with autosomal dominant retinitis pigmentosa.

PURPOSE: Mutations in genes encoding proteins from the tri-snRNP complex of the spliceosome account for more than 12% of cases of autosomal dominant retinitis pigmentosa (adRP). Although the exact mechanism by which splicing factor defects trigger photoreceptor death is not completely clear, their role in retinitis pigmentosa has been demonstrated by several genetic and functional studies. To test for possible novel associations between splicing factors and adRP, we screened four tri-snRNP splicing factor genes (EFTUD2, PRPF4, NHP2L1, and AAR2) as candidate disease genes. METHODS: We screened up to 303 patients with adRP from Europe and North America who did not carry known RP mutations. Exon-PCR and Sanger methods were used to sequence the NHP2L1 and AAR2 genes, while the sequences of EFTUD2 and PRPF4 were obtained by using long-range PCRs spanning coding and non-coding regions followed by next-generation sequencing. RESULTS: We detected novel missense changes in individual patients in the sequence of the genes PRPF4 and EFTUD2, but the role of these changes in relationship to disease could not be verified. In one other patient we identified a novel nucleotide substitution in the 5' untranslated region (UTR) of NHP2L1, which did not segregate with the disease in the family. CONCLUSIONS: The absence of clearly pathogenic mutations in the candidate genes screened in our cohort suggests that EFTUD2, PRPF4, NHP2L1, and AAR2 are either not involved in adRP or are associated with the disease in rare instances, at least as observed in this study in patients of European and North American origin

Burden and challenges of heart failure in patients with chronic kidney disease. A call to action

Patients with the dual burden of chronic kidney disease (CKD) and chronic congestive heart failure (HF) experience unacceptably high rates of symptom load, hospitalization, and mortality. Currently, concerted efforts to identify, prevent and treat HF in CKD patients are lacking at the institutional level, with emphasis still being placed on individual specialty views on this topic. The authors of this review paper endorse the need for a dedicated cardiorenal interdisciplinary team that includes nephrologists and renal nurses and jointly manages appropriate clinical interventions across the inpatient and outpatient settings. There is a critical need for guidelines and best clinical practice models from major cardiology and nephrology professional societies, as well as for research funding in both specialties to focus on the needs of future therapies for HF in CKD patients. The implementation of crossspecialty educational programs across all levels in cardiology and nephrology will help train future specialists and nurses who have the ability to diagnose, treat, and prevent HF in CKD patients in a precise, clinically effective, and cost-favorable manner.Los pacientes con enfermedad renal crónica (ERC) que desarrollan insuficiencia cardíaca (IC) congestiva crónica presentan cifras inaceptablemente altas de síntomas, hospitalización y mortalidad. Actualmente, se echan en falta iniciativas institucionales dirigidas a identificar, prevenir y tratar la IC en los pacientes con ERC de manera multidisciplinar, prevaleciendo las actuaciones de las especialidades individuales. Los autores de este artículo de revisión respaldan la necesidad de crear equipos multidisciplinares cardiorrenales, en los que participen nefrólogos y enfermeras renales, que gestionen colaborativamente las intervenciones clínicas apropiadas en los entornos de pacientes con ERC e IC hospitalizados y ambulatorios. Es necesario y urgente que se elaboren guías y modelos de práctica clínica sobre la ERC con IC por parte de las sociedades profesionales de cardiología y nefrología, así como financiación para la investigación concertada entre ambas especialidades sobre la necesidad de futuros tratamientos para la IC en pacientes con ERC. La implementación de programas educativos cardiorrenales a todos los niveles en cardiología y nefrología ayudará a formar a los futuros especialistas y enfermeras para que tengan la capacidad de diagnosticar, tratar y prevenir la IC en pacientes con ERC de manera precisa, clínicamente efectiva y económicamente favorabl

Identification of the Photoreceptor Transcriptional Co-Repressor SAMD11 as Novel Cause of Autosomal Recessive Retinitis Pigmentosa

Retinitis pigmentosa (RP), the most frequent form of inherited retinal dystrophy is characterized by progressive photoreceptor degeneration. Many genes have been implicated in RP development, but several others remain to be identified. Using a combination of homozygosity mapping, whole-exome and targeted next-generation sequencing, we found a novel homozygous nonsense mutation in SAMD11 in five individuals diagnosed with adult-onset RP from two unrelated consanguineous Spanish families. SAMD11 is ortholog to the mouse major retinal SAM domain (mr-s) protein that is implicated in CRX-mediated transcriptional regulation in the retina. Accordingly, protein-protein network analysis revealed a significant interaction of SAMD11 with CRX. Immunoblotting analysis confirmed strong expression of SAMD11 in human retina. Immunolocalization studies revealed SAMD11 was detected in the three nuclear layers of the human retina and interestingly differential expression between cone and rod photoreceptors was observed. Our study strongly implicates SAMD11 as novel cause of RP playing an important role in the pathogenesis of human degeneration of photoreceptors.This work was supported by several grants from the Spanish Centre for Biomedical Network Research on Rare Diseases (CIBERER)(06/07/0036), Instituto de Salud Carlos III (ISCIII, Spanish Ministry of Health)/FEDER, including FIS (PI013/00226) and RETICS (RD09/0076/00101 and RD12/0034/0010), Ministry of Economy and Competitiveness (MINECO), including FEDER (BFU2012-36845), and BIO2011-27069, Conselleria de Educació of the Valencia Community (PROMETEOII/2014/025), Spanish National Organization of the Blind (ONCE) and the Spanish Fighting Blindness Foundation (FUNDALUCE). M.C. was sponsored by the Miguel Servet Program for Researchers in the Spanish National Health Service (CP12/03256) and RSA by Sara Borrel Postdoctoral Program (CD12/00676), both from the ISCIII/FEDER. A.A-F. was sponsored by CIBERER, RPC is supported by Fundación Conchita Rábago (FCR), L.C is sponsored by RETICS (RD12/0034/0010) from ISCIII and L.d.S. was supported by CAPES Foundation, Ministry of Education of Brazil

Time-of-Flight Detector for the Characterisation of Laser-Accelerated Protons

[Otros] Lasers of ultra-high intensity focused on thin targets can form plasmas and release large numbers of charged particles with kinetic energies in the MeV region. The characterization of the accelerated particles requires suitable detectors. We present a time-of-flight detector based on a plastic scintillator optimized for the spectral analysis of laser-accelerated protons. All details of the detector layout are adapted to the expected properties of the proton beam. Particle energies will be separated by the time-of-flight technique over 200 cm path length. The active area (25 mm width) corresponds to a few mrad opening angle. With 5 mm thickness the detector is capable of absorbing protons up to 22.5 MeV. A very thin, aluminized mylar foil shields the scintillator from outer light while absorbing very little particle energy. The scintillation photons are measured with a photomultiplier tube coupled through a bundle of optical fibres. The coupling of these fibres via a PMMA light guide has been previously optimized in simulations with Litrani. A critical aspect of the detection of virtually large numbers of protons emitted in femtosecond pulses is the saturation of the PMT. The latter can be avoided by use of appropriate optical filters. With these the effective dynamic range starts from single particles over several orders of magnitude. Our time-of-flight detector has been calibrated at the Spanish National Accelerator Centre at Sevilla. Proton beams from 0.46 to 5.6 MeV from a tandem accelerator have been used to measure the relation between particle energy and pulse heights. Further tests have been performed with a pulsed electron beam to simulate many-particle hits.Project funded by the Spanish Ministry of Economy and Competitiveness and co-funded with FEDER¿s funds within the INNPACTO 2011 program, Grant No. IPT-2011-0862- 900000. This work was supported by the Spanish Plan Nacional de Investigacion Científica, Desarrollo e Innovacion Tecnológica (I+D+i) under Grant No. FIS2010-21216-CO2-01 and the Valencian Local Government under Grants PROMETEOII/2013/010 and ISIC 2011/013Seimetz, M.; Bellido, P.; Soriano, A.; Huertas, C.; García Lopez, J.; Jimenez-Ramos, MC.; Fernandez, B.... (2013). Time-of-Flight Detector for the Characterisation of Laser-Accelerated Protons. IEEE. 25-28. https://doi.org/10.1109/NSSMIC.2013.6829804S252

Dosimetric Calibration of Radiochromic Film For Laser-accelerated Proton Beams

[Otros] When an ultra-intense and ultra-short laser pulse interacts with solid matter a fraction of the laser pulse can be converted into kinetic energy of a beam of charged particles. Radiochromic film (RCF), widely used as radiation detector in the field of conventional radiotherapy, can be used as detector for laser-accelerated protons. If used in stack configuration it is a useful and versatile tool to obtain 2D spatial distribution and energetic information of proton beams. In order to obtain dosimetric information from RCF it must be properly calibrated. Irradiating film pieces under well known conditions allows us to establish a relation between the optical density (OD) of the radiochromic film, which is measured through a flat bed scanner operating in transmission mode, and the deposited energy in the active layer. A calibration curve over a large dynamic range (3 orders of magnitude) has been obtained for few MeV protons. Our calibration process has been performed at the Spanish National Accelerator Center at Sevilla. We have irradiated several areas of a single RCF with a constant 50 pA beam current and fixed 4 MeV energy from a 3 MV tandem accelerator. We have calculated the deposited energy in the films under the same conditions. We demonstrate that this technique can be used to measure the spectrum and total energy of a laser-accelerated mixed-energy proton beam. This detector has been calibrated for a near future application at the Center of Pulsed, Ultra-short, Ultra-intense Lasers (CLPU) at Salamanca (Spain). We present the calibration procedure and results, the design optimization, and a comparison with similar experiments.Project funded by the Spanish Ministry of Economy and Competitiveness and co-funded with FEDERs funds within the INNPACTO 2011 program. This work was supported by the Spanish Plan Nacional de Investigacion Cientifica, Desarrollo e InnovacionTecnologica (I+D+i) under Grant No. FIS2010-21216-CO2-01 and the Valencian Local Government under Grants PROMETEOII/2013/010 and ISIC 2011/013.Bellido, P.; Seimetz, M.; Soriano, A.; Huertas, C.; García Lopez, J.; Jimenez-Ramos, MC.; Fernandez, B.... (2013). Dosimetric Calibration of Radiochromic Film For Laser-accelerated Proton Beams. IEEE. 20-23. https://doi.org/10.1109/NSSMIC.2013.6829806S202

Genotype x environment interactions in eggplant for fruit phenolic acid content

Eggplant fruit are a rich source of phenolic acids that influence fruit culinary quality and antioxidant content. We evaluated the influence of production environments and stability of diverse genotypes across environments for eggplant fruit phenolic acid content. Ten Solanum melongena accessions consisting of five F-1 hybrid cultivars, three open-pollinated cultivars and two land race accessions, plus one S. macrocarpon and one S. aethiopicum accession, were grown at two locations under greenhouse and open field environments. Twenty phenolic acid conjugates were identified in fruit flesh and assigned to six classes that included hydroxycinnamic acid amides, caffeoylquinic acid esters, hydroxycinnamoylquinic acid esters, malonylcaffeoylquinic acid esters, di-hydroxycinnamoylquinic acid esters, and other hydroxycinnamic acid conjugates. There were significant differences among accessions for total phenolic acid conjugate content and for all six classes. There were no significant differences detected among the environments for any of the variables. However, the environment x accession interaction was highly significant for all phenolic acid classes. Broad-sense heritability estimates for all six phenolic acid classes were high, ranging from 0.64 to 0.96. Stability analysis demonstrated widespread instability for phenolic acid content across environments. Stability of the predominant caffeoylquinic acid esters class positively influenced stability of total phenolic acid content for some but not all genotypes. High heritability, coupled with highly significant genotype x environment interactions suggests that stability estimates may improve the efficiency of breeding new genotypes with predictable performance across environments.Stommel, JR.; Whitaker, B.; Haynes, K.; Prohens Tomás, J. (2015). Genotype x environment interactions in eggplant for fruit phenolic acid content. 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Biol Pharm Bull 29:2236–2240Fernandez GCJ (1991) Analysis of genotype × environment interaction by stability estimates. HortScience 26:947–950García-Salas P, Gómez-Caravaca AM, Morales-Soto A, Segura-Carretero A, Fernández-Gutiérrez A (2014) Identification and quantification of phenolic compounds in diverse cultivars of eggplant grown in different seasons by high-performance liquid chromatography coupled to diode array detector and electrospray-quadrupole-time of flight-mass spectrometry. Food Res Int 57:114–122Hanson PM, Yang RY, Tsou SCS, Ledesma K, Engle L, Lee TC (2006) Diversity in eggplant (Solanum melongena) for superoxide scavenging activity, total phenolics, and ascorbic acid. J Food Compos Anal 19:594–600Kang MS (1989) A new SAS program for calculating stability variance parameters. J Hered 80:415Klein RM (1990) Failure of supplementary ultraviolet radiation to enhance flower color under greenhouse conditions. HortScience 25:307–308Knapp SJ, Stroup WW, Ross WM (1985) Exact confidence intervals for heritability on a progeny mean basis. Crop Sci 25:192–194Luthria D, Singh AP, Wilson T, Vorsa N, Banuelos GS, Vinyard BT (2010) Influence of conventional and organic agricultural practices on the phenolic content in eggplant pulp: plant to plant variation. Food Chem 121:406–411Ma C, Whitaker BD, Kennelly EJ (2010) New 5-O-caffeoylquinic acid derivatives in fruit of wild eggplant relative S. viarum. J Agric Food Chem 58:9645–9651Manach C, Scalbert A, Morand C, Remesy C, Jimenez L (2004) Polyphenols: food sources and bioavailability. Am J Clin Nutr 79:727–747Mennella G, Scalzo R, Fibiani M, D’Alessandro A, Francese G, Toppino L, Acciarri N, Almeida AE, Rotino GL (2012) Chemical and bioactive quality traits during fruit ripening in eggplant (S. melongena L.) and allied species. J Agric Food Chem 60:11821–11831Meyer RS, Karol KG, Little DP, Nee MH, Litt A (2012) Phylogeographic relationships among Asian eggplants and new perspectives on eggplant domestication. Mol Phylogenet Evol 63:685–701Ong KW, Hsu A, Tan BK (2012) Chlorogenic acid stimulates glucose transport in skeletal muscle via AMPK activation: a contributor to the beneficial effects of coffee on diabetes. PLoS One 7:e32718Payyavula RS, Duroy AN, Kuhl JC, Pantoha A, Pillai SS (2012) Differential effects of environment on potato phenylpropanoid and carotenoid expression. BMC Plant Biol 12:39Plazas M, Prohens J, Cuñat AN, Vilanova S, Gramazio P, Herraiz FJ, Andújar I (2014) Reducing capacity, chlorogenic acid content and biological activity in a collection of scarlet (Solanum aethiopicum) and gboma (S. macrocarpon) eggplants. Int J Mol Sci 15:17221–17241Prior RL (2003) Fruits and vegetables in the prevention of cellular oxidative damage. Am J Clin Nutr 78:570S–578SPritts M, Luby J (1990) Stability indices for horticultural crops. HortScience 25:740–745Prohens J, Rodriguez-Burruezo A, Raigon MD, Nuez F (2007) Total phenolic acid concentration and browning susceptibility in a collection of different varietal types and hybrids of eggplant: implications for breeding for higher nutritional quality and reduced browning. J Am Soc Hortic Sci 132:638–646Prohens J, Whitaker BD, Plazas M, Vilanova S, Hurtado M, Blasco M, Gramazio P, Stommel JR (2013) Genetic diversity in morphological characters and phenolic acids content resulting from an interspecific cross between eggplant, Solanum melongena, and its wild ancestor (S. incancum). Ann Appl Biol 162:242–257Raigon MD, Prohens J, Munoz-Falcon JE, Nuez F (2008) Comparison of eggplant landraces and commercial varieties for fruit content of phenolics, minerals, dry matter and protein. J Food Compos Anal 21:370–376Raigon MD, Rodriguez-Burruezo A, Prohens J (2010) Effects of organic and conventional cultivation methods on composition of eggplant fruits. Agric Food Chem 58:6833–6840San Jose R, Sanchez-Mata MC, Camara M, Prohens J (2014) Eggplant fruit composition as affected by the cultivation environment and genetic constitution. J Sci Food Agric 94:2774–2784Sato Y, Itagaki S, Kurokawa T, Ogur J, Kobayashi M, Hirano T, Sugawara M, Iseki K (2011) In vitro and in vivo antioxidant properties of chlorogenic acid and caffeic acid. Int J Pharm 403:136–138Setimela PS, Vivek B, Banziger M, Crossa J, Maideni F (2007) Evaluation of early to medium maturing open pollinated maize varieties in SADC region using GGE biplot based on the SREG model. Field Crop Res 103:161–169Shukla GK (1972) Some statistical aspects of partitioning genotype environment components of variability. 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Effectiveness of an mHealth intervention combining a smartphone app and smart band on body composition in an overweight and obese population: Randomized controlled trial (EVIDENT 3 study)

Background: Mobile health (mHealth) is currently among the supporting elements that may contribute to an improvement in health markers by helping people adopt healthier lifestyles. mHealth interventions have been widely reported to achieve greater weight loss than other approaches, but their effect on body composition remains unclear. Objective: This study aimed to assess the short-term (3 months) effectiveness of a mobile app and a smart band for losing weight and changing body composition in sedentary Spanish adults who are overweight or obese. Methods: A randomized controlled, multicenter clinical trial was conducted involving the participation of 440 subjects from primary care centers, with 231 subjects in the intervention group (IG; counselling with smartphone app and smart band) and 209 in the control group (CG; counselling only). Both groups were counselled about healthy diet and physical activity. For the 3-month intervention period, the IG was trained to use a smartphone app that involved self-monitoring and tailored feedback, as well as a smart band that recorded daily physical activity (Mi Band 2, Xiaomi). Body composition was measured using the InBody 230 bioimpedance device (InBody Co., Ltd), and physical activity was measured using the International Physical Activity Questionnaire. Results: The mHealth intervention produced a greater loss of body weight (–1.97 kg, 95% CI –2.39 to –1.54) relative to standard counselling at 3 months (–1.13 kg, 95% CI –1.56 to –0.69). Comparing groups, the IG achieved a weight loss of 0.84 kg more than the CG at 3 months. The IG showed a decrease in body fat mass (BFM; –1.84 kg, 95% CI –2.48 to –1.20), percentage of body fat (PBF; –1.22%, 95% CI –1.82% to 0.62%), and BMI (–0.77 kg/m2, 95% CI –0.96 to 0.57). No significant changes were observed in any of these parameters in men; among women, there was a significant decrease in BMI in the IG compared with the CG. When subjects were grouped according to baseline BMI, the overweight group experienced a change in BFM of –1.18 kg (95% CI –2.30 to –0.06) and BMI of –0.47 kg/m2 (95% CI –0.80 to –0.13), whereas the obese group only experienced a change in BMI of –0.53 kg/m2 (95% CI –0.86 to –0.19). When the data were analyzed according to physical activity, the moderate-vigorous physical activity group showed significant changes in BFM of –1.03 kg (95% CI –1.74 to –0.33), PBF of –0.76% (95% CI –1.32% to –0.20%), and BMI of –0.5 kg/m2 (95% CI –0.83 to –0.19). Conclusions: The results from this multicenter, randomized controlled clinical trial study show that compared with standard counselling alone, adding a self-reported app and a smart band obtained beneficial results in terms of weight loss and a reduction in BFM and PBF in female subjects with a BMI less than 30 kg/m2 and a moderate-vigorous physical activity level. Nevertheless, further studies are needed to ensure that this profile benefits more than others from this intervention and to investigate modifications of this intervention to achieve a global effect

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Semiconductor Spintronics

Spintronics refers commonly to phenomena in which the spin of electrons in a solid state environment plays the determining role. In a more narrow sense spintronics is an emerging research field of electronics: spintronics devices are based on a spin control of electronics, or on an electrical and optical control of spin or magnetism. This review presents selected themes of semiconductor spintronics, introducing important concepts in spin transport, spin injection, Silsbee-Johnson spin-charge coupling, and spindependent tunneling, as well as spin relaxation and spin dynamics. The most fundamental spin-dependent nteraction in nonmagnetic semiconductors is spin-orbit coupling. Depending on the crystal symmetries of the material, as well as on the structural properties of semiconductor based heterostructures, the spin-orbit coupling takes on different functional forms, giving a nice playground of effective spin-orbit Hamiltonians. The effective Hamiltonians for the most relevant classes of materials and heterostructures are derived here from realistic electronic band structure descriptions. Most semiconductor device systems are still theoretical concepts, waiting for experimental demonstrations. A review of selected proposed, and a few demonstrated devices is presented, with detailed description of two important classes: magnetic resonant tunnel structures and bipolar magnetic diodes and transistors. In most cases the presentation is of tutorial style, introducing the essential theoretical formalism at an accessible level, with case-study-like illustrations of actual experimental results, as well as with brief reviews of relevant recent achievements in the field.Comment: tutorial review; 342 pages, 132 figure

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research