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A deep survey of the Large Magellanic Cloud at ~0.1-100TeV photon energies with the Cherenkov Telescope Array is planned. We assess the detection prospects based on a model for the emission of the galaxy, comprising the four known TeV emitters, mock populations of sources, and interstellar emission on galactic scales. We also assess the detectability of 30 Doradus and SN 1987A, and the constraints that can be derived on the nature of dark matter. The survey will allow for fine spectral studies of N157B, N132D, LMC P3, and 30 Doradus C, and half a dozen other sources should be revealed, mainly pulsar-powered objects. The remnant from SN 1987A could be detected if it produces cosmic-ray nuclei with a flat power-law spectrum at high energies, or with a steeper index 2.3-2.4 pending a flux increase by a factor >3-4 over ~2015-2035. Large-scale interstellar emission remains mostly out of reach of the survey if its >10GeV spectrum has a soft photon index ~2.7, but degree-scale 0.1-10TeV pion-decay emission could be detected if the cosmic-ray spectrum hardens above >100GeV. The 30 Doradus star-forming region is detectable if acceleration efficiency is on the order of 1-10% of the mechanical luminosity and diffusion is suppressed by two orders of magnitude within, Accepted for publication in MNRAS. Corresponding authors: Pierrick Martin, Maria Isabel Bernardos Martin, Fabio Iocco

El oceano representa el 97% del espacio fisico habitable del planeta y es fundamental para mantener la vida en la Tierra. Solo desde el ano 2000 se han realizado esfuerzos importantes y dedicados a aumentar la sensibilizacion y comprension de las consecuencias de las emisiones de gases de efecto invernadero en los oceanos. Actualmente sabemos que el dioxido de carbono que emiten las actividades humanas esta dando lugar a condiciones de mayor acidez en el oceano. Solo en la ultima decada se ha empezado a reconocer mas ampliamente que la temperatura de los oceanos del mundo tambien esta siendo afectada considerablemente como consecuencia del efecto que el dioxido de carbono y otros potentes gases de efecto invernadero estan teniendo en la atmosfera de la Tierra. El calentamiento del agua de los oceanos y su acidificacion progresiva no son en modo alguno las unicas consecuencias importantes a escala mundial de las emisiones de gases de efecto invernadero en el ambito marino. Desde hace algunas decadas se sabe que la escorrentia de nutrientes de la agricultura ocasiona que se formen zonas sin oxigeno en el mar, ya que el oxigeno vital se agota en la columna de agua y en el fondo del mar. Sin embargo, no se ha podido establecer la verdadera escala de las causas y repercusiones del fenomeno llamado “desoxigenacion de los oceanos”. Este resumen y el informe tecnico completo que lo acompana presentan el hecho ineludible de que las actividades humanas estan reduciendo el oxigeno que sostiene la vida en el oceano.

L’ocean represente 97% de l’espace physique habitable de la planete et joue un role central dans le maintien de la vie sur Terre. Depuis les annees 2000 que des efforts considerables et specifiques ont ete deployes pour mieux faire connaitre et comprendre les consequences des emissions de gaz a effet de serre sur les oceans. Le dioxyde de carbone emis par les activites humaines conduit les oceans vers des conditions plus acides, phenomene connu sous le nom d’acidification des oceans. Ce n’est qu’au cours de la derniere decennie que l’on a commence a reconnaitre de que la temperature mondiale des oceans est egalement affectee de maniere significative par les effets que le dioxyde de carbone et autres gaz a effet de serre puissants ont sur l’atmosphere terrestre. Le rechauffement et l’acidification progressive de l’eau de mer sont loin d’etre les seules consequences mondiales majeures des emissions de gaz a effet de serre pour le domaine marin. On sait depuis quelques decennies que le ruissellement de nutriments provenant de l’agriculture entraine la formation de zones depourvues d’oxygene dans la mer, la ou l’oxygene vital est consomme dans la colonne d’eau et sur les fonds marins. Mais les causes et l’ampleur reelle des impacts de ce phenomene appele « desoxygenation des oceans » etaient jusqu’alors inconnues. Ce resume et le rapport technique complet qui l’accompagne montrent de maniere indeniable que les activites humaines extraient aujourd’hui l’oxygene vital des oceans.

We here investigate static, spherically symmetric solutions to $\mathfrak{su}(\infty)$ Einstein-Yang-Mills theory with a negative cosmological constant $\Lambda$ in the case of dyonic solutions, which possess a non-trivial electric sector of the gauge field. We are able to find non-trivial solutions to this system, and show that some may be uniquely characterised by a countably infinite set of global charges, which may have implications for Bizon's modified `No Hair' theorem., Comment: 38 pages, 4 figures

Mobile marine species can exhibit vast movements both horizontally and vertically. Spatial analysis of vertical movements may help improve an understanding of the processes that influence space use. Previously, vertical space use of basking sharks (Cetorhinus maximus) in the north-east Atlantic described movements largely within waters of the continental shelf during summer and autumn months, with few records of detailed vertical behaviour during winter. We use archival satellite telemetry data from 32 basking sharks (12 females, 6 males, and 14 of unknown sex measuring 4–5 m (n = 6), 5–6 m (n = 10), 6–7 m (n = 7), 7–8 m (n = 8), and 8–9 m (n = 1) estimated total length) tracked over 4 years (2012–2015). The satellite tags provided depth and temperature data for a cumulative 4489 days (mean 140 ± 97 days per shark, range 10–292 days) to describe vertical space use and thermal range of basking sharks in the north-east Atlantic. Basking sharks exhibit seasonality in vertical space use, revealing repeated ‘yo-yo’ movement behaviour with periods of occupancy at depths greater than 1000 m in late winter/early spring. Describing seasonal vertical space use in marine megavertebrates can increase knowledge of movements throughout their environment including physiological and morphological constraints to movement, nutrient transfer, and overlap with anthropogenic threats to inform future conservation strategies.

Here we study the global existence of `hairy' dyonic black hole and dyon solutions to four dimensional, anti-de Sitter Einstein-Yang-Mills theories for a general simply-connected and semisimple gauge group $G$, for so-called topologically symmetric systems, concentrating here on the regular case. We generalise here cases in the literature which considered purely magnetic spherically symmetric solutions for a general gauge group and topological dyonic solutions for $\mathfrak{su}(N)$. We are able to establish the global existence of non-trivial solutions to all such systems, both near existing embedded solutions and as $|\Lambda|\rightarrow\infty$. In particular, we can identify non-trivial solutions where the gauge field functions have no zeroes, which in the $\mathfrak{su}(N)$ case proved important to stability. We believe that these are the most general analytically proven solutions in 4D anti-de Sitter Einstein-Yang-Mills systems to date., Comment: 58 pages, 1 table. arXiv admin note: text overlap with arXiv:1604.05012

Convergence is proved for solutions of Dirichlet problems in regions with many small excluded sets (holes), as the holes become smaller and more numerous. The problem is formulated in the context of Markov processes associated with general Dirichlet forms, for random and nonrandom excluded sets. Sufficient conditions are given under which the sequence of entrance times or hitting times of the excluded sets converges in the stable topology. Convergence in the stable topology is a strengthened form of convergence in distribution, introduced by Renyi. Stable convergence of the entrance times implies convergence of the solutions of the corresponding Dirichlet problems. Some additional results are given in a supplement on random center models., Comment: Fixed some typos which were introduced while "de-macroing"

PurposeTo determine the opinions from a patient perspective on relevant variables in the delivery of treatment for neovascular age-related macular degeneration (nAMD).MethodsPilot interviews with patients and doctors were conducted to identify what variables in the provision of a nAMD service were important. This led to the generation of two sets of scenario options. Subsequently 100 patients undergoing active treatment for nAMD in the National Health Service University Hospital, United Kingdom underwent interview assessment. They were asked to rank their preferences for provision of their care with reference to these two sets of scenario options. Using conjoint analysis, percentage preferences, and utility scores for each variable in each scenario design were calculated.ResultsNinety-five patients completed the preference ranking for both scenarios. Eight patients ranked worse vision as preferable to better vision and were excluded on the basis that they had not understood the task. The results of the remaining 87 patients are presented. The most important factor to patients was having good vision, followed by a one-stop service and less frequent follow up. The least important factors were label status of the drug, cost to the health service, and grade of the injector.ConclusionPatients regard good vision and minimal visits to the hospital above the status of injector, label status of drug, or cost to the NHS.

We investigate the stability of spherically symmetric, purely magnetic, soliton and black hole solutions of four-dimensional ${\mathfrak {su}}(N)$ Einstein-Yang-Mills theory with a negative cosmological constant $\Lambda $. These solutions are described by $N-1$ magnetic gauge field functions $\omega _{j}$. We consider linear, spherically symmetric, perturbations of these solutions. The perturbations decouple into two sectors, known as the sphaleronic and gravitational sectors. For any $N$, there are no instabilities in the sphaleronic sector if all the magnetic gauge field functions $\omega _{j}$ have no zeros, and satisfy a set of $N-1$ inequalities. In the gravitational sector, we are able to prove that there are solutions which have no instabilities in a neighbourhood of stable embedded ${\mathfrak {su}}(2)$ solutions, provided the magnitude of the cosmological constant $\left| \Lambda \right| $ is sufficiently large., Comment: 43 pages, 4 figures, minor changes, discussion expanded and references updated. Matches version accepted for publication in J. Math. Phys

During normal active life a dog may damage its teeth in a number of ways: through inappropriate interactive behaviour with the owner, for example, when the dog is encouraged to catch thrown objects such as sticks or stones. The dog may misjudge the distance and snap its mouth shut with excessive force on nothing, causing fractures of the cusps of the teeth. Or it may close its mouth with excessive force on the object and cause trauma to the teeth. The traumatised tooth or teeth will require a range of veterinary treatments.

The ocean moderates anthropogenic climate change at the cost of profound alterations of its physics, chemistry, ecology, and services. Here, we evaluate and compare the risks of impacts on marine and coastal ecosystems—and the goods and services they provide—for growing cumulative carbon emissions under two contrasting emissions scenarios. The current emissions trajectory would rapidly and significantly alter many ecosystems and the associated services on which humans heavily depend. A reduced emissions scenario—consistent with the Copenhagen Accord's goal of a global temperature increase of less than 2°C—is much more favorable to the ocean but still substantially alters important marine ecosystems and associated goods and services. The management options to address ocean impacts narrow as the ocean warms and acidifies. Consequently, any new climate regime that fails to minimize ocean impacts would be incomplete and inadequate.

The ability to detect and respond to predation risk while foraging may have important fitness consequences for prey organisms. Anti-predator behaviours may reduce the probability of mortality because of predation, but they may also be associated with reduced foraging efficiency. Several behaviours of bats have been suggested to serve as anti-predator responses, and there is evidence that predation, particularly by avian predators such as owls, may be an important cause of bat mortality. Previous studies have attempted to determine whether predator presence affects bat behaviour when emerging from roost sites, but few have examined effects of predator presence on bat behaviour while foraging. In this study, we investigated whether foraging bats respond to predator cues by presenting bats with an acoustic cue simulating the presence of an owl. Within matched trials, which were conducted at different locations each of 18 nights, significantly fewer bat detections were recorded at owl playback stations than at control stations (no auditory cue), suggesting an avoidance response by bats. An acoustic control (i.e. station playing woodpecker calls), however, did not have significantly more detections than the stations playing the owl calls, suggesting that bats may simply be avoiding noise and more detailed investigation is warranted. Although evidence for owl predation on bats is minimal in North America, results of this study may indicate that the perceived presence of owls may represent a factor influencing the behaviour of bats while foraging.

The p53 gene is the most frequently inactivated tumour suppressor gene identified in human cancers to date (Han et al, 2002). Over 15 000 p53 mutations have been documented from tumour and cell line samples (www.iarc.fr), with loss of p53 function most commonly induced through point mutation (Bates and Vousden, 1996). More than 30% of p53 mutations occur at methylated CpG sites in codons 157, 175, 245, 248, 273 and 282 (Chen et al, 1998). Thus, CpG sites frequently act as mutational hot spots, which warrant their investigation to determine their potential role in tumour aetiology. p53 gene mutations appear to be key factors in the development of gastric cancer (Gomyo et al, 1996) having been documented in more than 60% of the reported cancer cases (Tamura et al, 1991). Classically, gastric cancer can be divided into two histological subtypes: diffuse or intestinal (Lauren, 1965). The intestinal type is believed to arise from a sequence of gastritis, intestinal metaplasia and increasing grades of dysplasia. There is controversy regarding the stage at which genetic alterations of the p53 gene occur within the metaplasia – dysplasia sequence (Uchino et al, 1993; Becker et al, 2000). p53 mutations detected in gastritis have been documented by Stemmermann et al (1994) and Kodama et al (1998), while studies by Zheng and YouYoung (1998), Shiao et al (1994) and Ochiai et al (1996) show p53 alterations only in intestinal metaplasia. Mutations of p53 in early gastric cancer have been found by Tohodo et al (1993) and Uchino et al (1993), while Romitti et al (1998), Brito et al (1994) and Joypaul et al (1993) claim that p53 mutations are late events in gastric cancer. However, p53 alterations in these studies have been detected using a variety of methods such as the polymerase chain reaction (PCR), PCR – single-strand conformation polymorphism, direct sequencing and immunohistochemistry. Thus, it appears that the frequency and stage at which p53 alterations are detected may depend on the methods used to detect them (Stemmermann et al, 1994). To investigate the timing of p53 mutations in gastric cancer, we employed the restriction site mutation (RSM) assay (Myers and Parry, 1994). This method detects mutations at restriction enzyme sites in human genes. Fortuitously, five of the eight main p53 mutational hot spots (codons 175, 213, 248, 249 and 282) contain restriction sites and are amenable to RSM analysis in patients with gastritis and intestinal metaplasia. Exhaustive digestion of the target DNA followed by amplification of the enzyme-resistant (mutated) sequences by PCR means that RSM is capable of detecting low levels of mutations (one mutated sequence among 104 – 105 wild-type sequences) (Jenkins et al, 1999). This, in turn, allows for the molecular selection of mutated samples and makes mutation detection in premalignant samples feasible.

SUMMARYThe antibiotic tylosin was found to be effective in controlling oxytetracycline-resistant American foulbrood (Paenibacillus larvae) in honey bee (Apis mellifera) colonies, while not affecting adult and larval honey bee mortality. An optimal rate of 200 mg tylosin, applied in 20 g of confectioners' sugar at weekly intervals for three weeks, resulted in complete remission of detectable disease symptoms 45 days after initial treatment. No detectable disease symptoms were observed seven months after treatment with this rate. Various higher doses of tylosin (600 mg and 1000 mg per 20 g confectioners' sugar) applied over three honey bee brood cycles, resulted in no significant increase in adult and larval bee mortality when compared with controls. Discussion is given as to long term American foulbrood control and tactics for resistance management.

HIV-1 transmitted drug resistance (TDR) in treatment-naïve individuals is a well-described phenomenon. Baseline genotypic resistance testing is considered standard of care in most developed areas of the world. The aim of this analysis was to characterize HIV-1 TDR and the use of resistance testing in START trial participants.In the Strategic Timing of AntiRetroviral Treatment (START) trial, baseline genotypic resistance testing results were collected at study entry and analysed centrally to determine the prevalence of TDR in the study population. Resistance was based on a modified 2009 World Health Organization definition to reflect newer resistance mutations.Baseline resistance testing was available in 1946 study participants. Higher rates of testing occurred in Europe (86.7%), the USA (81.3%) and Australia (89.9%) as compared with Asia (22.2%), South America (1.8%) and Africa (0.1%). The overall prevalence of TDR was 10.1%, more commonly to nonnucleoside reverse transcriptase inhibitors (4.5%) and nucleoside reverse transcriptase inhibitors (4%) compared with protease inhibitors (2.8%). The most frequent TDR mutations observed were M41L, D67N/G/E, T215F/Y/I/S/C/D/E/V/N, 219Q/E/N/R, K103N/S, and G190A/S/E in reverse transcriptase, and M46I/L and L90M in protease. By country, the prevalence of TDR was highest in Australia (17.5%), France (16.7%), the USA (12.6%) and Spain (12.6%). No participant characteristics were identified as predictors of the presence of TDR.START participants enrolled in resource-rich areas of the world were more likely to have baseline resistance testing. In Europe, the USA and Australia, TDR prevalence rates varied by country.

We investigate the existence of black hole solutions of four dimensional $\mathfrak{su}(N)$ EYM theory with a negative cosmological constant. Our analysis differs from previous works in that we generalise the field equations to certain non-spherically symmetric spacetimes. We prove the existence of non-trivial solutions for any integer $N$, with $N-1$ gauge degrees of freedom. Specifically, we prove two results: existence of solutions for fixed values of the initial parameters and as $|\Lambda|\rightarrow\infty$, and existence of solutions for any $\Lambda

Oesophageal adenocarcinoma (OA) incidence is rising and prognosis is poor. Understanding the molecular basis of this malignancy is key to finding new prevention and treatment strategies. Gastroesophageal reflux disease is the primary cause of OA, usually managed with acid suppression therapy. However, this often does little to control carcinogenic bile acid reflux. The transcription factor nuclear factor kappa B (NF-κB) plays a key role in the pathogenesis of OA and its activity is associated with a poor response to chemotherapy, making it an attractive therapeutic target. We sought to decipher the role of different bile acids in NF-κB activation in oesophageal cell lines using short, physiologically relevant exposure times. The effect of an acidic or neutral extracellular pH was investigated concurrently, to mimic in vivo conditions associated with or without acid suppression. We found that some bile acids activated NF-κB to a greater extent when combined with acid, whereas others did so in its absence, at neutral pH. The precise composition of an individual's reflux, coupled with whether they are taking acid suppressants may therefore dictate the extent of NF-κB activation in the oesophagus, and hence the likelihood of histological progression and chemotherapy success. Regardless of pH, the kinase inhibitor of κB kinase was pivotal in mediating reflux induced NF-κB activation. Its importance was confirmed further as its increased activation was associated with histological progression in patient samples. We identified further kinases important in acid or bile induced NF-κB signalling in oesophageal cells, which may provide suitable targets for therapeutic intervention.

We have analysed five mutation hotspots within the p53 gene (codons 175, 213, 248, 249, and 282) for mutations induced by hydrogen peroxide (H(2)O(2)), employing the restriction site mutation (RSM) assay. In addition, four other restriction sites covering non-hotspot codons of exons 5-9 of the p53 gene (codons 126, 153/54, 189 and the 3' splice site of exon 9) were analysed by the RSM assay for H(2)O(2)-induced mutations. Two cell types were concurrently analysed in this study, i.e. primary fibroblast cells and a gastric cancer cell line. Using the RSM assay, H(2)O(2)-induced mutations were only detected in exon 7 of the p53 gene. This was true for both cell types. These mutations were mainly induced in the Msp I restriction site (codon 247/248) and were predominantly GC to AT transitions (71%). Hence these GC to AT mutations were presumably due to H(2)O(2) exposure, possibly implicating the 5OHdC adduct, which is known to induce C to T mutations upon misreplication. Importantly, this study demonstrates that the RSM methodology is capable of detecting rare oxidative mutations within the hotspot codons of the p53 tumour suppressor gene. Hence, this methodology may allow the detection of early p53 mutations in pre-malignant tissues.

In the past 15 years considerable advances have been made in our understanding of the molecular pharmacology of the mechanisms whereby somatostatin and its analogs mediate their direct and indirect antineoplastic effects. However, some important issues remain to be resolved, in particular the functional roles of the individual somatostatin receptors (SSTR-1–5) in tumor tissue and up- or downregulation of the hSSTRs with prolonged administration of somatostatin analogs. Answers to these questions are essential before we can maximize the therapeutic efficacy of somatostatin analogs in cancer. For example, is continuous administration more or less effective than intermittent therapy? The role of somatostatin analogs in the management of acromegaly and to a lesser extent neuroendocrine tumors is firmly established. The development of depot preparations of all 3 somatostatin analogs currently available for clinical use will undoubtedly improve both patient compliance and quality of life in patients with these conditions. There are only likely to be minor differences in the therapeutic efficacy of octreotide, lanreotide and vapreotide since all three analogs exert the majority of their antineoplastic effects via hSSTR-2 and hSSTR-5 and at the end of the day, price may well dictate which of these drugs oncologists use to provide symptomatic palliation of acromegaly and neuroendocrine tumors. Apart from some notable exceptions, somatostatin analog therapy has proven to be very disappointing in the management of advanced malignancy. Improvements in the management of solid tumors are likely to come only from combination therapy of somatostatin analogs with cytotoxic agents or other hormones in both advanced malignancy and in the adjuvant setting. Clinical trials with clear-cut objective outcome measures and health-related quality of life assessment are needed to evaluate the therapeutic efficacy of combination treatment in advanced malignancy and as an adjuvant to surgery. Particular attention needs to be paid to possible adverse effects of somatostatin analog therapy on the immune response to cancer. Further studies are required to establish whether the adverse effects of somatostatin analog therapy alone or in combination with cytotoxics or other hormones can be reversed with appropriate immunomodulatory treatment. Targeted somatostatin analog radiotherapy and chemotherapy are currently being investigated and the results of these studies are awaited with interest. Novel approaches using combinations of somatostatin analogs with antiangiogenic drugs or gene therapy are of particular interest and may provide important advances in the management of cancer in the not too distant future.

BACKGROUND Patients who undergo surgery are at risk of malnutrition due to periods of starvation, the stress of surgery, and subsequent increase in metabolic rate. There are limited data on nutritional outcome of surgical patients. AIMS To investigate changes in nutritional status and the influence of oral supplements on nutritional status, morbidity, and quality of life in postoperative surgical patients. METHODS Entry was determined by the presence of malnutrition, as defined by a body mass index (BMI) ⩽20 kg/m 2 , anthropometric measurements ⩽15th percentile on admission, or initiation of oral diet postoperatively and/or a weight loss of 5% or more during the operative period. We studied 101 patients: 52 were randomised to the treatment group (TG) and prescribed a 1.5 kcal/ml nutritional supplement; 49 patients were randomised to the control group (CG) and continued with routine nutritional management. Nutritional status was assessed by weight, anthropometry, and grip strength, with measurements taken at two weekly intervals for 10 weeks. Complications, namely wound infection, chest infection, and antibiotic use were documented. Quality of life (QOL) was assessed using the UK SF-36 questionnaire. RESULTS Patients in the control group lost a maximum mean (SD) of 5.96 (4.21) kg in weight over a period of eight weeks while patients in group TG lost less weight overall (maximum mean (SD) 3.40 (0.89) kg (p CONCLUSIONS Nutritional status declined for two months after discharge. Postoperative nutritional supplementation improved nutritional status, QOL, and morbidity in these patients.

International audience; We conducted laboratory tests investigating the mortality of mites infesting honey bee colonies in Minnesota after exposure to fluvalinate, amitraz, or coumaphos. Results indicated that these mites were not only resistant to fluvalinate, but also to amitraz. Coumaphos was effective against these resistant mites. A separate field trial was conducted with the same hives as those used in the laboratory test. The field trial supported the laboratory results, showing that mites in Minnesota are resistant to both fluvalinate and amitraz, and that coumaphos is effective in controlling these mites. This represents the first known reported case of amitraz resistance in Varroa jacobsoni in the U.S.A.; Contrôle, à l'aide du coumaphos, de Varroa jacobsoni Oud. résistant au fluvalinate et à l'amitraz. L'acarien parasite Varroa jacobsoni Oud. cause de gros dégâts aux populations d'abeilles domestiques (Apis mellifera L.) depuis son introduction aux Etats-Unis en 1987. Il n'existe actuellement qu'un seul produit autorisé aux États-Unis pour lutter contre V. jacobsoni : le fluvalinate (Apistan$^{\circledR}$). Nous avons effectué des tests sur le terrain et au laboratoire pour déterminer la sensibilité de V. jacobsoni à trois pesticides. un pyréthrinoïde, le fluvalinate, une formamidine, l'amitraz, et un organophosphoré, le coumaphos. Une résistance significative au fluvalinate été trouvée : la mortalité de l'acarien n'a été que de 14,2 % au cours du test en laboratoire et la population d'acariens s'est accrue de 89,1 % pendant la période de traitement au cours du test au champ. Une résistance significative de cette population à l'amitraz a été également trouvée : 32,3 % de mortalité au laboratoire et 75,4 % au champ. C'est le premier cas de résistance de V. jacobsoni à l'amitraz mentionné aux États-Unis. Le coumaphos s'est montré très efficace pour lutter contre les acariens devenus résistants au fluvalinate et à l'amitraz : la mortalité a atteint 85,4 % dans le test de laboratoire et la population au champ a été réduite de 97 % après traitement

A current review of nutritional complications following bariatric procedures is presented, focusing on the most common and clinically important deficiencies. A brief outline of nutritional supplementation protocol is presented, highlighting the need for a standardized, national or international set of guidelines for pre- and postoperative nutritional screening and appropriate supplementation.